The role of hair follicles in the percutaneous absorption of caffeine.

PubMed

Otberg, Nina; Patzelt, Alexa; Rasulev, Utkur; Hagemeister, Timo; Linscheid, Michael; Sinkgraven, Ronald; Sterry, Wolfram; Lademann, Jürgen

2008-04-01

* In recent years, it has been suggested that hair follicles represent important shunt routes into the skin for drugs and chemicals [1-3]. * In vitro studies have shown the importance of skin appendages for skin penetration by hydrophilic compounds [4]. Investigation of follicular penetration in vivo has been difficult due to the absence of appropriate analytical methods or suitable animal model systems. * Recently, a new method was described that quantifies follicular penetration in vivo by using selective closure of hair follicles [5]. * Caffeine is frequently used in skin penetration experiments as a model for highly water-soluble compounds. Occlusion [6] and skin thickness [7] seem to have little influence on the penetration of caffeine. However, percutaneous absorption rates for caffeine exhibit regional skin differences in humans in vivo[1]. * The results of the present study demonstrate that a fast drug delivery of caffeine occurs through shunt routes. Therefore, hair follicles are considerable weak spots in our protective sheath against penetration into the body by hydrophilic substances. * We showed that there is a quantitative distinction between follicular penetration and interfollicular diffusion of caffeine in vivo. * These findings are of importance for the development and optimization of topically applied drugs and cosmetics. In addition, such properties must be considered in the development of skin protection measures. The skin and its appendages are our protective shield against the environment and are necessary for the maintenance of homeostasis. Hypotheses concerning the penetration of substances into the skin have assumed diffusion through the lipid domains of the stratum corneum. It is believed that while hair follicles represent a weakness in the shield, they play a subordinate role in the percutaneous penetration processes. Previous investigation of follicular penetration has mostly addressed methodical and technical problems. Our study utilized a selective closure technique of hair follicle orifices in vivo, for the comparison of interfollicular and follicular absorption rates of caffeine in humans. Every single hair follicle within a delimited area of skin was blocked with a microdrop of a special varnish-wax-mixture in vivo. Caffeine in solution was topically applied and transcutaneous absorption into the blood was measured by a new surface ionization mass spectrometry (SI/MS) technique, which enabled a clear distinction to be made between interfollicular and follicular penetration of a topically applied substance. Caffeine (3.75 ng ml(-1)) was detected in blood samples, 5 min after topical application, when the follicles remained open. When the follicles were blocked, caffeine was detectable after 20 min (2.45 ng ml(-1)). Highest values (11.75 ng caffeine ml(-1)) were found 1 h after application when the follicles were open. Our findings demonstrate that hair follicles are considerable weak spots in our protective sheath against certain hydrophilic drugs and may allow a fast delivery of topically applied substances.

High interpatient variability of raltegravir CSF concentrations in HIV-positive patients: a pharmacogenetic analysis.

PubMed

Calcagno, Andrea; Cusato, Jessica; Simiele, Marco; Motta, Ilaria; Audagnotto, Sabrina; Bracchi, Margherita; D'Avolio, Antonio; Di Perri, Giovanni; Bonora, Stefano

2014-01-01

To analyse the determinants of raltegravir CSF penetration, including the pharmacogenetics of drug transporters located at the blood-brain barrier or blood-CSF barrier. Plasma and CSF raltegravir concentrations were determined by a validated HPLC coupled with mass spectrometry method in adults on raltegravir-based combination antiretroviral therapy undergoing a lumbar puncture. Single nucleotide polymorphisms in the genes encoding drugs transporters (ABCB1 3435, SLCO1A2, ABCC2 and SLC22A6) and the gene encoding hepatocyte nuclear factor 4 α (HNF4α) were determined by real-time PCR. In 41 patients (73.2% male, 95.1% Caucasians), the median raltegravir plasma and CSF concentrations were 165 ng/mL (83-552) and 31 ng/mL (21-56), respectively. CSF-to-plasma ratios (CPRs) ranged from 0.005 to 1.33 (median 0.20, IQR 0.04-0.36). Raltegravir trough CSF concentrations (n = 35) correlated with raltegravir plasma levels (ρ = 0.395, P = 0.019); CPRs were higher in patients with blood-brain barrier damage (0.47 versus 0.18, P = 0.02). HNF4α 613 CG genotype carriers had lower trough CSF concentrations (20 versus 37 ng/mL, P = 0.03) and CPRs (0.12 versus 0.27, P = 0.02). Following multivariate linear regression analysis, the CSF-to-serum albumin ratio was the only independent predictor of raltegravir penetration into the CSF. Raltegravir penetration into the CSF shows a large interpatient variability, although CSF concentrations were above the wild-type IC50 in all patients (and above IC95 in 28.6%). In this cohort, blood-brain barrier permeability is the only independent predictor of raltegravir CPR. The impact of single nucleotide polymorphisms in selected genes on raltegravir penetration warrants further studies.

The double-layer of penetrable ions: an alternative route to charge reversal.

PubMed

Frydel, Derek; Levin, Yan

2013-05-07

We investigate a double-layer of penetrable ions near a charged wall. We find a new mechanism for charge reversal that occurs in the weak-coupling regime and, accordingly, the system is suitable for the mean-field analysis. The penetrability is achieved by smearing-out the ionic charge inside a sphere, so there is no need to introduce non-electrostatic forces and the system in the low coupling limit can be described by a modified version of the Poisson-Boltzmann equation. The predictions of the theory are compared with the Monte Carlo simulations.

Mixed-Penetrant Sorption in Ultrathin Films of Polymer of Intrinsic Microporosity PIM-1.

PubMed

Ogieglo, Wojciech; Furchner, Andreas; Ghanem, Bader; Ma, Xiaohua; Pinnau, Ingo; Wessling, Matthias

2017-11-02

Mixed-penetrant sorption into ultrathin films of a superglassy polymer of intrinsic microporosity (PIM-1) was studied for the first time by using interference-enhanced in situ spectroscopic ellipsometry. PIM-1 swelling and the concurrent changes in its refractive index were determined in ultrathin (12-14 nm) films exposed to pure and mixed penetrants. The penetrants included water, n-hexane, and ethanol and were chosen on the basis of their significantly different penetrant-penetrant and penetrant-polymer affinities. This allowed studying microporous polymer responses at diverse ternary compositions and revealed effects such as competition for the sorption sites (for water/n-hexane or ethanol/n-hexane) or enhancement in sorption of typically weakly sorbing water in the presence of more highly sorbing ethanol. The results reveal details of the mutual sorption effects which often complicate comprehension of glassy polymers' behavior in applications such as high-performance membranes, adsorbents, or catalysts. Mixed-penetrant effects are typically very challenging to study directly, and their understanding is necessary owing to a broadly recognized inadequacy of simple extrapolations from measurements in a pure component environment.

TNF-alpha and IL-10 gene polymorphisms show a weak association with pemphigus vulgaris in the Slovak population.

PubMed

Javor, J; Chmurova, N; Parnicka, Z; Ferencik, S; Grosse-Wilde, H; Buc, M; Svecova, D

2010-01-01

Pemphigus vulgaris is a rare chronic autoimmune disease of skin and mucous membranes, with several cytokines participating in its development. The role of their gene polymorphisms in susceptibility to the disease is, however, not fully understood. The aim of our case-control study was to investigate whether some of 22 single nucleotide polymorphisms (SNPs) in 13 cytokine genes (IL-1alpha, IL-1beta, IL-1RI, IL-1Ra, IL-4Ralpha, IL-12, IFN-gamma, TGF-beta1, TNF-alpha, IL-2, IL-4, IL-6 and IL-10) are associated with pemphigus vulgaris in the Slovak population. DNA samples were obtained from 34 pemphigus vulgaris patients and 140 healthy controls of Slovak origin. Cytokine gene SNPs were determined using the polymerase chain reaction with sequence-specific primers (PCR-SSP) method. Results We found a weak association between pemphigus vulgaris and polymorphic variants in TNF-alpha and IL-10 genes only, with haplotypes TNF-alpha-308G/-238G and IL-10 -1082A/-819C/-592C being significantly overrepresented in pemphigus vulgaris patients (TNF-alpha GG: 94.12% vs. 82.86%, P = 0.0216; IL-10 ACC: 44.12% vs. 30.00%, P = 0.0309). Our preliminary results suggest that certain TNF-alpha and IL-10 gene polymorphisms might contribute to genetic susceptibility to pemphigus vulgaris; however, their overall impact on disease development will be rather limited.

13 CFR 315.16 - Adjustment proposal requirements.

Code of Federal Regulations, 2011 CFR

2011-01-01

... analysis of the Firm's problems, strengths and weaknesses and an assessment of its prospects for recovery... generally consists of knowledge-based services such as market penetration studies, customized business...

Regression Models and Fuzzy Logic Prediction of TBM Penetration Rate

NASA Astrophysics Data System (ADS)

Minh, Vu Trieu; Katushin, Dmitri; Antonov, Maksim; Veinthal, Renno

2017-03-01

This paper presents statistical analyses of rock engineering properties and the measured penetration rate of tunnel boring machine (TBM) based on the data of an actual project. The aim of this study is to analyze the influence of rock engineering properties including uniaxial compressive strength (UCS), Brazilian tensile strength (BTS), rock brittleness index (BI), the distance between planes of weakness (DPW), and the alpha angle (Alpha) between the tunnel axis and the planes of weakness on the TBM rate of penetration (ROP). Four (4) statistical regression models (two linear and two nonlinear) are built to predict the ROP of TBM. Finally a fuzzy logic model is developed as an alternative method and compared to the four statistical regression models. Results show that the fuzzy logic model provides better estimations and can be applied to predict the TBM performance. The R-squared value (R2) of the fuzzy logic model scores the highest value of 0.714 over the second runner-up of 0.667 from the multiple variables nonlinear regression model.

Unraveling the sequence-dependent polymorphic behavior of d(CpG) steps in B-DNA.

PubMed

Dans, Pablo Daniel; Faustino, Ignacio; Battistini, Federica; Zakrzewska, Krystyna; Lavery, Richard; Orozco, Modesto

2014-10-01

We have made a detailed study of one of the most surprising sources of polymorphism in B-DNA: the high twist/low twist (HT/LT) conformational change in the d(CpG) base pair step. Using extensive computations, complemented with database analysis, we were able to characterize the twist polymorphism in the d(CpG) step in all the possible tetranucleotide environment. We found that twist polymorphism is coupled with BI/BII transitions, and, quite surprisingly, with slide polymorphism in the neighboring step. Unexpectedly, the penetration of cations into the minor groove of the d(CpG) step seems to be the key element in promoting twist transitions. The tetranucleotide environment also plays an important role in the sequence-dependent d(CpG) polymorphism. In this connection, we have detected a previously unexplored intramolecular C-H···O hydrogen bond interaction that stabilizes the low twist state when 3'-purines flank the d(CpG) step. This work explains a coupled mechanism involving several apparently uncorrelated conformational transitions that has only been partially inferred by earlier experimental or theoretical studies. Our results provide a complete description of twist polymorphism in d(CpG) steps and a detailed picture of the molecular choreography associated with this conformational change. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Discovering genetic variants in Crohn's disease by exploring genomic regions enriched of weak association signals.

PubMed

D'Addabbo, Annarita; Palmieri, Orazio; Maglietta, Rosalia; Latiano, Anna; Mukherjee, Sayan; Annese, Vito; Ancona, Nicola

2011-08-01

A meta-analysis has re-analysed previous genome-wide association scanning definitively confirming eleven genes and further identifying 21 new loci. However, the identified genes/loci still explain only the minority of genetic predisposition of Crohn's disease. To identify genes weakly involved in disease predisposition by analysing chromosomal regions enriched of single nucleotide polymorphisms with modest statistical association. We utilized the WTCCC data set evaluating 1748 CD and 2938 controls. The identification of candidate genes/loci was performed by a two-step procedure: first of all chromosomal regions enriched of weak association signals were localized; subsequently, weak signals clustered in gene regions were identified. The statistical significance was assessed by non parametric permutation tests. The cytoband enrichment analysis highlighted 44 regions (P≤0.05) enriched with single nucleotide polymorphisms significantly associated with the trait including 23 out of 31 previously confirmed and replicated genes. Importantly, we highlight further 20 novel chromosomal regions carrying approximately one hundred genes/loci with modest association. Amongst these we find compelling functional candidate genes such as MAPT, GRB2 and CREM, LCT, and IL12RB2. Our study suggests a different statistical perspective to discover genes weakly associated with a given trait, although further confirmatory functional studies are needed. Copyright © 2011 Editrice Gastroenterologica Italiana S.r.l. All rights reserved.

A low-temperature polymorph of m-quinquephenyl.

PubMed

Gomes, Ligia R; Howie, R Alan; Low, John Nicolson; Rodrigues, Ana S M C; Santos, Luís M N B F

2012-12-01

A low-temperature polymorph of 1,1':3',1'':3'',1''':3''',1''''-quinquephenyl (m-quinquephenyl), C(30)H(22), crystallizes in the space group P2(1)/c with two molecules in the asymmetric unit. The crystal is a three-component nonmerohedral twin. A previously reported room-temperature polymorph [Rabideau, Sygula, Dhar & Fronczek (1993). Chem. Commun. pp. 1795-1797] also crystallizes with two molecules in the asymmetric unit in the space group P-1. The unit-cell volume for the low-temperature polymorph is 4120.5 (4) Å(3), almost twice that of the room-temperature polymorph which is 2102.3 (6) Å(3). The molecules in both structures adopt a U-shaped conformation with similar geometric parameters. The structural packing is similar in both compounds, with the molecules lying in layers which stack perpendicular to the longest unit-cell axis. The molecules pack alternately in the layers and in the stacked columns. In both polymorphs, the only interactions between the molecules which can stabilize the packing are very weak C-H...π interactions.

Crohn's Disease Candidate Gene Alleles Predict Time to Progression from Inflammatory B1 to Stricturing B2, or Penetrating B3 Phenotype.

PubMed

Pernat Drobež, Cvetka; Ferkolj, Ivan; Potočnik, Uroš; Repnik, Katja

2018-03-01

Crohn's disease (CD) patients are mostly diagnosed with the uncomplicated inflammatory form of disease; however, the majority will progress to complicated stricturing or penetrating disease over time. It is important to identify patients at risk for disease progression at an early stage. The aim of our study was to examine the role of 33 candidate CD genes as possible predictors of disease progression and their influence on time to progression from an inflammatory to a stricturing or penetrating phenotype. Patients with an inflammatory phenotype at diagnosis were followed for 10 years and 33 CD-associated polymorphisms were genotyped. To test for association with CD, 449 healthy individuals were analyzed as the control group. Ten years after diagnosis, 39.1% of patients had not progressed beyond an inflammatory phenotype, but 60.9% had progressed to complicated disease, with average time to progression being 5.91 years. Association analyses of selected single nucleotide polymorphisms (SNPs) confirmed associations with CD for 12 SNPs. Furthermore, seven loci were associated with disease progression, out of which SNP rs4263839 in the gene TNFSF15 showed the strongest association with disease progression and the frameshift mutation rs2066847 in the gene NOD2 showed the strongest association with time to progression. The results of our study identified specific genetic biomarkers as useful predictors of both disease progression and speed of disease progression in patients with CD.

Variants in the ATM-CHEK2-BRCA1 axis determine genetic predisposition and clinical presentation of papillary thyroid carcinoma.

PubMed

Wójcicka, Anna; Czetwertyńska, Małgorzata; Świerniak, Michał; Długosińska, Joanna; Maciąg, Monika; Czajka, Agnieszka; Dymecka, Kinga; Kubiak, Anna; Kot, Adam; Płoski, Rafał; de la Chapelle, Albert; Jażdżewski, Krystian

2014-06-01

The risk of developing papillary thyroid carcinoma (PTC), the most frequent form of thyroid malignancy, is elevated up to 8.6-fold in first-degree relatives of PTC patients. The familial risk could be explained by high-penetrance mutations in yet unidentified genes, or polygenic action of low-penetrance alleles. Since the DNA-damaging exposure to ionizing radiation is a known risk factor for thyroid cancer, polymorphisms in DNA repair genes are likely to affect this risk. In a search for low-penetrance susceptibility alleles we employed Sequenom technology to genotype deleterious polymorphisms in ATM, CHEK2, and BRCA1 in 1,781 PTC patients and 2,081 healthy controls. As a result of the study, we identified CHEK2 rs17879961 (OR = 2.2, P = 2.37e-10) and BRCA1 rs16941 (odds ratio [OR] = 1.16, P = 0.005) as risk alleles for PTC. The ATM rs1801516 variant modifies the risk associated with the BRCA1 variant by 0.78 (P = 0.02). Both the ATM and BRCA1 variants modify the impact of male gender on clinical variables: T status (P = 0.007), N status (P = 0.05), and stage (P = 0.035). Our findings implicate an important role of variants in the ATM- CHEK2- BRCA1 axis in modification of the genetic predisposition to PTC and its clinical manifestations. Copyright © 2014 Wiley Periodicals, Inc.

Cooperative Activated Transport of Dilute Penetrants in Viscous Molecular and Polymer Liquids

NASA Astrophysics Data System (ADS)

Schweizer, Kenneth; Zhang, Rui

We generalize the force-level Elastically Collective Nonlinear Langevin Equation theory of activated relaxation in one-component supercooled liquids to treat the hopping transport of a dilute penetrant in a dense hard sphere fluid. The new idea is to explicitly account for the coupling between penetrant displacement and a local matrix cage re-arrangement which facilitates its hopping. A temporal casuality condition is employed to self-consistently determine a dimensionless degree of matrix distortion relative to the penetrant jump distance using the dynamic free energy concept. Penetrant diffusion becomes increasingly coupled to the correlated matrix displacements for larger penetrant to matrix particle size ratio (R) and/or attraction strength (physical bonds), but depends weakly on matrix packing fraction. In the absence of attractions, a nearly exponential dependence of penetrant diffusivity on R is predicted in the intermediate range of 0.2

Fluctuating Selection in the Moran

PubMed Central

Dean, Antony M.; Lehman, Clarence; Yi, Xiao

2017-01-01

Contrary to classical population genetics theory, experiments demonstrate that fluctuating selection can protect a haploid polymorphism in the absence of frequency dependent effects on fitness. Using forward simulations with the Moran model, we confirm our analytical results showing that a fluctuating selection regime, with a mean selection coefficient of zero, promotes polymorphism. We find that increases in heterozygosity over neutral expectations are especially pronounced when fluctuations are rapid, mutation is weak, the population size is large, and the variance in selection is big. Lowering the frequency of fluctuations makes selection more directional, and so heterozygosity declines. We also show that fluctuating selection raises dn/ds ratios for polymorphism, not only by sweeping selected alleles into the population, but also by purging the neutral variants of selected alleles as they undergo repeated bottlenecks. Our analysis shows that randomly fluctuating selection increases the rate of evolution by increasing the probability of fixation. The impact is especially noticeable when the selection is strong and mutation is weak. Simulations show the increase in the rate of evolution declines as the rate of new mutations entering the population increases, an effect attributable to clonal interference. Intriguingly, fluctuating selection increases the dn/ds ratios for divergence more than for polymorphism, a pattern commonly seen in comparative genomics. Our model, which extends the classical neutral model of molecular evolution by incorporating random fluctuations in selection, accommodates a wide variety of observations, both neutral and selected, with economy. PMID:28108586

Update on breast cancer risk prediction and prevention.

PubMed

Sestak, Ivana; Cuzick, Jack

2015-02-01

Breast cancer is the most common cancer in women worldwide. This review will focus on current prevention strategies for women at high risk. The identification of women who are at high risk of developing breast cancer is key to breast cancer prevention. Recent findings have shown that the inclusion of breast density and a panel of low-penetrance genetic polymorphisms can improve risk estimation compared with previous models. Preventive therapy with aromatase inhibitors has produced large reductions in breast cancer incidence in postmenopausal women. Tamoxifen confers long-term protection and is the only proven preventive treatment for premenopausal women. Several other agents, including metformin, bisphosphonates, aspirin and statins, have been found to be effective in nonrandomized settings. There are many options for the prevention of oestrogen-positive breast cancer, in postmenopausal women who can be given a selective oestrogen receptor modulator or an aromatase inhibitor. It still remains unclear how to prevent oestrogen-negative breast cancer, which occurs more often in premenopausal women. Identification of women at high risk of the disease is crucial, and the inclusion of breast density and a panel of genetic polymorphisms, which individually have low penetrance, can improve risk assessment.

Powder diffraction and crystal structure prediction identify four new coumarin polymorphs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shtukenberg, Alexander G.; Zhu, Qiang; Carter, Damien J.

Coumarin, a simple, commodity chemical isolated from beans in 1820, has, to date, only yielded one solid state structure. Here, we report a rich polymorphism of coumarin grown from the melt. Four new metastable forms were identified and their crystal structures were solved using a combination of computational crystal structure prediction algorithms and X-ray powder diffraction. With five crystal structures, coumarin has become one of the few rigid molecules showing extensive polymorphism at ambient conditions. We demonstrate the crucial role of advanced electronic structure calculations including many-body dispersion effects for accurate ranking of the stability of coumarin polymorphs and themore » need to account for anharmonic vibrational contributions to their free energy. As such, coumarin is a model system for studying weak intermolecular interactions, crystallization mechanisms, and kinetic effects.« less

Mechanochemical synthesis of N-salicylidene­aniline: thermosalient effect of polymorphic crystals

PubMed Central

Mittapalli, Sudhir; Sravanakumar Perumalla, D.

2017-01-01

Polymorphs of the dichloro derivative of N-salicylideneaniline exhibit mechanical responses such as jumping (Forms I and III) and exploding (Form II) in its three polymorphs. The molecules are connected via the amide N—H⋯O dimer synthon and C—Cl⋯O halogen bond in the three crystal structures. A fourth high-temperature Form IV was confirmed by variable-temperature single-crystal X-ray diffraction at 180°C. The behaviour of jumping exhibited by the polymorphic crystals of Forms I and III is due to the layered sheet morphology and the transmission of thermal stress in a single direction, compared with the corrugated sheet structure of Form II such that heat dissipation is more isotropic causing blasting. The role of weak C—Cl⋯O interactions in the thermal response of molecular crystals is discussed. PMID:28512571

Powder diffraction and crystal structure prediction identify four new coumarin polymorphs

DOE PAGES

Shtukenberg, Alexander G.; Zhu, Qiang; Carter, Damien J.; ...

2017-05-15

Coumarin, a simple, commodity chemical isolated from beans in 1820, has, to date, only yielded one solid state structure. Here, we report a rich polymorphism of coumarin grown from the melt. Four new metastable forms were identified and their crystal structures were solved using a combination of computational crystal structure prediction algorithms and X-ray powder diffraction. With five crystal structures, coumarin has become one of the few rigid molecules showing extensive polymorphism at ambient conditions. We demonstrate the crucial role of advanced electronic structure calculations including many-body dispersion effects for accurate ranking of the stability of coumarin polymorphs and themore » need to account for anharmonic vibrational contributions to their free energy. As such, coumarin is a model system for studying weak intermolecular interactions, crystallization mechanisms, and kinetic effects.« less

Toll-like receptor 4 gene polymorphism modulates phenotypic expression in patients with hereditary hemochromatosis.

PubMed

Krayenbuehl, Pierre-Alexandre; Hersberger, Martin; Truninger, Kaspar; Müllhaupt, Beat; Maly, Friedrich E; Bargetzi, Mario; Schulthess, Georg

2010-07-01

Clinical penetrance of hereditary hemochromatosis is highly variable. We hypothesized that it might be modified by factors involved in the cellular immune response, such as toll-like receptors (TLRs) or nucleotide oligomerization domain proteins (NODs). Clinical expression of hemochromatosis was assessed as a function of TLR4, TLR9, and NOD2 polymorphisms in 99 homozygous carriers of the HFE C282Y mutation with mild-to-severe iron overload. Thirteen (13%) of the 99 hemochromatosis patients were heterozygous for a TLR4 Asp299Gly polymorphism and 86 (87%) were TLR4 wild-type-only carriers. Clinical expression of hemochromatosis was observed more frequently in carriers of the TLR4 polymorphism (100%) than in TLR4 wild-type carriers (56%, P = 0.002). This was based on higher prevalences of liver disease (92 vs. 45%, P = 0.002) and arthropathy of metacarpophalangeal joints (69 vs. 35%, P = 0.018) in TLR4 polymorphism carriers. The finding was strengthened by the strong association of TLR4 polymorphism with liver fibrosis in the subgroup of 52 patients who underwent a liver biopsy (P = 0.011). The TLR4 polymorphism did, however, not correlate with body iron overload. The study results remained significant in multiple regression analyses after excluding possible confounding effects, such as age, sex, alcohol, or meat intake, and in the subgroup of 84 patients presenting as the first members of their families. TLR4 Asp299Gly polymorphism modulates clinical expression in patients with hereditary hemochromatosis. The polymorphism does not correlate with iron overload suggesting that TLR4 plays a role in an inflammatory process arising from toxic effects of iron accumulation.

Genetic Polymorphisms of Glutathione-Related Enzymes (GSTM1, GSTT1, and GSTP1) and Schizophrenia Risk: A Meta-Analysis

PubMed Central

Kim, Su Kang; Kang, Sang Wook; Chung, Joo-Ho; Park, Hae Jeong; Cho, Kyu Bong; Park, Min-Su

2015-01-01

The association between polymorphisms of glutathione-related enzyme (GST) genes and the risk of schizophrenia has been investigated in many published studies. However, their results were inconclusive. Therefore, we performed a meta-analysis to explore the association between the GSTM1, GSTT1, and GSTP1 polymorphisms and the risk of schizophrenia. Twelve case-control studies were included in this meta-analysis. The odds ratio (OR) and 95% confidence interval (95% CI) were used to investigate the strength of the association. Our meta-analysis results revealed that GSTM1, GSTT1, and GSTP1 polymorphisms were not related to risk of schizophrenia (p > 0.05 in each model). Further analyses based on ethnicity, GSTM polymorphism showed weak association with schizophrenia in East Asian population (OR = 1.314, 95% CI = 1.025–1.684, p = 0.031). In conclusion, our meta-analysis indicated the GSTM1 polymorphism may be the only genetic risk factor for schizophrenia in East Asian population. However, more meta-analysis with a larger sample size were needed to provide more precise evidence. PMID:26295386

Leptons from decay of mesons in the laser-induced particle pulse from ultra-dense protium p(0)

NASA Astrophysics Data System (ADS)

Holmlid, Leif

2016-10-01

Kaons and pions are observed by their characteristic decay times of 12, 52 and 26 ns after impact of relatively weak ns-long laser pulses on ultra-dense hydrogen H(0), as reported previously. The signal using an ultra-dense protium p(0) generator with natural hydrogen is now studied. Deflection in a weak magnetic field or penetration through metal foils cannot distinguish between the types of decaying mesons. The signals observed are thus not caused by the decaying mesons themselves, but by the fast particles often at >50MeV u-1 formed in their decay. The fast particles are concluded to be mainly muons from their relatively small magnetic deflection and strong penetration. This is further supported by published studies on the direct observation of the beta decay of muons in scintillators and solid converters using the same type of p(0) generator.

Spatially resolved penetration depth measurements and vortex manipulation in the ferromagnetic superconductor ErNi 2 B 2 C

DOE PAGES

Wulferding, Dirk; Yang, Ilkyu; Yang, Jinho; ...

2015-07-31

We present a local probe study of the magnetic superconductor ErNi 2B 2C, using magnetic force microscopy at sub-Kelvin temperatures. ErNi 2B 2C is an ideal system to explore the effects of concomitant superconductivity and ferromagnetism. At 500 mK, far below the transition to a weakly ferromagnetic state, we directly observe a structured magnetic background on the micrometer scale. We determine spatially resolved absolute values of the magnetic penetration depth λ and study its temperature dependence as the system undergoes magnetic phase transitions from paramagnetic to antiferromagnetic, and to weak ferromagnetic, all within the superconducting regime. We estimate the absolutemore » pinning force of Abrikosov vortices, which shows a position dependence and temperature dependence as well, and discuss the possibility of the purported spontaneous vortex formation.« less

The evolution of mimicry under constraints.

PubMed

Holen, Øistein Haugsten; Johnstone, Rufus A

2004-11-01

The resemblance between mimetic organisms and their models varies from near perfect to very crude. One possible explanation, which has received surprisingly little attention, is that evolution can improve mimicry only at some cost to the mimetic organism. In this article, an evolutionary game theory model of mimicry is presented that incorporates such constraints. The model generates novel and testable predictions. First, Batesian mimics that are very common and/or mimic very weakly defended models should evolve either inaccurate mimicry (by stabilizing selection) or mimetic polymorphism. Second, Batesian mimics that are very common and/or mimic very weakly defended models are more likely to evolve mimetic polymorphism if they encounter predators at high rates and/or are bad at evading predator attacks. The model also examines how cognitive constraints acting on signal receivers may help determine evolutionarily stable levels of mimicry. Surprisingly, improved discrimination abilities among signal receivers may sometimes select for less accurate mimicry.

Synthesis, characterization, crystal structure and DFT study of two new polymorphs of a Schiff base (E)-2-((2,6-dichlorobenzylidene)amino)benzonitrile

NASA Astrophysics Data System (ADS)

Benarous, N.; Cherouana, A.; Aubert, Emmanuel; Durand, Pierrick; Dahaoui, S.

2016-02-01

Two new polymorphs of Schiff base, (E)-2-((2,6-dichlorobenzylidene)amino)benzonitrile, were prepared from the condensation of 4-amino-benzonitrile and 2,6-dichlorobenzaldehyde. The two polymorphs crystallize in two different space groups: P21/c for polymorph (I) with volume 1264.23(2) Å3 and Pbca for polymorph (II) with volume 2469.3(2) Å3. The two polymorphs have been characterized by FT-IR and UV-VIS spectroscopy. The crystal structures of both compounds were determined by single X-ray analysis. The difference between the two polymorphs was observed at the angle between the two phenyl rings which is 4.81° for the first one and 82.27° for the second one. Both crystal structures are built on the basis of moderate and weak hydrogen bonds. Theoretical calculations on isolated molecules at the MP2 cc-pVDZ level show that the two polymorphs correspond to two molecular conformations that are within less than 1 kJ mol-1 and DFT periodic calculations indicate that (II) is more stable than (I) by 4.1 kJ mol-1 of formula unit. Additionally, we performed TD-DFT calculation for free ligands to support the experimental data.

Methylenetetrahydrofolate reductase C677T polymorphism in patients with lung cancer in a Korean population

PubMed Central

2011-01-01

Background This study was designed to investigate an association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of lung cancer in a Korean population. Methods We conducted a large-scale, case-control study involving 3938 patients with newly diagnosed lung cancer and 1700 healthy controls. Genotyping was performed with peripheral blood DNA for MTHFR C677T polymorphisms. Statistical significance was estimated by logistic regression analysis. Results The MTHFR C677T frequencies of CC, CT, and TT genotypes were 34.5%, 48.5%, and 17% among lung cancer patients, and 31.8%, 50.7%, and 17.5% in the controls, respectively. The MTHFR 677CT and TT genotype showed a weak protection against lung cancer compared with the homozygous CC genotype, although the results did not reach statistical significance. The age- and gender-adjusted odds ratio (OR) of overall lung cancer was 0.90 (95% confidence interval (CI), 0.77-1.04) for MTHFR 677 CT and 0.88 (95% CI, 0.71-1.07) for MTHFR 677TT. However, after stratification analysis by histological type, the MTHFR 677CT genotype showed a significantly decreased risk for squamous cell carcinoma (age- and gender-adjusted OR, 0.78; 95% CI, 0.64-0.96). The combination of 677 TT homozygous with 677 CT heterozygous also appeared to have a protection effect on the risk of squamous cell carcinoma. We observed no significant interaction between the MTHFR C677T polymorphism and age and gender or smoking habit. Conclusions This is the first reported study focusing on the association between MTHFR C677T polymorphisms and the risk of lung cancer in a Korean population. The T allele was found to provide a weak protective association with lung squamous cell carcinoma. PMID:21342495

Fluctuating Selection in the Moran.

PubMed

Dean, Antony M; Lehman, Clarence; Yi, Xiao

2017-03-01

Contrary to classical population genetics theory, experiments demonstrate that fluctuating selection can protect a haploid polymorphism in the absence of frequency dependent effects on fitness. Using forward simulations with the Moran model, we confirm our analytical results showing that a fluctuating selection regime, with a mean selection coefficient of zero, promotes polymorphism. We find that increases in heterozygosity over neutral expectations are especially pronounced when fluctuations are rapid, mutation is weak, the population size is large, and the variance in selection is big. Lowering the frequency of fluctuations makes selection more directional, and so heterozygosity declines. We also show that fluctuating selection raises d n / d s ratios for polymorphism, not only by sweeping selected alleles into the population, but also by purging the neutral variants of selected alleles as they undergo repeated bottlenecks. Our analysis shows that randomly fluctuating selection increases the rate of evolution by increasing the probability of fixation. The impact is especially noticeable when the selection is strong and mutation is weak. Simulations show the increase in the rate of evolution declines as the rate of new mutations entering the population increases, an effect attributable to clonal interference. Intriguingly, fluctuating selection increases the d n / d s ratios for divergence more than for polymorphism, a pattern commonly seen in comparative genomics. Our model, which extends the classical neutral model of molecular evolution by incorporating random fluctuations in selection, accommodates a wide variety of observations, both neutral and selected, with economy. Copyright © 2017 by the Genetics Society of America.

Study of the HFE gene common polymorphisms in French patients with sporadic amyotrophic lateral sclerosis.

PubMed

Praline, Julien; Blasco, Hélène; Vourc'h, Patrick; Rat, Valérian; Gendrot, Chantal; Camu, William; Andres, Christian R

2012-06-15

Our objective was to investigate whether the C282Y (p.Cys 282 Tyr) and H63D (p. His 63 Asp) HFE polymorphisms were associated with sporadic amyotrophic lateral sclerosis (SALS) in the French population. We searched for a relation of HFE polymorphisms with the clinical characteristics of the disease. The HFE polymorphisms were studied in 824 patients with SALS and 583 controls. We compared the frequency of the polymorphisms between SALS and controls groups by univariate and multivariate statistics, taking into account gender, site, age-at-onset and survival. We did not observe significant difference in the frequency of H63D polymorphism between SALS and control group. We observed a significant difference for C282Y between patients and controls with a low frequency of the Y allele in patients (3.2%) compared to our control group (5.9%). Disease duration, distribution of gender, site-of-onset, age-at-onset did not differ between groups taking into account genotypes of each polymorphism. Our results in this large cohort of ALS patients indicate that H63D polymorphism is not associated with SALS in the French population. This conclusion does not exclude a weak effect of the HFE gene polymorphisms in certain ALS populations, or an effect of other rare HFE gene variants. Copyright © 2012 Elsevier B.V. All rights reserved.

Dopamine and the Creative Mind: Individual Differences in Creativity Are Predicted by Interactions between Dopamine Genes DAT and COMT.

PubMed

Zabelina, Darya L; Colzato, Lorenza; Beeman, Mark; Hommel, Bernhard

2016-01-01

The dopaminergic (DA) system may be involved in creativity, however results of past studies are mixed. We attempted to clarify this putative relation by considering the mediofrontal and the nigrostriatal DA pathways, uniquely and in combination, and their contribution to two different measures of creativity--an abbreviated version of the Torrance Test of Creative Thinking, assessing divergent thinking, and a real-world creative achievement index. We found that creativity can be predicted from interactions between genetic polymorphisms related to frontal (COMT) and striatal (DAT) DA pathways. Importantly, the Torrance test and the real-world creative achievement index related to different genetic patterns, suggesting that these two measures tap into different aspects of creativity, and depend on distinct, but interacting, DA sub-systems. Specifically, we report that successful performance on the Torrance test is linked with dopaminergic polymorphisms associated with good cognitive flexibility and medium top-down control, or with weak cognitive flexibility and strong top-down control. The latter is particularly true for the originality factor of divergent thinking. High real-world creative achievement, on the other hand, as assessed by the Creative Achievement Questionnaire, is linked with dopaminergic polymorphisms associated with weak cognitive flexibility and weak top-down control. Taken altogether, our findings support the idea that human creativity relies on dopamine, and on the interaction between frontal and striatal dopaminergic pathways in particular. This interaction may help clarify some apparent inconsistencies in the prior literature, especially if the genes and/or creativity measures were analyzed separately.

Dopamine and the Creative Mind: Individual Differences in Creativity Are Predicted by Interactions between Dopamine Genes DAT and COMT

PubMed Central

Zabelina, Darya L.; Colzato, Lorenza; Beeman, Mark; Hommel, Bernhard

2016-01-01

The dopaminergic (DA) system may be involved in creativity, however results of past studies are mixed. We attempted to clarify this putative relation by considering the mediofrontal and the nigrostriatal DA pathways, uniquely and in combination, and their contribution to two different measures of creativity–an abbreviated version of the Torrance Test of Creative Thinking, assessing divergent thinking, and a real-world creative achievement index. We found that creativity can be predicted from interactions between genetic polymorphisms related to frontal (COMT) and striatal (DAT) DA pathways. Importantly, the Torrance test and the real-world creative achievement index related to different genetic patterns, suggesting that these two measures tap into different aspects of creativity, and depend on distinct, but interacting, DA sub-systems. Specifically, we report that successful performance on the Torrance test is linked with dopaminergic polymorphisms associated with good cognitive flexibility and medium top-down control, or with weak cognitive flexibility and strong top-down control. The latter is particularly true for the originality factor of divergent thinking. High real-world creative achievement, on the other hand, as assessed by the Creative Achievement Questionnaire, is linked with dopaminergic polymorphisms associated with weak cognitive flexibility and weak top-down control. Taken altogether, our findings support the idea that human creativity relies on dopamine, and on the interaction between frontal and striatal dopaminergic pathways in particular. This interaction may help clarify some apparent inconsistencies in the prior literature, especially if the genes and/or creativity measures were analyzed separately. PMID:26783754

Inhomogeneous fluid of penetrable-spheres: Application of the random phase approximation

NASA Astrophysics Data System (ADS)

Xiang, Yan; Frydel, Derek

2017-05-01

The focus of the present work is the application of the random phase approximation (RPA), derived for inhomogeneous fluids [Frydel and Ma, Phys. Rev. E 93, 062112 (2016)], to penetrable-spheres. As penetrable-spheres transform into hard-spheres with increasing interactions, they provide an interesting case for exploring the RPA, its shortcomings, and limitations, the weak- versus the strong-coupling limit. Two scenarios taken up by the present study are a one-component and a two-component fluid with symmetric interactions. In the latter case, the mean-field contributions cancel out and any contributions from particle interactions are accounted for by correlations. The accuracy of the RPA for this case is the result of a somewhat lucky cancellation of errors.

Preservation of General Intelligence following Traumatic Brain Injury: Contributions of the Met66 Brain-Derived Neurotrophic Factor

PubMed Central

Barbey, Aron K.; Colom, Roberto; Paul, Erick; Forbes, Chad; Krueger, Frank; Goldman, David; Grafman, Jordan

2014-01-01

Brain-derived neurotrophic factor (BDNF) promotes survival and synaptic plasticity in the human brain. The Val66Met polymorphism of the BDNF gene interferes with intracellular trafficking, packaging, and regulated secretion of this neurotrophin. The human prefrontal cortex (PFC) shows lifelong neuroplastic adaption implicating the Val66Met BDNF polymorphism in the recovery of higher-order executive functions after traumatic brain injury (TBI). In this study, we examined the effect of this BDNF polymorphism on the preservation of general intelligence following TBI. We genotyped a sample of male Vietnam combat veterans (n = 156) consisting of a frontal lobe lesion group with focal penetrating head injuries for the Val66Met BDNF polymorphism. Val/Met did not differ from Val/Val genotypes in general cognitive ability before TBI. However, we found substantial average differences between these groups in general intelligence (≈ half a standard deviation or 8 IQ points), verbal comprehension (6 IQ points), perceptual organization (6 IQ points), working memory (8 IQ points), and processing speed (8 IQ points) after TBI. These results support the conclusion that Val/Met genotypes preserve general cognitive functioning, whereas Val/Val genotypes are largely susceptible to TBI. PMID:24586380

The TNF-α -308 polymorphism may affect the severity of Crohn's disease

PubMed Central

Santana, Genoile; Bendicho, Maria Teresita; Santana, Tamara Celi; dos Reis, Lidiane Bianca; Lemaire, Denise; Lyra, André Castro

2011-01-01

OBJECTIVE: The goal of this project was to analyze the association between Crohn's disease, its clinical features, and the tumor necrosis factor alpha (TNF-α) -308 polymorphism. METHODS: This is a case-control and cross-sectional study that enrolled 91 patients with Crohn's disease and 91 controls. Patients with Crohn's disease were characterized according to the Montreal Classification, along with their clinical and surgical treatment history. Analysis of the TNF-α -308 polymorphism was performed using a commercial kit. A stratified analysis was applied using an OR (odds ratio) with a 95% confidence interval. The chi-square and Fisher's exact tests were utilized for analysis of the association between the polymorphism and the clinical features of Crohn's disease. RESULTS: The low producer predicted phenotype was present in 76.9% of Crohn's disease cases and 75.8% of controls (OR 0.94 [0.45-1.97]). The TNF2 allele and the high producer predicted phenotype were more frequent among patients with Crohn's disease penetrating behavior (p = 0.004). The TNF2 allele and the high producer predicted phenotype were also associated with a history of colectomy (p = 0.02), and the TNF2 allele was associated with small bowel resection (p = 0.03). CONCLUSIONS: The TNF-α -308 polymorphism appears to affect the severity of the disease. However, TNF-α -308 polymorphism does not appear to be important for the susceptibility in the development of Crohn's disease. PMID:21915486

The Development of a Beta-Gamma Personnel Dosimeter

NASA Astrophysics Data System (ADS)

Tsakeres, Frank Steven

The assessment of absorbed dose in mixed beta and gamma radiation fields is an extremely complex task. For many years, the assessment of the absorbed dose to tissue from the weakly penetrating components of a radiation field (i.e., beta particles, electrons) has been largely ignored. Beta radiation fields are encountered routinely in a nuclear facility and may represent the major radiation component under certain accident or emergency conditions. Many attempts have been made to develop an accurate mixed field personnel dosimeter. However, all of these dosimeters have exhibited numerous response problems which have limited their usefulness for personnel dose assessment. Consequently, the determination of the absorbed dose at the epidermal depth (i.e., 7 mg/cm('2)) has been difficult to measure accurately. The objective of this research project was to design, build, and test a sensitive and accurate personnel dosimeter for mixed field applications. The selection of the various dosimeter elements were determined by evaluating several types of phosphors, filters, and backscatter materials. After evaluating the various response characteristics of the badge components, a prototype dosimeter, the CHEMM (CaF(,2):Dy Highly Efficient Multiple Element Multiple Filter) personnel dosimeter, was developed and tested at Georgia Tech, Emory University and the National Bureau of Standards. This dosimeter was comprised of four large CaF(,2):Dy (TLD-200) TLD's and a standard LiF (TLD-100) chip. The weakly penetrating and penetrating components of a radiation field were separated using a series of TLD/filter combinations and a new dose assessment algorithm. The large TLD-200 chips, along with a series of tissue-equivalent filters, were used to determine the absorbed dose due to the weakly penetrating radiation while a LiF/filter combination was used to measure the penetrating component. In addition, a new backscatter material was included in the badge design to better simulate a tissue-equivalent response. The CHEMM personnel dosimeter performance tests were conducted to simulate actual mixed radiation field environments. This dosimeter provided a high degree of sensitivity with accuracies well within the ANSI recommended performance standards for personnel dosimeters. In addition, it was concluded that the CHEMM dosimetry system provided a practical dosimeter alternative with a higher dose assessment accuracy and measurement sensitivity than the personnel dosimetry systems presently used in the nuclear power industry.

The DRD4 exon 3 VNTR polymorphism and addiction-related phenotypes: a review

PubMed Central

McGeary, John

2009-01-01

In addition to the large literatures on associations of the DRD4 VNTR polymorphism with ADHD and personality traits, there is an emerging literature linking this variant to addiction and addiction-related phenotypes. When only diagnosis-based studies are considered, an inconsistent picture emerges raising doubts as to the relevance of this polymorphism to addiction. However the use of multiple levels of analysis in examining the importance of this polymorphism has raised the possibility of an urge-related “intermediate phenotype” that puts one at risk for developing addiction but may not be found in all persons with an addiction diagnosis. From cellular assays through neuroimaging and behavioral phenotypes, these studies highlight the power of the “intermediate phenotype” approach and suggest a possible explanation of the mixed findings when diagnosis is used as the phenotype. Strengths and weaknesses of alternative DRD4 VNTR genotype grouping strategies are discussed. In sum, converging evidence across multiple methodologies supports the possibility of a robust relationship between the DRD4 exon 3 VNTR polymorphism and urge for addictive substances. PMID:19336242

Physiological characteristics of dysphagia following thermal burn injury.

PubMed

Rumbach, Anna F; Ward, Elizabeth C; Cornwell, Petrea L; Bassett, Lynell V; Muller, Michael J

2012-09-01

The study aim was to document the acute physiological characteristics of swallowing impairment following thermal burn injury. A series of 19 participants admitted to a specialised burn centre with thermal burn injury were identified with suspected aspiration risk by a clinical swallow examination (CSE) conducted by a speech-language pathologist and referred to the study. Once medically stable, each then underwent more detailed assessment using both a CSE and fiberoptic evaluation of swallowing (FEES). FEES confirmed six individuals (32%) had no aspiration risk and were excluded from further analyses. Of the remaining 13, CSE confirmed that two had specific oral-phase deficits due to orofacial scarring and contractures, and all 13 had generalised oromotor weakness. FEES revealed numerous pharyngeal-phase deficits, with the major findings evident in greater than 50% being impaired secretion management, laryngotracheal edema, delayed swallow initiation, impaired sensation, inadequate movement of structures within the hypopharynx and larynx, and diffuse pharyngeal residue. Penetration and/or aspiration occurred in 83% (n = 10/12) of thin fluids trials, with a lack of response to the penetration/aspiration noted in 50% (n = 6/12 penetration aspiration events) of the cases. Most events occurred post swallow. Findings support the fact that individuals with dysphagia post thermal burn present with multiple risk factors for aspiration that appear predominantly related to generalised weakness and inefficiency and further impacted by edema and sensory impairments. Generalised oromotor weakness and orofacial contractures (when present) impact oral-stage swallow function. This study has identified a range of factors that may contribute to both oral- and pharyngeal-stage dysfunction in this clinical population and has highlighted the importance of using a combination of clinical and instrumental assessments to fully understand the influence of burn injury on oral intake and swallowing.

Association between LEPR, FTO, MC4R, and PPARG-2 polymorphisms with obesity traits and metabolic phenotypes in school-aged children.

PubMed

Almeida, Sílvia M; Furtado, José M; Mascarenhas, Paulo; Ferraz, Maria E; Ferreira, José C; Monteiro, Mariana P; Vilanova, Manuel; Ferraz, Fernando P

2018-06-01

Evaluate the relationship of leptin receptor (LEPR) rs1137101, fat mass obesity-associated (FTO) receptors 9939609, melanocortin-4 receptors (MC4R) rs2229616 and rs17782313, and proliferator-activated receptor-gamma (PPARG) rs1801282 with clinical and metabolic phenotypes in prepubertal children. What is the effect of polymorphisms on clinical and metabolic phenotypes in prepubertal children? A cross-sectional descriptive study was performed to evaluate anthropometric features, percentage body fat (%BF), biochemical parameters, and genotype in 773 prepubertal children. FTO rs9939609 was associated with an increase in body mass index (BMI) and BMI z-score (zBMI). MC4R rs17782313 was associated with a decrease in BMI and +0.06 units in zBMI. LEPR, and PPARG-2 polymorphisms were associated with decreases in BMI and an increase and decrease units in zBMI, respectively. The homozygous SNPs demonstrated increases (FTO rs993609 and MC4R rs17782313) and decreases (LEPR rs1137101, PPARG rs1801282) in zBMI than the homozygous form of the major allele. In the overweight/obese group, the MC4R rs17782313 CC genotype showed higher average weight, zBMI, waist circumference, waist-circumference-to-height ratio, and waist-hip ratio, and lower BMI, mid-upper arm circumference, calf circumference, and %BF (P< 0.05). FTO rs9939609 AT and AA genotypes were associated with lower triglycerides (P < 0.05). We showed that MC4R rs17782313 and FTO rs9939609 were positively associated with zBMI, with weak and very weak effects, respectively, suggesting a very scarce contribution to childhood obesity. LEPR rs1137101 and PPARG-2 rs1801282 had weak and medium negative effects on zBMI, respectively, and may slightly protect against childhood obesity.

Methylenetetrahydrofolate reductase C677T polymorphism in patients with gastric and colorectal cancer in a Korean population

PubMed Central

2010-01-01

Background This study was designed to investigate an association between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and the risk of gastric and colorectal cancer in the Korean population. Methods We conducted a population-based large-scale case-control study involving 2,213 patients with newly diagnosed gastric cancer, 1,829 patients with newly diagnosed colorectal cancer, and 1,700 healthy controls. Genotyping was performed with peripheral blood DNA for MTHFR C677T polymorphisms. The statistical significance was estimated by logistic regression analysis. Results The MTHFR C677T frequencies of CC, CT, and TT genotypes were 35.2%, 47.5%, and 17.3% among stomach cancer, 34%, 50.5%, and 15.5% in colorectal cancer, and 31.8%, 50.7%, and 17.5% in the controls, respectively. The MTHFR 677TT genotype showed a weak opposite association with colorectal cancer compared to the homozygous CC genotype [adjusted age and sex odds ratio (OR) = 0.792, 95% confidence interval (CI) = 0.638-0.984, P = 0.035]. Subjects with the MTHFR 677CT showed a significantly reduced risk of gastric cancer compared whose with the 677CC genotype (age- and sex-adjusted OR = 0.810; 95% CI = 0.696-0.942, P = 0.006). We also observed no significant interactions between the MTHFR C677T polymorphism and smoking or drinking in the risk of gastric and colorectal cancer. Conclusions The T allele was found to provide a weak protective association with gastric cancer and colorectal cancer. PMID:20504332

Analysis of the convective evaporation of nondilute clusters of drops

NASA Technical Reports Server (NTRS)

Bellan, J.; Harstad, K.

1987-01-01

The penetration distance of an outer flow into a drop cluster volume is the critical, evaporation mode-controlling parameter in the present model for nondilute drop clusters' convective evaporation. The model is found to perform well for such low penetration distances as those obtained for dense clusters in hot environments and low relative velocities between the outer gases and the cluster. For large penetration distances, however, the predictive power of the model deteriorates; in addition, the evaporation time is found to be a weak function of the initial relative velocity and a strong function of the initial drop temperature. The results generally show that the interior drop temperature was transient throughout the drop lifetime, although temperature nonuniformities persisted up to the first third of the total evaporation time at most.

An explicit analytical solution for sound propagation in a three-dimensional penetrable wedge with small apex angle.

PubMed

Petrov, Pavel S; Sturm, Frédéric

2016-03-01

A problem of sound propagation in a shallow-water waveguide with a weakly sloping penetrable bottom is considered. The adiabatic mode parabolic equations are used to approximate the solution of the three-dimensional (3D) Helmholtz equation by modal decomposition of the acoustic pressure field. The mode amplitudes satisfy parabolic equations that admit analytical solutions in the special case of the 3D wedge. Using the analytical formula for modal amplitudes, an explicit and remarkably simple expression for the acoustic pressure in the wedge is obtained. The proposed solution is validated by the comparison with a solution of the 3D penetrable wedge problem obtained using a fully 3D parabolic equation that includes a leading-order cross term correction.

Polymorphisms in BRCA1 and BRCA2 and risk of epithelial ovarian cancer.

PubMed

Wenham, Robert M; Schildkraut, Joellen M; McLean, Kia; Calingaert, Brian; Bentley, Rex C; Marks, Jeffrey; Berchuck, Andrew

2003-10-01

Because inherited BRCA1 or BRCA2 mutations strikingly increase ovarian cancer risk, polymorphisms in these genes could represent low penetrance susceptibility alleles. Previous studies of the BRCA2 N372H polymorphism suggested that HH homozygotes have a modestly increased risk of both breast and ovarian cancer. We have examined whether BRCA2 N372H or common amino acid-changing polymorphisms in BRCA1 predispose to ovarian cancer. A population-based, case control study of ovarian cancer was performed in North Carolina. Cases included 312 women with ovarian cancer (76% invasive and 24% borderline) and 401 age- and race-matched controls. Blood DNA from subjects was genotyped for BRCA2 N372H and BRCA1 Q356R and P871L. There was no association between BRCA2 N372H and risk of borderline or invasive epithelial ovarian cancer. The overall odds ratio (OR) for HH homozygotes was 0.8 [95% confidence interval (CI) = 0.4-1.5] and was similar in all subsets, including invasive serous cases. In addition, neither the BRCA1 Q356R (OR = 0.9, 95% CI 0.5-1.4) nor P871L (OR = 0.9, 95% CI 0.6-1.9) polymorphisms were associated with ovarian cancer risk. There was a significant racial difference in allele frequencies of the P871L polymorphism (P = 0.64 in Caucasians, L = 0.76 in African-Americans, P < 0.0001). In this population-based, case control study, common amino acid changing BRCA1 and 2 polymorphisms were not found to affect the risk of developing ovarian cancer.

Health maintenance organization penetration and the practice location choices of new physicians: a study of large metropolitan areas in the United States.

PubMed

Escarce, J J; Polsky, D; Wozniak, G D; Pauly, M V; Kletke, P R

1998-11-01

The rapid growth of health maintenance organizations is reshaping the practice opportunities available to physicians. The practice location decisions of new physicians provide a sensitive bellwether of these changes. This study assessed the effect of health maintenance organization penetration on practice location for physicians completing graduate medical education (GME). Conditional logit regression analysis was used to determine the effect of health maintenance organization penetration on practice location, controlling for other market characteristics. Subjects were physicians who finished GME between 1989 and 1994 and who located in one of the 98 US metropolitan areas with more than 500,000 population. The outcome measure was the particular metropolitan area chosen by each new physician. Early in the study period, new generalists were significantly more likely to locate in metropolitan areas with high health maintenance organization penetration than in low penetration areas, whereas new specialists' practice location choices were not associated with health maintenance organization penetration. The likelihood of choosing a high penetration relative to a low penetration area declined with time, however, for both generalists and specialists. Consequently, by the end of the study period, health maintenance organization penetration had a weak but significant negative effect on practice location for generalists and a strong negative influence on practice location for specialists. New generalists who completed graduate medical education between 1989 and 1994 were more likely than new specialists to locate in market areas with high health maintenance organization penetration; however, the proportions of both generalists and specialists who chose high penetration areas decreased during the study period. This finding may reflect reduced practice opportunities in high penetration areas relative to low penetration areas as health maintenance organizations' systems for controlling utilization began to yield results. Alternatively, new physicians may have become more hesitant to accept available positions in high penetration areas.

Polymorphic drugs examined with neutron spectroscopy: Is making more stable forms really that simple?

NASA Astrophysics Data System (ADS)

Tsapatsaris, Nikolaos; Landsgesell, Sven; Koza, Michael M.; Frick, Bernhard; Boldyreva, Elena V.; Bordallo, Heloisa N.

2013-12-01

Understanding polymorphism in pharmaceutical ingredients is a long-standing challenge in formulation science. A well-known example is paracetamol, C8H9NO2. The marketed stable form I crystallizes with corrugated molecular layers. In contrast, form II, which is thermodynamically favorable at high pressures, has relatively planar layers that can slip over each other without difficulty, but is metastable at ambient conditions. By means of inelastic neutron scattering we demonstrated that the lattice modes of form II exhibit a sudden 1 meV energy shift at 300 K under a pressure of ca 0.4 GPa. Moreover, evidence of an increase of the vibrational energy in both polymorphs was found, which was accompanied, in form I, by an unexpectedly weak increase of the tunnel splitting. These results indicate an anisotropy of the potential surface probed by the methyl rotor, and are discussed in relation to the differences of the strength of the hydrogen bond environment for each polymorph.

CR1 rs3818361 Polymorphism Contributes to Alzheimer's Disease Susceptibility in Chinese Population.

PubMed

Li, Yongning; Song, Dongjing; Jiang, Yongshuai; Wang, Jingwei; Feng, Rennan; Zhang, Liangcai; Wang, Guangyu; Chen, Zugen; Wang, Renzhi; Jiang, Qinghua; Liu, Guiyou

2016-08-01

Recent genome-wide association studies (GWAS) reported CR1 rs3818361 polymorphism to be an Alzheimer's disease (AD) susceptibility variant in European ancestry. Three independent studies investigated this association in Chinese population. However, these studies reported weak or no significant association. Here, we reinvestigated the association using all the samples from three independent studies in Chinese population (N = 4047, 1244 AD cases and 2803 controls). We also selected three independent studies in European ancestry population (N = 11787, 3939 AD cases and 7848 controls) to evaluate the effect of rs3818361 polymorphism on AD risk in different ethnic backgrounds. In Chinese population, we did not identified significant heterogeneity using additive, recessive, and dominant genetic models. Meta-analysis showed significant association between rs3818361 and AD with P = 6.00E-03 and P = 5.00E-03. We further identified no heterogeneity of rs3818361 polymorphism between Chinese and European populations. We found that rs3818361 polymorphism contributed to AD with similar genetic risk in Chinese and European populations. In summary, this is the first study to show significant association between rs3818361 polymorphism and AD in Chinese population by a meta-analysis method. Our findings indicate that the effect of CR1 rs3818361 polymorphism on AD risk in Chinese cohorts is consistent with the increased risk observed in European AD cohorts.

Population genetics of polymorphism and divergence for diploid selection models with arbitrary dominance.

PubMed

Williamson, Scott; Fledel-Alon, Adi; Bustamante, Carlos D

2004-09-01

We develop a Poisson random-field model of polymorphism and divergence that allows arbitrary dominance relations in a diploid context. This model provides a maximum-likelihood framework for estimating both selection and dominance parameters of new mutations using information on the frequency spectrum of sequence polymorphisms. This is the first DNA sequence-based estimator of the dominance parameter. Our model also leads to a likelihood-ratio test for distinguishing nongenic from genic selection; simulations indicate that this test is quite powerful when a large number of segregating sites are available. We also use simulations to explore the bias in selection parameter estimates caused by unacknowledged dominance relations. When inference is based on the frequency spectrum of polymorphisms, genic selection estimates of the selection parameter can be very strongly biased even for minor deviations from the genic selection model. Surprisingly, however, when inference is based on polymorphism and divergence (McDonald-Kreitman) data, genic selection estimates of the selection parameter are nearly unbiased, even for completely dominant or recessive mutations. Further, we find that weak overdominant selection can increase, rather than decrease, the substitution rate relative to levels of polymorphism. This nonintuitive result has major implications for the interpretation of several popular tests of neutrality.

38 CFR 4.56 - Evaluation of muscle disabilities.

Code of Federal Regulations, 2011 CFR

2011-07-01

..., the cardinal signs and symptoms of muscle disability are loss of power, weakness, lowered threshold of... signs or symptoms of muscle disability as defined in paragraph (c) of this section. (iii) Objective... injury. Through and through or deep penetrating wound of short track from a single bullet, small shell or...

38 CFR 4.56 - Evaluation of muscle disabilities.

Code of Federal Regulations, 2010 CFR

2010-07-01

..., the cardinal signs and symptoms of muscle disability are loss of power, weakness, lowered threshold of... signs or symptoms of muscle disability as defined in paragraph (c) of this section. (iii) Objective... injury. Through and through or deep penetrating wound of short track from a single bullet, small shell or...

Mutagen Sensitivity and DNA Repair Gene Polymorphisms in Hereditary and Sporadic Breast Cancer

DTIC Science & Technology

2005-03-01

exposures trigger breast cancer in the general population; BRCA] mutation carriers are just substantially more susceptible to these gene -environment...repair complex Genes that affect BRCAJ mutation penetrance might be those involved in DNA repair, because BRCA1 is itself believed to be involved in...without founder mutations (187delAG and 5382insC) had complete BRCA] and BRCA2 gene sequencing. Some patients are related (n=34). Patient demographics

Molecular Genotyping of Anisakis Larvae in Middle Eastern Japan and Endoscopic Evidence for Preferential Penetration of Normal over Atrophic Mucosa

PubMed Central

Arai, Toshio; Akao, Nobuaki; Seki, Takenori; Kumagai, Takashi; Ishikawa, Hirofumi; Ohta, Nobuo; Hirata, Nobuto; Nakaji, So; Yamauchi, Kenji; Hirai, Mitsuru; Shiratori, Toshiyasu; Kobayashi, Masayoshi; Fujii, Hiroyuki; Ishii, Eiji; Naito, Mikio; Saitoh, Shin-ichi; Yamaguchi, Toshikazu; Shibata, Nobumitsu; Shimo, Masamune; Tokiwa, Toshihiro

2014-01-01

Background Anisakiasis is a parasitic disease caused primarily by Anisakis spp. larvae in Asia and in Western countries. The aim of this study was to investigate the genotype of Anisakis larvae endoscopically removed from Middle Eastern Japanese patients and to determine whether mucosal atrophy affects the risk of penetration in gastric anisakiasis. Methods In this study, 57 larvae collected from 44 patients with anisakiasis (42 gastric and 2 colonic anisakiasis) were analyzed retrospectively. Genotyping was confirmed by restriction fragment length polymorphism (RFLP) analysis of ITS regions and by sequencing the mitochondrial small subunit (SSU) region. In the cases of gastric anisakiasis, correlation analyses were conducted between the frequency of larval penetration in normal/atrophic area and the manifestation of clinical symptoms. Results Nearly all larvae were A. simplex seusu stricto (s.s.) (99%), and one larva displayed a hybrid genotype. The A. simplex larvae penetrated normal mucosa more frequently than atrophic area (p = 0.005). Finally, patients with normal mucosa infection were more likely to exhibit clinical symptoms than those with atrophic mucosa infection (odds ratio, 6.96; 95% confidence interval, 1.52–31.8). Conclusions In Japan, A. simplex s.s. is the main etiological agent of human anisakiasis and tends to penetrate normal gastric mucosa. Careful endoscopic examination of normal gastric mucosa, particularly in the greater curvature of the stomach will improve the detection of Anisakis larvae. PMID:24586583

Studies on the Effects of High Renewable Penetrations on Driving Point Impedance and Voltage Regulator Performance: National Renewable Energy Laboratory/Sacramento Municipal Utility District Load Tap Changer Driving Point Impedance Project

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nagarajan, Adarsh; Coddington, Michael H.; Brown, David

Voltage regulators perform as desired when regulating from the source to the load and when regulating from a strong source (utility) to a weak source (distributed generation). (See the glossary for definitions of a strong source and weak source.) Even when the control is provisioned for reverse operation, it has been observed that tap-changing voltage regulators do not perform as desired in reverse when attempting regulation from the weak source to the strong source. The region of performance that is not as well understood is the regulation between sources that are approaching equal strength. As part of this study, wemore » explored all three scenarios: regulator control from a strong source to a weak source (classic case), control from a weak source to a strong source (during reverse power flow), and control between equivalent sources.« less

Microscopic investigation of the weakly correlated noncentrosymmetric superconductor SrAuSi3

NASA Astrophysics Data System (ADS)

Barbero, N.; Biswas, P. K.; Isobe, M.; Amato, A.; Morenzoni, E.; Hillier, A. D.; Ott, H.-R.; Mesot, J.; Shiroka, T.

2018-01-01

SrAuSi3 is a noncentrosymmetric superconductor (NCS) with Tc=1.54 K, which to date has been studied only via macroscopic techniques. By combining nuclear-magnetic-resonance and muon-spin-rotation measurements, we investigate both the normal and the superconducting phase of SrAuSi3 at a local level. In the normal phase, our data indicate a standard metallic behavior with weak electron correlations and a Korringa constant Sexp=1.31 ×10-5 sK. The latter, twice the theoretical value, can be justified by the Moriya theory of exchange enhancement. In the superconducting phase, the material exhibits conventional BCS-type superconductivity with a weak-coupling s -wave pairing, a gap value Δ (0 )=0.213 (2 ) meV, and a magnetic penetration depth λ (0 )=398 (2 ) nm. The experimental proof of weak correlations in SrAuSi3 implies that correlation effects can be decoupled from those of antisymmetric spin-orbit coupling, thus enabling accurate band-structure calculations in the weakly correlated NCSs.

Limits on deeply penetrating particles in the 10(17) eV cosmic ray flux

NASA Technical Reports Server (NTRS)

Baltrusaitis, R. M.; Cassiday, G. L.; Cooper, R.; Elbert, J. W.; Gerhardy, J. W.; Loh, P. R.; Mizumoto, Y.; Sokolsky, P.; Sommers, P.; Steck, D.

1985-01-01

Deeply penetrating particles in the 10 to the 17th power eV cosmic ray flux were investigated. No such events were found in 8.2 x 10 to the 6th power sec of running time. Limits were set on the following: quark-matter in the primary cosmic ray flux; long-lived, weakly interacting particles produced in p-air collisions; the astrophysical neutrino flux. In particular, the neutrino flux limit at 10 to the 17th power eV implies that z, the red shift of maximum activity is 10 in the model of Hill and Schramm.

Association of CRTC1 polymorphisms with obesity markers in subjects from the general population with lifetime depression.

PubMed

Quteineh, Lina; Preisig, Martin; Rivera, Margarita; Milaneschi, Yuri; Castelao, Enrique; Gholam-Rezaee, Mehdi; Vandenberghe, Frederik; Saigi-Morgui, Nuria; Delacrétaz, Aurélie; Cardinaux, Jean-René; Willemsen, Gonneke; Boomsma, Dorret I; Penninx, Brenda W J H; Ching-López, Ana; Conus, Philippe; Eap, Chin B

2016-07-01

Psychiatric disorders have been hypothesized to share common etiological pathways with obesity, suggesting related neurobiological bases. We aimed to examine whether CRTC1 polymorphisms were associated with major depressive disorder (MDD) and to test the association of these polymorphisms with obesity markers in several large case-control samples with MDD. The association between CRTC1 polymorphisms and MDD was investigated in three case-control samples with MDD (PsyCoLaus n1=3,362, Radiant n2=3,148 and NESDA/NTR n3=4,663). The effect of CRTC1 polymorphisms on obesity markers was then explored. CRTC1 polymorphisms were not associated with MDD in the three samples. CRTC1 rs6510997C>T was significantly associated with fat mass in the PsyCoLaus study. In fact, a protective effect of this polymorphism was found in MDD cases (n=1,434, β=-1.32%, 95% CI -2.07 to -0.57, p<0.001), but not in controls. In the Radiant study, CRTC1 polymorphisms were associated with BMI, exclusively in individuals with MDD (n=2,138, β=-0.75kg/m(2), 95% CI -1.30 to -0.21, p=0.007), while no association with BMI was found in the NESDA/NTR study. Estimated fat mass using bioimpedance that capture more accurately adiposity was only present in the PsyCoLaus sample. CRTC1 polymorphisms seem to play a role with obesity markers in individuals with MDD rather than non-depressive individuals. Therefore, the weak association previously reported in the population-based samples was driven by cases diagnosed with lifetime MDD. However, CRTC1 seems not to be implicated directly in the development of psychiatric diseases. Copyright © 2016 Elsevier B.V. All rights reserved.

Terminal ballistics of a reduced-mass penetrator. Final report, January 1990--December 1995

DOE Office of Scientific and Technical Information (OSTI.GOV)

Silsby, G.F.

1996-07-01

This report presents the results of an experimental program to examine the performance of a reduced-mass concept penetrator impacting semi-infinite rolled homogeneous armor (RHA) at normal incidence. The reduced-mass penetrator used in this program is a solid tungsten alloy rod with eight holes drilled parallel to its axis, equally spaced on a circle, with axes parallel to the rod axis. Its performance was contrasted with baseline data for length-to- diameter ratios (L/D) 4 and 5 solid tungsten alloy penetrators. Striking velocity was nominally 1.6 km/s. A determined effort to reduce the scatter in the data by analysis of collateral datamore » from the US Army Research Laboratory (ARL) and literature sources suggested only a rather weak influence of L/D on penetration even at L/Ds approaching 1 and provided a tentative relationship to remove the influence of target lateral edge effects. It tightened up the holed-out rod data enough to be able to conclude with a moderate degree of certainty that there was no improvement in penetration as suggested by a simplistic density law model. A companion work by Kimsey of ARL examines the performance of this novel penetrator concept computationally, using the Eulerian code CTH. His work explains the possible causes of reduced performance suggested by analysis by Zook and Frank of ARL, though with some relative improvement in performance at higher velocities.« less

Managed care market share and cesarean section rates in the United States: is there a link?

PubMed

Hueston, W J; Sutton, A

2000-11-01

After peaking during the early 1980s, cesarean section rates in the United States have been falling for the last decade. At the same time, managed care enrollment has increased dramatically. This study examines whether managed care penetration in local markets is associated with lower cesarean section rates in those geographic area. A cross-sectional comparison of cesarean section rates and health maintenance organization (HMO) market penetration in 61 selected metropolitan areas in the United States was conducted. National birth certificate data for 1996 were used to calculate crude and race-adjusted cesarean section rates for residents in each area. No relationship between overall cesarean section rates in the metropolitan areas and managed care penetration was observed. Subanalyses of racial groups demonstrated the existence of a weak association between managed care penetration and cesarean section rates for white women (21.2% for the highest quartile of HMO penetration, compared with 19.1% for the lowest quartile; P = .03), but not for African-Americans or other minorities. Managed care penetration in a market may have an association with cesarean section rates for white women, but the strength of this relationship is small. Even if managed care delivery systems reduce cesarean section rates in their own populations, this change is likely to have only a small impact on overall cesarean rates. HMO penetration is unlikely to influence national cesarean section rates, nor does it appear to explain state variations in these rates.

PCR-based study of conserved and variable DNA sequences of Tritrichomonas foetus isolates from Saskatchewan, Canada.

PubMed Central

Riley, D E; Wagner, B; Polley, L; Krieger, J N

1995-01-01

The protozoan parasite Tritrichomonas foetus causes infertility and spontaneous abortion in cattle. In Saskatchewan, Canada, the culture prevalence of trichomonads was 65 of 1,048 (6%) among 1,048 bulls tested within a 1-year period ending in April 1994. Saskatchewan was previously thought to be free of the parasite. To confirm the culture results, possible T. foetus DNA presence was determined by the PCR. All of the 16 culture-positive isolates tested were PCR positive by a single-band test, but one PCR product was weak. DNA fingerprinting by both T17 PCR and randomly amplified polymorphic DNA PCR revealed genetic variation or polymorphism among the T. foetus isolates. T17 PCR also revealed conserved loci that distinguished these T. foetus isolates from Trichomonas vaginalis, from a variety of other protozoa, and from prokaryotes. TCO-1 PCR, a PCR test designed to sample DNA sequence homologous to the 5' flank of a highly conserved cell division control gene, detected genetic polymorphism at low stringency and a conserved, single locus at higher stringency. These findings suggested that T. foetus isolates exhibit both conserved genetic loci and polymorphic loci detectable by independent PCR methods. Both conserved and polymorphic genetic loci may prove useful for improved clinical diagnosis of T. foetus. The polymorphic loci detected by PCR suggested either a long history of infection or multiple lines of T. foetus infection in Saskatchewan. Polymorphic loci detected by PCR may provide data for epidemiologic studies of T. foetus. PMID:7615746

Analysis of Ethnic Admixture in Prostate Cancer

DTIC Science & Technology

2006-12-01

low penetrant genes have been identified as potential PCA suscept- ibility genes. These candidate genes include SRD5A2 (MIM 607306), CYP3A4 (MIM 124010...progression [13]. The CDH1gene is located at 16q22.1 and consists of 16 exons spanning approximately 100 kb of genomic DNA. Several polymorphisms, germline and...upstreamof theATGstart site and all 16 exons of CDH1 were screened for DNA sequence variation by denaturing high-performance liquid chro- matography

Investigations on the sensitivity of a stepped-frequency radar utilizing a vector network analyzer for Ground Penetrating Radar

NASA Astrophysics Data System (ADS)

Seyfried, Daniel; Schubert, Karsten; Schoebel, Joerg

2014-12-01

Employing a continuous-wave radar system, with the stepped-frequency radar being one type of this class, all reflections from the environment are present continuously and simultaneously at the receiver. Utilizing such a radar system for Ground Penetrating Radar purposes, antenna cross-talk and ground bounce reflection form an overall dominant signal contribution while reflections from objects buried in the ground are of quite weak amplitude due to attenuation in the ground. This requires a large dynamic range of the receiver which in turn requires high sensitivity of the radar system. In this paper we analyze the sensitivity of our vector network analyzer utilized as stepped-frequency radar system for GPR pipe detection. We furthermore investigate the performance of increasing the sensitivity of the radar by means of appropriate averaging and low-noise pre-amplification of the received signal. It turns out that the improvement in sensitivity actually achievable may differ significantly from theoretical expectations. In addition, we give a descriptive explanation why our appropriate experiments demonstrate that the sensitivity of the receiver is independent of the distance between the target object and the source of dominant signal contribution. Finally, our investigations presented in this paper lead to a preferred setting of operation for our vector network analyzer in order to achieve best detection capability for weak reflection amplitudes, hence making the radar system applicable for Ground Penetrating Radar purposes.

DNA polymorphisms predict time to progression from uncomplicated to complicated Crohn's disease.

PubMed

Pernat Drobež, Cvetka; Repnik, Katja; Gorenjak, Mario; Ferkolj, Ivan; Weersma, Rinse K; Potočnik, Uroš

2018-04-01

Most patients with Crohn's disease (CD) are diagnosed with the uncomplicated inflammatory form of the disease (Montreal stage B1). However, the majority of them will progress to complicated stricturing (B2) and penetrating (B3) CD during their lifetimes. The aim of our study was to identify the genetic factors associated with time to progression from uncomplicated to complicated CD. Patients with an inflammatory phenotype at diagnosis were followed up for 10 years. Genotyping was carried out using Illumina ImmunoChip. After quality control, association analyses, Bonferroni's adjustments, linear and Cox's regression, and Kaplan-Meier analysis were carried out for 111 patients and Manhattan plots were constructed. Ten years after diagnosis, 39.1% of the patients still had the inflammatory form and 60.9% progressed to complicated disease, with an average time to progression of 5.91 years. Ileal and ileocolonic locations were associated with the complicated CD (P=1.08E-03). We found that patients with the AA genotype at single-nucleotide polymorphism rs16857259 near the gene CACNA1E progressed to the complicated form later (8.80 years) compared with patients with the AC (5.11 years) or CC (2.00 years) genotypes (P=3.82E-07). In addition, nine single-nucleotide polymorphisms (near the genes RASGRP1, SULF2, XPO1, ZBTB44, HLA DOA/BRD2, HLA DRB1/HLA DQA1, PPARA, PUDP, and KIAA1614) showed a suggestive association with disease progression (P<10). Multivariate Cox's regression analysis on the basis of clinical and genetic data confirmed the association of the selected model with disease progression (P=5.73E-16). Our study confirmed the association between the locus on chromosome 1 near the gene CACNA1E with time to progression from inflammatory to stricturing or penetrating CD. Predicting the time to progression is useful to the clinician in terms of individualizing patients' management.

Systematic meta-analyses and field synopsis of genetic association studies in colorectal adenomas

PubMed Central

Montazeri, Zahra; Theodoratou, Evropi; Nyiraneza, Christine; Timofeeva, Maria; Chen, Wanjing; Svinti, Victoria; Sivakumaran, Shanya; Gresham, Gillian; Cubitt, Laura; Carvajal-Carmona, Luis; Bertagnolli, Monica M; Zauber, Ann G; Tomlinson, Ian; Farrington, Susan M; Dunlop, Malcolm G; Campbell, Harry; Little, Julian

2018-01-01

Background Low penetrance genetic variants, primarily single nucleotide polymorphisms, have substantial influence on colorectal cancer (CRC) susceptibility. Most CRCs develop from colorectal adenomas (CRA). Here, we report the first comprehensive field synopsis that catalogues all genetic association studies on CRA, with a parallel online database (http://www.chs.med.ed.ac.uk/CRAgene/). Methods We performed a systematic review, reviewing 9750 titles and then extracted data from 130 publications reporting on 181 polymorphisms in 74 genes. We conducted meta-analyses to derive summary effect estimates for 37 polymorphisms in 26 genes. We applied the Venice criteria and Bayesian False Discovery Probability (BFDP) to assess the levels of the credibility of associations. Results We considered the association with the rs6983267 variant at 8q24 as “highly credible”, reaching genome wide statistical significance in at least one meta-analysis model. We identified “less credible” associations (higher heterogeneity, lower statistical power, BFDP>0.02) with a further four variants of four independent genes: MTHFR c.677C>T p.A222V (rs1801133), TP53 c.215C>G p.R72P (rs1042522), NQO1 c.559C>T p.P187S (rs1800566), and NAT1 alleles imputed as fast acetylator genotypes. For the remaining 32 variants of 22 genes for which positive associations with CRA risk have been previously reported, the meta-analyses revealed no credible evidence to support these as true associations. Conclusions The limited number of credible associations between low penetrance genetic variants and CRA reflects the lower volume of evidence and associated lack of statistical power to detect associations of the magnitude typically observed for genetic variants and chronic diseases. The CRAgene database provides context for CRA genetic association data and will help inform future research directions. PMID:26451011

Risk prediction for early-onset gastric carcinoma: a case-control study of polygenic gastric cancer in Han Chinese with hereditary background.

PubMed

Yuan, Jiajia; Li, Yanyan; Tian, Tiantian; Li, Na; Zhu, Yan; Zou, Jianling; Gao, Jing; Shen, Lin

2016-06-07

Recent genomewide studies have identified several germline variations associated with gastric cancer. The aim of the present study was to identify, in a Chinese Han population, the individual and combined effects of those single nucleotide polymorphisms (SNPs) that increase the risk of early-onset gastric cancer. We conducted a case-control study comprising 116 patients with gastric cancer as well as 102 sex- and age-matched controls and confirmed that the SNPs MUC1 (mucin 1) rs9841504 and ZBTB20 (zinc finger and BTB domain containing 20) rs4072037 were associated with an increased gastric cancer risk. Of the 116 patients diagnosed with cancer, 65 had at least 1 direct lineal relative with carcinoma of the digestive system or breast/ovarian cancer. These 65 had another 4 SNPs associated with gastric cancer susceptibility: PSCA (prostate stem cell antigen) rs2294008, PLCE1 (phospholipase C epsilon 1) rs2274223, PTGER4/PRKAA1 (prostaglandin E receptor 4/ protein kinase AMP-activated catalytic subunit alpha 1) rs13361707, and TYMS (thymidylate synthetase) rs2790. However, each of these low-penetrance susceptibility polymorphisms alone is not considered influential enough to predict the absolute risk of early-onset gastric cancer. Thus we decided to study different combinations of polygenes as they affected for our population. Those subjects with both the risk alleles MUC1 rs9841504 and ZBTB20 rs4072037 had a greater than 3-fold increased risk of gastric cancer. Also those with a hereditary background including the risk alleles PLCE1 rs2274223 and PTGER4/PRKAA1 rs13361707 were 3 times more susceptible to cardia cancer than those without. These findings show that the study of combined polymorphisms, instead of single low-penetrance variations in susceptibility, may lead to a high-risk classification for a specific population.

Risk prediction for early-onset gastric carcinoma: a case-control study of polygenic gastric cancer in Han Chinese with hereditary background

PubMed Central

Yuan, Jiajia; Li, Yanyan; Tian, Tiantian; Li, Na; Zhu, Yan; Zou, Jianling; Gao, Jing; Shen, Lin

2016-01-01

Recent genomewide studies have identified several germline variations associated with gastric cancer. The aim of the present study was to identify, in a Chinese Han population, the individual and combined effects of those single nucleotide polymorphisms (SNPs) that increase the risk of early-onset gastric cancer. We conducted a case-control study comprising 116 patients with gastric cancer as well as 102 sex- and age-matched controls and confirmed that the SNPs MUC1 (mucin 1) rs9841504 and ZBTB20 (zinc finger and BTB domain containing 20) rs4072037 were associated with an increased gastric cancer risk. Of the 116 patients diagnosed with cancer, 65 had at least 1 direct lineal relative with carcinoma of the digestive system or breast/ovarian cancer. These 65 had another 4 SNPs associated with gastric cancer susceptibility: PSCA (prostate stem cell antigen) rs2294008, PLCE1 (phospholipase C epsilon 1) rs2274223, PTGER4/PRKAA1 (prostaglandin E receptor 4/protein kinase AMP-activated catalytic subunit alpha 1) rs13361707, and TYMS (thymidylate synthetase) rs2790. However, each of these low-penetrance susceptibility polymorphisms alone is not considered influential enough to predict the absolute risk of early-onset gastric cancer. Thus we decided to study different combinations of polygenes as they affected for our population. Those subjects with both the risk alleles MUC1 rs9841504 and ZBTB20 rs4072037 had a greater than 3-fold increased risk of gastric cancer. Also those with a hereditary background including the risk alleles PLCE1 rs2274223 and PTGER4/PRKAA1 rs13361707 were 3 times more susceptible to cardia cancer than those without. These findings show that the study of combined polymorphisms, instead of single low-penetrance variations in susceptibility, may lead to a high-risk classification for a specific population. PMID:27127881

DNA repair gene polymorphisms and risk of cutaneous melanoma: a systematic review and meta-analysis.

PubMed

Mocellin, Simone; Verdi, Daunia; Nitti, Donato

2009-10-01

Polymorphisms of DNA repair-related genes might modulate cancer predisposition. We performed a systematic review and meta-analysis of the available evidence regarding the relationship between these polymorphisms and the risk of developing cutaneous melanoma. Relevant studies were searched using PubMed, Medline, Embase, Cancerlit, Cochrane and ISI Web of Knowledge databases. Data were gathered according to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. The model-free approach was adopted to perform the meta-analysis of the retrieved data. We identified 20 original reports that describe the relationship between melanoma risk and the single-nucleotide polymorphisms (SNPs) of 16 genes (cases = 4195). For seven SNPs considered in at least two studies, the findings were heterogeneous. Data were suitable for meta-analysis only in the case of the XPD/ERCC2 SNP rs13181 (cases = 2308, controls = 3698) and demonstrated that the variant C allele is associated with increased melanoma risk (odds ratio = 1.12, 95% confidence interval = 1.03-1.21, P = 0.01; population attributable risk = 9.6%). This is the first meta-analysis suggesting that XPD/ERCC2 might represent a low-penetrance melanoma susceptibility gene. Much work is still to be done before definitive conclusions can be drawn on the role of DNA repair alterations in melanomagenesis since for the other genes involved in this highly complex process, the available information is scarce or null.

VEGFA polymorphisms and cardiovascular anomalies in 22q11 microdeletion syndrome: a case-control and family-based study.

PubMed

Calderón, Juan Francisco; Puga, Alonso R; Guzmán, M Luisa; Astete, Carmen Paz; Arriaza, Marta; Aracena, Mariana; Aravena, Teresa; Sanz, Patricia; Repetto, Gabriela M

2009-01-01

Microdeletion 22q11 in humans causes velocardiofacial and DiGeorge syndromes. Most patients share a common 3Mb deletion, but the clinical manifestations are very heterogeneous. Congenital heart disease is present in 50-80% of patients and is a significant cause of morbidity and mortality. The phenotypic variability suggests the presence of modifiers. Polymorphisms in the VEGFA gene, coding for the vascular endothelial growth factor A, have been associated with non-syndromic congenital heart disease, as well as with the presence of cardiovascular anomalies in patients with microdeletion 22q11. We evaluated the association of VEGFA polymorphisms c.-2578C>A (rs699947), c.-1154G>A (rs1570360) and c.-634C>G (rs2010963) with congenital heart disease in Chilean patients with microdeletion 22q11. The study was performed using case-control and family-based association designs. We evaluated 122 patients with microdeletion 22q11 and known anatomy of the heart and great vessels, and their parents. Half the patients had congenital heart disease. We obtained no evidence of association by either method of analysis. Our results provide further evidence of the incomplete penetrance of the cardiovascular phenotype of microdeletion 22ql 1, but do not support association between VEGFA promoter polymorphisms and the presence of congenital heart disease in Chilean patients with this syndrome.

[The morphology, typical combinations of polymorphic genes of hemostasis, and specific features of the pathogenesis of retrochorial hematoma in missed abortion].

PubMed

Milovanov, A P; Kuznetsova, N B; Bushtyreva, I O

to identify mutations and hemostatic gene polymorphisms typical for retrochorial hematoma (RCH) and to study its pathogenesis in missed abortion. A PCR assay was used to detect the genetic forms of thrombophilia in 270 patients with ultrasonographically verified RCH. Logistic regression analysis revealed that with the F7 (proconvertin, coagulation factor (CF) VII G10976A polymorphism or with the F13 (fibrinase, CF XIII) G>T, or FGB (fibrinogen β-chain) G455A polymorphism, the risk of RCH was 2.72, 2.16, and 1.92 times higher, respectively. First trimester missed abortion was found in 42 (15.5%) cases; among them there were 24 (8.8%) women with different polymorphism combinations: F7 (G10976A), F13 (fibrinase, G>T), FGB (G455A). A total of 18 cases of missed abortion due to morphologically verified endometritis, endocrinopathies, and antiphospholipid syndrome were excluded from the sample. Compared to the morphology of medical abortions of the same period (16 women), patients with polymorphic genes of hemostasis were found to have statistically significant incomplete endometrial decidualization, thinning or absence of a Rohr's fibrinoid layer, a smaller number and shortening of syncytiotrophoblast microvilli, and the maximum amount of dissecting hemorrhage and RCH in the utero-chorionic region. The stages of RCH pathogenesis were determined; these included penetration of maternal erythrocytes deep into the decidua ~ dissociation of a layer of decidual cells with impairment of a «hemostatic envelope» ~ formation of RCH with a dense network of fibrin threads ~ final necrosis of surrounding cells and tissues. The investigators identified for the first time the typical combinations of polymorphic genes of predisposition to a high risk for RCH; its complete formation requires additional changes in maternal and placental components that provide local hemostasis.

Analysis of the Functional Polymorphism in the Cytochrome P450 CYP2C8 Gene rs11572080 with Regard to Colorectal Cancer Risk

PubMed Central

Ladero, José M.; Agúndez, José A. G.; Martínez, Carmen; Amo, Gemma; Ayuso, Pedro; García-Martín, Elena

2012-01-01

In addition to the known effects on drug metabolism and response, functional polymorphisms of genes coding for xenobiotic-metabolizing enzymes (XME) play a role in cancer. Genes coding for XME act as low-penetrance genes and confer modest but consistent and significant risks for a variety of cancers related to the interaction of environmental and genetic factors. Consistent evidence supports a role for polymorphisms of the cytochrome P450 CYP2C9 gene as a protecting factor for colorectal cancer susceptibility. It has been shown that CYP2C8 and CYP2C9 overlap in substrate specificity. Because CYP2C8 has the common functional polymorphisms rs11572080 and rs10509681 (CYP2C8*3), it could be speculated that part of the findings attributed to CYP2C9 polymorphisms may actually be related to the presence of polymorphisms in the CYP2C8 gene. Nevertheless, little attention has been paid to the role of the CYP2C8 polymorphism in colorectal cancer. We analyzed the influence of the CYP2C8*3 allele in the risk of developing colorectal cancer in genomic DNA from 153 individuals suffering colorectal cancer and from 298 age- and gender-matched control subjects. Our findings do not support any effect of the CYP2C8*3 allele (OR for carriers of functional CYP2C8 alleles = 0.50 (95% CI = 0.16–1.59; p = 0.233). The absence of a relative risk related to CYP2C8*3 did not vary depending on the tumor site. We conclude that the risk of developing colorectal cancer does not seem to be related to the commonest functional genetic variation in the CYP2C8 gene. PMID:23420707

Superconducting Effects in Optimization of Magnetic Penetration Thermometers for X-ray Microcalorimeters

NASA Technical Reports Server (NTRS)

Stevenson, Thomas R.; Balvin, M. A.; Denis, K. L.; Hsieh, W.-T.; Sadleir, J. E.; Bandler, Simon E.; Busch, Sarah E.; Merrell, W.; Kelly, Daniel P.; Nagler, Peter C.;

A second ortho-rhom-bic polymorph of (Z)-3-(9-anthr-yl)-1-(2-thien-yl)prop-2-en-1-one.

PubMed

Chantrapromma, Suchada; Suwunwong, Thitipone; Boonnak, Nawong; Fun, Hoong-Kun

2010-01-09

The title heteroaryl chalcone, C(21)H(14)OS, is a second ortho-rhom-bic polymorph which crystallizes in the space group P2(1)2(1)2(1). The structure was previously reported [Fun et al. (2009 ▶). Acta Cryst. E65, o2168-o2169] in the space group Pna2(1). The bond distances and angles are similar in both structures. In contrast, the overall crystal packing is different from that in the first ortho-rhom-bic Pna2(1) polymorph in which mol-ecules were stacked into columns along the b axis and the thio-phene units of two adjacent columns were stacked in a head to tail fashion. In the present polymorph, mol-ecules are found to dimerize through a weak S⋯S inter-action [3.6513 (7) Å] and these dimers are arranged into sheets parallel to the bc plane. There are no classical hydrogen bonds in the packing which features short C⋯O [3.2832 (2)-3.6251 (9) Å], C⋯S [3.4879 (17)-3.6251 (19) Å] and S⋯O [2.9948 (16) Å] contacts, together with C-H⋯π inter-actions. Similar contacts were found in the other polymorph.

PICALM gene rs3851179 polymorphism contributes to Alzheimer's disease in an Asian population.

PubMed

Liu, Guiyou; Zhang, Shuyan; Cai, Zhiyou; Ma, Guoda; Zhang, Liangcai; Jiang, Yongshuai; Feng, Rennan; Liao, Mingzhi; Chen, Zugen; Zhao, Bin; Li, Keshen

2013-06-01

PICALM gene rs3851179 polymorphism was reported to an Alzheimer's disease (AD) susceptibility locus in a Caucasian population. However, recent studies reported consistent and inconsistent results in an Asian population. Four studies indicated no association between rs3851179 and AD in a Chinese population and one study reported weak association in a Japanese population. We consider that the failure to replicate the significant association between rs3851179 and AD may be caused by at least two reasons. The first reason may be the genetic heterogeneity in AD among different populations, and the second may be the relatively small sample size compared with large-scale GWAS in Caucasian ancestry. In order to confirm this view, in this research, we first evaluated the genetic heterogeneity of rs3851179 polymorphism in Caucasian and Asian populations. We then investigated rs3851179 polymorphism in an Asian population by a pooled analysis method and a meta-analysis method. We did not observe significant genetic heterogeneity of rs3851179 in the Caucasian and Asian populations. Our results indicate that rs3851179 polymorphism is significantly associated with AD in the Asian population by both pooled analysis and meta-analysis methods. We believe that our findings will be very useful for future genetic studies in AD.

CLU rs9331888 Polymorphism Contributes to Alzheimer's Disease Susceptibility in Caucasian But Not East Asian Populations.

PubMed

Zhang, Shuyan; Li, Xuling; Ma, Guoda; Jiang, Yongshuai; Liao, Mingzhi; Feng, Rennan; Zhang, Liangcai; Liu, Jiafeng; Wang, Guangyu; Zhao, Bin; Jiang, Qinghua; Li, Keshen; Liu, Guiyou

2016-04-01

Large-scale genome-wide association studies (GWAS) identified three single nucleotide polymorphisms rs11136000, rs2279590, and rs9331888 in CLU gene to be significantly associated with Alzheimer's disease (AD) in Caucasian ancestry. Both rs11136000 and rs2279590 variants were successfully replicated in Asian population. However, previous studies reported either a weak association or no association between rs9331888 polymorphism and AD in Asian population. Here, we searched the PubMed, AlzGene, and Google Scholar databases. We selected 12 independent studies that evaluated the association between the rs9331888 polymorphism and AD using a case-control design. Using an additive model, we did not identify significant heterogeneity among these 12 studies. We observed significant association between rs9331888 polymorphism and AD in pooled populations (P = 2.26E - 07, odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.06-1.14). In subgroup analysis, we did not identify significant heterogeneity in both Asian and Caucasian populations. We identified significant association in Caucasian population (P = 1.67E - 08, OR = 1.13, 95% CI 1.08-1.18) but not in East Asian population (P = 0.49, OR = 1.02, 95% CI 0.96-1.10).

Polymorphism of the renalase gene in gestational diabetes mellitus.

PubMed

Fatima, Syeda Sadia; Jamil, Zehra; Alam, Faiza; Malik, Hajira Zafar; Madhani, Sarosh Irfan; Ahmad, Muhammad Saad; Shabbir, Tayyab; Rehmani, Muhammed Noman; Rabbani, Amna

2017-01-01

Renalase is considered as a novel candidate gene for type 2 diabetes. In this study, we aimed to investigate the relationship of serum renalase and two single nucleotide polymorphisms with gestational diabetes mellitus. One hundred and ninety-eight normotensive pregnant females (n = 99 gestational diabetes mellitus; n = 99 euglycemic pregnant controls) were classified according to the International Association of the Diabetes and Pregnancy Study criteria. Fasting and 2-h post glucose load blood levels and anthropometric assessment was performed. Serum renalase was measured using enzyme-linked immunosorbent assay, whereas DNA samples were genotyped for renalase single nucleotide polymorphisms rs2576178 and rs10887800 using Polymerase chain reaction-Restriction fragment length polymorphism method. In an age-matched case control study, no difference was observed in the serum levels of renalase (p > 0.05). The variant rs10887800 showed an association with gestational diabetes mellitus and remained significant after multiple adjustments (p < 0.05), whereas rs2576178 showed weak association (p = 0.030) that was lost after multiple adjustments (p = 0.09). We inferred a modest association of the rs10887800 polymorphism with gestational diabetes. Although gestational diabetes mellitus is self-reversible, yet presence of this minor G allele might predispose to metabolic syndrome phenotypes in near the future.

Telomerase Reverse Transcriptase Locus Polymorphisms and Cancer Risk: A Field Synopsis and Meta-Analysis

PubMed Central

Verdi, Daunia; Pooley, Karen A.; Landi, Maria T.; Egan, Kathleen M.; Baird, Duncan M.; Prescott, Jennifer; De Vivo, Immaculata; Nitti, Donato

2012-01-01

Background Several recent studies have provided evidence that polymorphisms in the telomerase reverse transcriptase (TERT) gene sequence are associated with cancer development, but a comprehensive synopsis is not available. We conducted a systematic review and meta-analysis of the available molecular epidemiology data regarding the association between TERT locus polymorphisms and predisposition to cancer. Methods A systematic review of the English literature was conducted by searching PubMed, Embase, Cancerlit, Google Scholar, and ISI Web of Knowledge databases for studies on associations between TERT locus polymorphisms and cancer risk. Random-effects meta-analysis was performed to pool per-allele odds ratios for TERT locus polymorphisms and risk of cancer, and between-study heterogeneity and potential bias sources (eg, publication and chasing bias) were assessed. Because the TERT locus includes the cleft lip and palate transmembrane 1-like (CLPTM1L) gene, which is in linkage disequilibrium with TERT, CLPTM1L polymorphisms were also analyzed. Cumulative evidence for polymorphisms with statistically significant associations was graded as “strong,” “moderate,” and “weak” according to the Venice criteria. The joint population attributable risk was calculated for polymorphisms with strong evidence of association. Results Eighty-five studies enrolling 490 901 subjects and reporting on 494 allelic contrasts were retrieved. Data were available on 67 TERT locus polymorphisms and 24 tumor types, for a total of 221 unique combinations of polymorphisms and cancer types. Upon meta-analysis, a statistically significant association with the risk of any cancer type was found for 22 polymorphisms. Strong, moderate, and weak cumulative evidence for association with at least one tumor type was demonstrated for 11, 9, and 14 polymorphisms, respectively. For lung cancer, which was the most studied tumor type, the estimated joint population attributable risk for three polymorphisms (TERT rs2736100, intergenic rs4635969, and CLPTM1L rs402710) was 41%. Strong evidence for lack of association was identified for five polymorphisms in three tumor types. Conclusions To our knowledge, this is the largest collection of data for associations between TERT locus polymorphisms and cancer risk. Our findings support the hypothesis that genetic variability in this genomic region can modulate cancer susceptibility in humans. PMID:22523397

Strong and weak plasma response to dietary carotenoids identified by cluster analysis and linked to beta-carotene 15,15'-monooxygenase 1 single nucleotide polymorphisms

USDA-ARS?s Scientific Manuscript database

The mechanisms as well the genetics underlying bioavailability and metabolism of carotenoids in humans remains unclear. The individual temporal response of plasma carotenoids was analyzed in adults who consumed carotenoid-containing juices on a controlled-diet study using cluster analysis. Treatmen...

Extensive shared polymorphism at non-MHC immune genes in recently diverged North American prairie grouse

USGS Publications Warehouse

Minias, Piotr; Bateson, Zachary W.; Whittingham, Linda A.; Johnson, Jeff A.; Oyler-McCance, Sara J.; Dunn, Peter O.

2018-01-01

Gene polymorphisms shared between recently diverged species are thought to be widespread and most commonly reflect introgression from hybridization or retention of ancestral polymorphism through incomplete lineage sorting. Shared genetic diversity resulting from incomplete lineage sorting is usually maintained for a relatively short period of time, but under strong balancing selection it may persist for millions of years beyond species divergence (balanced trans-species polymorphism), as in the case of the major histocompatibility complex (MHC) genes. However, balancing selection is much less likely to act on non-MHC immune genes. The aim of this study was to investigate the patterns of shared polymorphism and selection at non-MHC immune genes in five grouse species from Centrocercus and Tympanuchus genera. For this purpose, we genotyped five non-MHC immune genes that do not interact directly with pathogens, but are involved in signaling and regulate immune cell growth. In contrast to previous studies with MHC, we found no evidence for balancing selection or balanced trans-species polymorphism among the non-MHC immune genes. No haplotypes were shared between genera and in most cases more similar allelic variants sorted by genus. Between species within genera, however, we found extensive shared polymorphism, which was most likely attributable to introgression or incomplete lineage sorting following recent divergence and large ancestral effective population size (i.e., weak genetic drift). Our study suggests that North American prairie grouse may have attained relatively low degree of reciprocal monophyly at nuclear loci and reinforces the rarity of balancing selection in non-MHC immune genes.

Anomalous skin effects in a weakly magnetized degenerate electron plasma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abbas, G., E-mail: gohar.abbas@gcu.edu.pk; Sarfraz, M.; Shah, H. A.

2014-09-15

Fully relativistic analysis of anomalous skin effects for parallel propagating waves in a weakly magnetized degenerate electron plasma is presented and a graphical comparison is made with the results obtained using relativistic Maxwellian distribution function [G. Abbas, M. F. Bashir, and G. Murtaza, Phys. Plasmas 18, 102115 (2011)]. It is found that the penetration depth for R- and L-waves for degenerate case is qualitatively small in comparison with the Maxwellian plasma case. The quantitative reduction due to weak magnetic field in the skin depth in R-wave for degenerate plasma is large as compared to the non-degenerate one. By ignoring themore » ambient magnetic field, previous results for degenerate field free case are salvaged [A. F. Alexandrov, A. S. Bogdankevich, and A. A. Rukhadze, Principles of Plasma Electrodynamics (Springer-Verlag, Berlin/Heidelberg, 1984), p. 90].« less

Regional difference of the vertical structure of seasonal thermocline and its impact on sea surface temperature in the North Pacific

NASA Astrophysics Data System (ADS)

Yamaguchi, R.; Suga, T.

2016-12-01

Recent observational studies show that, during the warming season, a large amount of heat flux is penetrated through the base of thin mixed layer by vertical eddy diffusion, in addition to penetration of solar radiation [1]. In order to understand this heat penetration process due to vertical eddy diffusivity and its contribution to seasonal variation of sea surface temperature, we investigated the evolution of thermal stratification below the summertime thin mixed layer (i.e. evolution of seasonal thermocline) and its vertical structure in the North Pacific using high vertical resolution temperature profile observed by Argo floats. We quantified the vertical structure of seasonal thermocline as deviations from the linear structure where the vertical gradient of temperature is constant, that is, "shape anomaly". The shape anomaly is variable representing the extent of the bend of temperature profiles. We found that there are larger values of shape anomaly in the region where the seasonal sea surface temperature warming is relatively faster. To understand the regional difference of shape anomalies, we investigated the relationship between time changes in shape anomalies and net surface heat flux and surface kinetic energy flux. From May to July, the analysis indicated that, in a large part of North Pacific, there's a tendency for shape anomalies to develop strongly (weakly) under the conditions of large (small) downward net surface heat flux and small (large) downward surface kinetic energy flux. Since weak (strong) development of shape anomalies means efficient (inefficient) downward heat transport from the surface, these results suggest that the regional difference of the downward heat penetration below mixed layer is explained reasonably well by differences in surface heat forcing and surface wind forcing in a vertical one dimensional framework. [1] Hosoda et al. (2015), J. Oceanogr., 71, 541-556.

Analysis of Computational Models of Shaped Charges for Jet Formation and Penetration

NASA Astrophysics Data System (ADS)

Haefner, Jonah; Ferguson, Jim

2016-11-01

Shaped charges came into use during the Second World War demonstrating the immense penetration power of explosively formed projectiles and since has become a tool used by nearly every nation in the world. Penetration is critically dependent on how the metal liner is collapsed into a jet. The theory of jet formation has been studied in depth since the late 1940s, based on simple models that neglect the strength and compressibility of the metal liner. Although attempts have been made to improve these models, simplifying assumptions limit the understanding of how the material properties affect the jet formation. With a wide range of material and strength models available for simulation, a validation study was necessary to guide code users in choosing models for shaped charge simulations. Using PAGOSA, a finite-volume Eulerian hydrocode designed to model hypervelocity materials and strong shock waves developed by Los Alamos National Laboratory, and experimental data, we investigated the effects of various equations of state and material strength models on jet formation and penetration of a steel target. Comparing PAGOSA simulations against modern experimental data, we analyzed the strengths and weaknesses of available computational models. LA-UR-16-25639 Los Alamos National Laboratory.

Unusual penetration of a construction nail through the orbit to the cranium: a case report.

PubMed

Erkutlu, Ibrahim; Alptekin, Mehmet; Dokur, Mehmet; Geyik, Murat; Gök, Abdulvahap

2011-01-01

Penetrating head and neck trauma with construction nails are uncommon life-threatening injuries and an important problem in developing countries. Assessment of the neurovascular and systemic physical status is a first requirement, and the decision concerning which surgical approach to perform for the removal of the nail is of critical importance. A 10-year-old girl was presented one hour after a fall injury with complaint of a swelling and foreign body lodgment on the left forehead. Neurological and systemic physical examinations were normal except for weak direct pupillary light reflex on the left side and the patient's state of uneasiness. Radiological investigations showed that the head of the nail had entered from the left infra-orbital region and become lodged through the orbital roof, below the frontal bone. Surgical extraction of the nail in the operating room was performed successfully using left pterional craniotomy and lateral orbitotomy technique, and there was no complication after surgery. Here, we report a case with a rare craniocerebral penetrating wound and type, with the head of the nail lodged in the anterior fossa through the orbital roof, which may be defined as 'reverse penetration of the nail'.

A helium burst biolistic device adapted to penetrate fragile insect tissues

PubMed Central

Thomas, Jean-Luc; Bardou, Jérôme; L'hoste, Sebastien; Mauchamp, Bernard; Chavancy, Gérard

2001-01-01

To compensate for the extremely low penetration efficiency of the original PDS/1000-He Bio Rad biolistic® device and the deleterious blast effect, design modifications have been made to the launching module. These modifications were evaluated on Bombyx mori embryos and fragile tissues, such as oocytes and imaginal wing disks. The original floppy macrocarrier was replaced by a rigid macrocarrier to avoid the effects of the helium blast. The efficiency of the gene gun bombardment was reinforced by the addition of a focusing nozzle. The reduced blast effect allowed us to carry out high-pressure shootings to small organs with improved penetration. This system allowed potentially all the internal embryonic tissues to be transfected with optimal survival rates. The new module was effective on tissues that are difficult to transfect, such as the epithelial wing disk that is covered by a peripodial membrane, and the ovarian follicle cells that lie under the ovariole cell membrane. The new macrocarrier allowed both an aqueous delivery of particles and an ethanolic dry delivery. No significant differences were noted between these two modes of delivery. The major improvement is the possibility of high pressure shooting correlated with appreciable penetration and a weak blast effect. PMID:15455069

Dopamine D{sub 3} receptor gene: Organization transcript variants, and polymorphism associated with schizophrenia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Griffon, N.; Pilon, C.; Martres, M.P.

1996-02-16

DNA fragments from a genomic library were used to establish the partial structure of the human dopamine D{sub 3} receptor gene (DRD3). Its coding sequence contains 6 exons and stretches over 40,000 base pairs. The complete DRD3 transcript and three shorter variants, in which the second and/or third exon are deleted, were detected in similar proportions in brains from four controls and three psychiatric patients. The Msp I polymorphism was localized in the fifth intron of the gene, 40,000 base pairs downstream the Bal I polymorphism and a PCR-based method was developed for genotyping this polymorphism. The distributions of themore » Msp I and Bal I genotypes were not independent in 297 individuals ({chi}{sup 2} = 10.5, df = 4, P = 0.03), but only a weak association was found between allele 1 of the Bal I polymorphism and allele 2 of the Msp I polymorphism ({chi}{sup 2} = 3.99, df = 1, P = 0.04). The previously reported association between homozygosity at both alleles of the Bal I polymorphism and schizophrenia was presently maintained in an extended sample, comprising 119 DSM-III-R chronic schizophrenics and 85 controls ({chi}{sup 2}= 5.3, df = 1, P = 0.02) and found more important in males than in females. The presence of the Bal I allele 2 is associated with an early age at onset, particularly in males (df = 35, t value = 2.6, P = 0.014). In the same sample, allelic frequencies, genotype counts, and proportion of homozygotes for the Msp I polymorphism did not differ between schizophrenics and controls ({chi}{sup 2}= 0.06, df = 1, P = 0.80, {chi}{sup 2} = 0.22, df = 1, P = 0.90 and {chi}{sup 2} = 0.16, df = 1, P = 0.69, respectively). The large distance of the Msp I polymorphism from the Bal I polymorphism and its localization in the 3{prime} part of the gene may explain the discrepant results obtained with the two polymorphisms. 36 refs., 2 figs., 4 tabs.« less

Transfusion strategy for weak D type 4.0 based on RHD alleles and RH haplotypes in Tunisia

PubMed Central

Ouchari, Mouna; Srivastava, Kshitij; Romdhane, Houda; Yacoub, Saloua Jemni; Flegel, Willy Albert

2017-01-01

Background With more than 460 RHD alleles, this gene is the most complex and polymorphic among all blood group systems. The Tunisian population has the largest known prevalence of weak D type 4.0 alleles, occurring in 1 of 105 RH haplotypes. We aimed to establish a rationale for the transfusion strategy of weak D type 4.0 in Tunisia. Study design and methods Donors were randomly screened for the serological weak D phenotype. The RHD coding sequence and parts of the introns were sequenced. To establish the RH haplotype, the RHCE gene was tested for characteristic single nucleotide positions. Results We determined all RHD alleles and the RH haplotypes coding for the serologic weak D phenotype among 13,431 Tunisian donations. A serologic weak D phenotype was found in 67 individuals (0.50%). Among them, 60 carried a weak D type 4 allele: 53 weak D type 4.0, 6 weak D type 4.2.2 (DAR), and 1 weak D type 4.1. Another 4 donors had 1 variant allele each: DVII, weak D type 1, weak D type 3, and weak D type 100, while 3 donors showed a normal RHD sequence. The weak D type 4.0 was most often linked to RHCE*ceVS.04.01, weak D type 4.2.2 to RHCE*ceAR, and weak D type 4.1 to RHCE*ceVS.02, while the other RHD alleles were linked to one of the common RHCE alleles. Conclusions Among the weak D phenotypes in Tunisia, no novel RHD allele was found and almost 90% were caused by alleles of the weak D type 4 cluster, of which 88% represented the weak D type 4.0 allele. Based on established RH haplotypes for variant RHD and RHCE alleles and the lack of adverse clinical reports, we recommend D positive transfusions for patients with weak D type 4.0 in Tunisia. PMID:29193104

Transfusion strategy for weak D Type 4.0 based on RHD alleles and RH haplotypes in Tunisia.

PubMed

Ouchari, Mouna; Srivastava, Kshitij; Romdhane, Houda; Jemni Yacoub, Saloua; Flegel, Willy Albert

2018-02-01

With more than 460 RHD alleles, this gene is the most complex and polymorphic among all blood group systems. The Tunisian population has the largest known prevalence of weak D Type 4.0 alleles, occurring in one of 105 RH haplotypes. We aimed to establish a rationale for the transfusion strategy of weak D Type 4.0 in Tunisia. Donors were randomly screened for the serologic weak D phenotype. The RHD coding sequence and parts of the introns were sequenced. To establish the RH haplotype, the RHCE gene was tested for characteristic single-nucleotide positions. We determined all RHD alleles and the RH haplotypes coding for the serologic weak D phenotype among 13,431 Tunisian donations. A serologic weak D phenotype was found in 67 individuals (0.50%). Among them, 60 carried a weak D Type 4 allele: 53 weak D Type 4.0, six weak D Type 4.2.2 (DAR), and one weak D Type 4.1. An additional four donors had one variant allele each: DVII, weak D Type 1, weak D Type 3, and weak D type 100, while three donors showed a normal RHD sequence. The weak D Type 4.0 was most often linked to RHCE*ceVS.04.01, weak D Type 4.2.2 to RHCE*ceAR, and weak D Type 4.1 to RHCE*ceVS.02, while the other RHD alleles were linked to one of the common RHCE alleles. Among the weak D phenotypes in Tunisia, no novel RHD allele was found and almost 90% were caused by alleles of the weak D Type 4 cluster, of which 88% represented the weak D Type 4.0 allele. Based on established RH haplotypes for variant RHD and RHCE alleles and the lack of adverse clinical reports, we recommend D+ transfusions for patients with weak D Type 4.0 in Tunisia. © 2017 AABB.

Temperature dependent polymorphism of pyrazinamide: An in situ Raman and DFT study

NASA Astrophysics Data System (ADS)

Sharma, Poornima; Nandi, Rajib; Gangopadhyay, Debraj; Singh, Anurag; Singh, Ranjan K.

2018-02-01

The α and γ polymorphs of drug pyrazinamide have been detected with the help of temperature dependent Raman spectroscopic technique. Pyrazinamide is a very useful drug used for the treatment of tuberculosis (TB) and plays a significant role in destroying the dormant tubercle bacilli which are not destroyed by other common TB drugs. Temperature dependent Raman spectra suggest polymorphic phase change from α → γ form of pyrazinamide between 145 and 146 °C. In situ Raman spectra of pyrazinamide between 145 and 146 °C show the conversion of α → γ form by the shift in Cdbnd O stretching vibration accompanied by several other changes. The phase change is characterized by the breaking of two linear Nsbnd H ⋯ O type hydrogen bonds associated with Cdbnd O stretching vibration in α dimer and formation of one linear Nsbnd H ⋯ N type hydrogen bond along with a weak intramolecular Csbnd H ⋯ O type hydrogen bond in the γ dimer.

Heme Oxygenase 1 and 2 Common Genetic Variants and Risk for Essential Tremor

PubMed Central

Ayuso, Pedro; Agúndez, José A.G.; Alonso-Navarro, Hortensia; Martínez, Carmen; Benito-León, Julián; Ortega-Cubero, Sara; Lorenzo-Betancor, Oswaldo; Pastor, Pau; López-Alburquerque, Tomás; García-Martín, Elena; Jiménez-Jiménez, Félix J.

2015-01-01

Abstract Several reports suggested a role of heme oxygenase genes 1 and 2 (HMOX1 and HMOX2) in modifying the risk to develop Parkinson disease (PD). Because essential tremor (ET) and PD share phenotypical and, probably, etiologic factors of the similarities, we analyzed whether such genes are related with the risk to develop ET. We analyzed the distribution of allelic and genotype frequencies of the HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363, and HMOX2 rs1051308 single nucleotide polymorphisms, as well as the presence of copy number variations of these genes in 202 subjects with familial ET and 747 healthy controls. Allelic frequencies of rs2071746T and rs1051308G were significantly lower in ET patients than in controls. None of the studied polymorphisms influenced the disease onset. The present study suggests a weak association between HMOX1 rs2071746 and HMOX2 rs1051308 polymorphisms and the risk to develop ET in the Spanish population. PMID:26091465

Heme Oxygenase 1 and 2 Common Genetic Variants and Risk for Essential Tremor.

PubMed

Ayuso, Pedro; Agúndez, José A G; Alonso-Navarro, Hortensia; Martínez, Carmen; Benito-León, Julián; Ortega-Cubero, Sara; Lorenzo-Betancor, Oswaldo; Pastor, Pau; López-Alburquerque, Tomás; García-Martín, Elena; Jiménez-Jiménez, Félix J

2015-06-01

Several reports suggested a role of heme oxygenase genes 1 and 2 (HMOX1 and HMOX2) in modifying the risk to develop Parkinson disease (PD). Because essential tremor (ET) and PD share phenotypical and, probably, etiologic factors of the similarities, we analyzed whether such genes are related with the risk to develop ET. We analyzed the distribution of allelic and genotype frequencies of the HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363, and HMOX2 rs1051308 single nucleotide polymorphisms, as well as the presence of copy number variations of these genes in 202 subjects with familial ET and 747 healthy controls. Allelic frequencies of rs2071746T and rs1051308G were significantly lower in ET patients than in controls. None of the studied polymorphisms influenced the disease onset. The present study suggests a weak association between HMOX1 rs2071746 and HMOX2 rs1051308 polymorphisms and the risk to develop ET in the Spanish population.

Relationship between iris constitution analysis and TNF-alpha gene polymorphism in hypertensives.

PubMed

Yoo, Chun-Sang; Hwang, Woo-Jun; Hong, Seung-Heon; Lee, Hye-Jung; Jeong, Hyun-Ja; Kim, Su-Jin; Kim, Hyung-Min; Um, Jae-Young

2007-01-01

Iridology is a complementary and alternative medicine that involves the diagnosis of medical conditions by noting irregularities of the pigmentation in the iris. Iris constitution has a strong hereditary component. Tumor necrosis factor-alpha (TNFalpha), a pleiotropic cytokine, has been implicated in many pathological processes including hypertension. In this paper, the relationship between iris constitution and TNFalpha gene polymorphism in those with hypertension is investigated. Eighty seven hypertensive individuals and 79 controls were classified according to iris constitution and the TNFalpha genotype of each individual determined. Compared to the controls, the frequency of the TNFalpha GA heterozygote was lower in the hypertensive group, although the statistical significance was marginal (p = 0.08). This result implies an association with resistance to the disease. In addition, the frequency of the cardio-renal connective tissue weakness type was significantly higher in the hypertensive group with the TNFalpha GG genotype, as compared to the controls (p = 0.001). An association is demonstrated among TNFalpha gene polymorphism, Koreans with hypertension, and iris constitution.

TNFalpha and IL-10 gene polymorphisms in inflammatory bowel disease. Association of -1082 AA low producer IL-10 genotype with steroid dependency.

PubMed

Castro-Santos, Patricia; Suarez, Ana; López-Rivas, Laureano; Mozo, Lourdes; Gutierrez, Carmen

2006-05-01

An altered production of cytokines underlies inflammatory bowel disease (IBD) susceptibility. Various polymorphisms at the IL-10 and TNFalpha gene promoters control cytokine production levels. The influence of these polymorphisms on susceptibility to ulcerative colitis (UC) and Crohn's disease (CD) and their association with clinical features were analyzed. Genetic polymorphisms of TNFalpha (-308 G/A) and IL-10 (-1082 G/A, -812 C/T, and -592 C/A) were determined using the LightCycler system with hybridization probes matched with one sequence variant. The study population included 99 UC patients, 146 CD patients, and 343 matched controls. We did not find association between TNFalpha or IL-10 gene polymorphisms and UC or CD susceptibility, though a slight influence of -1082*G allele in UC appearance was observed. In a stratified analysis, a highly significant association between the -1082 AA IL-10 genotype and the steroid dependency was observed in IBD (p < 0.0001), contributing both UC (p = 0.004) and CD (p = 0.003) to this association. In contrast, TNFalpha genotypes did not influence steroid dependency in IBD. Further, the contribution of cytokine genotypes and of clinical features to the appearance of steroid-dependent status (dependent variable) was studied by multivariate analysis. The steroid-dependent phenotype correlated in UC with extensive disease (p = 0.010) and with the low producer -1082 AA IL-10 genotype (p = 0.002) and in CD with penetrating disease (p = 0.010), arthritis (p = 0.011), and the -1082 AA IL-10 genotype (p = 0.006). The main conclusion is that carriage of the -1082 AA IL-10 genotype (low producer) is a relevant risk factor for developing steroid-dependent IBD.

Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study

PubMed Central

Jakubowska, A; Rozkrut, D; Antoniou, A; Hamann, U; Scott, R J; McGuffog, L; Healy, S; Sinilnikova, O M; Rennert, G; Lejbkowicz, F; Flugelman, A; Andrulis, I L; Glendon, G; Ozcelik, H; Thomassen, M; Paligo, M; Aretini, P; Kantala, J; Aroer, B; von Wachenfeldt, A; Liljegren, A; Loman, N; Herbst, K; Kristoffersson, U; Rosenquist, R; Karlsson, P; Stenmark-Askmalm, M; Melin, B; Nathanson, K L; Domchek, S M; Byrski, T; Huzarski, T; Gronwald, J; Menkiszak, J; Cybulski, C; Serrano, P; Osorio, A; Cajal, T R; Tsitlaidou, M; Benítez, J; Gilbert, M; Rookus, M; Aalfs, C M; Kluijt, I; Boessenkool-Pape, J L; Meijers-Heijboer, H E J; Oosterwijk, J C; van Asperen, C J; Blok, M J; Nelen, M R; van den Ouweland, A M W; Seynaeve, C; van der Luijt, R B; Devilee, P; Easton, D F; Peock, S; Frost, D; Platte, R; Ellis, S D; Fineberg, E; Evans, D G; Lalloo, F; Eeles, R; Jacobs, C; Adlard, J; Davidson, R; Eccles, D; Cole, T; Cook, J; Godwin, A; Bove, B; Stoppa-Lyonnet, D; Caux-Moncoutier, V; Belotti, M; Tirapo, C; Mazoyer, S; Barjhoux, L; Boutry-Kryza, N; Pujol, P; Coupier, I; Peyrat, J-P; Vennin, P; Muller, D; Fricker, J-P; Venat-Bouvet, L; Johannsson, O Th; Isaacs, C; Schmutzler, R; Wappenschmidt, B; Meindl, A; Arnold, N; Varon-Mateeva, R; Niederacher, D; Sutter, C; Deissler, H; Preisler-Adams, S; Simard, J; Soucy, P; Durocher, F; Chenevix-Trench, G; Beesley, J; Chen, X; Rebbeck, T; Couch, F; Wang, X; Lindor, N; Fredericksen, Z; Pankratz, V S; Peterlongo, P; Bonanni, B; Fortuzzi, S; Peissel, B; Szabo, C; Mai, P L; Loud, J T; Lubinski, J

2012-01-01

Background: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. Methods: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively. Results: There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10–2.04 and HR 2.16, 95%CI 1.24–3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. Conclusion: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers. PMID:22669161

Site-specific epsilon-NH2 monoacylation of pancreatic phospholipase A2. 2. Transformation of soluble phospholipase A2 into a highly penetrating "membrane-bound" form.

PubMed

Van der Wiele, F C; Atsma, W; Roelofsen, B; van Linde, M; Van Binsbergen, J; Radvanyi, F; Raykova, D; Slotboom, A J; De Haas, G H

1988-03-08

Long-chain lecithins present in bilayer structures like vesicles or membranes are only very poor substrates for pancreatic phospholipases A2. This is probably due to the fact that pancreatic phospholipases A2 cannot penetrate into the densely packed bilayer structures. To improve the weak penetrating properties of pancreatic phospholipases A2, we prepared and characterized a number of pancreatic phospholipase A2 mutants that have various long acyl chains linked covalently to Lys116 in porcine and to Lys10 in bovine phospholipase A2 [Van der Wiele, F.C., Atsma, W., Dijkman, R., Schreurs, A.M.M., Slotboom, A.J., & De Haas, G.H. (1988) Biochemistry (preceding paper in this issue)]. When monomolecular surface layers of L- and D-didecanoyllecithin were used, it was found that the introduction of caprinic, lauric, palmitic, and oleic acid at Lys116 in the porcine enzyme increases its penetrating power from 13 to about 17, 20, 32, and 22 dyn/cm, respectively, before long lag periods were obtained. Incorporation of a palmitoyl moiety at Lys10 in the bovine enzyme shifted the penetrating power from 11 to about 25 dyn/cm. Only the best penetrating mutant, viz., porcine phospholipase A2 having a palmitoyl moiety at Lys116, was able to cause complete leakage of 6-carboxyfluorescein entrapped in small unilamellar vesicles of egg lecithin under nonhydrolytic conditions. Similarly, only this latter palmitoylphospholipase A2 completely hydrolyzed all lecithin in the outer monolayer of the human erythrocyte at a rate much faster than Naja naja phospholipase A2, the most powerful penetrating snake venom enzyme presently known.

Genetic association studies of the FOXP3 gene in Graves' disease and autoimmune Addison's disease in the United Kingdom population.

PubMed

Owen, Catherine J; Eden, James A; Jennings, Claire E; Wilson, Valerie; Cheetham, Tim D; Pearce, Simon H S

2006-08-01

Regulatory T lymphocytes play a crucial role in modulating potentially self-reactive clones, and dysfunction of this cell type contributes to autoimmune disease. FOXP3 is a critical determinant of CD(4+)CD(25+)T regulatory (T(reg)) cell development and function. The aim of this study was to investigate whether genetic polymorphisms at the FOXP3 locus predispose to autoimmune endocrinopathies. Five single nucleotide polymorphisms (SNPs) and two microsatellite polymorphisms were genotyped in our Caucasian cohorts of 633 unrelated Graves' disease (GD) subjects, 104 autoimmune Addison's disease (AAD) subjects and 528 healthy controls. SNP genotyping was performed by either restriction enzyme digestion or by primer-extension-MALDI-TOF (matrix-assisted laser desorption/ionisation time-of-flight) assay. Microsatellites were analysed using fluorescent PCR. Case-control analysis was performed using chi(2) testing on contingency tables for allele frequency. Haplotype analysis was performed using the UNPHASED package. No evidence for disease association was found with any of the seven polymorphisms in either of the GD or AAD subjects as compared with controls (P = 0.26-0.94). Haplotype analysis found a weak evidence for the association of a minor haplotype with GD; this was not significant when corrected for multiple testing. This study has found no robust evidence that FOXP3 gene polymorphism contributes to the susceptibility to GD or AAD in the UK population.

A second ortho­rhom­bic polymorph of (Z)-3-(9-anthr­yl)-1-(2-thien­yl)prop-2-en-1-one1

PubMed Central

Chantrapromma, Suchada; Suwunwong, Thitipone; Boonnak, Nawong; Fun, Hoong-Kun

2010-01-01

The title heteroaryl chalcone, C21H14OS, is a second ortho­rhom­bic polymorph which crystallizes in the space group P212121. The structure was previously reported [Fun et al. (2009 ▶). Acta Cryst. E65, o2168-o2169] in the space group Pna21. The bond distances and angles are similar in both structures. In contrast, the overall crystal packing is different from that in the first ortho­rhom­bic Pna21 polymorph in which mol­ecules were stacked into columns along the b axis and the thio­phene units of two adjacent columns were stacked in a head to tail fashion. In the present polymorph, mol­ecules are found to dimerize through a weak S⋯S inter­action [3.6513 (7) Å] and these dimers are arranged into sheets parallel to the bc plane. There are no classical hydrogen bonds in the packing which features short C⋯O [3.2832 (2)–3.6251 (9) Å], C⋯S [3.4879 (17)–3.6251 (19) Å] and S⋯O [2.9948 (16) Å] contacts, together with C—H⋯π inter­actions. Similar contacts were found in the other polymorph. PMID:21579743

Mismatch repair polymorphisms and the risk of colorectal cancer.

PubMed

Berndt, Sonja I; Platz, Elizabeth A; Fallin, M Daniele; Thuita, Lucy W; Hoffman, Sandra C; Helzlsouer, Kathy J

2007-04-01

Rare germline variants in mismatch repair genes have been linked to hereditary nonpolyposis colorectal cancer; however, it is unknown whether common polymorphisms in these genes alter the risk of colorectal cancer. To examine the association between common variants in mismatch repair genes and colorectal cancer, we conducted a case-cohort study within the CLUE II cohort. Four single nucleotide polymorphisms in 3 mismatch repair genes (MSH3 R940Q, MSH3 T1036A, MSH6 G39E and MLH1 I219V) were genotyped in 237 colorectal cancer cases and a subcohort of 2,189 participants. Incidence rate ratios (RRs) and 95% confidence intervals (95% CIs) for each polymorphism were estimated. The MSH3 1036A variant was found to be associated with an increased risk of colorectal cancer (RR=1.28, 95% CI: 0.94-1.74 and RR=1.65, 95% CI: 1.01-2.70 for the AT and TT genotypes, respectively, with p(trend)=0.02), particularly proximal colon cancer. Although the MSH3 940Q variant was only weakly associated with colorectal cancer overall (p(trend)=0.07), it was associated with a significant increased risk of proximal colon cancer (RR=1.69, 95% CI: 1.10-2.61 and RR=2.68, 95% CI: 0.96-7.47 for the RQ and QQ genotypes, respectively with p(trend)=0.005). Processed meat intake appeared to modify the association between the MSH3 polymorphisms and colorectal cancer (p(interaction) < 0.10 for both). No association was observed with the MSH6 and MLH1 polymorphisms overall. This study suggests that common polymorphisms in the mismatch repair gene, MSH3, may increase the risk of colorectal cancer, especially proximal colon cancer. (c) 2006 Wiley-Liss, Inc.

Methylenetetrahydrofolate reductase polymorphism C677T is a protective factor for pediatric acute lymphoblastic leukemia in the Chinese population: a meta-analysis.

PubMed

Wang, Haigang; Meng, Lujing; Zhao, Lixia; Wang, Jiali; Liu, Xinchun; Mi, Wenjie

2012-12-01

Two polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C, were hypothesized to decrease the risk of acute lymphoblastic leukemia (ALL). Studies examining the associations between these two polymorphisms and ALL susceptibility drew inconsistent results. To obtain a reliable conclusion in a Chinese population, we carried out a meta-analysis. In total, 11 studies on C677T polymorphism (1597 cases and 2295 controls) and 10 studies on A1298C polymorphism (1553 cases and 2224 controls) were included in the meta-analysis. We found a significant association between the 677T variant and reduced ALL risk in Chinese children (Dominant model: odds ratio [OR(FE)]=0.73, 95% confidence interval [CI]: 0.63-0.86, p<0.01). Heterogeneity between the studies in the children subgroup was weak and vanished after excluding one study deviating from HWE in the control group (p>0.1). In the adult subgroup, there was no significant association between the C677T variant and ALL risk (Dominant model: OR(RE)=0.88, 95% CI: 0.45-1.72, p=0.72). Significant heterogeneity was found in the adult subgroup in all the genetic model tests (p<0.1). The A1298C polymorphism had an effect on ALL risk neither in adults (Dominant model: OR(FE)=0.95, 95% CI: 0.71-1.27, p=0.72) nor in children (Dominant model: OR(FE)=1.02, 95% CI: 0.87-1.21, p=0.77). No significant heterogeneity between studies on A1298C polymorphism was found in the meta-analysis (p>0.1). The results showed that there was a protective effect of the MTHFR C677T variant on ALL risk in Chinese children.

Penetration Depth Study of Superconducting Gap Structure of 2H-NbSe2

NASA Astrophysics Data System (ADS)

Fletcher, J. D.; Carrington, A.; Diener, P.; Rodière, P.; Brison, J. P.; Prozorov, R.; Olheiser, T.; Giannetta, R. W.

2007-02-01

We report measurements of the temperature dependence of both in-plane and out-of-plane penetration depths (λa and λc, respectively) in 2H-NbSe2. Measurements were made with a radio-frequency tunnel diode oscillator circuit at temperatures down to 100 mK. Analysis of the anisotropic superfluid density shows that a reduced energy gap is located on one or more of the quasi-two-dimensional Nb Fermi surface sheets rather than on the Se sheet, in contrast with some previous reports. This result suggests that the gap structure is not simply related to the weak electron-phonon coupling on the Se sheet and is therefore important for microscopic models of anisotropic superconductivity in this compound.

Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 3: In a penetrating chest wound is a three-sided dressing or a one-way chest seal better at preventing respiratory complications?

PubMed

Walthall, Kirsten

2012-04-01

A short-cut review was carried out to establish whether the traditional three-sided dressing is better than a one-way chest seal at preventing the respiratory complications from penetrating chest trauma. Only one animal study, two guidelines and two case reports provided published evidence relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line is that there is very little evidence, but that the one-way seals may have practical advantages, particularly in the out-of-hospital setting.

Sequential feature selection for detecting buried objects using forward looking ground penetrating radar

NASA Astrophysics Data System (ADS)

Shaw, Darren; Stone, Kevin; Ho, K. C.; Keller, James M.; Luke, Robert H.; Burns, Brian P.

2016-05-01

Forward looking ground penetrating radar (FLGPR) has the benefit of detecting objects at a significant standoff distance. The FLGPR signal is radiated over a large surface area and the radar signal return is often weak. Improving detection, especially for buried in road targets, while maintaining an acceptable false alarm rate remains to be a challenging task. Various kinds of features have been developed over the years to increase the FLGPR detection performance. This paper focuses on investigating the use of as many features as possible for detecting buried targets and uses the sequential feature selection technique to automatically choose the features that contribute most for improving performance. Experimental results using data collected at a government test site are presented.

The 5-HT2C receptor gene Cys23Ser polymorphism influences the intravaginal ejaculation latency time in Dutch Caucasian men with lifelong premature ejaculation

PubMed Central

Janssen, Paddy KC; van Schaik, Ron; Olivier, Berend; Waldinger, Marcel D

2014-01-01

It has been postulated that the persistent short intravaginal ejaculation latency time (IELT) of men with lifelong premature ejaculation (LPE) is related to 5-hydroxytryptamine (HT)2C receptor functioning. The aim of this study was to investigate the relationship of Cys23Ser 5-HT2C receptor gene polymorphism and the duration of IELT in men with LPE. Therefore, a prospective study was conducted in 64 Dutch Caucasian men with LPE. Baseline IELT during coitus was assessed by stopwatch over a 1-month period. All men were genotyped for Cys23Ser 5-HT2C receptor gene polymorphism. Allele frequencies and genotypes of Cys and Ser variants of 5-HT2C receptor gene polymorphism were determined. Association between Cys/Cys and Ser/Ser genotypes and the natural logarithm of the IELT in men with LPE were investigated. As a result, the geometric mean, median and natural mean IELT were 25.2, 27.0, 33.9 s, respectively. Of all men, 20.0%, 10.8%, 23.1% and 41.5% ejaculated within 10, 10–20, 20–30 and 30–60 s after vaginal penetration. Of the 64 men, the Cys/Cys and Ser/Ser genotype frequency for the Cys23Ser polymorphism of the 5-HT2C receptor gene was 81% and 19%, respectively. The geometric mean IELT of the wildtypes (Cys/Cys) is significantly lower (22.6 s; 95% CI 18.3–27.8 s) than in male homozygous mutants (Ser/Ser) (40.4 s; 95% CI 20.3–80.4 s) (P = 0.03). It is concluded that Cys23Ser 5-HT2C receptor gene polymorphism is associated with the IELT in men with LPE. Men with Cys/Cys genotype have shorter IELTs than men with Ser/Ser genotypes. PMID:24799636

The 5-HT2C receptor gene Cys23Ser polymorphism influences the intravaginal ejaculation latency time in Dutch Caucasian men with lifelong premature ejaculation.

PubMed

Janssen, Paddy Kc; Schaik, Ron van; Olivier, Berend; Waldinger, Marcel D

2014-01-01

It has been postulated that the persistent short intravaginal ejaculation latency time (IELT) of men with lifelong premature ejaculation (LPE) is related to 5-hydroxytryptamine (HT)2C receptor functioning. The aim of this study was to investigate the relationship of Cys23Ser 5-HT2C receptor gene polymorphism and the duration of IELT in men with LPE. Therefore, a prospective study was conducted in 64 Dutch Caucasian men with LPE. Baseline IELT during coitus was assessed by stopwatch over a 1-month period. All men were genotyped for Cys23Ser 5-HT2C receptor gene polymorphism. Allele frequencies and genotypes of Cys and Ser variants of 5-HT2C receptor gene polymorphism were determined. Association between Cys/Cys and Ser/Ser genotypes and the natural logarithm of the IELT in men with LPE were investigated. As a result, the geometric mean, median and natural mean IELT were 25.2, 27.0, 33.9 s, respectively. Of all men, 20.0%, 10.8%, 23.1% and 41.5% ejaculated within 10, 10-20, 20-30 and 30-60 s after vaginal penetration. Of the 64 men, the Cys/Cys and Ser/Ser genotype frequency for the Cys23Ser polymorphism of the 5-HT2C receptor gene was 81% and 19%, respectively. The geometric mean IELT of the wildtypes (Cys/Cys) is significantly lower (22.6 s; 95% CI 18.3-27.8 s) than in male homozygous mutants (Ser/Ser) (40.4 s; 95% CI 20.3-80.4 s) (P = 0.03). It is concluded that Cys23Ser 5-HT2C receptor gene polymorphism is associated with the IELT in men with LPE. Men with Cys/Cys genotype have shorter IELTs than men with Ser/Ser genotypes.

Non-London electrodynamics in a multiband London model: Anisotropy-induced nonlocalities and multiple magnetic field penetration lengths

NASA Astrophysics Data System (ADS)

Silaev, Mihail; Winyard, Thomas; Babaev, Egor

2018-05-01

The London model describes strongly type-2 superconductors as massive vector field theories, where the magnetic field decays exponentially at the length scale of the London penetration length. This also holds for isotropic multiband extensions, where the presence of multiple bands merely renormalizes the London penetration length. We show that, by contrast, the magnetic properties of anisotropic multiband London models are not this simple, and the anisotropy leads to the interband phase differences becoming coupled to the magnetic field. This results in the magnetic field in such systems having N +1 penetration lengths, where N is the number of field components or bands. That is, in a given direction, the magnetic field decay is described by N +1 modes with different amplitudes and different decay length scales. For certain anisotropies we obtain magnetic modes with complex masses. That means that magnetic field decay is not described by a monotonic exponential increment set by a real penetration length but instead is oscillating. Some of the penetration lengths are shown to diverge away from the superconducting phase transition when the mass of the phase-difference mode vanishes. Finally the anisotropy-driven hybridization of the London mode with the Leggett modes can provide an effectively nonlocal magnetic response in the nominally local London model. Focusing on the two-component model, we discuss the magnetic field inversion that results from the effective nonlocality, both near the surface of the superconductor and around vortices. In the regime where the magnetic field decay becomes nonmonotonic, the multiband London superconductor is shown to form weakly-bound states of vortices.

Greenland Subglacial Drainage Evolution Regulated by Weakly Connected Regions of the Bed

NASA Technical Reports Server (NTRS)

Hoffman, Matthew J.; Andrews, Lauren C.; Price, Stephen F.; Catania, Ginny A.; Neumann, Thomas A.; Luthi, Martin P.; Gulley, Jason; Ryser, Claudia; Hawley, Robert L.; Morriss, Blaine

2016-01-01

Penetration of surface meltwater to the bed of the Greenland Ice Sheet each summer causes an initial increase in ice speed due to elevated basal water pressure, followed by slowdown in late summer that continues into fall and winter. While this seasonal pattern is commonly explained by an evolution of the subglacial drainage system from an inefficient distributed to efficient channelized configuration, mounting evidence indicates that subglacial channels are unable to explain important aspects of hydrodynamic coupling in late summer and fall. Here we use numerical models of subglacial drainage and ice flow to show that limited, gradual leakage of water and lowering of water pressure in weakly connected regions of the bed can explain the dominant features in late and post melt season ice dynamics. These results suggest that a third weakly connected drainage component should be included in the conceptual model of subglacial hydrology.

Greenland subglacial drainage evolution regulated by weakly connected regions of the bed

PubMed Central

Hoffman, Matthew J.; Andrews, Lauren C.; Price, Stephen A.; Catania, Ginny A.; Neumann, Thomas A.; Lüthi, Martin P.; Gulley, Jason; Ryser, Claudia; Hawley, Robert L.; Morriss, Blaine

2016-01-01

Penetration of surface meltwater to the bed of the Greenland Ice Sheet each summer causes an initial increase in ice speed due to elevated basal water pressure, followed by slowdown in late summer that continues into fall and winter. While this seasonal pattern is commonly explained by an evolution of the subglacial drainage system from an inefficient distributed to efficient channelized configuration, mounting evidence indicates that subglacial channels are unable to explain important aspects of hydrodynamic coupling in late summer and fall. Here we use numerical models of subglacial drainage and ice flow to show that limited, gradual leakage of water and lowering of water pressure in weakly connected regions of the bed can explain the dominant features in late and post melt season ice dynamics. These results suggest that a third weakly connected drainage component should be included in the conceptual model of subglacial hydrology. PMID:27991518

Greenland subglacial drainage evolution regulated by weakly connected regions of the bed

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hoffman, Matthew J.; Andrews, Lauren C.; Price, Stephen A.

Penetration of surface meltwater to the bed of the Greenland Ice Sheet each summer causes an initial increase in ice speed due to elevated basal water pressure, followed by slowdown in late summer that continues into fall and winter. While this seasonal pattern is commonly explained by an evolution of the subglacial drainage system from an inefficient distributed to efficient channelized configuration, mounting evidence indicates that subglacial channels are unable to explain important aspects of hydrodynamic coupling in late summer and fall. Here we use numerical models of subglacial drainage and ice flow to show that limited, gradual leakage ofmore » water and lowering of water pressure in weakly connected regions of the bed can explain the dominant features in late and post melt season ice dynamics. Finally, these results suggest that a third weakly connected drainage component should be included in the conceptual model of subglacial hydrology.« less

Greenland subglacial drainage evolution regulated by weakly connected regions of the bed.

PubMed

Hoffman, Matthew J; Andrews, Lauren C; Price, Stephen A; Catania, Ginny A; Neumann, Thomas A; Lüthi, Martin P; Gulley, Jason; Ryser, Claudia; Hawley, Robert L; Morriss, Blaine

2016-12-19

Penetration of surface meltwater to the bed of the Greenland Ice Sheet each summer causes an initial increase in ice speed due to elevated basal water pressure, followed by slowdown in late summer that continues into fall and winter. While this seasonal pattern is commonly explained by an evolution of the subglacial drainage system from an inefficient distributed to efficient channelized configuration, mounting evidence indicates that subglacial channels are unable to explain important aspects of hydrodynamic coupling in late summer and fall. Here we use numerical models of subglacial drainage and ice flow to show that limited, gradual leakage of water and lowering of water pressure in weakly connected regions of the bed can explain the dominant features in late and post melt season ice dynamics. These results suggest that a third weakly connected drainage component should be included in the conceptual model of subglacial hydrology.

Greenland subglacial drainage evolution regulated by weakly connected regions of the bed

DOE PAGES

Hoffman, Matthew J.; Andrews, Lauren C.; Price, Stephen A.; ...

2016-12-19

Penetration of surface meltwater to the bed of the Greenland Ice Sheet each summer causes an initial increase in ice speed due to elevated basal water pressure, followed by slowdown in late summer that continues into fall and winter. While this seasonal pattern is commonly explained by an evolution of the subglacial drainage system from an inefficient distributed to efficient channelized configuration, mounting evidence indicates that subglacial channels are unable to explain important aspects of hydrodynamic coupling in late summer and fall. Here we use numerical models of subglacial drainage and ice flow to show that limited, gradual leakage ofmore » water and lowering of water pressure in weakly connected regions of the bed can explain the dominant features in late and post melt season ice dynamics. Finally, these results suggest that a third weakly connected drainage component should be included in the conceptual model of subglacial hydrology.« less

Greenland subglacial drainage evolution regulated by weakly connected regions of the bed

NASA Astrophysics Data System (ADS)

Hoffman, Matthew J.; Andrews, Lauren C.; Price, Stephen A.; Catania, Ginny A.; Neumann, Thomas A.; Lüthi, Martin P.; Gulley, Jason; Ryser, Claudia; Hawley, Robert L.; Morriss, Blaine

2016-12-01

Penetration of surface meltwater to the bed of the Greenland Ice Sheet each summer causes an initial increase in ice speed due to elevated basal water pressure, followed by slowdown in late summer that continues into fall and winter. While this seasonal pattern is commonly explained by an evolution of the subglacial drainage system from an inefficient distributed to efficient channelized configuration, mounting evidence indicates that subglacial channels are unable to explain important aspects of hydrodynamic coupling in late summer and fall. Here we use numerical models of subglacial drainage and ice flow to show that limited, gradual leakage of water and lowering of water pressure in weakly connected regions of the bed can explain the dominant features in late and post melt season ice dynamics. These results suggest that a third weakly connected drainage component should be included in the conceptual model of subglacial hydrology.

Association of interleukin-1 beta (-511C/T) polymorphisms with osteoporosis in postmenopausal women.

PubMed

Chao, Tai-Hung; Yu, Hsing-Ning; Huang, Chi-Chuan; Liu, Wen-Shen; Tsai, Ya-Wen; Wu, Wen-Tung

2010-01-01

Osteoporosis is a common disease of the elderly, in which genetic and clinical factors contribute to the disease phenotype. Since the production of interleukin-1 (IL-1) has been implicated in the bone mass and skeletal disorders, we investigated whether IL-1 system gene polymorphisms are associated with the pathogenesis of osteoporosis in postmenopausal Taiwanese women. Osteoporosis is diagnosed by dual-energy x-ray absorptiometry, which measures bone mineral density (BMD) at multiple skeletal sites. We studied the IL-1α (-889C/T), IL-1β (-511C/T) and the 86 base pair variable number tandem repeat (VNTR) in intron 2 of the IL-1 receptor antagonist (IL-1ra) gene in 117 postmenopausal women with osteoporosis and 135 control subjects without a history of symptomatic osteoporosis. These gene polymorphisms were analyzed by polymerase chain reaction and restriction fragment length polymerase. Blood sugar and other risk factors were also determined. The frequencies of IL-1β (-511C/T) genotypes (P=.022, odds ratio=1.972) and alleles (P=.02, odds ratio=2.909) showed a statistically significant difference between the two groups. However, we did not find any statistically significant difference in IL-1β and IL-1ra polymorphisms (P>.05). We also observed a positive relationship between osteoporosis and cholesterol and a weak inverse relationship between blood sugar and osteoporosis in postmenopausal women. These experimental results suggest that the pathogenesis of osteoporosis is associated with IL-1β (-511C/T) polymorphism in postmenopausal women. This polymorphism is an independent risk factor for osteoporosis.

Interactions between cauliflower and Rhizoctonia anastomosis groups with different levels of aggressiveness

PubMed Central

Pannecoucque, Joke; Höfte, Monica

2009-01-01

Background The soil borne fungus Rhizoctonia is one of the most important plant pathogenic fungi, with a wide host range and worldwide distribution. In cauliflower (Brassica oleracea var. botrytis), several anastomosis groups (AGs) including both multinucleate R. solani and binucleate Rhizoctonia species have been identified showing different levels of aggressiveness. The infection and colonization process of Rhizoctonia during pathogenic interactions is well described. In contrast, insights into processes during interactions with weak aggressive or non-pathogenic isolates are limited. In this study the interaction of cauliflower with seven R. solani AGs and one binucleate Rhizoctonia AG differing in aggressiveness, was compared. Using microscopic and histopathological techniques, the early steps of the infection process, the colonization process and several host responses were studied. Results For aggressive Rhizoctonia AGs (R. solani AG 1-1B, AG 1-1C, AG 2-1, AG 2-2 IIIb and AG 4 HGII), a higher developmental rate was detected for several steps of the infection process, including directed growth along anticlinal cell walls and formation of T-shaped branches, infection cushion formation and stomatal penetration. Weak or non-aggressive AGs (R. solani AG 5, AG 3 and binucleate Rhizoctonia AG K) required more time, notwithstanding all AGs were able to penetrate cauliflower hypocotyls. Histopathological observations indicated that Rhizoctonia AGs provoked differential host responses and pectin degradation. We demonstrated the pronounced deposition of phenolic compounds and callose against weak and non-aggressive AGs which resulted in a delay or complete block of the host colonization. Degradation of pectic compounds was observed for all pathogenic AGs, except for AG 2-2 IIIb. Ranking the AGs based on infection rate, level of induced host responses and pectin degradation revealed a strong correlation with the disease severity caused by the AGs. Conclusion The differences in aggressiveness towards cauliflower observed among Rhizoctonia AGs correlated with the infection rate, induction of host defence responses and pectin breakdown. All Rhizoctonia AGs studied penetrated the plant tissue, indicating all constitutive barriers of cauliflower were defeated and differences in aggressiveness were caused by inducible defence responses, including cell wall fortifications with phenolic compounds and callose. PMID:19622152

Suppressed Release of Clarithromycin from Tablets by Crystalline Phase Transition of Metastable Polymorph Form I.

PubMed

Fujiki, Sadahiro; Watanabe, Narumi; Iwao, Yasunori; Noguchi, Shuji; Mizoguchi, Midori; Iwamura, Takeru; Itai, Shigeru

2015-08-01

The pharmaceutical properties of clarithromycin (CAM) tablets containing the metastable form I of crystalline CAM were investigated. Although the dissolution rate of form I was higher than that of stable form II, the release of CAM from form I tablet was delayed. Disintegration test and liquid penetration test showed that the disintegration of the tablet delayed because of the slow penetration of an external solution into form I tablet. Investigation by scanning electron microscopy revealed that the surface of form I tablet was covered with fine needle-shaped crystals following an exposure to the external solution. These crystals were identified as form IV crystals by powder X-ray diffraction. The phenomenon that CAM releases from tablet was inhibited by fine crystals spontaneously formed on the tablet surface could be applied to the design of sustained-release formulation systems with high CAM contents by minimizing the amount of functional excipients. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Germline Mutations and Polymorphisms in the Origins of Cancers in Women

PubMed Central

Hirshfield, Kim M.; Rebbeck, Timothy R.; Levine, Arnold J.

2010-01-01

Several female malignancies including breast, ovarian, and endometrial cancers can be characterized based on known somatic and germline mutations. Initiation and propagation of tumors reflect underlying genomic alterations such as mutations, polymorphisms, and copy number variations found in genes of multiple cellular pathways. The contributions of any single genetic variation or mutation in a population depend on its frequency and penetrance as well as tissue-specific functionality. Genome wide association studies, fluorescence in situ hybridization, comparative genomic hybridization, and candidate gene studies have enumerated genetic contributors to cancers in women. These include p53, BRCA1, BRCA2, STK11, PTEN, CHEK2, ATM, BRIP1, PALB2, FGFR2, TGFB1, MDM2, MDM4 as well as several other chromosomal loci. Based on the heterogeneity within a specific tumor type, a combination of genomic alterations defines the cancer subtype, biologic behavior, and in some cases, response to therapeutics. Consideration of tumor heterogeneity is therefore important in the critical analysis of gene associations in cancer. PMID:20111735

Box simulations of rotating magnetoconvection. Effects of penetration and turbulent pumping

NASA Astrophysics Data System (ADS)

Ziegler, U.; Rüdiger, G.

2003-04-01

Various effects of penetration in rotating magnetoconvection are studied by means of three-dimensional numerical simulations employing the code NIRVANA. A local, 2-layer model is applied dividing the computational domain (which is a rectangular box placed tangentially on a sphere at latitude 45deg) in an unstable polytropic region on top of a stable polytropic region. Different realizations of convection are examined parameterized by Taylor numbers Ta=0,6 x 104, 6x 105 and magnetic field strengths β = 5,50,500,5000,infty . We find a rather distinctive behavior of the penetration depth Delta on the system parameters (Ta,β). In non-rotating convection Delta is a monotonically decreasing function of β-1 which is due to magnetic quenching effects. Also, penetration is subject to rotational quenching, i.e. Delta is reduced for increasing rotation rate. In the intermediate regime of (Ta,β), the effects of rotation and magnetic field on Delta do not simply add (see Fig. 3). We find, nevertheless, a very strong reduction of the penetration depth of overshooting turbulence by both rotation and magnetism. Penetrative convection is closely associated with the mixing of a passive scalar quantity advected with the flow. In the long term, the tracer material penetrates significantly deeper into the stable layer than suggested by Delta which is due to the cumulative effect of isolated, fast-moving plumes. In case of a weak magnetic field, penetrative convection also serves to ensure a downward transport of magnetic flux by turbulent pumping with an average rate gammaz ~ -7x 10-3 measured in units of the sound speed at the top z-boundary. For larger magnetic fields the pumping effect is quenched and even changes sign in the convection zone. This effect is suggested as being due to the effect of ``turbulent buoyancy'' which in density-stratified media transports a given magnetic field upwards if it is not too strong (Kichatinov & Rüdiger \\cite{Kichatinov92}).

Transdermal permeation of drugs with differing lipophilicity: Effect of penetration enhancer camphor.

PubMed

Xie, Feng; Chai, Jia-Ke; Hu, Quan; Yu, Yong-Hui; Ma, Li; Liu, Ling-Ying; Zhang, Xu-Long; Li, Bai-Ling; Zhang, Dong-Hai

2016-06-30

The aim of the present study was to investigate the potential application of (+)-camphor as a penetration enhancer for the transdermal delivery of drugs with differing lipophilicity. The skin irritation of camphor was evaluated by in vitro cytotoxicity assays and in vivo transdermal water loss (TEWL) measurements. A series of model drugs with a wide span of lipophilicity (logP value ranging from 3.80 to -0.95), namely indometacin, lidocaine, aspirin, antipyrine, tegafur and 5-fluorouracil, were tested using in vitro transdermal permeation experiments to assess the penetration-enhancing profile of camphor. Meanwhile, the in vivo skin microdialysis was carried out to further investigate the enhancing effect of camphor on the lipophilic and hydrophilic model drugs (i.e. lidocaine and tegafur). SC (stratum corneum)/vehicle partition coefficient and Fourier transform infrared spectroscopy (FTIR) were performed to probe the regulation action of camphor in the skin permeability barrier. It was found that camphor produced a relatively low skin irritation, compared with the frequently-used and standard penetration enhancer laurocapram. In vitro skin permeation studies showed that camphor could significantly facilitate the transdermal absorption of model drugs with differing lipophilicity, and the penetration-enhancing activities were in a parabola curve going downwards with the drug logP values, which displayed the optimal penetration-enhancing efficiency for the weak lipophilic or hydrophilic drugs (an estimated logP value of 0). In vivo skin microdialysis showed that camphor had a similar penetration behavior on transdermal absorption of model drugs. Meanwhile, the partition of lipophilic drugs into SC was increased after treatment with camphor, and camphor also produced a shift of CH2 vibration of SC lipid to higher wavenumbers and decreased the peak area of the CH2 vibration, probably resulting in the alteration of the skin permeability barrier. This suggests that camphor might be a safe and effective penetration enhancer for transdermal drug delivery. Copyright © 2016 Elsevier B.V. All rights reserved.

The CLU gene rs11136000 variant is significantly associated with Alzheimer's disease in Caucasian and Asian populations.

PubMed

Liu, Guiyou; Wang, Haiyang; Liu, Jiafeng; Li, Jingbo; Li, Hali; Ma, Guoda; Jiang, Yongshuai; Chen, Zugen; Zhao, Bin; Li, Keshen

2014-03-01

Large-scale genomewide association studies have reported that the CLU rs11136000 polymorphism is significantly associated with Alzheimer's disease (AD) in people of Caucasian ancestry. Recently, this association was investigated in Asian populations (Chinese, Japanese, and Korean). However, these studies reported either a weak association or no association between the rs11136000 polymorphism and AD. We believe that this discrepancy may be caused by the relatively small sample size of the previous studies and the genetic heterogeneity of the rs11136000 polymorphism in AD among different populations. For this study, we searched the PubMed and AlzGene databases. We selected 18 independent studies (6 studies of Asian populations and 12 of populations of Caucasian ancestry) that evaluated the association between the rs11136000 polymorphism and AD using a case-control experimental design. We evaluated the genetic heterogeneity of the rs11136000 polymorphism in Caucasian and Asian populations. We then investigated the rs11136000 polymorphism by a meta-analysis in Asian populations using allele, dominant, and recessive models. We identified a significant association between rs11136000 and AD with the allele model (P = 2.00 × 10(-4)) and the dominant model (P = 5.00 × 10(-3)). Meanwhile, a similar genetic risk of the rs11136000 polymorphism in AD was observed in Asian and Caucasian populations. Further meta-analysis in pooled Asian and Caucasian populations indicated a more significant association with the allele (P = 8.30 × 10(-24)), dominant (P = 4.46 × 10(-17)), and recessive (P = 3.92 × 10(-12)) models. Collectively, our findings from this meta-analysis indicate that the effect of the CLU rs11136000 polymorphism on AD risk in Asian cohorts (Chinese, Japanese, and Korean) is consistent with the protective effect observed in Caucasian AD cohorts.

Density scaling on n  =  1 error field penetration in ohmically heated discharges in EAST

NASA Astrophysics Data System (ADS)

Wang, Hui-Hui; Sun, You-Wen; Shi, Tong-Hui; Zang, Qing; Liu, Yue-Qiang; Yang, Xu; Gu, Shuai; He, Kai-Yang; Gu, Xiang; Qian, Jin-Ping; Shen, Biao; Luo, Zheng-Ping; Chu, Nan; Jia, Man-Ni; Sheng, Zhi-Cai; Liu, Hai-Qing; Gong, Xian-Zu; Wan, Bao-Nian; Contributors, EAST

2018-05-01

Density scaling of error field penetration in EAST is investigated with different n  =  1 magnetic perturbation coil configurations in ohmically heated discharges. The density scalings of error field penetration thresholds under two magnetic perturbation spectra are br\\propto n_e0.5 and br\\propto n_e0.6 , where b r is the error field and n e is the line averaged electron density. One difficulty in understanding the density scaling is that key parameters other than density in determining the field penetration process may also be changed when the plasma density changes. Therefore, they should be determined from experiments. The estimated theoretical analysis (br\\propto n_e0.54 in lower density region and br\\propto n_e0.40 in higher density region), using the density dependence of viscosity diffusion time, electron temperature and mode frequency measured from the experiments, is consistent with the observed scaling. One of the key points to reproduce the observed scaling in EAST is that the viscosity diffusion time estimated from energy confinement time is almost constant. It means that the plasma confinement lies in saturation ohmic confinement regime rather than the linear Neo-Alcator regime causing weak density dependence in the previous theoretical studies.

Critical fields and vortex pinning in overdoped Ba 0.2 K 0.8 Fe 2 As 2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shen, B.; Leroux, M.; Wang, Y. L.

2015-05-19

We determine the upper and lower critical fields, the penetration depth and the vortex pinning characteristics of single crystals of overdoped Ba 0.2K 0.8Fe 2As 2 with T c ~ 10 K. We find that bulk vortex pinning is weak and vortex dynamics to be dominated by the geometrical surface barrier. The temperature dependence of the lower critical field, H c1, displays a distinctive upturn at low temperatures, which is suggestive of two distinct superconducting gaps. Furthermore, the penetration depth, λ, varies linearly with temperature below 4 K indicative of line nodes in the superconducting gap. As a result, thesemore » observations can be well described in a model based on a multi-band nodal superconducting gap.« less

Study on four polymorphs of bifendate based on X-ray crystallography.

PubMed

Nie, Jinju; Yang, Dezhi; Hu, Kun; Lu, Yang

2016-05-01

Bifendate, a synthetic anti-hepatitis drug, exhibits polycrystalline mode phenomena with 2 polymorphs reported (forms A and B). Single crystals of the known crystalline form B and 3 new crystallosolvates involving bifendate solvated with tetrahydrofuran (C), dioxane (D), and pyridine (E) in a stoichiometric ratio of 1:1 were obtained and characterized by X-ray crystallography, thermal analysis, and Fourier transform infrared (FT-IR) spectroscopy. The differences in molecular conformation, intermolecular interaction and crystal packing arrangement for the four polymorphs were determined and the basis for the polymorphisms was investigated. The rotation of single bonds resulted in different orientations for the biphenyl, methyl ester and methoxyl groups. All guest solvent molecules interacted with the host molecule via an interesting intercalative mode along the [1 0 0] direction in the channel formed by the host molecules through weak aromatic stacking interactions or non-classical hydrogen bonds, of which the volume and planarity played an important role in the intercalation of the host with the guest. The incorporation of solvent-augmented rotation of the C-C bond of the biphenyl group had a striking effect on the host molecular conformation and contributed to the formation of bifendate polymorphs. Moreover, the simulated powder X-ray diffraction (PXRD) patterns for each form were calculated on the basis of the single-crystal data and proved to be unique. The single-crystal structures of the four crystalline forms are reported in this paper.

The gender-specific association of rs334558 in GSK3β with major depressive disorder.

PubMed

Liu, Sha; Wang, Le; Sun, Ning; Yang, Chunxia; Liu, Zhifen; Li, Xinrong; Cao, Xiaohua; Xu, Yong; Zhang, Kerang

2017-01-01

Major depressive disorder (MDD) is one of the most prevalent psychiatric illnesses with a heritability ranging from 40% to 50%. The single nucleotide polymorphism (SNP) rs334558 on the glycogen synthase kinase-3β (GSK3β) gene has been identified as a genetic risk loci associated with schizophrenia and bipolar disorder. However, results from replication studies examining the association between rs334558 and MDD remain inconsistent.In the present study, first, we conducted a meta-analysis of the association between rs334558 and MDD by combining 5 available case-control samples totaling 2311 cases and 2535 controls. Second, genotyping data from patients with MDD at our institution, after further stratification by gender, were analyzed to determine the association between rs334558 and MDD.All studies retrieved and included in the meta-analysis were from Korea and China. The meta-analysis suggested that the functional polymorphism rs334558 within the GSK3β promoter region was associated with MDD risk (P < 0.05). The associations were observed both in the allelic and genetic models. Analysis of the genotyping data extracted from our hospital database revealed that rs334558 exhibited exclusive association with MDD in female patients (P=0.015).Our findings suggest that GSK3β rs334558 polymorphisms might be a potential risk for MDD, and females with GSK3β rs334558 polymorphisms might have higher penetrance of MDD. If validated in larger scale samples and in different ethnic populations, these findings might be of value as diagnostic references for MDD.

Advances in cancer epidemiology in Japan.

PubMed

Tanaka, Hideo

2014-02-15

Epidemiologists in Japan have been performing calculations to estimate nationwide cancer incidence rates as well as 5-year survival rates using population-based cancer registry data. There have been remarkable changes in cancer incidence and/or mortality in cancers of the lung, liver and stomach, which were thought to be attributed to the changing impact of exposure to cigarette smoking, chronic hepatitis C virus infection and Helicobacter pylori infection, respectively. In systematic reviews providing evidence in risk/protective factors for cancer sites using case-control and cohort studies of the Japanese population, there were associations between cancer sites (esophagus, stomach, colo-rectum, liver, pancreas, lung and breast) and various lifestyle factors. In the past 10 years, a hospital-based case-control study at Aichi Cancer Center provided valuable evidence of gene-environment interaction on the development of cancer [i.e., the effects of aldehyde dehydrogenase-2 (ALDH2) polymorphism and heavy alcohol drinking on esophageal cancer, ALDH2 polymorphism and smoking on lung cancer, methylenetetrahydrofolate reductase polymorphism and heavy alcohol drinking on pancreatic cancer]. The database with stored DNA was also used and identified seven loci containing significant but low-penetrance polymorphisms associated with the development of breast cancer. These findings together with established risk factors are likely to be useful to predict personalized breast cancer risk in East Asian women. In 2005, the Japan Multi-Institution Collaborative Cohort (J-MICC) study was launched to elucidate gene-environment interactions as well as to confirm preclinical diagnostic biomarkers of cancer. J-MICC, which has recruited 92,000 healthy individuals by the end of 2012, will follow the individuals until 2025. © 2013 UICC.

Weak interband-coupling superconductivity in the filled skutterudite LaPt4Ge12

NASA Astrophysics Data System (ADS)

Zhang, J. L.; Pang, G. M.; Jiao, L.; Nicklas, M.; Chen, Y.; Weng, Z. F.; Smidman, M.; Schnelle, W.; Leithe-Jasper, A.; Maisuradze, A.; Baines, C.; Khasanov, R.; Amato, A.; Steglich, F.; Gumeniuk, R.; Yuan, H. Q.

2015-12-01

The superconducting pairing state of LaPt4Ge12 is studied by measuring the magnetic penetration depth λ (T ,B ) and superfluid density ρs(T ) using a tunnel-diode-oscillator (TDO)-based method and transverse-field muon-spin rotation (TF -μ SR ) spectroscopy. The penetration depth follows an exponential-type temperature dependence at T ≪Tc , but increases linearly with magnetic field at T =1.5 K. A detailed analysis demonstrates that both λL(T ) and ρsTDO(T ) , measured in the Meissner state using the TDO method, are well described by a two-gap γ model with gap sizes of Δ1(0 ) =1.31 kBTc and Δ2(0 ) =1.80 kBTc , and weak interband coupling. In contrast, ρsμ SR(T ) , derived from the μ SR data, can be fitted by a single-gap BCS model with a gap close to Δ2(0 ) . We conclude that LaPt4Ge12 is a marginal two-gap superconductor and the small gap Δ1 seems to be suppressed by a small magnetic field applied in the μ SR experiments. In comparison, the 4 f electrons in PrPt4Ge12 may enhance the interband coupling and, therefore, give rise to more robust multiband superconductivity.

Successful treatment of an acute infective endocarditis secondary to fish bone penetrating into left atrium caused by Granulicatella adiacens and Candida albicans: A case report.

PubMed

Tong, Ya Ling; Qu, Ting Ting; Xu, Jia; Chen, Nai Yun; Yang, Mei Fang

2017-12-01

Infective endocarditis caused by a foreign body of the upper digestive tract is rare. We report a rare case of Granulicatella adiacens and Candida albicans coinfection acute endocarditis combined with systematic embolization caused by a fish bone from the esophagus penetrating into the left atrium. A 42-year-old woman was admitted to our hospital because of fever, abdominal pain, headache, and right limb weakness. Clinical examination indicated endocarditis and systemic embolisms secondary to a fish bone from the esophagus penetrating into the left atrium. The emergency surgery confirmed the diagnosis. Cultures of blood and vegetation show G adiacens and C albicans. Antimicrobial therapy lasted 6 weeks after surgery. The patient was discharged with excellent condition7 weeks after hospitalization and was well when followed 6 months later. The successful treatment of this patient combines quick diagnosis, timely surgery, and effective antimicrobial regimen. This rare possibility should be kept up in mind in acute infective endocarditis cases. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

An autopsy case related to a terrorist attack using a ball-bearing bomb.

PubMed

Takamiya, Masataka; Biwasaka, Hitoshi; Niitsu, Hisae; Saigusa, Kiyoshi; Aoki, Yasuhiro

2009-03-01

We encountered an autopsy case related to a terrorist attack using a ball-bearing bomb. The decedent was a 51-year-old male without significant medical histories. During dinner in a restaurant, the perpetrator suddenly exploded a ball-bearing bomb, the blast from which blew the victim off his chair. The victim was found to be unresponsive, and pronounced dead. X-ray photographs taken before autopsy revealed six spherical shadows. Three penetrating wounds in the head, one in the neck and chest, and two in the left upper arm were observed in vivo. Six projectiles recovered from the body were identified as ball-bearings, one of which traveled through the midbrain, diencephalon, and left temporal lobe. Although blast injuries and penetrating wounds are often combined in bomb attack victims, penetrating brain injury would be the cause of death in this case. Lethal injuries to major organs can thus occur even though the destructive force of a ball-bearing bomb is weak. X-ray films were informative for detecting the ball-bearings in this case, suggesting that autopsy imaging is essential in cases of terrorism victims.

Polymorphic Nature of Iron and Degree of Lattice Preferred Orientation Beneath the Earth's Inner Core Boundary

NASA Astrophysics Data System (ADS)

Mattesini, Maurizio; Belonoshko, Anatoly B.; Tkalčić, Hrvoje

2018-01-01

Deciphering the polymorphic nature and the degree of iron lattice-preferred orientation in the Earth's inner core holds a key to understanding the present status and evolution of the inner core. A multiphase lattice-preferred orientation pattern is obtained for the top 350 km of the inner core by means of the ab initio based Candy Wrapper Velocity Model coupled to a Monte Carlo phase discrimination scheme. The achieved geographic distribution of lattice alignment is characterized by two regions of freezing, namely within South America and the Western Central Pacific, that exhibit an uncommon high degree of lattice orientation. In contrast, widespread regions of melting of relatively weak lattice ordering permeate the rest of the inner core. The obtained multiphase lattice-preferred orientation pattern is in line with mantle-constrained geodynamo simulations and allows to setup an ad hoc mineral physics scenario for the complex Earth's inner core. It is found that the cubic phase of iron is the dominating iron polymorph in the outermost part of the inner core.

The APOC3 SstI polymorphism is weakly associated with sporadic Alzheimer's disease in a Chinese population.

PubMed

Sun, Yan; Shi, Jiajun; Zhang, Sizhong; Tang, Mouni; Han, Haiying; Guo, Yangbo; Ma, Cui; Liu, Xiehe; Li, Tao

2005-06-03

In order to clarify the relationship of apolipoprotein CIII (APOC3) polymorphism and sporadic Alzheimer's disease (AD) in Chinese, 165 sporadic AD patients and 174 age-matched elderly individuals were genotyped for the APOC3 SstI and apolipoprotein E (APOE) HhaI polymorphisms. As the result, the APOC3 3017G allele was found to be associated with AD in APOE epsilon4 allele noncarriers (chi2=4.433, P=0.035), and the risk estimate of allele C versus G resulted in an OR of 1.56 (95% CI: 1.03-2.37), although in total no significant differences of allelic or genotypic frequencies between patients and controls were found. Assessment of interaction between APOE epsilon4 and APOC3 3017G status presented an adjusted odds ratio of 0.62 (95% CI: 0.37-1.03) with a borderline significant P-value (P=0.066). Therefore, we conclude that the rare APOC3 G allele may offer some protection against the development of sporadic AD in APOE epsilon4 noncarriers in Chinese.

Theoretical Study of near Neutrality. II. Effect of Subdivided Population Structure with Local Extinction and Recolonization

PubMed Central

Ohta, T.

1992-01-01

There are several unsolved problems concerning the model of nearly neutral mutations. One is the interaction of subdivided population structure and weak selection that spatially fluctuates. The model of nearly neutral mutations whose selection coefficient spatially fluctuates has been studied by adopting the island model with periodic extinction-recolonization. Both the number of colonies and the migration rate play significant roles in determining mutants' behavior, and selection is ineffective when the extinction-recolonization is frequent with low migration rate. In summary, the number of mutant substitutions decreases and the polymorphism increases by increasing the total population size, and/or decreasing the extinction-recolonization rate. However, by increasing the total size of the population, the mutant substitution rate does not become as low when compared with that in panmictic populations, because of the extinction-recolonization, especially when the migration rate is limited. It is also found that the model satisfactorily explains the contrasting patterns of molecular polymorphisms observed in sibling species of Drosophila, including heterozygosity, proportion of polymorphism and fixation index. PMID:1582566

Novel approach of molecular genetic understanding of iridology: relationship between iris constitution and angiotensin converting enzyme gene polymorphism.

PubMed

Um, Jae-Young; An, Nyeon-Hyoung; Yang, Gui-Bi; Lee, Geon-Mok; Cho, Ju-Jang; Cho, Jae-Woon; Hwang, Woo-Jun; Chae, Han-Jung; Kim, Hyung-Ryong; Hong, Seung-Heon; Kim, Hyung-Min

2005-01-01

Iridology is the study of the iris of the eye to detect the conditions of the body and its organs, genetic strengths and weaknesses, etc. Although iridology is not widely used as a scientific tool for healthcare professionals to get to the source of people's health conditions, it has been used as a supplementary source to help the diagnosis of medical conditions by noting irregularities of the pigmentation in the iris among some Korean Oriental medical doctors. Angiotensin converting enzyme (ACE) gene polymorphism is one of the most well studied genetic markers of vascular disease. We investigated the relationship between iridological constitution and ACE polymorphism in hypertensives. We classified 87 hypertensives and 79 controls according to iris constitution and determined the ACE genotype of each individual. DD genotype was more prevalent in patients with a neurogenic constitution than in controls. This finding supports the hypothesis that D allele is a candidate gene for hypertension and demonstrates the association among ACE genotype, Korean hypertensives and iris constitution.

Polymorphism in the IL18 gene and epithelial ovarian cancer in non-Hispanic white women

PubMed Central

Palmieri, Rachel T.; Wilson, Melanie A.; Iversen, Edwin S.; Clyde, Merlise A.; Calingaert, Brian; Moorman, Patricia G.; Poole, Charles; Anderson, A. Rebecca; Anderson, Stephanie; Anton-Culver, Hoda; Beesley, Jonathan; Hogdall, Estrid; Brewster, Wendy; Carney, Michael E.; Chen, Xiaoqing; Chenevix-Trench, Georgia; Chang-Claude, Jenny; Cunningham, Julie M.; DiCioccio, Richard A.; Doherty, Jennifer A.; Easton, Douglas F.; Edlund, Christopher K.; Gayther, Simon A.; Gentry-Maharaj, Aleksandra; Goode, Ellen L.; Goodman, Marc T.; Kjaer, Susanne Kruger; Hogdall, Claus K; Hopkins, Michael P.; Jenison, Eric L.; Blaakaer, Jan; Lurie, Galina; McGuire, Valerie; Menon, Usha; Moysich, Kirsten B.; Ness, Roberta B.; Pearce, Celeste Leigh; Pharoah, Paul D.P.; Pike, Malcolm C.; Ramus, Susan J.; Rossing, Mary Anne; Song, Honglin; Terada, Keith Y.; Van Den Berg, David; Vierkant, Robert A.; Wang-Gohrke, Shan; Webb, Penelope M.; Whittemore, Alice S.; Wu, Anna H.; Ziogas, Argyrios; Berchuck, Andrew; Schildkraut, Joellen M.

2009-01-01

Over 22,000 cases of ovarian cancer were diagnosed in 2007 in the United States but only a fraction of them can be attributed to mutations in highly penetrant genes such as BRCA1. To determine whether low penetrance genetic variants contribute to ovarian cancer risk, we genotyped 1,536 single nucleotide polymorphisms (SNPs) in several candidate gene pathways in 848 epithelial ovarian cancer cases and 798 controls in the North Carolina Ovarian Cancer Study (NCO) using a customized Illumina array. The inflammation gene interleukin-18 (IL18) showed the strongest evidence for association with epithelial ovarian cancer in a gene-by-gene analysis (p=0.002) with a <25% chance of being a false positive finding (q-value=0.240). Using a multivariate model search algorithm over eleven IL18 tagging SNPs, we found the association was best modeled by rs1834481. Further, this SNP uniquely tagged a significantly associated IL18 haplotype and there was an increased risk of epithelial ovarian cancer per rs1834481 allele (OR=1.24, 95% CI: 1.06, 1.45). In a replication stage, twelve independent studies from the Ovarian Cancer Association Consortium (OCAC) genotyped rs1834481 in an additional 5,877 cases and 7,791 controls. The fixed effects estimate per rs1834481 allele was null (OR=0.99, 95% CI: 0.94, 1.05) when data from the twelve OCAC studies were combined. The effect estimate remained unchanged with the addition of the initial NCO data. This analysis demonstrates the importance of consortia, like the OCAC, in either confirming or refuting the validity of putative findings in studies with smaller sample sizes. PMID:19064572

Genome-wide population structure and admixture analysis reveals weak differentiation among Ugandan goat breeds.

PubMed

Onzima, R B; Upadhyay, M R; Mukiibi, R; Kanis, E; Groenen, M A M; Crooijmans, R P M A

2018-02-01

Uganda has a large population of goats, predominantly from indigenous breeds reared in diverse production systems, whose existence is threatened by crossbreeding with exotic Boer goats. Knowledge about the genetic characteristics and relationships among these Ugandan goat breeds and the potential admixture with Boer goats is still limited. Using a medium-density single nucleotide polymorphism (SNP) panel, we assessed the genetic diversity, population structure and admixture in six goat breeds in Uganda: Boer, Karamojong, Kigezi, Mubende, Small East African and Sebei. All the animals had genotypes for about 46 105 SNPs after quality control. We found high proportions of polymorphic SNPs ranging from 0.885 (Kigezi) to 0.928 (Sebei). The overall mean observed (H O ) and expected (H E ) heterozygosity across breeds was 0.355 ± 0.147 and 0.384 ± 0.143 respectively. Principal components, genetic distances and admixture analyses revealed weak population sub-structuring among the breeds. Principal components separated Kigezi and weakly Small East African from other indigenous goats. Sebei and Karamojong were tightly entangled together, whereas Mubende occupied a more central position with high admixture from all other local breeds. The Boer breed showed a unique cluster from the Ugandan indigenous goat breeds. The results reflect common ancestry but also some level of geographical differentiation. admixture and f 4 statistics revealed gene flow from Boer and varying levels of genetic admixture among the breeds. Generally, moderate to high levels of genetic variability were observed. Our findings provide useful insights into maintaining genetic diversity and designing appropriate breeding programs to exploit within-breed diversity and heterozygote advantage in crossbreeding schemes. © 2018 The Authors. Animal Genetics published by John Wiley & Sons Ltd on behalf of Stichting International Foundation for Animal Genetics.

Duffy blood group phenotype-genotype correlations using high-resolution melting analysis PCR and microarray reveal complex cases including a new null FY*A allele: the role for sequencing in genotyping algorithms.

PubMed

Lopez, G H; Morrison, J; Condon, J A; Wilson, B; Martin, J R; Liew, Y-W; Flower, R L; Hyland, C A

2015-10-01

Duffy blood group phenotypes can be predicted by genotyping for single nucleotide polymorphisms (SNPs) responsible for the Fy(a) /Fy(b) polymorphism, for weak Fy(b) antigen, and for the red cell null Fy(a-b-) phenotype. This study correlates Duffy phenotype predictions with serotyping to assess the most reliable procedure for typing. Samples, n = 155 (135 donors and 20 patients), were genotyped by high-resolution melt PCR and by microarray. Samples were in three serology groups: 1) Duffy patterns expected n = 79, 2) weak and equivocal Fy(b) patterns n = 29 and 3) Fy(a-b-) n = 47 (one with anti-Fy3 antibody). Discrepancies were observed for five samples. For two, SNP genotyping predicted weak Fy(b) expression discrepant with Fy(b-) (Group 1 and 3). For three, SNP genotyping predicted Fy(a) , discrepant with Fy(a-b-) (Group 3). DNA sequencing identified silencing mutations in these FY*A alleles. One was a novel FY*A 719delG. One, the sample with the anti-Fy3, was homozygous for a 14-bp deletion (FY*01N.02); a true null. Both the high-resolution melting analysis and SNP microarray assays were concordant and showed genotyping, as well as phenotyping, is essential to ensure 100% accuracy for Duffy blood group assignments. Sequencing is important to resolve phenotype/genotype conflicts which here identified alleles, one novel, that carry silencing mutations. The risk of alloimmunisation may be dependent on this zygosity status. © 2015 International Society of Blood Transfusion.

Report from the Maryland epidemiology schizophrenia linkage study: No evidence for linkage between schizophrenia and a number of candidate and other genomic regions using a complex dominant model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Karayiorgou, M.; Hwang, J.; Elango, R.

Our collaborative group has undertaken a linkage study of schizophrenia, using a systematic sample of patients admitted to Maryland hospitals. An initial sample of 39 families, each having two or more affecteds, was available for genotyping candidate genes, candidate regions, and highly polymorphic markers randomly distributed throughout the genome. We used a single complex dominant model (with a disease gene frequency of 0.005 and age-dependent penetrance for affected phenotype: for under 35, penetrance = .45; for 35 and older, penetrance = .85). We report here 130 markers which met the exclusion criteria of LOD score < -2.00 at theta >more » 0.01 in at least 10 informative families, and no evidence for heterogeneity. We also report here markers that were tested as candidates for linkage to the schizophrenic phenotype. They were selected based on the following criteria: (a) proximity to reported chromosomal rearrangements (both 5q and 11q), (b) suggestions of linkage from other families (5q), or (c) presence of a candidate gene (5q, 11q, 3q: dopamine receptors 1, 2, and 3, respectively). We also tested for mutations of codon 717 in exon 17 of the amyloid precursor protein (APP) gene and were unable to detect the C to T substitution in our schizophrenic group. 48 refs., 2 tabs.« less

The hepcidin gene promoter nc.-1010C > T; -582A > G haplotype modulates serum ferritin in individuals carrying the common H63D mutation in HFE gene.

PubMed

Silva, Bruno; Pita, Lina; Gomes, Susana; Gonçalves, João; Faustino, Paula

2014-12-01

Hereditary hemochromatosis is an autosomal recessive disorder characterized by severe iron overload. It is usually associated with homozygosity for the HFE gene mutation c.845G > A; p.C282Y. However, in some cases, another HFE mutation (c.187C > G; p.H63D) seems to be associated with the disease. Its penetrance is very low, suggesting the possibility of other iron genetic modulators being involved. In this work, we have screened for HAMP promoter polymorphisms in 409 individuals presenting normal or increased serum ferritin levels together with normal or H63D-mutated HFE genotypes. Our results show that the hepcidin gene promoter TG haplotype, originated by linkage of the nc.-1010C > T and nc.-582A > G polymorphisms, is more frequent in the HFE_H63D individuals presenting serum ferritin levels higher than 300 μg/L than in those presenting the HFE_H63D mutation but with normal serum ferritin levels or in the normal control group.Moreover, it was observed that the TG haplotype was associated to increased serum ferritin levels in the overall pool of HFE_H63D individuals. Thus, our data suggest that screening for these polymorphisms could be of interest in order to explain the phenotype. However, this genetic condition seems to have no clinical significance.

The Effect of XPD Polymorphisms on Digestive Tract Cancers Risk: A Meta-Analysis

PubMed Central

Zhang, Qian; Chen, Zhipeng; Lu, Kai; Shu, Yongqian; Chen, Tao; Zhu, Lingjun

2014-01-01

Background The Xeroderma pigmento-sum group D gene (XPD) plays a key role in nucleotide excision repair. Single nucleotide polymorphisms (SNP) located in its functional region may alter DNA repair capacity phenotype and cancer risk. Many studies have demonstrated that XPD polymorphisms are significantly associated with digestive tract cancers risk, but the results are inconsistent. We conducted a comprehensive meta-analysis to assess the association between XPD Lys751Gln polymorphism and digestive tract cancers risk. The digestive tract cancers that our study referred to, includes oral cancer, esophageal cancer, gastric cancer and colorectal cancer. Methods We searched PubMed and EmBase up to December 31, 2012 to identify eligible studies. A total of 37 case-control studies including 9027 cases and 16072 controls were involved in this meta-analysis. Statistical analyses were performed with Stata software (version 11.0, USA). Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. Results The results showed that XPD Lys751Gln polymorphism was associated with the increased risk of digestive tract cancers (homozygote comparison (GlnGln vs. LysLys): OR = 1.12, 95% CI = 1.01–1.24, P = 0.029, P heterogeneity = 0.133). We found no statistical evidence for a significantly increased digestive tract cancers risk in the other genetic models. In the subgroup analysis, we also found the homozygote comparison increased the susceptibility of Asian population (OR = 1.28, 95% CI = 1.01–1.63, P = 0.045, P heterogeneity = 0.287). Stratified by cancer type and source of control, no significantly increased cancer risk was found in these subgroups. Additionally, risk estimates from hospital-based studies and esophageal studies were heterogeneous. Conclusions Our meta-analysis suggested that the XPD 751Gln/Gln genotype was a low-penetrate risk factor for developing digestive tract cancers, especially in Asian populations. PMID:24787743

The effect of XPD polymorphisms on digestive tract cancers risk: a meta-analysis.

PubMed

Du, Haina; Guo, Nannan; Shi, Bin; Zhang, Qian; Chen, Zhipeng; Lu, Kai; Shu, Yongqian; Chen, Tao; Zhu, Lingjun

2014-01-01

The Xeroderma pigmento-sum group D gene (XPD) plays a key role in nucleotide excision repair. Single nucleotide polymorphisms (SNP) located in its functional region may alter DNA repair capacity phenotype and cancer risk. Many studies have demonstrated that XPD polymorphisms are significantly associated with digestive tract cancers risk, but the results are inconsistent. We conducted a comprehensive meta-analysis to assess the association between XPD Lys751Gln polymorphism and digestive tract cancers risk. The digestive tract cancers that our study referred to, includes oral cancer, esophageal cancer, gastric cancer and colorectal cancer. We searched PubMed and EmBase up to December 31, 2012 to identify eligible studies. A total of 37 case-control studies including 9027 cases and 16072 controls were involved in this meta-analysis. Statistical analyses were performed with Stata software (version 11.0, USA). Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. The results showed that XPD Lys751Gln polymorphism was associated with the increased risk of digestive tract cancers (homozygote comparison (GlnGln vs. LysLys): OR = 1.12, 95% CI = 1.01-1.24, P = 0.029, P heterogeneity = 0.133). We found no statistical evidence for a significantly increased digestive tract cancers risk in the other genetic models. In the subgroup analysis, we also found the homozygote comparison increased the susceptibility of Asian population (OR = 1.28, 95% CI = 1.01-1.63, P = 0.045, P heterogeneity = 0.287). Stratified by cancer type and source of control, no significantly increased cancer risk was found in these subgroups. Additionally, risk estimates from hospital-based studies and esophageal studies were heterogeneous. Our meta-analysis suggested that the XPD 751Gln/Gln genotype was a low-penetrate risk factor for developing digestive tract cancers, especially in Asian populations.

Flexoelectro-optic effect and two-beam energy exchange in a hybrid photorefractive cholesteric cell with a short-pitch horizontal helix

NASA Astrophysics Data System (ADS)

Reshetnyak, V. Yu.; Pinkevych, I. P.; Evans, D. R.

2018-06-01

We develop a theoretical model to describe two-beam energy exchange in a hybrid photorefractive cholesteric cell with a short-pitch helix oriented parallel to the cell substrates (so-called uniformly lying helix configuration). Weak and strong light beams incident on the hybrid cell interfere and induce a periodic space-charge field in the photorefractive substrate of the cell, which penetrates into the cholesteric liquid crystal (LC). Due to the flexoelectro-optic effect an interaction of the photorefractive field with the LC flexopolarization causes the spatially periodic modulation of the helix axis in the plane parallel to the cell substrates. Coupling of a weak signal beam with a strong pump beam at the LC permittivity grating, induced by the periodically tilted helix axis, leads to the energy gain of the weak signal beam. Dependence of the signal beam gain coefficient on the parameters of the short-pitch cholesteric LC is studied.

Role of Polymorphism and Thin-Film Morphology in Organic Semiconductors Processed by Solution Shearing

PubMed Central

2018-01-01

Organic semiconductors (OSCs) are promising materials for cost-effective production of electronic devices because they can be processed from solution employing high-throughput techniques. However, small-molecule OSCs are prone to structural modifications because of the presence of weak van der Waals intermolecular interactions. Hence, controlling the crystallization in these materials is pivotal to achieve high device reproducibility. In this perspective article, we focus on controlling polymorphism and morphology in small-molecule organic semiconducting thin films deposited by solution-shearing techniques compatible with roll-to-roll systems. Special attention is paid to the influence that the different experimental deposition parameters can have on thin films. Further, the main characterization techniques for thin-film structures are reviewed, highlighting the in situ characterization tools that can provide crucial insights into the crystallization mechanisms. PMID:29503976

Multilocus patterns of polymorphism and selection across the X chromosome of Caenorhabditis remanei.

PubMed

Cutter, Asher D

2008-03-01

Natural selection and neutral processes such as demography, mutation, and gene conversion all contribute to patterns of polymorphism within genomes. Identifying the relative importance of these varied components in evolution provides the principal challenge for population genetics. To address this issue in the nematode Caenorhabditis remanei, I sampled nucleotide polymorphism at 40 loci across the X chromosome. The site-frequency spectrum for these loci provides no evidence for population size change, and one locus presents a candidate for linkage to a target of balancing selection. Selection for codon usage bias leads to the non-neutrality of synonymous sites, and despite its weak magnitude of effect (N(e)s approximately 0.1), is responsible for profound patterns of diversity and divergence in the C. remanei genome. Although gene conversion is evident for many loci, biased gene conversion is not identified as a significant evolutionary process in this sample. No consistent association is observed between synonymous-site diversity and linkage-disequilibrium-based estimators of the population recombination parameter, despite theoretical predictions about background selection or widespread genetic hitchhiking, but genetic map-based estimates of recombination are needed to rigorously test for a diversity-recombination relationship. Coalescent simulations also illustrate how a spurious correlation between diversity and linkage-disequilibrium-based estimators of recombination can occur, due in part to the presence of unbiased gene conversion. These results illustrate the influence that subtle natural selection can exert on polymorphism and divergence, in the form of codon usage bias, and demonstrate the potential of C. remanei for detecting natural selection from genomic scans of polymorphism.

Multivariate Linear Regression and CART Regression Analysis of TBM Performance at Abu Hamour Phase-I Tunnel

NASA Astrophysics Data System (ADS)

Jakubowski, J.; Stypulkowski, J. B.; Bernardeau, F. G.

2017-12-01

The first phase of the Abu Hamour drainage and storm tunnel was completed in early 2017. The 9.5 km long, 3.7 m diameter tunnel was excavated with two Earth Pressure Balance (EPB) Tunnel Boring Machines from Herrenknecht. TBM operation processes were monitored and recorded by Data Acquisition and Evaluation System. The authors coupled collected TBM drive data with available information on rock mass properties, cleansed, completed with secondary variables and aggregated by weeks and shifts. Correlations and descriptive statistics charts were examined. Multivariate Linear Regression and CART regression tree models linking TBM penetration rate (PR), penetration per revolution (PPR) and field penetration index (FPI) with TBM operational and geotechnical characteristics were performed for the conditions of the weak/soft rock of Doha. Both regression methods are interpretable and the data were screened with different computational approaches allowing enriched insight. The primary goal of the analysis was to investigate empirical relations between multiple explanatory and responding variables, to search for best subsets of explanatory variables and to evaluate the strength of linear and non-linear relations. For each of the penetration indices, a predictive model coupling both regression methods was built and validated. The resultant models appeared to be stronger than constituent ones and indicated an opportunity for more accurate and robust TBM performance predictions.

Genetic polymorphisms of GSTO2, GSTM1, and GSTT1 and risk of gastric cancer.

PubMed

Masoudi, Mohammad; Saadat, Iraj; Omidvari, Shahpour; Saadat, Mostafa

2009-04-01

The glutathione S-transferases (GSTs) are a superfamily of proteins that participates in detoxification. The GSTs were dividing into several classes including omega (GSTO), micro (GSTM) and theta (GSTT) classes. In human GSTO2, GSTM1, and GSTT1 are polymorphic. In order to study whether GSTO2, GSTM1, and GSTT1 polymorphisms are associated with increased gastric cancer risk in Iranian patients, the present case-control study was done. Genomic DNA was extracted from peripheral blood of 67 gastric cancer patients and 134 control subjects. The genotyping was performed using PCR-based method. The possible association of gastric cancer with the GSTO2 N142D polymorphism was estimated with assuming additive, dominant, and recessive effect of the variant 142D allele. To investigate whether profiles of GST genotypes are associated with the risk of gastric cancer, we used unconditional logistic regression analysis. The GSTO2 142D allele in additive, dominant and recessive models was not associated with the risk. Because GSTM1, GSTT1, and GSTO2 genes belong to low-penetrance genes which might be involved in the carcinogenesis, patients and controls without family of cancer in first-degree relatives were also analyzes separately. To investigate whether profiles of GST genotypes are associated with the risk of gastric cancer, we used unconditional logistic regression analysis with GSTM1, GSTT1, and GSTO2 genotypes as predictor factors. The GSTO2 DD genotype was associated with decreased risk as compared to GSTO2 NN genotype (OR = 0.21, 95% CI: 0.05-0.92, P = 0.038). Present findings show that GSTO2 DD genotype decreases the risk of gastric cancer in individuals without history of cancer in their first-degree relatives.

Analysis of Indium Tin Oxide Film Using Argon Fluroide (ArF) Laser-Excited Atomic Fluorescence of Ablated Plumes.

PubMed

Ho, Sut Kam; Garcia, Dario Machado

2017-04-01

A two-pulse laser-excited atomic fluorescence (LEAF) technique at 193 nm wavelength was applied to the analysis of indium tin oxide (ITO) layer on polyethylene terephthalate (PET) film. Fluorescence emissions from analytes were induced from plumes generated by first laser pulse. Using this approach, non-selective LEAF can be accomplished for simultaneous multi-element analysis and it overcomes the handicap of strict requirement for laser excitation wavelength. In this study, experimental conditions including laser fluences, times for gating and time delay between pulses were optimized to reveal high sensitivity with minimal sample destruction and penetration. With weak laser fluences of 100 and 125 mJ/cm 2 for 355 and 193 nm pulses, detection limits were estimated to be 0.10% and 0.43% for Sn and In, respectively. In addition, the relation between fluorescence emissions and number of laser shots was investigated; reproducible results were obtained for Sn and In. It shows the feasibility of depth profiling by this technique. Morphologies of samples were characterized at various laser fluences and number of shots to examine the accurate penetration. Images of craters were also investigated using scanning electron microscopy (SEM). The results demonstrate the imperceptible destructiveness of film after laser shot. With such weak laser fluences and minimal destructiveness, this LEAF technique is suitable for thin-film analysis.

Multi-OMICs and Genome Editing Perspectives on Liver Cancer Signaling Networks.

PubMed

Lin, Shengda; Yin, Yi A; Jiang, Xiaoqian; Sahni, Nidhi; Yi, Song

2016-01-01

The advent of the human genome sequence and the resulting ~20,000 genes provide a crucial framework for a transition from traditional biology to an integrative "OMICs" arena (Lander et al., 2001; Venter et al., 2001; Kitano, 2002). This brings in a revolution for cancer research, which now enters a big data era. In the past decade, with the facilitation by next-generation sequencing, there have been a huge number of large-scale sequencing efforts, such as The Cancer Genome Atlas (TCGA), the HapMap, and the 1000 genomes project. As a result, a deluge of genomic information becomes available from patients stricken by a variety of cancer types. The list of cancer-associated genes is ever expanding. New discoveries are made on how frequent and highly penetrant mutations, such as those in the telomerase reverse transcriptase (TERT) and TP53, function in cancer initiation, progression, and metastasis. Most genes with relatively frequent but weakly penetrant cancer mutations still remain to be characterized. In addition, genes that harbor rare but highly penetrant cancer-associated mutations continue to emerge. Here, we review recent advances related to cancer genomics, proteomics, and systems biology and suggest new perspectives in targeted therapy and precision medicine.

A Natural Polymorphism in rDNA Replication Origins Links Origin Activation with Calorie Restriction and Lifespan

PubMed Central

Kwan, Elizabeth X.; Foss, Eric J.; Tsuchiyama, Scott; Alvino, Gina M.; Kruglyak, Leonid; Kaeberlein, Matt; Raghuraman, M. K.; Brewer, Bonita J.; Kennedy, Brian K.; Bedalov, Antonio

2013-01-01

Aging and longevity are complex traits influenced by genetic and environmental factors. To identify quantitative trait loci (QTLs) that control replicative lifespan, we employed an outbred Saccharomyces cerevisiae model, generated by crossing a vineyard and a laboratory strain. The predominant QTL mapped to the rDNA, with the vineyard rDNA conferring a lifespan increase of 41%. The lifespan extension was independent of Sir2 and Fob1, but depended on a polymorphism in the rDNA origin of replication from the vineyard strain that reduced origin activation relative to the laboratory origin. Strains carrying vineyard rDNA origins have increased capacity for replication initiation at weak plasmid and genomic origins, suggesting that inability to complete genome replication presents a major impediment to replicative lifespan. Calorie restriction, a conserved mediator of lifespan extension that is also independent of Sir2 and Fob1, reduces rDNA origin firing in both laboratory and vineyard rDNA. Our results are consistent with the possibility that calorie restriction, similarly to the vineyard rDNA polymorphism, modulates replicative lifespan through control of rDNA origin activation, which in turn affects genome replication dynamics. PMID:23505383

A natural polymorphism in rDNA replication origins links origin activation with calorie restriction and lifespan.

PubMed

Kwan, Elizabeth X; Foss, Eric J; Tsuchiyama, Scott; Alvino, Gina M; Kruglyak, Leonid; Kaeberlein, Matt; Raghuraman, M K; Brewer, Bonita J; Kennedy, Brian K; Bedalov, Antonio

2013-01-01

Aging and longevity are complex traits influenced by genetic and environmental factors. To identify quantitative trait loci (QTLs) that control replicative lifespan, we employed an outbred Saccharomyces cerevisiae model, generated by crossing a vineyard and a laboratory strain. The predominant QTL mapped to the rDNA, with the vineyard rDNA conferring a lifespan increase of 41%. The lifespan extension was independent of Sir2 and Fob1, but depended on a polymorphism in the rDNA origin of replication from the vineyard strain that reduced origin activation relative to the laboratory origin. Strains carrying vineyard rDNA origins have increased capacity for replication initiation at weak plasmid and genomic origins, suggesting that inability to complete genome replication presents a major impediment to replicative lifespan. Calorie restriction, a conserved mediator of lifespan extension that is also independent of Sir2 and Fob1, reduces rDNA origin firing in both laboratory and vineyard rDNA. Our results are consistent with the possibility that calorie restriction, similarly to the vineyard rDNA polymorphism, modulates replicative lifespan through control of rDNA origin activation, which in turn affects genome replication dynamics.

Cathodoluminescent characteristics and light technical parameters of thin-film screens based on oxides and oxysulfides of rare-earth elements

NASA Astrophysics Data System (ADS)

Bondar, Vyacheslav D.; Grytsiv, Myroslav; Groodzinsky, Arkady; Vasyliv, Mykhailo

1995-11-01

Results on creation of thin-film single-crystal high-resolution screens with energy control of luminescence color are presented. In order to create phosphor films ion-plasma technology for deposition of yttrium and lanthanum oxides and oxysulfides activated by rare earth elements has been developed. The screen consists of phosphor film on phosphor substrate with different colors of luminescence (e.g. Y2O3-Eu film with red color on Y3Al5O12- Tb, Ce substrate with green color of luminescence). Electron irradiation causes luminescence with color that depends on energy of the electron beam. The physical reason for color change is that electron beam energy defines electron penetration depth. If the energy is weak, only the film is excited. More powerful beam penetrates into the substrate and thus changes the color of luminescence.

Tunable long persistent luminescence in the second near-infrared window via crystal field control.

PubMed

Nie, Jianmin; Li, Yang; Liu, Shanshan; Chen, Qiuqun; Xu, Qi; Qiu, Jianrong

2017-09-29

Construction of an active composite as a biomarker with deeper tissue penetration and higher signal-to-noise ratio (SNR) is of great importance for the application in bioimaging. Here, we report a strategy for tuning the emission bandwidth and intensity via crystal field control in long persistent phosphors (LPPs). Ni 2+ -doped Zn 1+y Sn y Ga 2-x-2y O 4 phosphors, with a tunable emission band peaking from 1270 to 1430 nm in the second near-infrared (NIR) window, have been successfully prepared. Such featured materials have the advantages of low absorption and scattering as well as more efficient tissue penetration. The emission spectra can be controlled by tailoring the local crystal field around the activator precisely via substitution of Zn and Sn for Ga. Moreover, with high resolution and weak light disturbance, these developed multi-band afterglow phosphors exhibit great application potential in advanced optical imaging.

In vivo nanoparticle-mediated radiopharmaceutical-excited fluorescence molecular imaging

PubMed Central

Hu, Zhenhua; Qu, Yawei; Wang, Kun; Zhang, Xiaojun; Zha, Jiali; Song, Tianming; Bao, Chengpeng; Liu, Haixiao; Wang, Zhongliang; Wang, Jing; Liu, Zhongyu; Liu, Haifeng; Tian, Jie

2015-01-01

Cerenkov luminescence imaging utilizes visible photons emitted from radiopharmaceuticals to achieve in vivo optical molecular-derived signals. Since Cerenkov radiation is weak, non-optimum for tissue penetration and continuous regardless of biological interactions, it is challenging to detect this signal with a diagnostic dose. Therefore, it is challenging to achieve useful activated optical imaging for the acquisition of direct molecular information. Here we introduce a novel imaging strategy, which converts γ and Cerenkov radiation from radioisotopes into fluorescence through europium oxide nanoparticles. After a series of imaging studies, we demonstrate that this approach provides strong optical signals with high signal-to-background ratios, an ideal tissue penetration spectrum and activatable imaging ability. In comparison with present imaging techniques, it detects tumour lesions with low radioactive tracer uptake or small tumour lesions more effectively. We believe it will facilitate the development of nuclear and optical molecular imaging for new, highly sensitive imaging applications. PMID:26123615

MECOM, HBS1L-MYB, THRB-RARB, JAK2, and TERT polymorphisms defining the genetic predisposition to myeloproliferative neoplasms: A study on 939 patients.

PubMed

Trifa, Adrian P; Bănescu, Claudia; Bojan, Anca S; Voina, Cristian M; Popa, Ștefana; Vișan, Simona; Ciubean, Alina D; Tripon, Florin; Dima, Delia; Popov, Viola M; Vesa, Ștefan C; Andreescu, Mihaela; Török-Vistai, Tünde; Mihăilă, Romeo G; Berbec, Nicoleta; Macarie, Ioan; Coliţă, Andrei; Iordache, Maria; Cătană, Alina C; Farcaș, Marius F; Tomuleasa, Ciprian; Vasile, Kinga; Truică, Cristina; Todincă, Adriana; Pop-Muntean, Lavinia; Manolache, Raluca; Bumbea, Horia; Vlădăreanu, Ana-Maria; Gaman, Mihaela; Ciufu, Cristina M; Popp, Radu A

2018-01-01

Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are classical myeloproliferative neoplasms (MPN), characterized by specific somatic mutations in JAK2, CALR or MPL genes. JAK2 46/1 and TERT rs2736100 polymorphisms are known to significantly predispose to MPN. This study aimed to establish the additional contribution of the recently described MECOM rs2201862, HBS1L-MYB rs9376092 and THRB-RARB rs4858647 polymorphisms to the occurrence of MPN. These three polymorphisms, along with JAK2 46/1 and TERT rs2736100 were genotyped in 939 MPN patients (454 with ET, 337 with PV and 148 with PMF) and 483 controls. MECOM rs2201862 associated significantly with each MPN entity, except for ET, and with all major molecular sub-types, especially those CALR-mutated (OR = 1.4; 95% CI = 1.1-1.8; P-value = .005). HBS1L-MYB rs9376092 associated only with JAK2 V617F-mutated ET (OR = 1.4; 95% CI = 1.1-1.7; P-value = .003). THRB-RARB rs4858647 had a weak association with PMF only (OR = 1.5; 95% CI = 1-2.1; P-value = .04). Surprisingly, JAK2 46/1 haplotype was associated significantly not only with JAK2 V617F-mutated MPN, but also with CALR-mutated MPN (OR = 1.4; 95% CI = 1.1-1.8; P-value = .01). TERT rs2736100 was associated equally strong with all MPN, regardless of phenotype or molecular sub-type. In conclusion, JAK2 46/1, TERT rs2736100 and MECOM rs2201862 are the chief predisposing polymorphisms to MPN. © 2017 Wiley Periodicals, Inc.

8-oxo-7,8-dihydro-2'-deoxyguanosine as a biomarker of oxidative damage in oesophageal cancer patients: lack of association with antioxidant vitamins and polymorphism of hOGG1 and GST

PubMed Central

2010-01-01

Background The present report was designed to investigate the origins of elevated oxidative stress measured in cancer patients in our previous work related to a case-control study (17 cases, 43 controls) on oesophageal cancers. The aim was to characterize the relationship between the levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), antioxidant vitamins and genetic susceptibility. Methods 8-oxodG was analysed in peripheral blood mononuclear cells (PBMCs) by High Performance Liquid Chromatography with Electrochemical Detection (HPLC-ED). Analysis of gene polymorphisms in GSTM1 and GSTT1 was performed by multiplex PCR and in GSTP1 and hOGG1 by a PCR-RFLP method. Reversed-phase HPLC with UV detection at 294 nm was used to measure vitamins A and E in serum from the same blood samples. Results We observed that in our combined population (cases and control, n = 60), there was no statistically significant correlation between the levels of 8-oxodG and (i) the serum concentration of antioxidant vitamins, vitamin A (P = 0.290) or vitamin E (P = 0.813), or (ii) the incidence of the Ser326Cys polymorphic variant (P = 0.637) of the hOGG1 gene. Also, the levels of 8-oxodG were not significantly associated with polymorphisms in metabolite-detoxifying genes, such as GSTs, except for the positive correlation with Val/Val GST P1 allele (P < 0.0001). Conclusions The weakness of our cohort size notwithstanding, vitamins levels in serum and genetic polymorphisms in the hOGG1 or GST genes do not appear to be important modulators of 8-oxodG levels. PMID:21134244

Genetic polymorphism of interleukin-1A (IL-1A), IL-1B, and IL-1 receptor antagonist (IL-1RN) and prostate cancer risk.

PubMed

Xu, Hua; Ding, Qiang; Jiang, Hao-Wen

2014-01-01

We aimed to investigate the associations between polymorphisms of interleukin-1A (IL-1A), IL-1B, and IL-1 receptor antagonist (IL-1RN) and prostate cancer (PCa) risk. A comprehensive search for articles of MEDLINE and EMBASE databases and bibliographies of retrieved articles published up to August 3, 2014 was performed. Methodological quality assessment of the trials was based on a standard quality scoring system. The meta-analysis was performed using STATA 12.0. We included 9 studies (1 study for IL-1A, 5 studies for IL-1B, and 3 studies for IL-1RN), and significant association was found between polymorphisms of IL-1B-511 (rs16944) as well as IL-1B-31 (rs1143627) and PCa risk. IL-1B-511 (rs16944) polymorphism was significantly associated with PCa risk in homozygote and recessive models, as well as allele contrast (TT vs CC: OR, 0.74; 95%CI, 0.58-0.94; P=0.012; TT vs TC+CC; OR, 0.79; 95%CI, 0.63-0.98; P=0.033; T vs C: OR, 0.86; 95%CI, 0.77-0.96; P=0.008). The association between IL-1B-31 (rs1143627) polymorphism and PCa risk was weakly significant under a heterozygote model (OR, 1.35; 95%CI, 1.00-1.80; P=0.047). Sequence variants in IL-1B-511 (rs16944) and IL-1B-31 (rs1143627) are significantly associated with PCa risk, which provides additional novel evidence that proinflammatory cytokines and inflammation play an important role in the etiology of PCa.

Association analysis of clinical aspects and vitamin D receptor gene polymorphism with external apical root resorption in orthodontic patients.

PubMed

Fontana, Maria Luiza S Simas Netta; de Souza, Cleber Machado; Bernardino, José Fabio; Hoette, Felix; Hoette, Maura Levi; Thum, Lotario; Ozawa, Terumi O; Capelozza Filho, Leopoldino; Olandoski, Marcia; Trevilatto, Paula Cristina

2012-09-01

Vitamin D is responsible for the regulation of certain genes at the transcription level, via interaction with the vitamin D receptor, and influences host immune responses and aspects of bone development, growth, and homeostasis. Our aim was to investigate the association of TaqI vitamin D receptor gene polymorphism with external apical root resorption during orthodontic treatment. Our subjects were 377 patients with Class II Division 1 malocclusion, divided into 3 groups: (1) 160 with external apical root resorption ≤1.43 mm, (2) 179 with external apical root resorption >1.43 mm), and (3) 38 untreated subjects. External apical root resorption of the maxillary incisors was evaluated on periapical radiographs taken before and after 6 months of treatment. After DNA collection and purification, vitamin D receptor TaqI polymorphism analysis was performed by polymerase chain reaction-restriction fragment length polymorphism. Univariate and multivariate analyses were performed to verify the association of clinical and genetic variables with external apical root resorption (P <0.05). There was a higher proportion of external apical root resorption in orthodontically treated patients compared with the untreated subjects. In patients orthodontically treated, age higher than 14 years old, initial size of the maxillary incisor root superior to 30 mm, and premolar extraction were associated with increased external apical root resorption. Genotypes containing the C allele were weakly associated with protection against external apical root resorption (CC + CT × TT [odds ratio, 0.29; 95% confidence interval, 0.07-1.23; P = 0.091]) when treated orthodontic patients were compared to untreated individuals. Clinical factors and vitamin D receptor TaqI polymorphism were associated with external apical root resorption in orthodontic patients. Copyright © 2012 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.

Natural variation of piRNA expression affects immunity to transposable elements.

PubMed

Ryazansky, Sergei; Radion, Elizaveta; Mironova, Anastasia; Akulenko, Natalia; Abramov, Yuri; Morgunova, Valeriya; Kordyukova, Maria Y; Olovnikov, Ivan; Kalmykova, Alla

2017-04-01

In the Drosophila germline, transposable elements (TEs) are silenced by PIWI-interacting RNA (piRNA) that originate from distinct genomic regions termed piRNA clusters and are processed by PIWI-subfamily Argonaute proteins. Here, we explore the variation in the ability to restrain an alien TE in different Drosophila strains. The I-element is a retrotransposon involved in the phenomenon of I-R hybrid dysgenesis in Drosophila melanogaster. Genomes of R strains do not contain active I-elements, but harbour remnants of ancestral I-related elements. The permissivity to I-element activity of R females, called reactivity, varies considerably in natural R populations, indicating the existence of a strong natural polymorphism in defense systems targeting transposons. To reveal the nature of such polymorphisms, we compared ovarian small RNAs between R strains with low and high reactivity and show that reactivity negatively correlates with the ancestral I-element-specific piRNA content. Analysis of piRNA clusters containing remnants of I-elements shows increased expression of the piRNA precursors and enrichment by the Heterochromatin Protein 1 homolog, Rhino, in weak R strains, which is in accordance with stronger piRNA expression by these regions. To explore the nature of the differences in piRNA production, we focused on two R strains, weak and strong, and showed that the efficiency of maternal inheritance of piRNAs as well as the I-element copy number are very similar in both strains. At the same time, germline and somatic uni-strand piRNA clusters generate more piRNAs in strains with low reactivity, suggesting the relationship between the efficiency of primary piRNA production and variable response to TE invasions. The strength of adaptive genome defense is likely driven by naturally occurring polymorphisms in the rapidly evolving piRNA pathway proteins. We hypothesize that hyper-efficient piRNA production is contributing to elimination of a telomeric retrotransposon HeT-A, which we have observed in one particular transposon-resistant R strain.

Evidence for adaptation from standing genetic variation on an antimicrobial peptide gene in the mussel Mytilus edulis.

PubMed

Gosset, Célia C; Do Nascimento, Joana; Augé, Marie-Thérèse; Bierne, Nicolas

2014-06-01

Genome scans of population differentiation identify candidate loci for adaptation but provide little information on how selection has influenced the genetic structure of these loci. Following a genome scan, we investigated the nature of the selection responsible for the outlying differentiation observed between populations of the marine mussel Mytilus edulis at a leucine/arginine polymorphism (L31R) in the antimicrobial peptide MGD2. We analysed DNA sequence polymorphisms, allele frequencies and population differentiation of polymorphisms closely linked to L31R, and pairwise and third-order linkage disequilibria. An outlying level of population differentiation was observed at L31R only, while no departure from panmixia was observed at linked loci surrounding L31R, as in most of the genome. Selection therefore seems to affect L31R directly. Three hypotheses can explain the lack of differentiation in the chromosomal region close to L31R: (i) hitchhiking has occurred but migration and recombination subsequently erased the signal, (ii) selection was weak enough and recombination strong enough to limit the hitchhiking effect to a very small chromosomal region or (iii) selection acted on a pre-existing polymorphism (i.e. standing variation) at linkage equilibrium with its background. Linkage equilibrium was observed between L31R and linked polymorphisms in every population analysed, as expected under the three hypotheses. However, linkage disequilibrium was observed in some populations between pairs of loci located upstream and downstream to L31R, generating a complex pattern of third-order linkage disequilibria which is best explained by the hypothesis of selection on a pre-existing polymorphism. We hypothesise that selection could be either balanced, maintaining alleles at different frequencies depending on the pathogen community encountered locally by mussels, or intermittent, resulting in sporadic fluctuations in allele frequency. © 2014 John Wiley & Sons Ltd.

[C677T-SNP of methylenetetrahydrofolate reductase gene and breast cancer in Mexican women].

PubMed

Calderón-Garcidueñas, Ana Laura; Cerda-Flores, Ricardo Martín; Castruita-Ávila, Ana Lilia; González-Guerrero, Juan Francisco; Barrera-Saldaña, Hugo Alberto

2017-01-01

Low-penetrance susceptibility genes such as 5,10-methylenetetrahydrofolate reductase gene (MTHFR) have been considered in the progression of breast cancer (BC). Cancer is a result of genetic, environmental and epigenetic interactions; therefore, these genes should be studied in environmental context, because the results can vary between populations and even within the same country. The objective was to analyze the allelic and genotypic frequencies of the MTHFR C667T SNP in Mexican Mestizo patients with BC and controls from Northeastern Mexico. 243 patients and 118 healthy women were studied. The analysis of the polymorphism was performed with a DNA microarray. Once the frequency of the polymorphism was obtained, Hardy-Weinberg equilibrium test was carried out for the genotypes. Chi square test was used to compare the distribution of frequencies. The allele frequency in patients was: C = 0.5406; T = 0.4594 and in controls C = 0.5678, T = 0.4322. Genotype in BC patients was: C / C = 29.9%, C / T = 48.3% and T / T = 21.8. The distribution in controls was: C / C = 31.4%, C / T = 50.8%, T / T = 17.8% (chi squared 0.77, p = 0.6801). Northeastern Mexican women in this study showed no association between MTFHR C667T SNP and the risk of BC. It seems that the contribution of this polymorphism to BC in Mexico varies depending on various factors, both genetic and environmental.

Molecular and genetic epidemiology of cancer in low- and medium-income countries.

PubMed

Malhotra, Jyoti

2014-01-01

Genetic and molecular factors can play an important role in an individual's cancer susceptibility and response to carcinogen exposure. Cancer susceptibility and response to carcinogen exposure can be either through inheritance of high penetrance but rare germline mutations that constitute heritable cancer syndromes, or it can be inherited as common genetic variations or polymorphisms that are associated with low to moderate risk for development of cancer. These polymorphisms can interact with environmental exposures and can influence an individual's cancer risk through multiple pathways, including affecting the rate of metabolism of carcinogens or the immune response to these toxins. Thus, these genetic polymorphisms can account for some of the geographical differences seen in cancer prevalence between different populations. This review explores the role of molecular epidemiology in the field of cancer prevention and control in low- and medium-income countries. Using data from Human Genome Project and HapMap Project, genome-wide association studies have been able to identify multiple susceptibility loci for different cancers. The field of genetic and molecular epidemiology has been further revolutionized by the discovery of newer, faster, and more efficient DNA-sequencing technologies including next-generation sequencing. The new DNA-sequencing technologies can play an important role in planning and implementation of cancer prevention and screening strategies. More research is needed in this area, especially in investigating new biomarkers and measuring gene-environment interactions. Copyright © 2014 Icahn School of Medicine at Mount Sinai. Published by Elsevier Inc. All rights reserved.

Silent polymorphisms in the RYR1 gene do not modify the phenotype of the p.4898 I>T pathogenic mutation in central core disease: a case report

PubMed Central

2014-01-01

Background Central core disease is a congenital myopathy, characterized by presence of central core-like areas in muscle fibers. Patients have mild or moderate weakness, hypotonia and motor developmental delay. The disease is caused by mutations in the human ryanodine receptor gene (RYR1), which encodes a calcium-release channel. Since the RYR1 gene is huge, containing 106 exons, mutation screening has been limited to three ‘hot spots’, with particular attention to the C-terminal region. Recent next- generation sequencing methods are now identifying multiple numbers of variants in patients, in which interpretation and phenotype prevision is difficult. Case presentation In a Brazilian Caucasian family, clinical, histopathological and molecular analysis identified a new case of central core disease in a 48-year female. Sanger sequencing of the C-terminal region of the RYR1 gene identified two different missense mutations: c.14256 A > C polymorphism in exon 98 and c.14693 T > C in exon 102, which have already been described as pathogenic. Trans-position of the 2 mutations was confirmed because patient’s daughter, mother and sister carried only the exon 98’s mutation, a synonymous variant that was subsequently found in the frequency of 013–0,05 of alleles. Further next generation sequencing study of the whole RYR1 gene in the patient revealed the presence of additional 5 common silent polymorphisms in homozygosis and 8 polymorphisms in heterozygosis. Conclusions Considering that patient’s relatives showed no pathologic phenotype, and the phenotype presented by the patient is within the range observed in other central core disease patients with the same mutation, it was concluded that the c.14256 A > C polymorphism alone is not responsible for disease, and the associated additional silent polymorphisms are not acting as modifiers of the primary pathogenic mutation in the affected patient. The case described above illustrates the present reality where new methods for wide genome screening are becoming more accessible and able to identify a great variety of mutations and polymorphisms of unknown function in patients and their families. PMID:25084811

No evidence of correlation between p53 codon 72 polymorphism and risk of bladder or breast carcinoma in Tunisian patients.

PubMed

Mabrouk, Imed; Baccouche, Sami; El-Abed, Rym; Mokdad-Gargouri, Raja; Mosbah, Ali; Saïd, Salem; Daoud, Jamel; Frikha, Mounir; Jlidi, Rachid; Gargouri, Ali

2003-12-01

The TP53 gene, frequently mutated in human cancers, carries several polymorphisms. The one most informative and studied concerns codon 72; a single base changes the CGC (arginine) to CCC (proline). The arginine form was considered to be a significant risk factor in the development of cancer. However, various reports on this polymorphism are controversial. We carried out the same investigation in two groups of patients, a group with bladder cancer and another with breast cancer, and in healthy controls in two regions of our country, using an improved PCR-RFLP method. The number of Arg/Arg, Arg/Pro, and Pro/Pro genotypes was as follows: 21, 23, 3 and 13, 19, 2 for patients (total 47) and controls (34), respectively, in the first group; 18, 9, 3 and 19, 26, 4 for patients (30) and controls (49), respectively, in the second group. Statistical analysis of the genotype and allele frequencies did not reveal any difference between patients and controls in both groups except for a weak difference between the homozygotes to heterozygotes in the second group with a chi square of 4.1 (P = 0.045); the number of breast cancer patients is actually low (30) and should be increased in order to assess such a conclusion. Our overall results are therefore not consistent with a high risk associated with TP53 codon 72 polymorphism in breast and in bladder cancers.

RAN/RANBP2 polymorphisms and neuroblastoma risk in Chinese children: a three-center case-control study.

PubMed

Wang, Juxiang; Zhuo, Zhenjian; Chen, Min; Zhu, Jinhong; Zhao, Jie; Zhang, Jiao; Chen, Shanshan; He, Jing; Zhou, Haixia

2018-04-28

The genetic etiology of sporadic neuroblastoma remains largely obscure. RAN and RANBP2 genes encode Ras-related nuclear protein and Ran-binding protein 2, respectively. These two proteins form Ran-RanBP2 complex that regulate various cellular activities including nuclear transport. Aberrant functions of the two proteins are implicated in carcinogenesis. Given the unknown role of RAN/RANBP2 single nucleotide polymorphisms (SNPs) in neuroblastoma risk, we performed a multi-center case-control study in Chinese children to assess the association of the RAN/RANBP2 SNPs with neuroblastoma risk. We analyzed three potentially functional SNPs in RAN gene (rs56109543 C>T, rs7132224 A>G, rs14035 C>T) and one in RANBP2 (rs2462788 C>T) in 429 cases and 884 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to access the association between these four polymorphisms and neuroblastoma risk. No single variant was found to statistically significantly associate with neuroblastoma risk. However, individuals with 3 protective genotypes were less likely to develop neuroblastoma, in comparison to non-carriers (adjusted OR=0.33; 95% CI=0.12-0.96; P =0.042), as well as those with 0-2 protective genotypes (adjusted OR=0.33; 95% CI=0.11-0.94; P =0.038). Stratified analysis revealed no significant association for any of the four polymorphisms. Further studies are warranted to validate the weak impact of RAN/RANBP2 SNPs on neuroblastoma risk.

Similar Efficacies of Selection Shape Mitochondrial and Nuclear Genes in Both Drosophila melanogaster and Homo sapiens.

PubMed

Cooper, Brandon S; Burrus, Chad R; Ji, Chao; Hahn, Matthew W; Montooth, Kristi L

2015-08-21

Deleterious mutations contribute to polymorphism even when selection effectively prevents their fixation. The efficacy of selection in removing deleterious mitochondrial mutations from populations depends on the effective population size (Ne) of the mitochondrial DNA and the degree to which a lack of recombination magnifies the effects of linked selection. Using complete mitochondrial genomes from Drosophila melanogaster and nuclear data available from the same samples, we reexamine the hypothesis that nonrecombining animal mitochondrial DNA harbor an excess of deleterious polymorphisms relative to the nuclear genome. We find no evidence of recombination in the mitochondrial genome, and the much-reduced level of mitochondrial synonymous polymorphism relative to nuclear genes is consistent with a reduction in Ne. Nevertheless, we find that the neutrality index, a measure of the excess of nonsynonymous polymorphism relative to the neutral expectation, is only weakly significantly different between mitochondrial and nuclear loci. This difference is likely the result of the larger proportion of beneficial mutations in X-linked relative to autosomal loci, and we find little to no difference between mitochondrial and autosomal neutrality indices. Reanalysis of published data from Homo sapiens reveals a similar lack of a difference between the two genomes, although previous studies have suggested a strong difference in both species. Thus, despite a smaller Ne, mitochondrial loci of both flies and humans appear to experience similar efficacies of purifying selection as do loci in the recombining nuclear genome. Copyright © 2015 Cooper et al.

Functional impact of the human mobilome.

PubMed

Babatz, Timothy D; Burns, Kathleen H

2013-06-01

The human genome is replete with interspersed repetitive sequences derived from the propagation of mobile DNA elements. Three families of human retrotransposons remain active today: LINE1, Alu, and SVA elements. Since 1988, de novo insertions at previously recognized disease loci have been shown to generate highly penetrant alleles in Mendelian disorders. Only recently has the extent of germline-transmitted retrotransposon insertion polymorphism (RIP) in human populations been fully realized. Also exciting are recent studies of somatic retrotransposition in human tissues and reports of tumor-specific insertions, suggesting roles in tissue heterogeneity and tumorigenesis. Here we discuss mobile elements in human disease with an emphasis on exciting developments from the last several years. Copyright © 2013 Elsevier Ltd. All rights reserved.

The single-nucleotide polymorphisms +936 C/T VEGF and -710 C/T VEGFR1 are associated with breast cancer protection in a Spanish population.

PubMed

Rodrigues, Patricia; Furriol, Jessica; Tormo, Eduardo; Ballester, Sandra; Lluch, Ana; Eroles, Pilar

2012-06-01

Vascular endothelial growth factor (VEGF) is a potent regulator of angiogenesis and thereby involved in the development and progression of solid tumours. The association between polymorphisms of angiogenesis pathway genes and risk of breast cancer (BC) has been widely studied, but the results are not conclusive. This information is especially limited in Spanish women, so we decided to conduct a case-control study. Here, we selected four commonly studied polymorphisms in VEGF, rs3025039 (known as +936 C/T), rs1109324, rs154765 and rs833052, one polymorphism at the promoter of the VEGFR1 (-710 C/T) and another in the FGF2, rs1449683, gene to explore their association with BC susceptibility. Genotyping was performed by TaqMan SNP assays and polymerase chain reaction-restriction fragment length polymorphis (PCR-RFLP) on 453 patients and 461 controls in a population from Valencia (Spain). We observed that women carriers of +936 CT + TT VEGF genotypes have a protective effect concerning this disease (p = 0.014; OR 0.67, 95% CI 0.48-0.92) in the global group of patients. The haplotype TGAC of VEGF (rs3025039, rs1109324, rs154764 and rs833052) shows a reduction of the risk to develop BC (p = 3e-04; OR 0.48, 95% CI 0.32-0.72). Furthermore, we found that carriers of -710 CT + TT VEGFR1 genotypes have also a protective effect (p = 0.039; OR 0.55, 95% CI 0.31-0.98). When we stratified by groups of ages these associations were maintained. Our data report for the first time the association of the polymorphism -710 C/T VEGFR1 with BC. Additional experiments focused on VEGF-A, VEGFR1 and sVEGFR1 gene expression demonstrated that carriers of T allele at -710 C/T VEGFR1 genotype have higher levels of sVEGFR1/VEGF-A than the C/C genotype carriers. This was consistent with the hypothesis that this polymorphism may act as low penetrance risk factor. The data provided suggest that +936 C/T VEGF and -710 C/T VEGFR1 genotypes are likely important genetic markers of susceptibility to BC.

Nano-antibiotics in chronic lung infection therapy against Pseudomonas aeruginosa.

PubMed

Hadinoto, Kunn; Cheow, Wean Sin

2014-04-01

Antibiotic encapsulation into nanoparticle carriers has emerged as a promising inhaled antibiotic formulation for treatment of chronic Pseudomonas aeruginosa lung infection prevalent in chronic obstructive pulmonary diseases. Attributed to their prolonged lung retention, sustained antibiotic release, and mucus penetrating ability, antibiotic nanoparticles, or nano-antibiotics in short, can address the principal weakness of inhaled antibiotic solution, i.e. low antibiotic exposure in the vicinity of P. aeruginosa biofilm colonies resulting in diminished anti-pseudomonal efficacy after repeated uses. This review details the current state of development and limitations of the two most widely studied forms of nano-antibiotics, i.e. liposomes and polymer nanoparticles. Factors in their formulation that influence the anti-pseudomonal efficacy in vitro and in vivo, such as liposome's membrane rigidity, surface charge, size, and polymer hydrophobicity, are discussed. This review reveals that the superior anti-pseudomonal efficacy of liposomal antibiotics to free antibiotics has been clearly established when they are correctly formulated, with several liposomal antibiotic formulations are currently undergoing clinical trials. Liposomal antibiotics, nevertheless, are not without limitation due to their weak physicochemical stability. In contrast, only mucus penetrating ability of the more stable polymeric nano-antibiotics has been established, while their anti-pseudomonal efficacy has only been examined in vitro from which their superiority to free antibiotics has not been ascertained. Lastly, future research needs to bring liposome and polymer-based nano-antibiotics closer to their clinical realization are identified. Copyright © 2014 Elsevier B.V. All rights reserved.

Various pharmacogenetic aspects of antiepileptic drug therapy: a review.

PubMed

Mann, Michael W; Pons, Gerard

2007-01-01

Pharmacogenetics concerns the influence of an individual's genetic background on the pharmacokinetics and pharmacodynamics of xenobiotics. Much of the pharmacogenetic data in the field of epilepsy deals with the pharmacokinetics of antiepileptic drugs (AEDs). In particular, two polymorphisms of cytochrome P450 2C9 are known to slow down the metabolism of phenytoin to a degree that increases the risk of the neurotoxic adverse effects of this drug among carriers of these polymorphisms. A significant number of patients with epilepsy do not respond to AEDs and such pharmacoresistance is a major, largely unsolved, problem that is likely to be multifactorial in nature. In this regard, genetic factors may influence transmembrane drug transporter proteins, thereby modifying the intracerebral penetration of AEDs. Monogenic idiopathic epilepsies are rare and frequently associated with ion channel mutations; however, to date, a consistent relationship between changes in channel properties and clinical phenotype has not been established nor has any association between genotype and response to specific treatment options. Polymorphisms of drug targets may represent another genetic facet in epilepsy: a recent study demonstrated for the first time a polymorphism of a drug target (the alpha-subunit of a voltage-gated sodium channel) associated in clinical practice with differing response to two classic AEDs. Adverse drug reactions and teratogenicity of AEDs remain a major concern. Whole-genome single nucleotide polymorphism profiling might in the future help to determine genetic predisposing factors for adverse drug reactions. Recently, in Han Chinese treated with carbamazepine and presenting with Stevens-Johnson syndrome, a strong association was found with HLA B*1502. If genetically targeted drug development becomes more affordable/cost efficient in the near future, the development of new drugs for relatively rare diseases could become economically viable for the pharmaceutical industry. The synergy of lower trial costs and efficacy-based prescribing may reduce the cost of medical treatment for a particular disease. This hypothetical advantage of the practical use of pharmacogenetics is, however, counterbalanced by several possible dangers, including illicit data mining and the development of a human 'genetic underclass' with the risk of exclusion from, for example employment or health insurance, because of an 'unfavourable' genetic profile.

Contribution of the MLH1 -93G>a promoter polymorphism in modulating susceptibility risk in Malaysian colorectal cancer patients.

PubMed

Nizam, Zahary Mohd; Abdul Aziz, Ahmad Aizat; Kaur, Gurjeet; Abu Hassan, Muhammad Radzi; Mohd Sidek, Ahmad Shanwani; Yeh, Lee Yeong; Mazuwin, Maya; Ankathil, Ravindran

2013-01-01

Colorectal cancer (CRC) exists in a more common sporadic form and less common hereditary forms, associated with the Lynch syndrome, familial adenomatous polyposis (FAP) and other rare syndromes. Sporadic CRC is believed to arise as a result of close interaction between environmental factors, including dietary and lifestyle habits, and genetic predisposition factors. In contrast, hereditary forms such as those related to the Lynch syndrome result from inheritance of germline mutations of mismatch repair (MMR) genes. However, in certain cases, the influence of low penetrance alleles in familial colorectal cancer susceptibility is also undeniable. To investigate the genotype frequencies of MLH1 promoter polymorphism -93G>A and to determine whether it could play any role in modulating familial and sporadic CRC susceptibility risk. A case-control study comprising of 104 histopathologically confirmed CRC patients as cases (52 sporadic CRC and 52 Lynch syndrome patients) and 104 normal healthy individuals as controls was undertaken. DNA was extracted from peripheral blood and the polymorphism was genotyped employing PCR-RFLP methods. The genotypes were categorized into homozygous wild type, heterozygous and homozygous variants. The risk association between these polymorphisms and CRC susceptibility risk was calculated using binary logistic regression analysis and deriving odds ratios (ORs). When risk association was investigated for all CRC patients as a single group, the heterozygous (G/A) genotype showed a significantly higher risk for CRC susceptibility with an OR of 2.273, (95%CI: 1.133-4.558 and p-value=0.021). When analyzed specifically for the 2 types of CRC, the heterozygous (G/A) genotype showed significantly higher risk for sporadic CRC susceptibility with and OR of 3.714, (95%CI: 1.416-9.740 and p-value=0.008). Despite high OR value was observed for Lynch syndrome (OR: 1.600, 95%CI: 0.715-3.581), the risk was not statistically significant (P=0.253). Our results suggest an influence of MLH1 promoter polymorphism -93G>A in modulating susceptibility risk in Malaysian CRC patients, especially those with sporadic disease.

Colonization and infection by Helicobacter pylori in humans.

PubMed

Andersen, Leif Percival

2007-11-01

When Helicobacter pylori arrives in the human stomach, it may penetrate the mucin layer and adhere to the gastric epithelial cells or it may pass through the stomach without colonizing the mucosa. In this paper, the colonization process and the ensuing immunological response will be briefly described. Urease production is necessary for H. pylori to establish a pH-neutral microenvironment around the bacteria. The flagella enable the bacteria to move and the shape of H. pylori makes it possible to penetrate the mucin layer where it comes into contact with the gastric epithelial cells. H. pylori contains several adhesins that enable it to adhere to the epithelial cells. This adherence activates IL-8 which, together with bacterial antigens, attracts polymorphs and monocytes and causes acute gastritis. Antigen-presenting cells activate lymphocytes and other mononuclear cells that are attracted to the inflamed mucosa, causing chronic superficial gastritis and initiating a cytotoxic or an antigen-producing Th response. The infection is established within a few weeks after the primary exposure to H. pylori. After this initial colonization, many chemical, biochemical, and immunologic reactions take place that are of importance in the progress of the infection and the development of disease.

Polymorphisms in DNA double-strand break repair genes and risk of breast cancer: two population-based studies in USA and Poland, and meta-analyses.

PubMed

García-Closas, Montserrat; Egan, Kathleen M; Newcomb, Polly A; Brinton, Louise A; Titus-Ernstoff, Linda; Chanock, Stephen; Welch, Robert; Lissowska, Jolanta; Peplonska, Beata; Szeszenia-Dabrowska, Neonila; Zatonski, Witold; Bardin-Mikolajczak, Alicja; Struewing, Jeffery P

2006-05-01

The double-strand break DNA repair pathway has been implicated in breast carcinogenesis. We evaluated the association between 19 polymorphisms in seven genes in this pathway (XRCC2, XRCC3, BRCA2, ZNF350, BRIP1, XRCC4, LIG4) and breast cancer risk in two population-based studies in USA (3,368 cases and 2,880 controls) and Poland (1,995 cases and 2,296 controls). These data suggested weak associations with breast cancer risk for XRCC3 T241M and IVS7-14A>G (pooled odds ratio (95% confidence interval): 1.18 (1.04-1.34) and 0.85 (0.73-0.98) for homozygous variant vs wild-type genotypes, respectively), and for an uncommon variant in ZNF350 S472P (1.24 (1.05-1.48)), with no evidence for study heterogeneity. The remaining variants examined had no significant relationships to breast cancer risk. Meta-analyses of studies in Caucasian populations, including ours, provided some support for a weak association for homozygous variants for XRCC3 T241M (1.16 (1.04-1.30); total of 10,979 cases and 10,423 controls) and BRCA2 N372H (1.13 (1.10-1.28); total of 13,032 cases and 13,314 controls), and no support for XRCC2 R188H (1.06 (0.59-1.91); total of 8,394 cases and 8,404 controls). In conclusion, the genetic variants evaluated are unlikely to have a substantial overall association with breast cancer risk; however, weak associations are possible for XRCC3 (T241M and IVS7-14A>G), BRCA2 N372H, and ZNF350 S472P. Evaluation of potential underlying gene-gene interactions or associations in population subgroups will require even larger sample sizes.

Rapid Water Transport through Organic Layers on Ice.

PubMed

Kong, Xiangrui; Toubin, Céline; Habartova, Alena; Pluharova, Eva; Roeselova, Martina; Pettersson, Jan B C

2018-05-31

Processes involving atmospheric aerosol and cloud particles are affected by condensation of organic compounds that are omnipresent in the atmosphere. On ice particles, organic compounds with hydrophilic functional groups form hydrogen bonds with the ice and orient their hydrophobic groups away from the surface. The organic layer has been expected to constitute a barrier to gas uptake, but recent experimental studies suggest that the accommodation of water molecules on ice is only weakly affected by condensed short-chain alcohol layers. Here, we employ molecular dynamics simulations to study the water interactions with n-butanol covered ice at 200 K and show that the small effect of the condensed layer is due to efficient diffusion of water molecules along the surface plane while seeking appropriate sites to penetrate, followed by penetration driven by the combined attractive forces from butanol OH groups and water molecules within the ice. The water molecules that penetrate through the n-butanol layer become strongly bonded by approximately three hydrogen bonds at the butanol-ice interface. The obtained accommodation coefficient (0.81 ± 0.03) is in excellent agreement with results from previous environmental molecular beam experiments, leading to a picture where an adsorbed n-butanol layer does not alter the apparent accommodation coefficient but dramatically changes the detailed molecular dynamics and kinetics.

Early Earth slab stagnation

NASA Astrophysics Data System (ADS)

Agrusta, R.; Van Hunen, J.

2016-12-01

At present day, the Earth's mantle exhibits a combination of stagnant and penetrating slabs within the transition zone, indicating a intermittent convection mode between layered and whole-mantle convection. Isoviscous thermal convection calculations show that in a hotter Earth, the natural mode of convection was dominated by double-layered convection, which may imply that slabs were more prone to stagnate in the transition zone. Today, slab penetration is to a large extent controlled by trench mobility for a plausible range of lower mantle viscosity and Clapeyron slope of the mantle phase transitions. Trench mobility is, in turn, governed by slab strength and density and upper plate forcing. In this study, we systematically investigate the slab-transition zone internation in the Early Earth, using 2D self-consistent numerical subduction models. Early Earth's higher mantle temperature facilitates decoupling between the plates and the underlying asthenosphere, and may result in slab sinking almost without trench retreat. Such behaviour together with a low resistance of a weak lower mantle may allow slabs to penetrate. The ability of slab to sink into the lower mantle throughout Earth's history may have important implications for Earth's evolution: it would provide efficient mass and heat flux through the transition zone therefore provide an efficient way to cool and mix the Earth's mantle.

Design strategy of pH-sensitive triblock copolymer micelles for efficient cellular uptake by computer simulations

NASA Astrophysics Data System (ADS)

Xia, Qiang-sheng; Ding, Hong-ming; Ma, Yu-qiang

2018-03-01

Efficient delivery of nanoparticles into specific cell interiors is of great importance in biomedicine. Recently, the pH-responsive micelle has emerged as one potential nanocarrier to realize such purpose since there exist obvious pH differences between normal tissues and tumors. Herein, by using dissipative particle dynamics simulation, we investigate the interaction of the pH-sensitive triblock copolymer micelles composed of ligand (L), hydrophobic block (C) and polyelectrolyte block (P) with cell membrane. It is found that the structure rearrangement of the micelle can facilitate its penetration into the lower leaflet of the bilayer. However, when the ligand-receptor specific interaction is weak, the micelles may just fuse with the upper leaflet of the bilayer. Moreover, the ionization degree of polyelectrolyte block and the length of hydrophobic block also play a vital role in the penetration efficiency. Further, when the sequence of the L, P, C beads in the copolymers is changed, the translocation pathways of the micelles may change from direct penetration to Janus engulfment. The present study reveals the relationship between the molecular structure of the copolymer and the uptake of the pH-sensitive micelles, which may give some significant insights into the experimental design of responsive micellar nanocarriers for highly efficient cellular delivery.

Impact of Satellite Remote Sensing Data on Simulations of ...

EPA Pesticide Factsheets

We estimated surface salinity flux and solar penetration from satellite data, and performed model simulations to examine the impact of including the satellite estimates on temperature, salinity, and dissolved oxygen distributions on the Louisiana continental shelf (LCS) near the annual hypoxic zone. Rainfall data from the Tropical Rainfall Measurement Mission (TRMM) were used for the salinity flux, and the diffuse attenuation coefficient (Kd) from Moderate Resolution Imaging Spectroradiometer (MODIS) were used for solar penetration. Improvements in the model results in comparison with in situ observations occurred when the two types of satellite data were included. Without inclusion of the satellite-derived surface salinity flux, realistic monthly variability in the model salinity fields was observed, but important inter-annual variability wasmissed. Without inclusion of the satellite-derived light attenuation, model bottom water temperatures were too high nearshore due to excessive penetration of solar irradiance. In general, these salinity and temperature errors led to model stratification that was too weak, and the model failed to capture observed spatial and temporal variability in water-column vertical stratification. Inclusion of the satellite data improved temperature and salinity predictions and the vertical stratification was strengthened, which improved prediction of bottom-water dissolved oxygen. The model-predicted area of bottom-water hypoxia on the

Methods, strengths, weaknesses, and limitations of bioequivalence tests with special regard to immunosuppressive drugs.

PubMed

van Gelder, Teun; Gabardi, Steven

2013-08-01

Within the field of solid organ transplantation, the patents for a number of immunosuppressive drugs have expired in the last few years. Tacrolimus, cyclosporine, and mycophenolate mofetil are now available as generic drugs. In some countries, the market penetration of these generic formulations is as high as 70%, whereas in some other countries, this figure is below 10%. Several professional societies have published position papers on the risks and benefits of generic substitution of immunosuppressive drugs. It often appears that transplant professionals are not fully aware of the requirements for registration of generic drugs. This article describes the registration requirements with a focus on bioequivalence testing, the strengths and weaknesses in this process, and the differences between Europe and the US. © 2013 The Authors Transplant International © 2013 European Society for Organ Transplantation. Published by Blackwell Publishing Ltd.

An efficient ionoluminescence analysis of turquoise gemstone as a weakly luminescent mineral.

PubMed

Nikbakht, T; Kakuee, O; Lamehi-Rachti, M

2017-05-15

The unique ionization pattern of MeV-energy ion beam is applied for efficient luminescence analysis of a collection of natural turquoise samples. The considerable penetration depth of tens of micrometer and enhancement of energy deposition with depth, suggests ionoluminescence as an appropriate technique for studying weakly luminescent minerals. Herein, the luminescence induced in deeper parts of turquoise samples is extracted through their relatively transparent adjacent host stones. The resulting intense spectra reveal the vibrational structure of the broad green luminescence band of turquoise which probably originates from O 2 - centers. Moreover, owing to the applied ionoluminescence approach, red and blue luminescence bands of turquoise were observed which can be ascribed to Fe 3+ ions and UO 2 2+ centers respectively. The elemental information of the samples is provided using micro-PIXE analysis technique. Copyright © 2017 Elsevier B.V. All rights reserved.

Coded Excitation Plane Wave Imaging for Shear Wave Motion Detection

PubMed Central

Song, Pengfei; Urban, Matthew W.; Manduca, Armando; Greenleaf, James F.; Chen, Shigao

2015-01-01

Plane wave imaging has greatly advanced the field of shear wave elastography thanks to its ultrafast imaging frame rate and the large field-of-view (FOV). However, plane wave imaging also has decreased penetration due to lack of transmit focusing, which makes it challenging to use plane waves for shear wave detection in deep tissues and in obese patients. This study investigated the feasibility of implementing coded excitation in plane wave imaging for shear wave detection, with the hypothesis that coded ultrasound signals can provide superior detection penetration and shear wave signal-to-noise-ratio (SNR) compared to conventional ultrasound signals. Both phase encoding (Barker code) and frequency encoding (chirp code) methods were studied. A first phantom experiment showed an approximate penetration gain of 2-4 cm for the coded pulses. Two subsequent phantom studies showed that all coded pulses outperformed the conventional short imaging pulse by providing superior sensitivity to small motion and robustness to weak ultrasound signals. Finally, an in vivo liver case study on an obese subject (Body Mass Index = 40) demonstrated the feasibility of using the proposed method for in vivo applications, and showed that all coded pulses could provide higher SNR shear wave signals than the conventional short pulse. These findings indicate that by using coded excitation shear wave detection, one can benefit from the ultrafast imaging frame rate and large FOV provided by plane wave imaging while preserving good penetration and shear wave signal quality, which is essential for obtaining robust shear elasticity measurements of tissue. PMID:26168181

Common breast cancer risk variants in the post-COGS era: a comprehensive review.

PubMed

Maxwell, Kara N; Nathanson, Katherine L

2013-12-20

Breast cancer has a strong heritable component, with approximately 15% of cases exhibiting a family history of the disease. Mutations in genes such as BRCA1, BRCA2 and TP53 lead to autosomal dominant inherited cancer susceptibility and confer a high lifetime risk of breast cancers. Identification of mutations in these genes through clinical genetic testing enables patients to undergo screening and prevention strategies, some of which provide overall survival benefit. In addition, a number of mutant alleles have been identified in genes such as CHEK2, PALB2, ATM and BRIP1, which often display incomplete penetrance and confer moderate lifetime risks of breast cancer. Studies are underway to determine how to use the identification of mutations in these genes to guide clinical practice. Altogether, however, mutations in high and moderate penetrance genes probably account for approximately 25% of familial breast cancer risk; the remainder may be due to mutations in as yet unidentified genes or lower penetrance variants. Common low penetrance alleles, which have been mainly identified through genome-wide association studies (GWAS), are generally present at 10 to 50% population frequencies and confer less than 1.5-fold increases in breast cancer risk. A number of single nucleotide polymorphisms (SNPs) have been identified and risk associations extensively replicated in populations of European ancestry, the number of which has substantially increased as a result of GWAS performed by the Collaborative Oncological Gene-environment Study consortium. It is now estimated that 28% of familial breast cancer risk is explained by common breast cancer susceptibility loci. In some cases, SNP associations may be specific to different subsets of women with breast cancer, as defined by ethnicity or estrogen receptor status. Although not yet clinically established, it is hoped that identification of common risk variants may eventually allow identification of women at higher risk of breast cancer and enable implementation of breast cancer screening, prevention or treatment strategies that provide clinical benefit.

Common breast cancer risk variants in the post-COGS era: a comprehensive review

PubMed Central

2013-01-01

Breast cancer has a strong heritable component, with approximately 15% of cases exhibiting a family history of the disease. Mutations in genes such as BRCA1, BRCA2 and TP53 lead to autosomal dominant inherited cancer susceptibility and confer a high lifetime risk of breast cancers. Identification of mutations in these genes through clinical genetic testing enables patients to undergo screening and prevention strategies, some of which provide overall survival benefit. In addition, a number of mutant alleles have been identified in genes such as CHEK2, PALB2, ATM and BRIP1, which often display incomplete penetrance and confer moderate lifetime risks of breast cancer. Studies are underway to determine how to use the identification of mutations in these genes to guide clinical practice. Altogether, however, mutations in high and moderate penetrance genes probably account for approximately 25% of familial breast cancer risk; the remainder may be due to mutations in as yet unidentified genes or lower penetrance variants. Common low penetrance alleles, which have been mainly identified through genome-wide association studies (GWAS), are generally present at 10 to 50% population frequencies and confer less than 1.5-fold increases in breast cancer risk. A number of single nucleotide polymorphisms (SNPs) have been identified and risk associations extensively replicated in populations of European ancestry, the number of which has substantially increased as a result of GWAS performed by the Collaborative Oncological Gene–environment Study consortium. It is now estimated that 28% of familial breast cancer risk is explained by common breast cancer susceptibility loci. In some cases, SNP associations may be specific to different subsets of women with breast cancer, as defined by ethnicity or estrogen receptor status. Although not yet clinically established, it is hoped that identification of common risk variants may eventually allow identification of women at higher risk of breast cancer and enable implementation of breast cancer screening, prevention or treatment strategies that provide clinical benefit. PMID:24359602

Common non-synonymous polymorphisms in the BRCA1 Associated RING Domain (BARD1) gene are associated with breast cancer susceptibility: a case-control analysis.

PubMed

Huo, Xiang; Hu, Zhibin; Zhai, Xiangjun; Wang, Yan; Wang, Shui; Wang, Xuechen; Qin, Jianwei; Chen, Wenseng; Jin, Guangfu; Liu, Jiyong; Gao, Jun; Wei, Qingyi; Wang, Xinru; Shen, Hongbing

2007-05-01

The BRCA1 Associated RING Domain (BARD1) gene has been identified as a high penetrance gene for breast cancer, whose germline and somatic mutations were reported in both non-BRCA1/2 hereditary site-specific and sporadic breast cancer cases. BARD1 plays a crucial role in tumor repression, along with its heterodimeric partner BRCA1. In the current study, we tested the hypothesis that common non-synonymous polymorphisms in BARD1 are associated with breast cancer susceptibility in a case-control study of 507 patients with incident breast cancer and 539 frequency-matched cancer-free controls in Chinese women. We genotyped all three common (minor allele frequency (MAF)>0.10) non-synonymous polymorphisms (Pro24Ser, Arg378Ser, and Val507Met) in BARD1. We found that the BARD1 Pro24Ser variant genotypes (24Pro/Ser and 24Ser/Ser) and Arg378Ser variant homozygote 378Ser/Ser were associated with a significantly decreased breast cancer risk, compared with their wild-type homozygotes, respectively. Furthermore, a significant locus-locus interaction was evident between Pro24Ser and Arg378Ser (P(int )= 0.032). Among the 378Ser variant allele carriers, the 24Pro/Pro wild-type homozygote was associated with a significantly increased breast cancer risk (adjusted OR=1.81, 95% CI=1.11-2.95), but the subjects having 24Pro/Ser or Ser/Ser variant genotypes had a significantly decreased risk (adjusted OR=0.74, 95% CI=0.56-0.99). In stratified analysis, this locus-locus interaction was more evident among subjects without family cancer history, those with positive estrogen receptor (ER) and individuals with negative progesterone receptor (PR). These findings indicate that the potentially functional polymorphisms Pro24Ser and Arg378Ser in BARD1 may jointly contribute to the susceptibility of breast cancer.

Clines in quantitative traits: The role of migration patterns and selection scenarios

PubMed Central

Geroldinger, Ludwig; Bürger, Reinhard

2015-01-01

The existence, uniqueness, and shape of clines in a quantitative trait under selection toward a spatially varying optimum is studied. The focus is on deterministic diploid two-locus n-deme models subject to various migration patterns and selection scenarios. Migration patterns may exhibit isolation by distance, as in the stepping-stone model, or random dispersal, as in the island model. The phenotypic optimum may change abruptly in a single environmental step, more gradually, or not at all. Symmetry assumptions are imposed on phenotypic optima and migration rates. We study clines in the mean, variance, and linkage disequilibrium (LD). Clines result from polymorphic equilibria. The possible equilibrium configurations are determined as functions of the migration rate. Whereas for weak migration, many polymorphic equilibria may be simultaneously stable, their number decreases with increasing migration rate. Also for intermediate migration rates polymorphic equilibria are in general not unique, however, for loci of equal effects the corresponding clines in the mean, variance, and LD are unique. For sufficiently strong migration, no polymorphism is maintained. Both migration pattern and selection scenario exert strong influence on the existence and shape of clines. The results for discrete demes are compared with those from models in which space varies continuously and dispersal is modeled by diffusion. Comparisons with previous studies, which investigated clines under neutrality or under linkage equilibrium, are performed. If there is no long-distance migration, the environment does not change abruptly, and linkage is not very tight, populations are almost everywhere close to linkage equilibrium. PMID:25446959

CCTTT pentanucleotide repeats in inducible nitric oxide synthase gene expression in patients with pulmonary arterial hypertension.

PubMed

Baloira Villar, Adolfo; Pousada Fernández, Guillermo; Vilariño Pombo, Carlos; Núñez Fernández, Marta; Cifrián Martínez, Jose; Valverde Pérez, Diana

2014-04-01

One of the pathways involved in pulmonary arterial hypertension (PAH) is the nitric oxide (NO) pathway. A polymorphism in the inducible NO synthase (NOS2) gene has been described, consisting of the CCTTT pentanucleotide repeat, which causes a reduction in NO production. The aim of this study was to determine if this polymorphism increases susceptibility to developing PAH. Sixty four patients with a diagnosis of PAH groupsi and iv and 50 healthy controls were compared. DNA genotyping of the samples for this polymorphism was performed using PCR. The distribution between both groups was compared and correlated with clinical and haemodynamic parameters and therapeutic response. A significantly different distribution was observed in the number of repeats between patients and controls (P<.0001). When the samples were categorised by short forms (both alleles with less than 12repeats) and long forms (≥12 repeats), it was observed that the former had an almost 4-fold risk of developing PAH (odds ratio: 3.83; 95%CI: 1.19-12.32, P=.024). There were no differences between the most common types of PAH, either in therapeutic response or survival. There was no correlation between haemodynamic parameters and the number of repeats in the patients, and only a weak correlation with systolic PAH. There are significant differences in the distribution of the NOS2 promotor CCTTT polymorphism between patients with PAH and the healthy population. A minor CCTTT pentanucleotide repeat in the NOS2 gene may increase the risk of developing PAH. Copyright © 2012 SEPAR. Published by Elsevier Espana. All rights reserved.

Density Functional Approach to Superfluid Phonon in Inner Crust of Neutron Stars

NASA Astrophysics Data System (ADS)

Inakura, Tsunenori; Matsuo, Masayuki

We investigate superfluid phonon emerging in inner crust of neutron stars by means of the nuclear density functional theory. Adopting the Wigner-Seitz approximation and a single spherical cell, we describe low-lying collective excitation with the dipole multipolarity. It is found that the superfluid phonon standing on the low-density neutron superfluid does not penetrate into the interior of the nuclear cluster. This suggests that the coupling between the superfluid phonon and the lattice phonon could be weak, and it may affect the thermal conductivity of inner crust.

Properties of the superconducting state in a two-band model

NASA Astrophysics Data System (ADS)

Nicol, E. J.; Carbotte, J. P.

2005-02-01

Eliashberg theory is used to investigate the range of thermodynamic properties possible within a two-band model for s -wave superconductivity and to identify signatures of its two-band nature. We emphasize dimensionless BCS ratios [those for the energy gaps, the specific heat jump, and the negative of its slope near Tc , the thermodynamic critical field Hc(0) , and the normalized slopes of the critical field and the penetration depth near Tc ], which are no longer universal even in weak coupling. We also give results for temperature-dependent quantities, such as the penetration depth and the energy gap. Results are presented both for microscopic parameters appropriate to MgB2 and for variations away from these. Strong coupling corrections are identified and found to be significant. Analytic formulas are provided that show the role played by the anisotropy in coupling in some special limits. Particular emphasis is placed on small interband coupling and on the opposite limit of no diagonal coupling. The effect of impurity scattering is considered, particularly for the interband case.

Penetration of magnetosonic waves into the plasmasphere observed by the Van Allen Probes

DOE PAGES

Xiao, Fuliang; Zhou, Qinghua; He, Yihua; ...

2015-09-11

During the small storm on 14–15 April 2014, Van Allen Probe A measured a continuously distinct proton ring distribution and enhanced magnetosonic (MS) waves along its orbit outside the plasmapause. Inside the plasmasphere, strong MS waves were still present but the distinct proton ring distribution was falling steeply with distance. We adopt a sum of subtracted bi-Maxwellian components to model the observed proton ring distribution and simulate the wave trajectory and growth. MS waves at first propagate toward lower L shells outside the plasmasphere, with rapidly increasing path gains related to the continuous proton ring distribution. The waves then graduallymore » cross the plasmapause into the deep plasmasphere, with almost unchanged path gains due to the falling proton ring distribution and higher ambient density. These results present the first report on how MS waves penetrate into the plasmasphere with the aid of the continuous proton ring distributions during weak geomagnetic activities.« less

[Analysis on the mechanism of acupuncture infrasound energy in treatment of diseases].

PubMed

Wang, Xi-ming

2009-03-01

Infrasound is a sound wave with vibration frequency of less than 20 Hz, characterized by a longer wavelength, weak attenuating and strong penetration power, etc. Since the inherent frequencies of the human body and the organs are within infrasound vibration range, so infrasound has a stronger effect on the human body. The study found that the process of acupuncture at acupoints could be regarded as one containing a forced vibration with damping, and in the acupuncture, a infrasound of 2-15 Hz could be produced, which can easily has a resonance with the human body and the organs. By calculation of the sound pressure and sound strength in acupuncture, it was found that acupuncture infrasound had four characteristics: small total energy, small amplitude, strong voice, and orientation spreading along the meridian line. Because the meridian lines are the good pathway to spread low-frequency sound, acupuncture infrasound energy can successfully pass the meridian lines to reach the focus, penetrate the morbid tissues and improve the functions of tissues or organs.

DNA Three-Way Junction for Differentiation of Single-Nucleotide Polymorphisms with Fluorescent Copper Nanoparticles.

PubMed

Sun, Feifei; You, Ying; Liu, Jie; Song, Quanwei; Shen, Xiaotong; Na, Na; Ouyang, Jin

2017-05-23

A label- and enzyme-free fluorescent sensor for the detection of single-nucleotide polymorphisms (SNPs) at room temperature is proposed, using new copper nanoparticles (CuNPs) as fluorescent reporters. The CuNPs were constructed by using a DNA three-way junction (3WJ) template. In this assay, two complementary adenine/thymine-rich probes can hybridize with the wild-type target simultaneously to construct a 3WJ structure, serving as an efficient scaffold for the generation of CuNPs. However, the CuNPs produce weak fluorescence when the probes bind with a mutant-type target. SNPs can be identified by the difference in fluorescence intensity of the CuNPs. This SNPs detection strategy is straightforward, cost-effective, and avoids the complicated procedures of labeling or enzymatic reactions. The fluorescent sensor is versatile and can be applied to all types of mutation because the probes are programmable. Moreover, the sensor exhibits good detection performance in biological samples. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Single nucleotide polymorphisms of DNA repair genes as predictors of radioresponse.

PubMed

Parliament, Matthew B; Murray, David

2010-10-01

Radiation therapy is a key modality in the treatment of cancer. Substantial progress has been made in unraveling the molecular events which underpin the responses of malignant and surrounding normal tissues to ionizing radiation. An understanding of the genes involved in processes such as DNA double-strand break repair, DNA damage response, cell-cycle control, apoptosis, cellular antioxidant defenses, and cytokine production, has evolved toward examination of how genetic variants, most often, single nucleotide polymorphisms (SNPs), may influence interindividual radioresponse. Experimental approaches, such as candidate SNP-association studies, genome-wide association studies, and massively parallel sequencing are being proposed to address these questions. We present a focused review of the evidence supporting an association between SNPs in DNA repair genes and radioresponse in normal tissues and tumors. Although preliminary results indicate possible associations, there are methodological weaknesses in many of the studies, and independent validation of SNPs as biomarkers of radioresponse in much larger cohorts will likely require research cooperation through international consortia. Copyright © 2010 Elsevier Inc. All rights reserved.

Search for a schizophrenia susceptibility locus of human chromosome 22

DOE Office of Scientific and Technical Information (OSTI.GOV)

Coon, H.; Hoff, M.; Holik, J.

1994-06-15

We used 10 highly informative DNA polymorphic markers and genetic linkage analysis to examine whether a gene locus predisposing to schizophrenia is located on chromosome 22, in 105 families with schizophrenia and schizoaffective disorder. The LOD score method, including analysis for heterogeneity, provided no conclusive evidence of linkage under a dominant, recessive, or penetrance free model of inheritance. Affected sib-pair analysis was inconclusive. Affected Pedigree Member (APM) analysis gave only suggestive evidence for linkage. Multipoint APM analysis, using 4 adjacent loci including D22S281 and IL2RB, a region of interest from the APM analysis, gave non-significant results for the three differentmore » weighting functions. 18 refs., 1 fig., 7 tabs.« less

Altools: a user friendly NGS data analyser.

PubMed

Camiolo, Salvatore; Sablok, Gaurav; Porceddu, Andrea

2016-02-17

Genotyping by re-sequencing has become a standard approach to estimate single nucleotide polymorphism (SNP) diversity, haplotype structure and the biodiversity and has been defined as an efficient approach to address geographical population genomics of several model species. To access core SNPs and insertion/deletion polymorphisms (indels), and to infer the phyletic patterns of speciation, most such approaches map short reads to the reference genome. Variant calling is important to establish patterns of genome-wide association studies (GWAS) for quantitative trait loci (QTLs), and to determine the population and haplotype structure based on SNPs, thus allowing content-dependent trait and evolutionary analysis. Several tools have been developed to investigate such polymorphisms as well as more complex genomic rearrangements such as copy number variations, presence/absence variations and large deletions. The programs available for this purpose have different strengths (e.g. accuracy, sensitivity and specificity) and weaknesses (e.g. low computation speed, complex installation procedure and absence of a user-friendly interface). Here we introduce Altools, a software package that is easy to install and use, which allows the precise detection of polymorphisms and structural variations. Altools uses the BWA/SAMtools/VarScan pipeline to call SNPs and indels, and the dnaCopy algorithm to achieve genome segmentation according to local coverage differences in order to identify copy number variations. It also uses insert size information from the alignment of paired-end reads and detects potential large deletions. A double mapping approach (BWA/BLASTn) identifies precise breakpoints while ensuring rapid elaboration. Finally, Altools implements several processes that yield deeper insight into the genes affected by the detected polymorphisms. Altools was used to analyse both simulated and real next-generation sequencing (NGS) data and performed satisfactorily in terms of positive predictive values, sensitivity, the identification of large deletion breakpoints and copy number detection. Altools is fast, reliable and easy to use for the mining of NGS data. The software package also attempts to link identified polymorphisms and structural variants to their biological functions thus providing more valuable information than similar tools.

The algorithm for Alzheimer risk assessment based on APOE promoter polymorphisms.

PubMed

Limon-Sztencel, Anna; Lipska-Ziętkiewicz, Beata S; Chmara, Magdalena; Wasag, Bartosz; Bidzan, Leszek; Godlewska, Beata R; Limon, Janusz

2016-05-19

Over the past two decades, the APOE gene and its polymorphisms have been among the most studied risk factors of Alzheimer disease (AD) development; yet, there are discrepancies between various studies regarding their impact. For this reason, the evaluation of the APOE genotype has not been included in the current European Federation of Neurological Societies guidelines for AD diagnosis and management. This aim of this study was to add to this discussion by assessing the possible influence of multiple polymorphisms in the promoter region of the APOE gene and genotypes of its allele E on the risk for dementia. We performed a comprehensive analysis of APOE gene polymorphisms, assessed the detected genotypes and correlated molecular findings with serum apolipoprotein E concentrations. The study comprised 110 patients with AD and 110 age-matched healthy individuals from the Polish population. Four polymorphisms of the APOE gene had minor allele frequency exceeding 5% and were included in the analysis: -491A/T (rs449647), -427T/C (rs769446), -219T/G (rs405509) in the promoter region and +113G/C (rs440446) in intron 1. A protective effect of the -219G allele on AD development was observed. Also, the -491T and -219G alleles were found to be underrepresented in the carriers of the APOE E4 variant. On the basis of the genotype and linkage disequilibrium studies, a relative score was attributed to given genotypes with respect to the estimated probability of their protective effects against AD, giving rise to the 'preventive score'. This 'preventive score', based on the total sums of the relative scores, expresses the protective effect deriving from the synergistic action of individual single-nucleotide polymorphisms. The 'preventive score' was identified as an independent predictive factor. We propose a novel, more complex approach to AD risk assessment based on the additive effect of multiple polymorphic loci within the APOE promoter region, which on their own may have too weak an impact to reach the level of significance. This has potentially practical implications, as it may help to improve the informative potential of APOE testing in a clinical setting. Subsequent studies of the proposed system in large, multi-ethnic cohorts are necessary for its validation and to assess its potential practical value for clinical applications.

Association Study between Coronary Artery Disease and rs1333049 and rs10757274 Polymorphisms at 9p21 Locus in South-West Iran

PubMed Central

Foroughmand, Ali Mohammad; Nikkhah, Emad; Galehdari, Hamid; Jadbabaee, Mohammad Hossin

2015-01-01

Objective Coronary artery disease (CAD) is a multi-factorial and heterogenic disease with atherosclerosis plaques formation in internal wall of coronary artery. Plaque formation results to limitation of the blood reaching to myocardium leading to appearance of some problems, such as ischemia, sudden thrombosis veins and myocardial infarction (MI). Several environmental and genetic factors are involved in prevalence and incident of CAD as follows: hypertension, high low density lipoprotein-cholesterol (LDL-C), age, diabetes mellitus, family history of early-onset heart disease and smoking. According to genome wide association studies (GWAS), five polymorphisms in the 9p21 locus seem to be associated with the CAD. We aimed to evaluate the remarkable association of two polymorphisms at 9p21 locus, rs1333049 and rs10757274, with CAD. Materials and Methods This experimental study was conducted in Golestan, Aria Hospitals and Genetics Lab of Shahid Chamran University in the city of Ahvaz, Iran, in 2010- 2011. The collected blood samples belonging to 170 CAD patients (case group) and 100 healthy individuals (control group) were analyzed by tetra-primer amplification refractory mutation system (ARMS)-polymerase chain reaction (PCR) technique. The results were analyzed using software package used for statistical analysis (SPSS; SPSS Inc., USA) version 16. A value of p<0.05 and an odd ratio (OR) with 95% confidence intervals (CI) were considered significant. Results The frequencies of CC, CG and GG genotypes for rs1333049 polymorphism in patients were 18.2, 65.3 and 16.5%, while in controls, the related values were 25, 67 and 8%, respectively. GG genotypes of rs1333049 polymorphism in CAD patients were more than control cases (OR: 0.354, 95%CI: 0.138-0.912, p=0.032). The frequencies of AA, AG and GG genotypes for rs10757274 in CAD patients were 8.2, 58.3 and 33.5%, while in controls, the related values were 35, 63 and 2%, respectively. GG Genotype in rs10757274 polymorphism in CAD patients was found more than control cases (OR: 0.014, 95% CI: 0.003 -0.065, p=0.0001). Conclusion The rs1333049 polymorphism at 9p21 locus shows a weak association with CAD, whereas rs10757274 polymorphism reveals a significant association with CAD. These variants may help the identification of patients with increased risk for coronary artery disease. PMID:25870838

A Case Study of Wind-PV-Thermal-Bundled AC/DC Power Transmission from a Weak AC Network

NASA Astrophysics Data System (ADS)

Xiao, H. W.; Du, W. J.; Wang, H. F.; Song, Y. T.; Wang, Q.; Ding, J.; Chen, D. Z.; Wei, W.

2017-05-01

Wind power generation and photovoltaic (PV) power generation bundled with the support by conventional thermal generation enables the generation controllable and more suitable for being sent over to remote load centre which are beneficial for the stability of weak sending end systems. Meanwhile, HVDC for long-distance power transmission is of many significant technique advantages. Hence the effects of wind-PV-thermal-bundled power transmission by AC/DC on power system have become an actively pursued research subject recently. Firstly, this paper introduces the technical merits and difficulties of wind-photovoltaic-thermal bundled power transmission by AC/DC systems in terms of meeting the requirement of large-scale renewable power transmission. Secondly, a system model which contains a weak wind-PV-thermal-bundled sending end system and a receiving end system in together with a parallel AC/DC interconnection transmission system is established. Finally, the significant impacts of several factors which includes the power transmission ratio between the DC and AC line, the distance between the sending end system and receiving end system, the penetration rate of wind power and the sending end system structure on system stability are studied.

Application of lap laser welding technology on stainless steel railway vehicles

NASA Astrophysics Data System (ADS)

Wang, Hongxiao; Wang, Chunsheng; He, Guangzhong; Li, Wei; Liu, Liguo

2016-10-01

Stainless steel railway vehicles with so many advantages, such as lightweight, antirust, low cost of maintenance and simple manufacturing process, so the production of high level stainless steel railway vehicles has become the development strategy of European, American and other developed nations. The current stainless steel railway vehicles body and structure are usually assembled by resistance spot welding process. The weak points of this process are the poor surface quality and bad airtight due to the pressure of electrodes. In this study, the partial penetration lap laser welding process was investigated to resolve the problems, by controlling the laser to stop at the second plate in the appropriate penetration. The lap laser welding joint of stainless steel railway vehicle car body with partial penetration has higher strength and surface quality than those of resistance spot welding joint. The biggest problem of lap laser welding technology is to find the balance of the strength and surface quality with different penetrations. The mechanism of overlap laser welding of stainless steel, mechanical tests, microstructure analysis, the optimization of welding parameters, analysis of fatigue performance, the design of laser welding stainless steel railway vehicles structure and the development of non-destructive testing technology were systematically studied before lap laser welding process to be applied in manufacture of railway vehicles. The results of the experiments and study show that high-quality surface state and higher fatigue strength can be achieved by the partial penetration overlap laser welding of the side panel structure, and the structure strength of the car body can be higher than the requirements of En12663, the standard of structural requirements of railway vehicles bodies. Our company has produced the stainless steel subway and high way railway vehicles by using overlap laser welding technology. The application of lap laser welding will be a big change of railway vehicles manufacturing technology.

Amyloid structure exhibits polymorphism on multiple length scales in human brain tissue

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Jiliang; Costantino, Isabel; Venugopalan, Nagarajan

Although aggregation of Aβ amyloid fibrils into plaques in the brain is a hallmark of Alzheimer's Disease (AD), the correlation between amyloid burden and severity of symptoms is weak. One possible reason is that amyloid fibrils are structurally polymorphic and different polymorphs may contribute differentially to disease. However, the occurrence and distribution of amyloid polymorphisms in human brain is poorly documented. Here we seek to fill this knowledge gap by using X-ray microdiffraction of histological sections of human tissue to map the abundance, orientation and structural heterogeneities of amyloid within individual plaques; among proximal plaques and in subjects with distinctmore » clinical histories. A 5 µ x-ray beam was used to generate diffraction data with each pattern arising from a scattering volume of only ~ 450 µ3 , making possible collection of dozens to hundreds of diffraction patterns from a single amyloid plaque. X-ray scattering from these samples exhibited all the properties expected for scattering from amyloid. Amyloid distribution was mapped using the intensity of its signature 4.7 Å reflection which also provided information on the orientation of amyloid fibrils across plaques. Margins of plaques exhibited a greater degree of orientation than cores and orientation around blood vessels frequently appeared tangential. Variation in the structure of Aβ fibrils is reflected in the shape of the 4.7 Å peak which usually appears as a doublet. Variations in this peak correspond to differences between the structure of amyloid within cores of plaques and at their periphery. Examination of tissue from a mismatch case - an individual with high plaque burden but no overt signs of dementia at time of death - revealed a diversity of structure and spatial distribution of amyloid that is distinct from typical AD cases. We demonstrate the existence of structural polymorphisms among amyloid within and among plaques of a single individual and suggest the existence of distinct differences in the organization of amyloid in subjects with different clinical presentations.« less

Amyloid structure exhibits polymorphism on multiple length scales in human brain tissue

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Jiliang; Costantino, Isabel; Venugopalan, Nagarajan

Although aggregation of Aβ amyloid fibrils into plaques in the brain is a hallmark of Alzheimer's Disease (AD), the correlation between amyloid burden and severity of symptoms is weak. One possible reason is that amyloid fibrils are structurally polymorphic and different polymorphs may contribute differentially to disease. However, the occurrence and distribution of amyloid polymorphisms in human brain is poorly documented. Here we seek to fill this knowledge gap by using X-ray microdiffraction of histological sections of human tissue to map the abundance, orientation and structural heterogeneities of amyloid within individual plaques; among proximal plaques and in subjects with distinctmore » clinical histories. A 5 µ x-ray beam was used to generate diffraction data with each pattern arising from a scattering volume of only ~ 450 µ3 , making possible collection of dozens to hundreds of diffraction patterns from a single amyloid plaque. X-ray scattering from these samples exhibited all the properties expected for scattering from amyloid. Amyloid distribution was mapped using the intensity of its signature 4.7 Å reflection which also provided information on the orientation of amyloid fibrils across plaques. Margins of plaques exhibited a greater degree of orientation than cores and orientation around blood vessels frequently appeared tangential. Variation in the structure of Aβ fibrils is reflected in the shape of the 4.7 Å peak which usually appears as a doublet. Variations in this peak correspond to differences between the structure of amyloid within cores of plaques and at their periphery. Examination of tissue from a mismatch case - an individual with high plaque burden but no overt signs of dementia at time of death - revealed a diversity of structure and spatial distribution of amyloid that is distinct from typical AD cases. As a result, we demonstrate the existence of structural polymorphisms among amyloid within and among plaques of a single individual and suggest the existence of distinct differences in the organization of amyloid in subjects with different clinical presentations.« less

Amyloid structure exhibits polymorphism on multiple length scales in human brain tissue

DOE PAGES

Liu, Jiliang; Costantino, Isabel; Venugopalan, Nagarajan; ...

2016-09-15

Although aggregation of Aβ amyloid fibrils into plaques in the brain is a hallmark of Alzheimer's Disease (AD), the correlation between amyloid burden and severity of symptoms is weak. One possible reason is that amyloid fibrils are structurally polymorphic and different polymorphs may contribute differentially to disease. However, the occurrence and distribution of amyloid polymorphisms in human brain is poorly documented. Here we seek to fill this knowledge gap by using X-ray microdiffraction of histological sections of human tissue to map the abundance, orientation and structural heterogeneities of amyloid within individual plaques; among proximal plaques and in subjects with distinctmore » clinical histories. A 5 µ x-ray beam was used to generate diffraction data with each pattern arising from a scattering volume of only ~ 450 µ3 , making possible collection of dozens to hundreds of diffraction patterns from a single amyloid plaque. X-ray scattering from these samples exhibited all the properties expected for scattering from amyloid. Amyloid distribution was mapped using the intensity of its signature 4.7 Å reflection which also provided information on the orientation of amyloid fibrils across plaques. Margins of plaques exhibited a greater degree of orientation than cores and orientation around blood vessels frequently appeared tangential. Variation in the structure of Aβ fibrils is reflected in the shape of the 4.7 Å peak which usually appears as a doublet. Variations in this peak correspond to differences between the structure of amyloid within cores of plaques and at their periphery. Examination of tissue from a mismatch case - an individual with high plaque burden but no overt signs of dementia at time of death - revealed a diversity of structure and spatial distribution of amyloid that is distinct from typical AD cases. As a result, we demonstrate the existence of structural polymorphisms among amyloid within and among plaques of a single individual and suggest the existence of distinct differences in the organization of amyloid in subjects with different clinical presentations.« less

Interleukin 1 beta promoter polymorphism is associated with keratoconus in a Japanese population

PubMed Central

Mikami, Takenori; Teshigawara, Takeshi; Takeuchi, Masaki; Uemoto, Riyo; Kawagoe, Tatsukata; Nomura, Eiichi; Asukata, Yuri; Ishioka, Misaki; Iwasaki, Miki; Fukagawa, Kazumi; Konomi, Kenji; Shimazaki, Jun; Nishida, Teruo; Mizuki, Nobuhisa

2013-01-01

Purpose Polymorphisms in the interleukin 1 alpha (IL1A) and IL1B gene regions were previously associated with keratoconus in a Korean population. In the present study, we investigated whether the IL1A and IL1B polymorphisms are associated with keratoconus in a Japanese population. Methods A total of 169 Japanese patients with keratoconus and 390 Japanese healthy controls were recruited. We genotyped one IL1A single nucleotide polymorphism (SNP; rs2071376) and two IL1B SNPs (rs1143627 and rs16944) to compare the frequencies of alleles, genotypes, and haplotypes between cases and controls. Results Statistically significant association was observed for rs1143627 (−31 T>C) in the IL1B promoter region; the T allele of rs1143627 was associated with an increased risk of keratoconus (p=0.014, corrected p value [pc]=0.043, odds ratio=1.38). The C allele of rs16944 (−511 C>T) in the IL1B promoter region had a 1.33-fold increased risk of keratoconus, although this increase did not reach statistical significance (p=0.033, pc=0.098). The TT genotype of rs1143627 was weakly associated with an increased risk of keratoconus (p=0.033, pc=0.099, odds ratio=1.52). However, no significant differences were found in the allele and genotype frequencies between the cases and controls for rs2071376 in IL1A. Regarding haplotypic diversity, the haplotype created by the T allele of rs1143627 and C allele of rs16944 was associated with a 1.72-fold increased risk of keratoconus (p=4.0×10−5, pc=1.6×10−4). Conclusions Our results replicate associations reported recently in a Korean population. Thus, IL1B may play an important role in the development of keratoconus through genetic polymorphisms. PMID:23592922

Interleukin 1 beta promoter polymorphism is associated with keratoconus in a Japanese population.

PubMed

Mikami, Takenori; Meguro, Akira; Teshigawara, Takeshi; Takeuchi, Masaki; Uemoto, Riyo; Kawagoe, Tatsukata; Nomura, Eiichi; Asukata, Yuri; Ishioka, Misaki; Iwasaki, Miki; Fukagawa, Kazumi; Konomi, Kenji; Shimazaki, Jun; Nishida, Teruo; Mizuki, Nobuhisa

2013-01-01

Polymorphisms in the interleukin 1 alpha (IL1A) and IL1B gene regions were previously associated with keratoconus in a Korean population. In the present study, we investigated whether the IL1A and IL1B polymorphisms are associated with keratoconus in a Japanese population. A total of 169 Japanese patients with keratoconus and 390 Japanese healthy controls were recruited. We genotyped one IL1A single nucleotide polymorphism (SNP; rs2071376) and two IL1B SNPs (rs1143627 and rs16944) to compare the frequencies of alleles, genotypes, and haplotypes between cases and controls. Statistically significant association was observed for rs1143627 (-31 T>C) in the IL1B promoter region; the T allele of rs1143627 was associated with an increased risk of keratoconus (p=0.014, corrected p value [pc]=0.043, odds ratio=1.38). The C allele of rs16944 (-511 C>T) in the IL1B promoter region had a 1.33-fold increased risk of keratoconus, although this increase did not reach statistical significance (p=0.033, pc=0.098). The TT genotype of rs1143627 was weakly associated with an increased risk of keratoconus (p=0.033, pc=0.099, odds ratio=1.52). However, no significant differences were found in the allele and genotype frequencies between the cases and controls for rs2071376 in IL1A. Regarding haplotypic diversity, the haplotype created by the T allele of rs1143627 and C allele of rs16944 was associated with a 1.72-fold increased risk of keratoconus (p=4.0×10(-5), pc=1.6×10(-4)). Our results replicate associations reported recently in a Korean population. Thus, IL1B may play an important role in the development of keratoconus through genetic polymorphisms.

Influence of ADRB2 Gln27Glu and ADRB3 Trp64Arg polymorphisms on body weight and body composition changes after a controlled weight-loss intervention.

PubMed

Szendrei, Barbara; González-Lamuño, Domingo; Amigo, Teresa; Wang, Guan; Pitsiladis, Yannis; Benito, Pedro J; Gomez-Candela, Carmen; Calderón, Francisco J; Cupeiro, Rocío

2016-03-01

The β-2 and β-3 adrenergic receptors (ADRB2 and ADRB3) are thought to play a role in energy expenditure and lipolysis. However, the effects of the ADRB2 glutamine (Gln) 27 glutamic acid (glutamate) (Glu) and ADRB3 tryptophan (Trp) 64 arginine (Arg) polymorphisms on weight loss remain controversial. The aim of this study was to investigate the effect of these polymorphisms on changes in weight and body composition during a controlled weight-loss program. One hundred seventy-three healthy overweight and obese participants (91 women, 82 men) aged 18-50 years participated in a 22-week-long intervention based on a hypocaloric diet and exercise. They were randomly assigned to 1 of 4 groups: strength, endurance, strength and endurance combined, and physical activity recommendations only. Body weight, body mass index (BMI), and body composition variables were assessed before and after the intervention. Genetic analysis was carried out according to standard protocols. No effect of the ADRB2 gene was shown on final weight, BMI, or body composition, although in the supervised male group, Glu27 carriers tended to have greater weight (p = 0.019, 2.5 kg) and BMI (p = 0.019, 0.88 kg/m(2)) reductions than did noncarriers. There seems to be an individual effect of the ADRB3 polymorphism on fat mass (p = 0.004) and fat percentage (p = 0.036), in addition to an interaction with exercise for fat mass (p = 0.038). After the intervention, carriers of the Arg64 allele had a greater fat mass and fat percentage than did noncarriers (p = 0.004, 2.8 kg). In conclusion, the ADRB2 Gln27Glu and ADRB3 Trp64Arg polymorphisms may influence weight loss and body composition, although the current evidence is weak; however, further studies are necessary to clarify their roles.

Toll-like receptor variation in the bottlenecked population of the Seychelles warbler: computer simulations see the 'ghost of selection past' and quantify the 'drift debt'.

PubMed

Gilroy, D L; Phillips, K P; Richardson, D S; van Oosterhout, C

2017-07-01

Balancing selection can maintain immunogenetic variation within host populations, but detecting its signal in a postbottlenecked population is challenging due to the potentially overriding effects of drift. Toll-like receptor genes (TLRs) play a fundamental role in vertebrate immune defence and are predicted to be under balancing selection. We previously characterized variation at TLR loci in the Seychelles warbler (Acrocephalus sechellensis), an endemic passerine that has undergone a historical bottleneck. Five of seven TLR loci were polymorphic, which is in sharp contrast to the low genomewide variation observed. However, standard population genetic statistical methods failed to detect a contemporary signature of selection at any TLR locus. We examined whether the observed TLR polymorphism could be explained by neutral evolution, simulating the population's demography in the software DIYABC. This showed that the posterior distributions of mutation rates had to be unrealistically high to explain the observed genetic variation. We then conducted simulations with an agent-based model using typical values for the mutation rate, which indicated that weak balancing selection has acted on the three TLR genes. The model was able to detect evidence of past selection elevating TLR polymorphism in the prebottleneck populations, but was unable to discern any effects of balancing selection in the contemporary population. Our results show drift is the overriding evolutionary force that has shaped TLR variation in the contemporary Seychelles warbler population, and the observed TLR polymorphisms might be merely the 'ghost of selection past'. Forecast models predict immunogenetic variation in this species will continue to be eroded in the absence of contemporary balancing selection. Such 'drift debt' occurs when a gene pool has not yet reached its new equilibrium level of polymorphism, and this loss could be an important threat to many recently bottlenecked populations. © 2017 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2017 European Society For Evolutionary Biology.

The resurgence of selective contracting restrictions.

PubMed

Marsteller, J A; Bovbjerg, R R; Nichols, L M; Verrilli, D K

1997-10-01

As managed care has spread, so has legislation to force plans to contract with any willing provider (AWP) and give patients freedom of choice (FOC). Managed care organizations' selective networks and provider integration reduce patient access to providers, along with provider access to paying patients, so many providers have lobbied for AWP-FOC laws. In opposition are managed care organizations (MCOs), which want full freedom to contract selectively to control prices and utilization. This article comprehensively describes laws in all fifty-one jurisdictions, classifies their relative strength, and assesses the implications of the laws. Most are relatively weak forms and all are limited in application by ERISA and the federal HMO Act. The article also uses an associative multivariate analysis to relate the selective contracting environments to HMO penetration rates, rural population, physician density, and other variables. States with weak laws also have higher HMO penetration and higher physician density, but smaller rural populations. We conclude that the strongest laws overly restrict the management of care, to the likely detriment of cost control. But where market power is rapidly concentrating, not restricting selective contracting could diminish long-term competition and patient access to care. In the face of uncertainty about the impact of these laws, an intermediate approach may be better than all or nothing. States should consider mandating that plans offer point-of-service options, for a separate premium. This option expands patient choice of plans at the time of enrollment and of providers at the time of care, yet maintains plans' ability to control core providers.

ULF waves and radiation belts: earthward penetration of Pc 4-5 waves and energetic electron flux enhancements during geospace magnetic storms

NASA Astrophysics Data System (ADS)

Georgiou, Marina; Daglis, Ioannis; Zesta, Eftyhia; Balasis, George; Tsinganos, Kanaris

2013-04-01

Energetic particle fluxes in the outer radiation belt can vary over orders of magnitude on time scales ranging from minutes, to days and years. Geospace magnetic storms when sufficiently strong to exceed key thresholds of the Dst index may either increase or decrease the fluxes of energetic electrons. We examine the responses of energetic electrons to nine moderate, intense and weak magnetic storms, which occurred at different phases of the solar cycle, and compare these with concurrent variations of ULF wave power. Pc 4-5 waves with frequencies in the range of a few mHz may be generated internally in the magnetosphere by low frequency instabilities of ring current ions and externally by shear instabilities at the magnetopause flanks, or compressive variations in the solar wind. Here, we present multipoint observations from ground-based magnetometer arrays collocated with electron drift orbits, which are complemented and measurements by conjugate multi-point satellites, such as CHAMP, Cluster, GOES and THEMIS. We discuss the excitation, growth and decay characteristics of Pc 4-5 waves during the different phases of the magnetic storms with particular emphasis on the distribution of Pc 4-5 wave power over a variety of L shells. We investigate whether Pc 4-5 wave power penetrates to lower L shell values during periods of relatively intense geomagnetic activity as compared to weak magnetic storms. Structural changes of the magnetosphere during intense geomagnetic storms can play an important role in the generation and penetration of Pc 4-5 waves deep into the inner magnetosphere, which in turn is of significance for the wave-particle interactions contributing to the acceleration, transport and loss of electrons in the outer radiation belt. We present preliminary statistics of Pc 4-5 waves observed during magnetic storms of varying intensity, which occurred over the course of the previous solar cycle. This work is supported by the European Community's Seventh Framework Programme under grant agreement no. 284520 for the MAARBLE (Monitoring, Analyzing and Assessing Radiation Belt Energization and Loss) collaborative research project.

GLYOXALASE I A111E, PARAOXONASE 1 Q192R AND L55M POLYMORPHISMS IN ITALIAN PATIENTS WITH SPORADIC CEREBRAL CAVERNOUS MALFORMATIONS: A PILOT STUDY.

PubMed

Rinaldi, C; Bramanti, P; Famà, A; Scimone, C; Donato, L; Antognelli, C; Alafaci, C; Tomasello, F; D'Angelo, R; Sidoti, A

2015-01-01

It is already known that the conditions of increased oxidative stress are associated to a greater susceptibility to vascular malformations including cerebral cavernous malformations (CCMs). These are vascular lesions of the CNS characterized by abnormally enlarged capillary cavities that can occur sporadically or as a familial autosomal dominant condition with incomplete penetrance and variable clinical expression attributable to mutations in three different genes: CCM1(Krit1), CCM2 (MGC4607) and CCM3 (PDCD10). Polymorphisms in the genes encoding for enzymes involved in the antioxidant systems such as glyoxalase I (GLO I) and paraoxonase I (PON I) could influence individual susceptibility to the vascular malformations. A single nucleotide polymorphism was identified in the exon 4 of GLO 1 gene that causes an amino acid substitution of Ala for Glu (Ala111Glu). Two common polymorphisms have been described in the coding region of PON1, which lead to glutamine → arginine substitution at 192 (Q192R) and a leucine → methionine substitution at 55 (L55M). The polymorphisms were characterized in 59 patients without mutations in the CCM genes versus 213 healthy controls by PCR/RFLP methods using DNA from lymphocytes. We found that the frequency of patients carrying the GLO1 A/E genotype among the case group (56%) was four-fold higher than among the controls (14.1%). In the cohort of CCM patients, an increase in the frequency of PON192 Q/R genotype was observed (39% in the CCM group versus 3.7% in the healthy controls). Similarly, an increase was observed in the proportion of individuals with the genotype R/R in the disease group (5%) in respect to the normal healthy cohort (0.5%). Finally, the frequency of the PON55 heterozygotes L/M genotype was 29% in patients with CCMs and 4% in the healthy controls. The same trend was observed in PON55 homozygous M/M genotype frequency (CCMs 20% vs controls 10%). The present study aimed to investigate the possible association of GLO1 A111E, PON1 Q192R and L55M polymorphisms with the risk of CCMs. We found that individuals with the GLO1 A /E genotype, PON192/QR-RR genotypes and PON55/LM-MM genotypes had a significantly higher risk of CCMs compared with the other genotypes. However, because CCM is a heterogeneous disease, other additional factors might be involved in the initiation and progression of CCM disease.

Genetic polymorphism of matrix metalloproteinase-1 and coronary artery disease susceptibility: a case-control study in a Han Chinese population.

PubMed

Qintao, Cui; Yan, Li; Changhong, Duan; Xiaoliang, Guo; Xiaochen, Liu

2014-12-01

Coronary artery disease (CAD) receives intensive research due to its high incidence and severe impact on the quality of life. One member of the matrix metalloproteinases (MMPs), MMP-1, has been reported to be associated with CAD. To identify the markers contributing to the genetic susceptibility to CAD, nine single-nucleotide polymorphisms (rs1799750, rs498186, rs475007, rs514921, rs494379, rs996999, rs2071232, rs1938901, and rs2239008) throughout the MMP-1 gene were genotyped using MALDI-TOF within the MassARRAY system, and the allele and genotype distributions were compared between 438 healthy controls and 411 patients with CAD from a Chinese Han population. The analysis revealed a weak association between the rs1799750 (in the promoter region) genotype distribution and CAD (p=0.022). An increased risk of CAD was significantly associated with the 2G allele of rs1799750 (p=0.005, odds ratio=1.329, 95% confidence interval=1.090-1.620, after Bonferroni corrections). Strong linkage disequilibrium was observed in three blocks (D'>0.9). Significantly more C-2G (rs498186-rs1799750) haplotypes (p=0.001 after Bonferroni corrections) were found in CAD subjects. These findings point to a role for the polymorphism in the MMP-1 promoter in CAD among a Han Chinese population and may be informative for future genetic or biological studies on CAD.

The dopamine transporter gene may not contribute to susceptibility and the specific personality traits of amphetamine dependence.

PubMed

Tzeng, Nian-Sheng; Lu, Ru-Band; Yeh, Hui-Wen; Yeh, Yi-Wei; Huang, Chang-Chih; Yen, Che-Hung; Kuo, Shin-Chang; Chen, Chun-Yen; Chang, Hsin-An; Ho, Pei-Shen; Cheng, Serena; Shih, Mei-Chen; Huang, San-Yuan

2015-04-01

A substantial amount of evidence suggests that dysfunction of the dopamine transporter may be involved in the pathophysiology of amphetamine dependence (AD). The aim of this study was to examine whether the dopamine transporter gene (DAT1, SLC6A3) is associated with development of AD and whether this gene influences personality traits in patients with AD. Eighteen polymorphisms of the DAT1 gene were analyzed in a case-control study that included 909 Han Chinese men (568 patients with AD and 341 control subjects). The patients fulfilled the DSM-IV-TR criteria for AD. The Tridimensional Personality Questionnaire (TPQ) was used to assess personality traits and to examine the association between these traits and DAT1 gene variants. A weak association was found between the rs27072 polymorphism and development of AD, but these borderline associations were unconfirmed by logistic regression and haplotype analysis. Although harm avoidance and novelty seeking scores were significantly higher in patients than in controls, DAT1 polymorphisms did not influence these scores. This study suggests that high harm avoidance and novelty seeking personality traits may be a risk factor for the development of AD. However, the DAT1 gene may not contribute to AD susceptibility and specific personality traits observed in AD among Han Chinese men. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Heme Oxygenase-1 and 2 Common Genetic Variants and Risk for Multiple Sclerosis

PubMed Central

Agúndez, José A. G.; García-Martín, Elena; Martínez, Carmen; Benito-León, Julián; Millán-Pascual, Jorge; Díaz-Sánchez, María; Calleja, Patricia; Pisa, Diana; Turpín-Fenoll , Laura; Alonso-Navarro, Hortensia; Pastor, Pau; Ortega-Cubero, Sara; Ayuso-Peralta, Lucía; Torrecillas, Dolores; García-Albea, Esteban; Plaza-Nieto, José Francisco; Jiménez-Jiménez, Félix Javier

2016-01-01

Several neurochemical, neuropathological, and experimental data suggest a possible role of oxidative stress in the ethiopathogenesis of multiple sclerosis(MS). Heme-oxygenases(HMOX) are an important defensive mechanism against oxidative stress, and HMOX1 is overexpressed in the brain and spinal cord of MS patients and in experimental autoimmune encephalomyelitis(EAE). We analyzed whether common polymorphisms affecting the HMOX1 and HMOX2 genes are related with the risk to develop MS. We analyzed the distribution of genotypes and allelic frequencies of the HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363, and HMOX2 rs1051308 SNPs, as well as the presence of Copy number variations(CNVs) of these genes in 292 subjects MS and 533 healthy controls, using TaqMan assays. The frequencies of HMOX2 rs1051308AA genotype and HMOX2 rs1051308A and HMOX1 rs2071746A alleles were higher in MS patients than in controls, although only that of the SNP HMOX2 rs1051308 in men remained as significant after correction for multiple comparisons. None of the studied polymorphisms was related to the age at disease onset or with the MS phenotype. The present study suggests a weak association between HMOX2 rs1051308 polymorphism and the risk to develop MS in Spanish Caucasian men and a trend towards association between the HMOX1 rs2071746A and MS risk. PMID:26868429

Heme Oxygenase-1 and 2 Common Genetic Variants and Risk for Multiple Sclerosis.

PubMed

Agúndez, José A G; García-Martín, Elena; Martínez, Carmen; Benito-León, Julián; Millán-Pascual, Jorge; Díaz-Sánchez, María; Calleja, Patricia; Pisa, Diana; Turpín-Fenoll, Laura; Alonso-Navarro, Hortensia; Pastor, Pau; Ortega-Cubero, Sara; Ayuso-Peralta, Lucía; Torrecillas, Dolores; García-Albea, Esteban; Plaza-Nieto, José Francisco; Jiménez-Jiménez, Félix Javier

2016-02-12

Several neurochemical, neuropathological, and experimental data suggest a possible role of oxidative stress in the ethiopathogenesis of multiple sclerosis(MS). Heme-oxygenases(HMOX) are an important defensive mechanism against oxidative stress, and HMOX1 is overexpressed in the brain and spinal cord of MS patients and in experimental autoimmune encephalomyelitis(EAE). We analyzed whether common polymorphisms affecting the HMOX1 and HMOX2 genes are related with the risk to develop MS. We analyzed the distribution of genotypes and allelic frequencies of the HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363, and HMOX2 rs1051308 SNPs, as well as the presence of Copy number variations(CNVs) of these genes in 292 subjects MS and 533 healthy controls, using TaqMan assays. The frequencies of HMOX2 rs1051308AA genotype and HMOX2 rs1051308A and HMOX1 rs2071746A alleles were higher in MS patients than in controls, although only that of the SNP HMOX2 rs1051308 in men remained as significant after correction for multiple comparisons. None of the studied polymorphisms was related to the age at disease onset or with the MS phenotype. The present study suggests a weak association between HMOX2 rs1051308 polymorphism and the risk to develop MS in Spanish Caucasian men and a trend towards association between the HMOX1 rs2071746A and MS risk.

Nonlinear Dynamics of Vortices in Different Types of Grain Boundaries

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sheikhzada, Ahmad

As a major component of linear particle accelerators, superconducting radio-frequency (SRF) resonator cavities are required to operate with lowest energy dissipation and highest accelerating gradient. SRF cavities are made of polycrystalline materials in which grain boundaries can limit maximum RF currents and produce additional power dissipation sources due to local penetration of Josephson vortices. The essential physics of vortex penetration and mechanisms of dissipation of vortices driven by strong RF currents along networks of grain boundaries and their contribution to the residual surface resistance have not been well understood. To evaluate how GBs can limit the performance of SRF materials,more » particularly Nb and Nb3Sn, we performed extensive numerical simulations of nonlinear dynamics of Josephson vortices in grain boundaries under strong dc and RF fields. The RF power due to penetration of vortices both in weakly-coupled and strongly-coupled grain boundaries was calculated as functions of the RF field and frequency. The result of this calculation manifested a quadratic dependence of power to field amplitude at strong RF currents, an illustration of resistive behavior of grain boundaries. Our calculations also showed that the surface resistance is a complicated function of field controlled by penetration and annihilation of vortices and antivortices in strong RF fields which ultimately saturates to normal resistivity of grain boundary. We found that Cherenkov radiation of rapidly moving vortices in grain boundaries can produce a new instability causing generation of expanding vortex-antivortex pair which ultimately drives the entire GB in a resistive state. This effect is more pronounced in polycrystalline thin film and multilayer coating structures in which it can cause significant increase in power dissipation and results in hysteresis effects in I-V characteristics, particularly at low temperatures.« less

Enhancement of Skin Penetration of Hydrophilic and Lipophilic Compounds by pH-sensitive Liposomes.

PubMed

Tokudome, Yoshihiro; Nakamura, Kaoru; Itaya, Yurina; Hashimoto, Fumie

2015-01-01

Enhance skin penetration of hydrophilic and lipophilic compounds using liposomes that are responsible to the pH of the skin surface. pH-sensitive liposomes were prepared by a thin layer and freeze-thaw method with dioleoyl phosphatidyl ethanolamine and cholesteryl hemisuccinate. Liposomal fusion with stratum corneum lipid liposomes was measured using fluorescence resonance energy transfer. Particle diameter and zeta potential of the liposomes after fusion were measured by dynamic light scattering and electrophoresis. Under neutral pH conditions, the diameter of the pH-sensitive liposomes was 130 nm and their zeta potential was -70 mV. In weakly acidic conditions, the diameter was larger than 3,000 nm and the zeta potential was -50 mV. In contrast, the particle diameter and the zeta potential of the non-pH-sensitive liposomes remained constant under various pH conditions. A skin penetration study was performed on hairless mice skin using vertical diffusion cells, showing that the fusion ability of pH-sensitive liposomes was higher than that of non-pH-sensitive liposomes. In the skin penetration study was carried out using hydrophilic (calcein) and lipophilic (N-(7-nitrobenz- 2-oxa-1,3-diazol-4yl)-PE) (NBD-PE) model compounds which were applied to the skin with pH-sensitive liposomes as carrier. The fluorescent compounds contained within the pH-sensitive liposomes permeated the skin more effectively than those within non-pH-sensitive liposomes, and this ability was further enhanced with the lipophilic compound. These studies suggest that pH-sensitive liposomes have potential as an important tool for delivery of compounds into the skin.

PROPAGATION OF RELATIVISTIC, HYDRODYNAMIC, INTERMITTENT JETS IN A ROTATING, COLLAPSING GRB PROGENITOR STAR

DOE Office of Scientific and Technical Information (OSTI.GOV)

Geng, Jin-Jun; Zhang, Bing; Kuiper, Rolf, E-mail: gengjinjun@gmail.com, E-mail: zhang@physics.unlv.edu

The prompt emission of gamma-ray bursts (GRBs) is characterized by rapid variabilities, which may be a direct reflection of the unsteady central engine. We perform a series of axisymmetric 2.5-dimensional simulations to study the propagation of relativistic, hydrodynamic, intermittent jets through the envelope of a GRB progenitor star. A realistic rapidly rotating star is incorporated as the background of jet propagation, and the star is allowed to collapse due to the gravity of the central black hole. By modeling the intermittent jets with constant-luminosity pulses with equal on and off durations, we investigate how the half period, T , affectsmore » the jet dynamics. For relatively small T values (e.g., 0.2 s), the jet breakout time t {sub bo} depends on the opening angle of the jet, with narrower jets more penetrating and reaching the surface at shorter times. For T  ≤ 1 s, the reverse shock (RS) crosses each pulse before the jet penetrates through the stellar envelope. As a result, after the breakout of the first group of pulses at t {sub bo}, several subsequent pulses vanish before penetrating the star, causing a quiescent gap. For larger half periods ( T = 2.0 and 4.0 s), all the pulses can successfully penetrate through the envelope, since each pulse can propagate through the star before the RS crosses the shell. Our results may interpret the existence of a weak precursor in some long GRBs, given that the GRB central engine injects intermittent pulses with a half period T  ≤ 1 s. The observational data seem to be consistent with such a possibility.« less

Association of hOGG1 Ser326Cys polymorphism with gastric cancer risk: a meta-analysis.

PubMed

Niu, Yanyang; Li, Fang; Tang, Bo; Shi, Yan; Yu, Peiwu

2012-06-01

Studies investigating the association between human 8-oxoguanine glycosylase 1(hOGG1) Ser326Cys polymorphism and gastric cancer (GC) risk have reported conflicting results. We performed a meta-analysis of published case-control studies to better compare results between studies. 11 eligible studies with 2,180 GC cases and 3,985 controls were selected. There were 5 studies involving Caucasians and 5 studies involving Asians. The combined result based on all studies did not show significant difference in any genetics models. Ser/Cys + Cys/Cys versus Ser/Ser (OR = 0.91, 95% CI 0.81-1.03), Cys/Cys versus Ser/Cys + Ser/Ser (OR = 1.07, 95% CI 0.80-1.44), Ser/Cys versus Ser/Ser (OR = 0.91, 95% CI 0.80-1.03), Sys/Cys versus Ser/Cys (OR = 1.10, 95% CI 0.83-1.47), Cys/Cys versus Ser/Ser (OR = 0.99, 95% CI 0.74-1.34), Cys versus Ser (OR = 1.01, 95% CI 0.88-1.17).When stratifying for ethnicity, there was still no significant association found between hOGG1 Ser326Cys polymorphism and GC risk. Funnel plot and Egger’s test showed some evidence of publication bias on the basis of all studies. Two studies were the main reason because their samples were too small. However, the result of sensitivity analysis suggested that the influence of these two studies and one mixed population study on the pooled OR was weak. Our result could explain the association between hOGG1 Ser326Cys polymorphism and GC risk. In conclusion, we did not found the evidence that the Cys allele at codon 326 of hOGG1 could increase GC risk in our analysis.

Using classical population genetics tools with heterochroneous data: time matters!

PubMed

Depaulis, Frantz; Orlando, Ludovic; Hänni, Catherine

2009-01-01

New polymorphism datasets from heterochroneous data have arisen thanks to recent advances in experimental and microbial molecular evolution, and the sequencing of ancient DNA (aDNA). However, classical tools for population genetics analyses do not take into account heterochrony between subsets, despite potential bias on neutrality and population structure tests. Here, we characterize the extent of such possible biases using serial coalescent simulations. We first use a coalescent framework to generate datasets assuming no or different levels of heterochrony and contrast most classical population genetic statistics. We show that even weak levels of heterochrony ( approximately 10% of the average depth of a standard population tree) affect the distribution of polymorphism substantially, leading to overestimate the level of polymorphism theta, to star like trees, with an excess of rare mutations and a deficit of linkage disequilibrium, which are the hallmark of e.g. population expansion (possibly after a drastic bottleneck). Substantial departures of the tests are detected in the opposite direction for more heterochroneous and equilibrated datasets, with balanced trees mimicking in particular population contraction, balancing selection, and population differentiation. We therefore introduce simple corrections to classical estimators of polymorphism and of the genetic distance between populations, in order to remove heterochrony-driven bias. Finally, we show that these effects do occur on real aDNA datasets, taking advantage of the currently available sequence data for Cave Bears (Ursus spelaeus), for which large mtDNA haplotypes have been reported over a substantial time period (22-130 thousand years ago (KYA)). Considering serial sampling changed the conclusion of several tests, indicating that neglecting heterochrony could provide significant support for false past history of populations and inappropriate conservation decisions. We therefore argue for systematically considering heterochroneous models when analyzing heterochroneous samples covering a large time scale.

The evaluation of endothelin 1 (EDN1) and endothelin receptor type A (EDNRA) gene polymorphisms in Hashimoto's thyroiditis.

PubMed

Aydin, A Fatih; Vural, Pervin; Oruç, Çoşkun Umut; Doğru-Abbasoğlu, Semra; Özderya, Ayşenur; Karadağ, Berrin; Uysal, Müjdat

2014-07-01

Endothelin1 (EDN1) is well established marker of inflammation. The functions of EDN1 are mediated mainly by endothelin receptors type A (EDNRA). The etiopathogenesis of Hashimoto's thyroiditis (HT) remains still elusive although the role of chronic inflammation and subsequent endothelial dysfunction has been established. This study examined firstly the possible association of EDN1 (G5665Tand T-1370G) and EDNRA (C+70G and G-231A) single nucleotide polymorphisms (SNPs) with the occurrence of HT, and evaluates the relationship between genotypes and clinical/laboratory manifestation of HT. We analyzed genotype and allele distributions of above mentioned polymorphisms in 163 patients with HT and 181 healthy controls by real-time PCR combined with melting curve analysis. No significant associations between HT and variant alleles of EDN1 5665 and -1370, as well as EDNRA +70 and -231 SNPs were found. Haplotype analysis demonstrated that there was a strong (D'=0.76, r(2)=0.487) and weak (D'=0.403, r(2)=0.086) linkage disequilibrium (LD) between EDN1 -1370 and 5665, and between EDNRA -231 and +70 SNPs, respectively. However, haplotype frequencies in patients were similar to those in controls. In addition, it was observed that the EDNRA +70 G allele had protective effect against early (at age before 40 years) disease onset of HT (OR: 0.51, 95% CI=0.32-0.79, p=0.003). Although no significant associations between susceptibility to HT with EDN1 5665 and -1370, as well as with EDNRA+70 and -231 SNPs were found, EDNRA +70 polymorphism was related with decreased risk for early onset HT. Copyright © 2014 Elsevier B.V. All rights reserved.

Association of Interleukin-1 gene clusters polymorphisms with primary open-angle glaucoma: a meta-analysis.

PubMed

Li, Junhua; Feng, Yifan; Sung, Mi Sun; Lee, Tae Hee; Park, Sang Woo

2017-11-28

Previous studies have associated the Interleukin-1 (IL-1) gene clusters polymorphisms with the risk of primary open-angle glaucoma (POAG). However, the results were not consistent. Here, we performed a meta-analysis to evaluate the role of IL-1 gene clusters polymorphisms in POAG susceptibility. PubMed, EMBASE and Cochrane Library (up to July 15, 2017) were searched by two independent investigators. All case-control studies investigating the association between single-nucleotide polymorphisms (SNPs) of IL-1 gene clusters and POAG risk were included. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for quantifying the strength of association that has been involved in at least two studies. Five studies on IL-1β rs16944 (c. -511C > T) (1053 cases and 986 controls), 4 studies on IL-1α rs1800587 (c. -889C > T) (822 cases and 714 controls), and 4 studies on IL-1β rs1143634 (c. +3953C > T) (798 cases and 730 controls) were included. The results suggest that all three SNPs were not associated with POAG risk. Stratification analyses indicated that the rs1143634 has a suggestive associated with high tension glaucoma (HTG) under dominant (P = 0.03), heterozygote (P = 0.04) and allelic models (P = 0.02), however, the weak association was nullified after Bonferroni adjustments for multiple tests. Based on current meta-analysis, we indicated that there is lack of association between the three SNPs of IL-1 and POAG. However, this conclusion should be interpreted with caution and further well designed studies with large sample-size are required to validate the conclusion as low statistical powers.

Associations among types of impulsivity, substance use problems and neurexin-3 polymorphisms.

PubMed

Stoltenberg, Scott F; Lehmann, Melissa K; Christ, Christa C; Hersrud, Samantha L; Davies, Gareth E

2011-12-15

Some of the genetic vulnerability for addiction may be mediated by impulsivity. This study investigated relationships among impulsivity, substance use problems and six neurexin-3 (NRXN3) polymorphisms. Neurexins (NRXNs) are presynaptic transmembrane proteins that play a role in the development and function of synapses. Impulsivity was assessed with the Barratt Impulsiveness Scale Version 11 (BIS-11), the Boredom Proneness Scale (BPS) and the TIME paradigm; alcohol problems with the Michigan Alcoholism Screening Test (MAST); drug problems with the Drug Abuse Screening Test (DAST-20); and regular tobacco use with a single question. Participants (n=439 Caucasians, 64.7% female) donated buccal cells for genotyping. Six NRXN3 polymorphisms were genotyped: rs983795, rs11624704, rs917906, rs1004212, rs10146997 and rs8019381. A dual luciferase assay was conducted to determine whether allelic variation at rs917906 regulated gene expression. In general, impulsivity was significantly higher in those who regularly used tobacco and/or had alcohol or drug problems. In men, there were modest associations between rs11624704 and attentional impulsivity (p=0.005) and between rs1004212 and alcohol problems (p=0.009). In women, there were weak associations between rs10146997 and TIME estimation (p=0.03); and between rs1004212 and drug problems (p=0.03). The dual luciferase assay indicated that C and T alleles of rs917906 did not differentially regulate gene expression in vitro. Associations between impulsivity, substance use problems and polymorphisms in NRXN3 may be gender specific. Impulsivity is associated with substance use problems and may provide a useful intermediate phenotype for addiction. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

A study of the possible association of plasminogen activator inhibitor type 1 4G/5G insertion/deletion polymorphism with susceptibility to schizophrenia and in its subtypes.

PubMed

Yenilmez, C; Ozdemir Koroglu, Z; Kurt, H; Yanas, M; Colak, E; Degirmenci, I; Gunes, H V

2017-02-01

Inhibition of the fibrinolytic system may occur at the level of plasminogen activation, mainly by PAI-1. Mental and physical stress caused to alterations of platelet function, and also decreased to fibrinolytic activity. Furthermore, stress-induced thrombosis regulation was proposed to be by PAI-1 in schizophrenia patients. In this study, the distribution of genotypes and frequency of alleles of the plasminogen activator inhibitor type 1 (PAI-1) gene 4G/5G polymorphism in different Turkish clinical schizophrenia subtypes was investigated for its role in schizophrenia development. The clinical schizophrenia subtypes include paranoid, catatonic, disorganized, undifferentiated and residual, as diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition IV (DSM-IV). Samples of genomic DNA (250 total, including 150 schizophrenia patients and 100 healthy subjects) were analysed. PAI-1 4G/5G genotyping was performed by polymerase chain reaction-allele-specific amplification. PCR products were separated by 2% agarose gel electrophoresis and then visualized. The genotype distributions (P = 0·136) and allele frequencies (P = 0·721 for 4G, P = 0. 097 for 5G) were not significantly different between patients with schizophrenia and control subjects for the 4G/5G polymorphism. Similar results were also found for the genotype distributions (P = 0·640) and allele frequencies (P = 0·763 for 4G, P = 0·448 for 5G) in the clinical schizophrenia subtypes compared to the each other. We conclude that PAI-1 4G/5G polymorphism was not significantly associated with schizophrenia or its subtypes in the Turkish population. However, we recognize that with our sample sizes, we cannot exclude weak associations. © 2016 John Wiley & Sons Ltd.

Genetic susceptibility to chronic wasting disease in free-ranging white-tailed deer: complement component C1q and Prnp polymorphisms

USGS Publications Warehouse

Blanchong, Julie A.; Heisey, Dennis M.; Scribner, Kim T.; Libants, Scot V.; Johnson, Chad; Aiken, Judd M.; Langenberg, Julia A.; Samuel, Michael D.

2009-01-01

The genetic basis of susceptibility to chronic wasting disease (CWD) in free-ranging cervids is of great interest. Association studies of disease susceptibility in free-ranging populations, however, face considerable challenges including: the need for large sample sizes when disease is rare, animals of unknown pedigree create a risk of spurious results due to population admixture, and the inability to control disease exposure or dose. We used an innovative matched case–control design and conditional logistic regression to evaluate associations between polymorphisms of complement C1q and prion protein (Prnp) genes and CWD infection in white-tailed deer from the CWD endemic area in south-central Wisconsin. To reduce problems due to admixture or disease-risk confounding, we used neutral genetic (microsatellite) data to identify closely related CWD-positive (n = 68) and CWD-negative (n = 91) female deer to serve as matched cases and controls. Cases and controls were also matched on factors (sex, location, age) previously demonstrated to affect CWD infection risk. For Prnp, deer with at least one Serine (S) at amino acid 96 were significantly less likely to be CWD-positive relative to deer homozygous for Glycine (G). This is the first characterization of genes associated with the complement system in white-tailed deer. No tests for association between any C1q polymorphism and CWD infection were significant at p < 0.05. After controlling for Prnp, we found weak support for an elevated risk of CWD infection in deer with at least one Glycine (G) at amino acid 56 of the C1qC gene. While we documented numerous amino acid polymorphisms in C1q genes none appear to be strongly associated with CWD susceptibility.

Linkage analysis of idiopathic generalized epilepsy (IGE) and marker loci on chromosome 6p in families of patients with juvenile myocloni epilepsy: No evidence for an epilepsy locus in the HLA region

DOE Office of Scientific and Technical Information (OSTI.GOV)

Whitehouse, W.P.; Rees, M.; Curtis, D.

1993-09-01

Evidence for a locus (EJM1) in the HLA region of chromosome 6p predisposing to idiopathic generalized epilepsy (IGE) in the families of patients with juvenile myoclonic epilepsy (JME) has been obtained in two previous studies of separately ascertained groups of kindreds. Linkage analysis has been undertaken in a third set of 25 families including a patient with JME and at least one first-degree relative with IGE. Family members were typed for eight polymorphic loci on chromosome 6p: F13A, D6889, D6S109, D6S105, D6S10, C4B, DQA1/A2, and TCTE1. Pairwise and multipoint linkage analysis was carried out assuming autosomal dominant and autosomal recessivemore » inheritance and age-dependent high or low penetrance. No significant evidence in favor of linkage was obtained at any locus. Multipoint linkage analysis generated significant exclusion data (lod score < -2.0) at HLA and for a region 10-30 cM telomeric to HLA, the extent of which varied with the level of penetrance assumed. These observations indicate that genetic heterogeneity exists within this epilepsy phenotype. 39 refs., 4 figs., 2 tabs.« less

Dystonia gene in Ashkenazi Jewish population is located on chromosome 9q32-34.

PubMed

Kramer, P L; de Leon, D; Ozelius, L; Risch, N; Bressman, S B; Brin, M F; Schuback, D E; Burke, R E; Kwiatkowski, D J; Shale, H

1990-02-01

Idiopathic torsion dystonia (ITD) is a neurological disorder characterized by sustained muscle contractions that appear as twisting movements of the limbs, trunk, and/or neck, which can progress to abnormal postures. Most familial forms of ITD follow autosomal dominant transmission with reduced penetrance. The frequency of ITD in the Ashkenazi Jewish population is five to ten times greater than that in other groups. Recently, a gene for ITD (DYT1) in a non-Jewish kindred was located on chromosome 9q32-34, with tight linkage to the gene encoding gelsolin (GSN). In the present study linkage analysis using DNA polymorphisms is used to locate a gene responsible for susceptibility to ITD in 12 Ashkenazi Jewish families. This dystonia gene exhibits close linkage with the gene encoding argininosuccinate synthetase (ASS), and appears by multipoint analysis to lie in the q32-34 region of chromosome 9, a region that also contains the loci for gelsolin and dopamine-beta-hydroxylase. The same gene may be responsible for ITD both in the non-Jewish kindred mentioned above and in the Ashkenazi Jewish families presented here. However, because there is substantial difference between the penetrance of the dominant allele in these two groups, two different mutations may be operating to produce susceptibility to this disease in the two groups.

Interaction of amino acid-functionalized silver nanoparticles and Candida albicans polymorphs: A deep-UV fluorescence imaging study.

PubMed

Dojčilović, Radovan; Pajović, Jelena D; Božanić, Dušan K; Bogdanović, Una; Vodnik, Vesna V; Dimitrijević-Branković, Suzana; Miljković, Miona G; Kaščaková, Slavka; Réfrégiers, Matthieu; Djoković, Vladimir

2017-07-01

The interaction of the tryptophan functionalized Ag nanoparticles and live Candida albicans cells was studied by synchrotron excitation deep-ultraviolet (DUV) fluorescence imaging at the DISCO beamline of Synchrotron SOLEIL. DUV imaging showed that incubation of the fungus with functionalized nanoparticles results in significant increase in the fluorescence signal. The analysis of the images revealed that the interaction of the nanoparticles with (pseudo)hyphae polymorphs of the diploid fungus was less pronounced than in the case of yeast cells or budding spores. The changes in the intensity of the fluorescence signals of the cells after incubation were followed in [327-353nm] and [370-410nm] spectral ranges that correspond to the fluorescence of tryptophan in non-polar and polar environment, respectively. As a consequence of the environmental sensitivity of the silver-tryptophan fluorescent nanoprobe, we were able to determine the possible accumulation sites of the nanoparticles. The analysis of the intensity decay kinetics showed that the photobleaching effects were more pronounced in the case of the functionalized nanoparticle treated cells. The results of time-integrated emission in the mentioned spectral ranges suggested that the nanoparticles penetrate the cells, but that the majority of the nanoparticles attach to the cells' surfaces. Copyright © 2017 Elsevier B.V. All rights reserved.

Displacement of plasma protein and conduction velocity in rats under action of acceleration forces and hypokinesia

NASA Technical Reports Server (NTRS)

Baranski, S.; Edelwejn, Z.; Wojtkowiak, M.

1980-01-01

The permeability of capillary vessels was investigated in order to determine if acceleration alone or following prolonged hypokinesia would induce changes in the vascular wall leading to the penetration by l-albumins and/or proteins with larger molecules. In rats undergoing action of +5 Gz accelerations, no increase in vascular permeability, as tested with the use of (Cr-5k)-globulin, was demostrated. In rats immobilized for 4 weeks before centrifugation, rather weak migration of (Cr-51)-globulin from the vessels was observed. Immobilization resulted also in lowering of conduction velocity in the sciatic nerve.

Cosmic dosimetry using TLD aboard spacecrafts of the "Cosmos" series

NASA Astrophysics Data System (ADS)

Hübner, K.; Schmidt, P.; Fellinger, J.

Thermoluminescent (TL) detectors were used for dosimetric investigations on the outer surface as well as inside Soviet spacecrafts of the "Cosmos" series. At the outer surface, ultrathin TL detectors, based on CaF 2-PTFE and LiF, were arranged in special stacks and exposed to unshielded cosmic radiation. The strong decrease of dose within a few mg/cm 2 demonstrates that weakly penetrating radiation is dominating in the radiation field under investigation. On the basis of glow curve analysis of LiF thermoluminescent detectors it could be shown, that the high doses are caused by electrons.

Cosmic dosimetry using TLD aboard spacecrafts of the "Cosmos" series.

PubMed

Hubner, K; Schmidt, P; Fellinger, J

1994-11-01

Thermoluminescent (TL) detectors were used for dosimetric investigations on the outer surface as well as inside Soviet spacecrafts of the "Cosmos" series. At the outer surface, ultrathin TL detectors, based on CaF2-PTFE and LiF, were arranged in special stacks and exposed to unshielded cosmic radiation. The strong decrease of dose within a few mg/cm2 demonstrates that weakly penetrating radiation is dominating in the radiation field under investigation. On the basis of glow curve analysis of LiF thermoluminescent detectors it could be shown, that the high doses are caused by electrons.

Out of the frying pan: New York City hospitals in an age of deregulation.

PubMed

Salit, Sharon; Fass, Steven; Nowak, Mark

2002-01-01

For several decades New York City hospitals had been distinguished by their tightly regulated environment, chronically weak finances, high occupancy rates, teaching intensity, dependency on public payers, low managed care penetration, and minimal merger activity. Then in the late 1990s a rapid convergence of forces--the Balanced Budget Act, managed care growth, state deregulation of commercial rates, escalating costs, and plunging hospital occupancy rates--threw the city's hospital industry into turmoil. In this paper we describe this period of turbulent change that has left most of the city's safety-net and small community hospitals near bankruptcy.

Life in extra dimensions of database world or penetration of NoSQL in HEP community

NASA Astrophysics Data System (ADS)

Kuznetsov, V.; Evans, D.; Metson, S.

2012-12-01

The recent buzzword in IT world is NoSQL. Major players, such as Facebook, Yahoo, Google, etc. are widely adopted different “NoSQL” solutions for their needs. Horizontal scalability, flexible data model and management of big data volumes are only a few advantages of NoSQL. In CMS experiment we use several of them in production environment. Here, we present CMS projects based on NoSQL solutions, their strengths and weaknesses as well as our experience with those tools and their coexistence with standard RDBMS solutions in our applications.

μ SR and magnetometry study of superconducting 5% Pt-doped IrTe 2

DOE PAGES

Wilson, M. N.; Medina, T.; Munsie, T. J.; ...

2016-11-11

In this paper, we present magnetometry and muon spin rotation ( SR) measurements of the superconducting dichalcogenide Ir 0.95Pt 0.05Te 2. From both sets of measurements we calculate the penetration depth and thence superfluid density as a function of temperature. The temperature dependence of the superfluid densities from both sets of data indicate fully gapped superconductivity that can be fit to a conventional s-wave model and yield fitting parameters consistent with a BCS weak coupling superconductor. Finally, we therefore see no evidence for exotic superconductivity in Ir 0.95Pt 0.05Te 2.

Investigation of the geometrical barrier in Bi-2212 using the magneto-optical technique

NASA Astrophysics Data System (ADS)

Lin, Z. W.; Gu, G. D.; Russell, G. J.

2000-08-01

It has been found that the penetration of vortices into a weak pinning crystal is governed by a geometrical barrier and they form a dome-shaped flux profile across the crystal. Using the powerful magneto-optical technique, we investigated this geometrical barrier in a high-purity Bi2Sr2CaCu2O8+x single-crystal platelet. Our results show that over the temperature range 20-70 K the dome-shaped profile is observed. Also, the influences of the edge shape and the roughness on the geometrical barrier are discussed.

μ SR and magnetometry study of superconducting 5% Pt-doped IrTe2

NASA Astrophysics Data System (ADS)

Wilson, M. N.; Medina, T.; Munsie, T. J.; Cheung, S. C.; Frandsen, B. A.; Liu, L.; Yan, J.; Mandrus, D.; Uemura, Y. J.; Luke, G. M.

2016-11-01

We present magnetometry and muon spin rotation (μ SR ) measurements of the superconducting dichalcogenide Ir0.95Pt0.05Te2 . From both sets of measurements, we calculate the penetration depth and thence superfluid density as a function of temperature. The temperature dependence of the superfluid densities from both sets of data indicate fully gapped superconductivity that can be fit to a conventional s -wave model and yield fitting parameters consistent with a BCS weak coupling superconductor. We therefore see no evidence for exotic superconductivity in Ir0.95Pt0.05Te2 .

Genetic susceptibility to neuroblastoma

PubMed Central

Tolbert, Vanessa P.; Coggins, Grace E.; Maris, John M.

2017-01-01

Until recently, the genetic basis of neuroblastoma, a heterogeneous neoplasm arising from the developing sympathetic nervous system, remained undefined. The discovery of gain-of-function mutations in the ALK receptor tyrosine kinase gene as the major cause of familial neuroblastoma led to the discovery of identical somatic mutations and rapid advancement of ALK as a tractable therapeutic target. Inactivating mutations in a master regulator of neural crest development, PHOX2B, have also been identified in a subset of familial neuroblastomas. Other high penetrance susceptibility alleles likely exist, but together these heritable mutations account for less than 10% of neuroblastoma cases. A genome-wide association study of a large neuroblastoma cohort identified common and rare polymorphisms highly associated with the disease. Ongoing resequencing efforts aim to further define the genetic landscape of neuroblastoma. PMID:28458126

Linkage analysis with chromosome 9 markers in hereditary essential tremor.

PubMed

Conway, D; Bain, P G; Warner, T T; Davis, M B; Findley, L J; Thompson, P D; Marsden, C D; Harding, A E

1993-07-01

Hereditary essential tremor (ET) is an autosomal dominant disorder with variable expression and reduced penetrance. A tremor indistinguishable from ET may be observed in patients with autosomal dominant idiopathic torsion dystonia (ITD), in which the disease locus has been mapped to 9q32-34 in some kindreds, tightly linked to the argininosuccinate synthetase (ASS) locus. We performed linkage analysis in 15 families with ET containing 60 definitely affected individuals, using dinucleotide repeat polymorphisms at the ASS locus and the Abelson locus (ABL). Cumulative lod scores were -19.5 for ASS and -10.8 for ABL at a recombination fraction of 0.01, and tight linkage to ASS was excluded individually in 11 of the families. These data indicate that the ET gene is not allelic to that causing ITD.

Weak Genetic Structure in Northern African Dromedary Camels Reflects Their Unique Evolutionary History

PubMed Central

Cherifi, Youcef Amine; Gaouar, Suheil Bechir Semir; Guastamacchia, Rosangela; El-Bahrawy, Khalid Ahmed; Abushady, Asmaa Mohammed Aly; Sharaf, Abdoallah Aboelnasr; Harek, Derradji; Lacalandra, Giovanni Michele; Saïdi-Mehtar, Nadhira

2017-01-01

Knowledge on genetic diversity and structure of camel populations is fundamental for sustainable herd management and breeding program implementation in this species. Here we characterized a total of 331 camels from Northern Africa, representative of six populations and thirteen Algerian and Egyptian geographic regions, using 20 STR markers. The nineteen polymorphic loci displayed an average of 9.79 ± 5.31 alleles, ranging from 2 (CVRL8) to 24 (CVRL1D). Average He was 0.647 ± 0.173. Eleven loci deviated significantly from Hardy-Weinberg proportions (P<0.05), due to excess of homozygous genotypes in all cases except one (CMS18). Distribution of genetic diversity along a weak geographic gradient as suggested by network analysis was not supported by either unsupervised and supervised Bayesian clustering. Traditional extensive/nomadic herding practices, together with the historical use as a long-range beast of burden and its peculiar evolutionary history, with domestication likely occurring from a bottlenecked and geographically confined wild progenitor, may explain the observed genetic patterns. PMID:28103238

Frictional constraints on crustal faulting

USGS Publications Warehouse

Boatwright, J.; Cocco, M.

1996-01-01

We consider how variations in fault frictional properties affect the phenomenology of earthquake faulting. In particular, we propose that lateral variations in fault friction produce the marked heterogeneity of slip observed in large earthquakes. We model these variations using a rate- and state-dependent friction law, where we differentiate velocity-weakening behavior into two fields: the strong seismic field is very velocity weakening and the weak seismic field is slightly velocity weakening. Similarly, we differentiate velocity-strengthening behavior into two fields: the compliant field is slightly velocity strengthening and the viscous field is very velocity strengthening. The strong seismic field comprises the seismic slip concentrations, or asperities. The two "intermediate" fields, weak seismic and compliant, have frictional velocity dependences that are close to velocity neutral: these fields modulate both the tectonic loading and the dynamic rupture process. During the interseismic period, the weak seismic and compliant regions slip aseismically, while the strong seismic regions remain locked, evolving into stress concentrations that fail only in main shocks. The weak seismic areas exhibit most of the interseismic activity and aftershocks but can also creep seismically. This "mixed" frictional behavior can be obtained from a sufficiently heterogenous distribution of the critical slip distance. The model also provides a mechanism for rupture arrest: dynamic rupture fronts decelerate as they penetrate into unloaded complaint or weak seismic areas, producing broad areas of accelerated afterslip. Aftershocks occur on both the weak seismic and compliant areas around a fault, but most of the stress is diffused through aseismic slip. Rapid afterslip on these peripheral areas can also produce aftershocks within the main shock rupture area by reloading weak fault areas that slipped in the main shock and then healed. We test this frictional model by comparing the seismicity and the coseismic slip for the 1966 Parkfield, 1979 Coyote Lake, and 1984 Morgan Hill earthquakes. The interevent seismicity and aftershocks appear to occur on fault areas outside the regions of significant slip: these regions are interpreted as either weak seismic or compliant, depending on whether or not they manifest interevent seismicity.

Temporal evolution of crack propagation propensity in snow in relation to slab and weak layer properties

NASA Astrophysics Data System (ADS)

Schweizer, Jürg; Reuter, Benjamin; van Herwijnen, Alec; Richter, Bettina; Gaume, Johan

2016-11-01

If a weak snow layer below a cohesive slab is present in the snow cover, unstable snow conditions can prevail for days or even weeks. We monitored the temporal evolution of a weak layer of faceted crystals as well as the overlaying slab layers at the location of an automatic weather station in the Steintälli field site above Davos (Eastern Swiss Alps). We focussed on the crack propagation propensity and performed propagation saw tests (PSTs) on 7 sampling days during a 2-month period from early January to early March 2015. Based on video images taken during the tests we determined the mechanical properties of the slab and the weak layer and compared them to the results derived from concurrently performed measurements of penetration resistance using the snow micro-penetrometer (SMP). The critical cut length, observed in PSTs, increased overall during the measurement period. The increase was not steady and the lowest values of critical cut length were observed around the middle of the measurement period. The relevant mechanical properties, the slab effective elastic modulus and the weak layer specific fracture, overall increased as well. However, the changes with time differed, suggesting that the critical cut length cannot be assessed by simply monitoring a single mechanical property such as slab load, slab modulus or weak layer specific fracture energy. Instead, crack propagation propensity is the result of a complex interplay between the mechanical properties of the slab and the weak layer. We then compared our field observations to newly developed metrics of snow instability related to either failure initiation or crack propagation propensity. The metrics were either derived from the SMP signal or calculated from simulated snow stratigraphy (SNOWPACK). They partially reproduced the observed temporal evolution of critical cut length and instability test scores. Whereas our unique dataset of quantitative measures of snow instability provides new insights into the complex slab-weak layer interaction, it also showed some deficiencies of the modelled metrics of instability - calling for an improved representation of the mechanical properties.

Damage evolution of bi-body model composed of weakly cemented soft rock and coal considering different interface effect.

PubMed

Zhao, Zenghui; Lv, Xianzhou; Wang, Weiming; Tan, Yunliang

2016-01-01

Considering the structure effect of tunnel stability in western mining of China, three typical kinds of numerical model were respectively built as follows based on the strain softening constitutive model and linear elastic-perfectly plastic model for soft rock and interface: R-M, R-C(s)-M and R-C(w)-M. Calculation results revealed that the stress-strain relation and failure characteristics of the three models vary between each other. The combination model without interface or with a strong interface presented continuous failure, while weak interface exhibited 'cut off' effect. Thus, conceptual models of bi-material model and bi-body model were established. Then numerical experiments of tri-axial compression were carried out for the two models. The relationships between stress evolution, failure zone and deformation rate fluctuations as well as the displacement of interface were detailed analyzed. Results show that two breakaway points of deformation rate actually demonstrate the starting and penetration of the main rupture, respectively. It is distinguishable due to the large fluctuation. The bi-material model shows general continuous failure while bi-body model shows 'V' type shear zone in weak body and failure in strong body near the interface due to the interface effect. With the increasing of confining pressure, the 'cut off' effect of weak interface is not obvious. These conclusions lay the theoretical foundation for further development of constitutive model for soft rock-coal combination body.

Shock waves in strongly coupled plasmas

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khlebnikov, Sergei; Kruczenski, Martin; Michalogiorgakis, Georgios

2010-12-15

Shock waves are supersonic disturbances propagating in a fluid and giving rise to dissipation and drag. Weak shocks, i.e., those of small amplitude, can be well described within the hydrodynamic approximation. On the other hand, strong shocks are discontinuous within hydrodynamics and therefore probe the microscopics of the theory. In this paper, we consider the case of the strongly coupled N=4 plasma whose microscopic description, applicable for scales smaller than the inverse temperature, is given in terms of gravity in an asymptotically AdS{sub 5} space. In the gravity approximation, weak and strong shocks should be described by smooth metrics withmore » no discontinuities. For weak shocks, we find the dual metric in a derivative expansion, and for strong shocks we use linearized gravity to find the exponential tail that determines the width of the shock. In particular, we find that, when the velocity of the fluid relative to the shock approaches the speed of light v{yields}1 the penetration depth l scales as l{approx}(1-v{sup 2}){sup 1/4}. We compare the results with second-order hydrodynamics and the Israel-Stewart approximation. Although they all agree in the hydrodynamic regime of weak shocks, we show that there is not even qualitative agreement for strong shocks. For the gravity side, the existence of shock waves implies that there are disturbances of constant shape propagating on the horizon of the dual black holes.« less

A scenario for solar wind penetration of earth's magnetic tail based on ion composition data from the ISEE 1 spacecraft

NASA Technical Reports Server (NTRS)

Lennartsson, W.

1992-01-01

Based on He(2+) and H(-) ion composition data from the Plasma Composition Experiment on ISEE 1, a scenario is proposed for the solar wind penetration of the earth's magnetic tail, which does not require that the solar wind plasma be magnetized. While this study does not take issue with the notion that earth's magnetic field merges with the solar wind magnetic field on a regular basis, it focuses on certain aspects of interaction between the solar wind particles and the earth's field, e.g, the fact that the geomagnetic tail always has a plasma sheet, even during times when the physical signs of magnetic merging are weak or absent. It is argued that the solar plasma enters along slots between the tail lobes and the plasma sheet, even quite close to earth, convected inward along the plasma sheet boundary layer or adjacent to it, by the electric fringe field of the ever present low-latitude magnetopause boundary layer (LLBL). The required E x B drifts are produced by closing LLBL equipotential surfaces through the plasma sheet.

Enhanced sub-micron colloidal particle separation with interdigitated microelectrode arrays using mixed AC/DC dielectrophoretic scheme.

PubMed

Swaminathan, Vikhram V; Shannon, Mark A; Bashir, Rashid

2015-04-01

Dielectrophoretic separation of particles finds a variety of applications in the capture of species such as cells, viruses, proteins, DNA from biological systems, as well as other organic and inorganic contaminants from water. The ability to capture particles is constrained by poor volumetric scaling of separation force with respect to particle diameter, as well as the weak penetration of electric fields in the media. In order to improve the separation of sub-micron colloids, we present a scheme based on multiple interdigitated electrode arrays under mixed AC/DC bias. The use of high frequency longitudinal AC bias breaks the shielding effects through electroosmotic micromixing to enhance electric fields through the electrolyte, while a transverse DC bias between the electrode arrays enables penetration of the separation force to capture particles from the bulk of the microchannel. We determine the favorable biasing conditions for field enhancement with the help of analytical models, and experimentally demonstrate the improved capture from sub-micron colloidal suspensions with the mixed AC/DC electrostatic excitation scheme over conventional AC-DEP methods.

Superconducting and magnetic properties of Sr 3 Ir 4 Sn 13

DOE PAGES

Biswas, P. K.; Amato, A.; Khasanov, R.; ...

2014-10-10

In this research, magnetization and muon spin relaxation or rotation (µSR) measurements have been performed to study the superconducting and magnetic properties of Sr₃Ir₄Sn₁₃. From magnetization measurements the lower and upper critical fields of Sr₃Ir₄Sn₁₃ are found to be 81(1) Oe and 14.4(2) kOe, respectively. Zero-field µSR data show no sign of any magnetic ordering or weak magnetism in Sr₃Ir₄Sn₁₃. Transverse-field µSR measurements in the vortex state provided the temperature dependence of the magnetic penetration depth λ. The dependence of λ⁻² with temperature is consistent with the existence of single s-wave energy gap in the superconducting state of Sr₃Ir₄Sn₁₃ withmore » a gap value of 0.82(2) meV at absolute zero temperature. The magnetic penetration depth at zero temperature λ(0) is 291(3) nm. The ratio Δ(0)/k BT c = 2.1(1) indicates that Sr₃Ir₄Sn₁₃ should be considered as a strong-coupling superconductor.« less

Facial-muscle weakness, speech disorders and dysphagia are common in patients with classic infantile Pompe disease treated with enzyme therapy.

PubMed

van Gelder, C M; van Capelle, C I; Ebbink, B J; Moor-van Nugteren, I; van den Hout, J M P; Hakkesteegt, M M; van Doorn, P A; de Coo, I F M; Reuser, A J J; de Gier, H H W; van der Ploeg, A T

2012-05-01

Classic infantile Pompe disease is an inherited generalized glycogen storage disorder caused by deficiency of lysosomal acid α-glucosidase. If left untreated, patients die before one year of age. Although enzyme-replacement therapy (ERT) has significantly prolonged lifespan, it has also revealed new aspects of the disease. For up to 11 years, we investigated the frequency and consequences of facial-muscle weakness, speech disorders and dysphagia in long-term survivors. Sequential photographs were used to determine the timing and severity of facial-muscle weakness. Using standardized articulation tests and fibreoptic endoscopic evaluation of swallowing, we investigated speech and swallowing function in a subset of patients. This study included 11 patients with classic infantile Pompe disease. Median age at the start of ERT was 2.4 months (range 0.1-8.3 months), and median age at the end of the study was 4.3 years (range 7.7 months -12.2 years). All patients developed facial-muscle weakness before the age of 15 months. Speech was studied in four patients. Articulation was disordered, with hypernasal resonance and reduced speech intelligibility in all four. Swallowing function was studied in six patients, the most important findings being ineffective swallowing with residues of food (5/6), penetration or aspiration (3/6), and reduced pharyngeal and/or laryngeal sensibility (2/6). We conclude that facial-muscle weakness, speech disorders and dysphagia are common in long-term survivors receiving ERT for classic infantile Pompe disease. To improve speech and reduce the risk for aspiration, early treatment by a speech therapist and regular swallowing assessments are recommended.

Use of Ground Penetrating Radar to Study Gradient Media

NASA Astrophysics Data System (ADS)

Titov, A.

2016-12-01

Nowadays Ground Penetrating Radar (GPR) is often used to solve different problems of applied geophysics including the hydrological ones. This work was motivated by detection of weak reflections in the body of water observed during the surveys on the freshwater lakes using GPR. The same reflections were first analyzed by John Bradford in 2007. These reflections can arise from the thermal gradient layer or thermocline due to different dielectric permittivity of cold and warm water. We employed physical and mathematical modeling to identify the properties of such thermoclines. We have constructed a special GPR stand to study the gradient media in our laboratory. The stand consists of a water-filled plastic tank and plastic tubes, which gather the cold water under the warm water. Our stand allows for changing parameters of the gradient layer, such as limits of dielectric permittivity and the thickness of the gradient layer. GPR antenna was placed slightly under the water surface to remove the parasitic reflections. To visualize the thermal distribution, an infrared camera and thermal sensors were used. Analysis of the GPR traces after physical modeling, performed in the MATLAB environment, allows us to locate the weak reflection from the gradient layer. We observed that (i) the change of the gradient boundary values alters the amplitude of the signal, (ii) the arrival time of the impulse reflected from the gradient layer corresponds to the arrival time of the impulse reflected from the top boundary of this layer, and (iii) the shape of the signal reflected from the gradient layer coincides with the shape of the signal reflected from the non-gradient boundary between two bodies. The quantitative properties of thermocline can be determined using amplitude analysis of GPR signals. Finally, the developed methods were successfully applied to real field data.

Clinical and genetic characterization of the autoinflammatory diseases diagnosed in an adult reference center.

PubMed

Hernández-Rodríguez, José; Ruíz-Ortiz, Estíbaliz; Tomé, Adrià; Espinosa, Gerard; González-Roca, Eva; Mensa-Vilaró, Anna; Prieto-González, Sergio; Espígol-Frigolé, Georgina; Mensa, Josep; Cardellach, Francesc; Grau, Josep M; Cid, Maria C; Yagüe, Jordi; Aróstegui, Juan I; Cervera, Ricard

2016-01-01

Autoinflammatory diseases (AID) are usually diagnosed during the pediatric age. However, adult-onset disease or diagnosis during adulthood has been occasionally described. To assess the clinical and genetic characteristics of adult patients diagnosed with an AID in an adult referral center for AID. We retrospectively evaluated clinical and genetic features of adult patients (≥16 years) diagnosed with an AID or referred after AID diagnosis to the Clinical Unit of AID, at the Department of Autoimmune Diseases, Hospital Clínic of Barcelona, from 2008 to 2014. During the study period, a genetic study for suspected AID was requested to 90 patients at the Department of Autoimmune Diseases. A final diagnosis of monogenic AID was achieved in 17 patients (19% of patients tested). Five additional cases were diagnosed with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome and 10 patients with AID were referred from other adult departments. Finally, a total of 32 patients with AID were finally diagnosed or monitored in our Clinical Unit. These included 12 (37.5%) familial Mediterranean fever, 6 (18.8%) tumour necrosis factor-receptor associated periodic syndrome, 8 (25%) cryopirin-associated periodic syndromes (Muckle-Wells syndrome [MWS] or overlap familial cold-associated periodic syndrome/MWS), 1 (3.1%) mevalonate kinase deficiency, and 5 (15.6%) PFAPA. Clinical evidence of disease-onset during childhood and adulthood was observed in 15 (47%) and 17 (53%) patients, respectively. Overall, the final diagnosis was obtained after a delay of a mean of 12 years (range 0-47 years). Compared to children, adult patients with AID in our series presented more frequently with non-severe manifestations and none of them developed amyloidosis during follow-up. Adult patients also carried higher proportion of low-penetrance mutations or polymorphisms and all genetic variants were presented in heterozygosis or as heterozygous compounds. Adult disease-onset or delayed diagnosis of AID during adulthood is associated with milder disease phenotypes, and seem to be driven by mild genotypes, with predominant presence of low-penetrance mutations or polymorphisms. Copyright © 2015 Elsevier B.V. All rights reserved.

Habitat edges have weak effects on duck nest survival at local spatial scales

USGS Publications Warehouse

Raquel, Amelia J; Ringelman, Kevin M.; Ackerman, Joshua T.; Eadie, John M.

2015-01-01

Edge effects on nesting success have been documented in breeding birds in a variety of contexts, but there is still uncertainty in how edge type and spatial scale determine the magnitude and detectability of edge effects. Habitat edges are often viewed as predator corridors that surround or penetrate core habitat and increase the risk of predation for nearby nests. We studied the effects of three different types of potential predator corridors (main perimeter roads, field boundaries, and ATV trails within fields) on waterfowl nest survival in California. We measured the distance from duck nests to the nearest edge of each type, and used distance as a covariate in a logistic exposure analysis of nest survival. We found only weak evidence for edge effects due to predation. The best supported model of nest survival included all three distance categories, and while all coefficient estimates were positive (indicating that survival increased with distance from edge), 85% coefficient confidence intervals approached or bounded zero indicating an overall weak effect of habitat edges on nest success. We suggest that given the configuration of edges at our site, there may be few areas far enough from hard edges to be considered ‘core’ habitat, making edge effects on nest survival particularly difficult to detect.

Selective Strolls: Fixation and Extinction in Diploids Are Slower for Weakly Selected Mutations Than for Neutral Ones.

PubMed

Mafessoni, Fabrizio; Lachmann, Michael

2015-12-01

In finite populations, an allele disappears or reaches fixation due to two main forces, selection and drift. Selection is generally thought to accelerate the process: a selected mutation will reach fixation faster than a neutral one, and a disadvantageous one will quickly disappear from the population. We show that even in simple diploid populations, this is often not true. Dominance and recessivity unexpectedly slow down the evolutionary process for weakly selected alleles. In particular, slightly advantageous dominant and mildly deleterious recessive mutations reach fixation slightly more slowly than neutral ones (at most 5%). This phenomenon determines genetic signatures opposite to those expected under strong selection, such as increased instead of decreased genetic diversity around the selected site. Furthermore, we characterize a new phenomenon: mildly deleterious recessive alleles, thought to represent a wide fraction of newly arising mutations, on average survive in a population slightly longer than neutral ones, before getting lost. Consequently, these mutations are on average slightly older than neutral ones, in contrast with previous expectations. Furthermore, they slightly increase the amount of weakly deleterious polymorphisms, as a consequence of the longer unconditional sojourn times compared to neutral mutations. Copyright © 2015 by the Genetics Society of America.

Blood-brain barrier permeation and efflux exclusion of anticholinergics used in the treatment of overactive bladder.

PubMed

Chancellor, Michael B; Staskin, David R; Kay, Gary G; Sandage, Bobby W; Oefelein, Michael G; Tsao, Jack W

2012-04-01

Overactive bladder (OAB) is a common condition, particularly in the elderly. Anticholinergic agents are the mainstay of pharmacological treatment of OAB; however, many anticholinergics can cross the blood-brain barrier (BBB) and may cause central nervous system (CNS) effects, including cognitive deficits, which can be especially detrimental in older patients. Many anticholinergics have the potential to cause adverse CNS effects due to muscarinic (M(1)) receptor binding in the brain. Of note, permeability of the BBB increases with age and can also be affected by trauma, stress, and some diseases and medications. Passive crossing of a molecule across the BBB into the brain is dependent upon its physicochemical properties. Molecular characteristics that hinder passive BBB penetration include a large molecular size, positive or negative ionic charge at physiological pH, and a hydrophilic structure. Active transport across the BBB is dependent upon protein-mediated transporter systems, such as that of permeability-glycoprotein (P-gp), which occurs only for P-gp substrates, such as trospium chloride, darifenacin and fesoterodine. Reliance on active transport can be problematic since genetic polymorphisms of P-gp exist, and many commonly used drugs and even some foods are P-gp inhibitors or are substrates themselves and, due to competition, can reduce the amount of the drug that is actively transported out of the CNS. Therefore, for drugs that are preferred not to cross into the CNS, such as potent anticholinergics intended for the bladder, it is optimal to have minimal passive crossing of the BBB, although it may also be beneficial for the drug to be a substrate for an active efflux transport system. Anticholinergics demonstrate different propensities to cross the BBB. Darifenacin, fesoterodine and trospium chloride are substrates for P-gp and, therefore, are actively transported away from the brain. In addition, trospium chloride has not been detected in cerebrospinal fluid assays and does not appear to have significant CNS penetration. This article reviews the properties of anticholinergics that affect BBB penetration and active transport out of the CNS, discusses issues of increased BBB permeability in patients with OAB, and examines the clinical implications of BBB penetration on adverse events associated with anticholinergics.

Non-ventricular, Clinical, and Functional Features of the RyR2(R420Q) Mutation Causing Catecholaminergic Polymorphic Ventricular Tachycardia.

PubMed

Domingo, Diana; Neco, Patricia; Fernández-Pons, Elena; Zissimopoulos, Spyros; Molina, Pilar; Olagüe, José; Suárez-Mier, M Paz; Lai, F Anthony; Gómez, Ana M; Zorio, Esther

2015-05-01

Catecholaminergic polymorphic ventricular tachycardia is a malignant disease, due to mutations in proteins controlling Ca(2+) homeostasis. While the phenotype is characterized by polymorphic ventricular arrhythmias under stress, supraventricular arrhythmias may occur and are not fully characterized. Twenty-five relatives from a Spanish family with several sudden deaths were evaluated with electrocardiogram, exercise testing, and optional epinephrine challenge. Selective RyR2 sequencing in an affected individual and cascade screening in the rest of the family was offered. The RyR2(R420Q) mutation was generated in HEK-293 cells using site-directed mutagenesis to conduct in vitro functional studies. The exercise testing unmasked catecholaminergic polymorphic ventricular tachycardia in 8 relatives (sensitivity = 89%; positive predictive value = 100%; negative predictive value = 93%), all of them carrying the heterozygous RyR2(R420Q) mutation, which was also present in the proband and a young girl without exercise testing, a 91% penetrance at the end of the follow-up. Remarkably, sinus bradycardia, atrial and junctional arrhythmias, and/or giant post-effort U-waves were identified in patients. Upon permeabilization and in intact cells, the RyR2(R420Q) expressing cells showed a smaller peak of Ca(2+) release than RyR2 wild-type cells. However, at physiologic intracellular Ca(2+) concentration, equivalent to the diastolic cytosolic concentration, the RyR2(R420Q) released more Ca(2+) and oscillated faster than RyR2 wild-type cells. The missense RyR2(R420Q) mutation was identified in the N-terminus of the RyR2 gene in this highly symptomatic family. Remarkably, this mutation is associated with sinus bradycardia, atrial and junctional arrhythmias, and giant U-waves. Collectively, functional heterologous expression studies suggest that the RyR2(R420Q) behaves as an aberrant channel, as a loss- or gain-of-function mutation depending on cytosolic intracellular Ca(2+) concentration. Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Conversion of ICRP male reference phantom to polygon-surface phantom

NASA Astrophysics Data System (ADS)

Yeom, Yeon Soo; Han, Min Cheol; Kim, Chan Hyeong; Jeong, Jong Hwi

2013-10-01

The International Commission on Radiological Protection (ICRP) reference phantoms, developed based on computed tomography images of human bodies, provide much more realism of human anatomy than the previously used MIRD5 (Medical Internal Radiation Dose) mathematical phantoms. It has been, however, realized that the ICRP reference phantoms have some critical limitations showing a considerable amount of holes for the skin and wall organs mainly due to the nature of voxels of which the phantoms are made, especially due to their low voxel resolutions. To address this problem, we are planning to develop the polygon-surface version of ICRP reference phantoms by directly converting the ICRP reference phantoms (voxel phantoms) to polygon-surface phantoms. The objective of this preliminary study is to see if it is indeed possible to construct the high-quality polygon-surface phantoms based on the ICRP reference phantoms maintaining identical organ morphology and also to identify any potential issues, and technologies to address these issues, in advance. For this purpose, in the present study, the ICRP reference male phantom was roughly converted to a polygon-surface phantom. Then, the constructed phantom was implemented in Geant4, Monte Carlo particle transport code, for dose calculations, and the calculated dose values were compared with those of the original ICRP reference phantom to see how much the calculated dose values are sensitive to the accuracy of the conversion process. The results of the present study show that it is certainly possible to convert the ICRP reference phantoms to surface phantoms with enough accuracy. In spite of using relatively less resources (<2 man-months), we were able to construct the polygon-surface phantom with the organ masses perfectly matching the ICRP reference values. The analysis of the calculated dose values also implies that the dose values are indeed not very sensitive to the detailed morphology of the organ models in the phantom for highly penetrating radiations such as photons and neutrons. The results of the electron beams, on the other hand, show that the dose values of the polygon-surface phantom are higher by a factor of 2-5 times than those of the ICRP reference phantom for the skin and wall organs which have large holes due to low voxel resolution. The results demonstrate that the ICRP reference phantom could provide significantly unreasonable dose values to thin or wall organs especially for weakly penetrating radiations. Therefore, when compared to the original ICRP reference phantoms, it is believed that the polygon-surface version of ICRP reference phantoms properly developed will not only provide the same or similar dose values (say, difference <5 or 10%) for highly penetrating radiations, but also provide correct dose values for the weakly penetrating radiations such as electrons and other charged particles.

A Randomized Trial Comparing Two Tongue-Pressure Resistance Training Protocols for Post-Stroke Dysphagia.

PubMed

Steele, Catriona M; Bayley, Mark T; Peladeau-Pigeon, Melanie; Nagy, Ahmed; Namasivayam, Ashwini M; Stokely, Shauna L; Wolkin, Talia

2016-06-01

The objective of this study was to compare the outcomes of two tongue resistance training protocols. One protocol ("tongue-pressure profile training") emphasized the pressure-timing patterns that are typically seen in healthy swallows by focusing on gradual pressure release and saliva swallowing tasks. The second protocol ("tongue-pressure strength and accuracy training") emphasized strength and accuracy in tongue-palate pressure generation and did not include swallowing tasks. A prospective, randomized, parallel allocation trial was conducted. Of 26 participants who were screened for eligibility, 14 received up to 24 sessions of treatment. Outcome measures of posterior tongue strength, oral bolus control, penetration-aspiration and vallecular residue were made based on videofluoroscopy analysis by blinded raters. Complete data were available for 11 participants. Significant improvements were seen in tongue strength and post-swallow vallecular residue with thin liquids, regardless of treatment condition. Stage transition duration (a measure of the duration of the bolus presence in the pharynx prior to swallow initiation, which had been chosen to capture impairments in oral bolus control) showed no significant differences. Similarly, significant improvements were not seen in median scores on the penetration-aspiration scale. This trial suggests that tongue strength can be improved with resistance training for individuals with tongue weakness following stroke. We conclude that improved penetration-aspiration does not necessarily accompany improvements in tongue strength; however, tongue-pressure resistance training does appear to be effective for reducing thin liquid vallecular residue.

Heterozygote Advantage in a Finite Population: Black Color in Wolves.

PubMed

Hedrick, Philip W; Stahler, Daniel R; Dekker, Dick

2014-01-01

There is a striking color polymorphism for wolves in the Yellowstone National Park where approximately half the wolves are black. The genetic basis for this polymorphism is known, and fitnesses of the genotypes are estimated. These estimates suggest that there is strong heterozygote advantage but substantial asymmetry in the fitness differences of the 2 homozygotes. Theoretically, such fitnesses in a finite population are thought to reduce genetic variation at least as fast as if there were no selection at all. Because the color polymorphism has remained at about the same frequency for 17 years, about 4 generations, we investigated whether this was consistent with the theoretical predictions. Counter to this general expectation of loss, given the initial frequency of black wolves, the theoretical expectation in this case was found to be that the frequency would only decline slowly over time. For example, if the effective population size is 20, then the expected black allele frequency after 4 generations would be 0.191, somewhat less than the observed value of 0.237. However, nearly 30% of the time the expected frequency is 0.25 or greater, consistent with the contemporary observed frequency. In other words and in contrast to general theoretical predictions, because of the short period of time in evolutionary terms and the relatively weak selection at low frequencies, the observed variation and the predicted theoretical variation are not inconsistent. © The American Genetic Association 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Polymorphism in 2-X-adamantane derivatives (X = Cl, Br).

PubMed

Negrier, Philippe; Barrio, María; Tamarit, Josep Ll; Mondieig, Denise

2014-08-14

The polymorphism of two 2-X-adamantane derivatives, X = Cl, X = Br, has been studied by X-ray powder diffraction and normal- and high-pressure (up to 300 MPa) differential scanning calorimetry. 2-Br-adamantane displays a low-temperature orthorhombic phase (space group P212121, Z = 4) and a high-temperature plastic phase (Fm3̅m, Z = 4) from 277.9 ± 1.0 K to the melting point at 413.4 ± 1.0 K. 2-Cl-adamantane presents a richer polymorphic behavior through the temperature range studied. At low temperature it displays a triclinic phase (P1̅, Z = 2), which transforms to a monoclinic phase (C2/c, Z = 8) at 224.4 ± 1.0 K, both phases being ordered. Two high-temperature orientationally disordered are found for this compound, one hexagonal (P63/mcm, Z = 6) at ca. 241 K and the highest one, cubic (Fm3̅m, Z = 4), being stable from 244 ± 1.0 K up to the melting point at 467.5 ± 1.0 K. No additional phase appears due to the increase in pressure within the studied range. The intermolecular interactions are found to be weak, especially for the 2-Br-adamantane compound for which the Br···Br as well as C-Br···H distances are larger than the addition of the van der Waals radii, thus confirming the availability of this compound for building up diamondoid blocks.

High-pressure synthesis of mesoporous stishovite: potential applications in mineral physics

NASA Astrophysics Data System (ADS)

Stagno, Vincenzo; Mandal, Manik; Landskron, Kai; Fei, Yingwei

2015-06-01

Recently, we have described a successful synthesis route to obtain mesoporous quartz and its high-pressure polymorph coesite by nanocasting at high pressure using periodic mesostructured precursors, such as SBA-16 and FDU-12/carbon composite as starting materials. Periodic mesoporous high-pressure silica polymorphs are of particular interest as they combine transport properties and physical properties such as hardness that potentially enable the industrial use of these materials. In addition, synthesis of mesoporous crystalline silica phases can allow more detailed geology-related studies such as water/mineral interaction, dissolution/crystallization rate and the surface contribution to the associated thermodynamic stability (free energy and enthalpy) of the various polymorphs and their crossover. Here, we present results of synthesis of mesoporous stishovite from cubic large-pore periodic mesoporous silica LP-FDU-12/C composite as precursor with an fcc lattice. We describe the synthesis procedure using multi-anvil apparatus at 9 GPa (about 90,000 atm) and temperature of 500 °C. The synthetic mesoporous stishovite is, then, characterized by wide and small-angle X-ray diffraction, scanning/transmission electron microscopy and gas adsorption. Results show that this new material is characterized by accessible mesopores with wide pore size distribution, surface area of ~45 m2/g and volume of pores of ~0.15 cm3/g. Results from gas adsorption indicate that both porosity and permeability are retained at the high pressures of synthesis but with weak periodic order of the pores.

Meta-analysis of the relevance of the OPRM1 118A>G genetic variant for pain treatment.

PubMed

Walter, Carmen; Lötsch, Jörn

2009-12-01

Regard of functional pharmacogenetic polymorphisms may further the success of pain therapy by adopting individualized approaches. The mu-opioid receptor gene (OPRM1) 118A>G polymorphism is a promising candidate for both opioid effects and pain because of both biological reasonability and apparent experimental and clinical evidence. We analyzed its importance for pain therapy using a meta-analytic approach to studies relating it to opioid pain therapy. Data from suitable studies selected from hits of a PubMed search for "OPRM1" were independently extracted by two authors. The meta-analysis included phenotypes by OPRM1 genotype (opioid dosing, pain, and side effects), publication year, diagnostic status, proportion of male study participants, and whether genotype frequencies agreed with Hardy-Weinberg equilibrium. We found no consistent association between OPRM1 118A>G genotypes and most of the phenotypes in a heterogeneous set of eight clinical studies. Only weak evidence of an association with less nausea (effect size, Cohen's d=-0.21, p=0.037) and of increased opioid dosage requirements (d=0.56, p=0.018) in homozygous carriers of the G allele was obtained. This indicates that despite initially promising results, available evidence of the clinical relevance of the OPRM1 118A>G polymorphism does not withhold a meta-analysis. This discourages basing personalized therapeutic concepts of pain therapy on OPRM1 118A>G genotyping at the present state of evidence.

PFMDR1 POLYMORPHISMS INFLUENCE ON IN VITRO SENSITIVITY OF THAI PLASMODIUM FALCIPARUM ISOLATES TO PRIMAQUINE, SITAMAQUINE AND TAFENOQUINE.

PubMed

Kaewpruk, Napaporn; Tan-ariya, Peerapan; Ward, Stephen A; Sitthichot, Naruemon; Suwandittakul, Nantana; Mungthin, Mathirut

2016-05-01

Primaquine (PQ), an 8-aminoquinoline, is considered a tissue schizonticide drug for radical cure in vivax and ovale malaria, with minimal impact on asexual erythrocytic stages at therapeutic concentrations. Tafenoquine (TQ), a new 8-aminoquinoline analog of PQ, is active against both malaria parasite tissue and blood stages and is being promoted as a drug candidate for antimalarial chemotherapy and chemoprophylaxis and potential transmission blocking against Plasmodium vivax and P. falciparum. This study compared in vitro sensitivity of Thai P. falciparum isolates against three 8-aminoquinolines, PQ, TQ and sitamaquine (SQ), a related 8-aminoquinoline and assessed the importance of pfmdr1 polymorphism on the in vitro response. Seventy-eight laboratory adapted Thai P. falciparum isolates were evaluated for in vitro sensitivity to the three 8-aminoquinolines using a radioisotopic assay, and pfmdr1 polymorphisms were determined using PCR-based methods. All three drugs have weak antiplasmodial activity against asexual erythrocytic stage with SQ being the most potent by almost 10 folds. Cross susceptibility was observed in all three 8-aminoquinolines. Parasites containing pfmdr1 86Y, 184Y or 1034S allele exhibit significantly higher PQ IC₅₀. TQ sensitivity was reduced in those parasites containing pfmdr1 86Y, 1034S or 1042N allele. However, there was no significant influence of pfmdr1 alleles on SQ sensitivity. The data highlight unique differences among three representative 8-aminoquinoline drugs that may be useful in understanding their potential utility in antimalarial development.

Cystic fibrosis screening using the College panel: platform comparison and lessons learned from the first 20,000 samples.

PubMed

Strom, Charles M; Huang, Donghui; Buller, Arlene; Redman, Joy; Crossley, Beryl; Anderson, Ben; Entwistle, Tom; Sun, Weimin

2002-01-01

To determine the accuracy of two commercially available kits for cystic fibrosis (CF) genotyping and determine allele frequencies for the ACMG/ACOG recommended mutations. A total of 1,040 consecutive analyses using Roche CF Gold Strips and the ABI CF Genotyper were performed. Subsequently we performed analyses of 20,103 samples. Both kits accurately determined CF genotypes. The I148T mutation was found >100 times more frequently in carrier screening than in CF patients. Asymptomatic patients were identified who are compound heterozygotes for delta F508 and I148T. Four of 13 patients heterozygous for delta F508 and the IVS8-5T polymorphism had some symptoms of CF. Accurate and timely analysis can be performed for the ACMG CF panel. I148T is a low penetrance CF allele.

Infarcts presenting with a combination of medial medullary and posterior inferior cerebellar artery syndromes.

PubMed

Lee, Hyung; Baik, Seung Kug

2004-09-15

Cerebellar and medial medullary infarctions are well-known vertebrobasilar stroke syndromes. However, their development in a patient with distal vertebral artery occlusion has not been previously reported. A 49-year-old man with longstanding hypertension suddenly developed vertigo, right-sided Horner syndrome, and left-sided weakness. An MRI of the brain showed acute infarcts in the right inferior cerebellum (posterior inferior cerebellar artery territory) and the right upper medial medulla (direct penetrating branches of vertebral artery). Magnetic resonance angiogram showed occlusion of the distal vertebral artery on the right side. Atherothrombotic occlusion of the distal vertebral artery may cause this unusual combination of vertebrobasilar stroke.

Western Wind and Solar Integration Study Phase 3A: Low Levels of Synchronous Generation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miller, Nicholas W.; Leonardi, Bruno; D'Aquila, Robert

The stability of the North American electric power grids under conditions of high penetrations of wind and solar is a significant concern and possible impediment to reaching renewable energy goals. The 33% wind and solar annual energy penetration considered in this study results in substantial changes to the characteristics of the bulk power system. This includes different power flow patterns, different commitment and dispatch of existing synchronous generation, and different dynamic behavior from wind and solar generation. The Western Wind and Solar Integration Study (WWSIS), sponsored by the U.S. Department of Energy, is one of the largest regional solar andmore » wind integration studies to date. In multiple phases, it has explored different aspects of the question: Can we integrate large amounts of wind and solar energy into the electric power system of the West? The work reported here focused on the impact of low levels of synchronous generation on the transient stability performance in one part of the region in which wind generation has displaced synchronous thermal generation under highly stressed, weak system conditions. It is essentially an extension of WWSIS-3. Transient stability, the ability of the power system to maintain synchronism among all elements following disturbances, is a major constraint on operations in many grids, including the western U.S. and Texas systems. These constraints primarily concern the performance of the large-scale bulk power system. But grid-wide stability concerns with high penetrations of wind and solar are still not thoroughly understood. This work focuses on 'traditional' fundamental frequency stability issues, such as maintaining synchronism, frequency, and voltage. The objectives of this study are to better understand the implications of low levels of synchronous generation and a weak grid on overall system performance by: 1) Investigating the Western Interconnection under conditions of both high renewable generation (e.g., wind and solar) and low synchronous generation (e.g., significant coal power plant decommitment or retirement); and 2) Analyzing both the large-scale stability of the Western Interconnection and regional stability issues driven by more geographically dispersed renewable generation interacting with a transmission grid that evolved with large, central station plants at key nodes. As noted above, the work reported here is an extension of the research performed in WWSIS-3.« less

Mutations in HAMP and HJV genes and their impact on expression of clinical hemochromatosis in a cohort of 100 Spanish patients homozygous for the C282Y mutation of HFE gene.

PubMed

Altès, Albert; Bach, Vanessa; Ruiz, Angels; Esteve, Anna; Felez, Jordi; Remacha, Angel F; Sardà, M Pilar; Baiget, Montserrat

2009-10-01

Most hereditary hemochromatosis (HH) patients are homozygous for the C282Y mutation of the HFE gene. Nevertheless, penetrance of the disease is very variable. In some patients, penetrance can be mediated by concomitant mutations in other iron master genes. We evaluated the clinical impact of hepcidin (HAMP) and hemojuvelin mutations in a cohort of 100 Spanish patients homozygous for the C282Y mutation of the HFE gene. HAMP and hemojuvelin mutations were evaluated in all patients by bidirectional direct cycle sequencing. Phenotype-genotype interactions were evaluated. A heterozygous mutation of the HAMP gene (G71D) was found in only one out of 100 cases. Following, we performed a study of several members of that family, and we observed several members had a digenic inheritance of the C282Y mutation of the HFE gene and the G71D mutation of the HAMP gene. This mutation in the HAMP gene did not modify the phenotype of the individuals who were homozygous for the C282Y mutation. One other patient presented a new polymorphism in the hemojuvelin gene, without consequences in iron load or clinical course of the disease. In conclusion, HAMP and hemojuvelin mutations are rare among Spanish HH patients, and their impact in this population is not significant.

Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease

PubMed Central

Lalli, M A; Bettcher, B M; Arcila, M L; Garcia, G; Guzman, C; Madrigal, L; Ramirez, L; Acosta-Uribe, J; Baena, A; Wojta, K J; Coppola, G; Fitch, R; de Both, M D; Huentelman, M J; Reiman, E M; Brunkow, M E; Glusman, G; Roach, J C; Kao, A W; Lopera, F; Kosik, K S

2015-01-01

We have sequenced the complete genomes of 72 individuals affected with early-onset familial Alzheimer's disease caused by an autosomal dominant, highly penetrant mutation in the presenilin-1 (PSEN1) gene, and performed genome-wide association testing to identify variants that modify age at onset (AAO) of Alzheimer's disease. Our analysis identified a haplotype of single-nucleotide polymorphisms (SNPs) on chromosome 17 within a chemokine gene cluster associated with delayed onset of mild-cognitive impairment and dementia. Individuals carrying this haplotype had a mean AAO of mild-cognitive impairment at 51.0±5.2 years compared with 41.1±7.4 years for those without these SNPs. This haplotype thus appears to modify Alzheimer's AAO, conferring a large (~10 years) protective effect. The associated locus harbors several chemokines including eotaxin-1 encoded by CCL11, and the haplotype includes a missense polymorphism in this gene. Validating this association, we found plasma eotaxin-1 levels were correlated with disease AAO in an independent cohort from the University of California San Francisco Memory and Aging Center. In this second cohort, the associated haplotype disrupted the typical age-associated increase of eotaxin-1 levels, suggesting a complex regulatory role for this haplotype in the general population. Altogether, these results suggest eotaxin-1 as a novel modifier of Alzheimer's disease AAO and open potential avenues for therapy. PMID:26324103

Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease.

PubMed

Lalli, M A; Bettcher, B M; Arcila, M L; Garcia, G; Guzman, C; Madrigal, L; Ramirez, L; Acosta-Uribe, J; Baena, A; Wojta, K J; Coppola, G; Fitch, R; de Both, M D; Huentelman, M J; Reiman, E M; Brunkow, M E; Glusman, G; Roach, J C; Kao, A W; Lopera, F; Kosik, K S

2015-11-01

We have sequenced the complete genomes of 72 individuals affected with early-onset familial Alzheimer's disease caused by an autosomal dominant, highly penetrant mutation in the presenilin-1 (PSEN1) gene, and performed genome-wide association testing to identify variants that modify age at onset (AAO) of Alzheimer's disease. Our analysis identified a haplotype of single-nucleotide polymorphisms (SNPs) on chromosome 17 within a chemokine gene cluster associated with delayed onset of mild-cognitive impairment and dementia. Individuals carrying this haplotype had a mean AAO of mild-cognitive impairment at 51.0 ± 5.2 years compared with 41.1 ± 7.4 years for those without these SNPs. This haplotype thus appears to modify Alzheimer's AAO, conferring a large (~10 years) protective effect. The associated locus harbors several chemokines including eotaxin-1 encoded by CCL11, and the haplotype includes a missense polymorphism in this gene. Validating this association, we found plasma eotaxin-1 levels were correlated with disease AAO in an independent cohort from the University of California San Francisco Memory and Aging Center. In this second cohort, the associated haplotype disrupted the typical age-associated increase of eotaxin-1 levels, suggesting a complex regulatory role for this haplotype in the general population. Altogether, these results suggest eotaxin-1 as a novel modifier of Alzheimer's disease AAO and open potential avenues for therapy.

Weak D caused by a founder deletion in the RHD gene.

PubMed

Fichou, Yann; Chen, Jian-Min; Le Maréchal, Cédric; Jamet, Déborah; Dupont, Isabelle; Chuteau, Claude; Durousseau, Cécile; Loirat, Marie-Jeanne; Bailly, Pascal; Férec, Claude

2012-11-01

The RhD blood group system exemplifies a genotype-phenotype correlation by virtue of its highly polymorphic and immunogenic nature. Weak D phenotypes are generally thought to result from missense mutations leading to quantitative change of the D antigen in the red blood cell membrane or intracellularly. Different sets of polymerase chain reaction primers were designed to map and clone a deletion involving RHD Exon 10, which was found in approximately 3% of approximately 2000 RHD hemizygous subjects with D phenotype ambiguity. D antigen density was measured by flow cytometry. Transcript analysis was carried out by 3'-rapid amplification of complementary DNA ends. Haplotype analysis was performed by microsatellite genotyping. A 5405-bp deletion that removed nearly two-thirds of Intron 9 and almost all of Exon 10 of the RHD gene was characterized. It is predicted to result in the replacement of the last eight amino acids of the wild-type RhD protein by another four amino acids. The mean RhD antigen density from two deletion carriers was determined to be only 30. A consensus haplotype could be deduced from the deletion carriers based on the microsatellite genotyping data. The currently reported deletion was derived from a common founder. This deletion appears to represent not only the first large deletion associated with weak D but also the weakest of weak D alleles so far reported. This highly unusual genotype-phenotype relationship may be attributable to the additive effect of three distinct mechanisms that affect mRNA formation, mRNA stability, and RhD/ankyrin-R interaction, respectively. © 2012 American Association of Blood Banks.

Effect of formulation pH on transdermal penetration of antiemetics formulated in poloxamer lecithin organogel.

PubMed

Woodall, Rachel; Arnold, John J; McKay, Doug; Asbill, C Scott

2013-01-01

The purpose of this study was to assess the impact of altering formulation pH on the transdermal penetration of several commonly used antiemetic, weakly basic drugs incorporated into poloxamer lecithin organogel vehicle. Poloxamer lecithin organogel formulations containing promethazine hydrochloride (25 mg/mL), metoclopramide hydrochloride (10 mg/mL), and ondansetron hydrochloride (8 mg/mL) were examined for both drug release and transdermal penetration across porcine skin in modified Franz diffusion cells for a period of 24 hours. For the transdermal studies, each antiemetic drug was formulated at a pH above and below their acid dissociation constant (pKa) in an attempt to assure that the drug would be primarily in their respective ionized or non-ionized states. In addition, drug content in skin was assessed at the end of the 24-hour experiment. Drug content analysis was determined via high-performance liquid chromatography. As a percent of total drug release from the poloxamer lecithin organogel vehicle, promethazine hydrochloride demonstrated the most transdermal drug penetration after 24 hours (30.2% +/- 20.2%), followed by ondansetron hydrochloride (2.7% +/- 1.1%) and metoclopramide hydrochloride (1.8% +/- 1.6%). Subsequently, the pH of the Pluronic F-127 gel was adjusted in order to ensure that each antiemetic drug would be primarily in its unionized state. The transdermal permeation of each antiemetic drug primarily in its unionized state increased over that observed with the drug primarily in its ionized state after 24 hours (promethazine: 1.6-fold increase; metoclopramide: 1.3-fold increase; ondansetron: 1.8-fold increase). A similar trend was noted in the amount of each drug found in the skin after 24 hours (promethazine: 1.2-fold increase; metoclopramide: 2.4-fold increase; ondansetron: 3.0-fold increase). These results suggest that proper optimization of drug ionization state may be a useful strategy for compounding pharmacists to increase the efficacy of drugs intended for inclusion in transdermal formulations.

Population-wide sampling of retrotransposon insertion polymorphisms using deep sequencing and efficient detection.

PubMed

Yu, Qichao; Zhang, Wei; Zhang, Xiaolong; Zeng, Yongli; Wang, Yeming; Wang, Yanhui; Xu, Liqin; Huang, Xiaoyun; Li, Nannan; Zhou, Xinlan; Lu, Jie; Guo, Xiaosen; Li, Guibo; Hou, Yong; Liu, Shiping; Li, Bo

2017-09-01

Active retrotransposons play important roles during evolution and continue to shape our genomes today, especially in genetic polymorphisms underlying a diverse set of diseases. However, studies of human retrotransposon insertion polymorphisms (RIPs) based on whole-genome deep sequencing at the population level have not been sufficiently undertaken, despite the obvious need for a thorough characterization of RIPs in the general population. Herein, we present a novel and efficient computational tool called Specific Insertions Detector (SID) for the detection of non-reference RIPs. We demonstrate that SID is suitable for high-depth whole-genome sequencing data using paired-end reads obtained from simulated and real datasets. We construct a comprehensive RIP database using a large population of 90 Han Chinese individuals with a mean ×68 depth per individual. In total, we identify 9342 recent RIPs, and 8433 of these RIPs are novel compared with dbRIP, including 5826 Alu, 2169 long interspersed nuclear element 1 (L1), 383 SVA, and 55 long terminal repeats. Among the 9342 RIPs, 4828 were located in gene regions and 5 were located in protein-coding regions. We demonstrate that RIPs can, in principle, be an informative resource to perform population evolution and phylogenetic analyses. Taking the demographic effects into account, we identify a weak negative selection on SVA and L1 but an approximately neutral selection for Alu elements based on the frequency spectrum of RIPs. SID is a powerful open-source program for the detection of non-reference RIPs. We built a non-reference RIP dataset that greatly enhanced the diversity of RIPs detected in the general population, and it should be invaluable to researchers interested in many aspects of human evolution, genetics, and disease. As a proof of concept, we demonstrate that the RIPs can be used as biomarkers in a similar way as single nucleotide polymorphisms. © The Authors 2017. Published by Oxford University Press.

Risk factor for clear cell renal cell carcinoma in Chinese population: a case-control study.

PubMed

Wang, Guoping; Hou, Jianguo; Ma, Liye; Xie, Jiaxin; Yin, Jianhua; Xu, Danfeng; Chang, Wenjun; Tan, Xiaojie; Su, Tong; Zhang, Hongwei; Cao, Guangwen

2012-04-01

Risk factors for clear cell renal cell carcinoma (ccRCC) differ among populations and remain controversial. We carried out a hospital-based case-control study to examine the effects of health status, lifestyle, and some genetic polymorphisms on ccRCC risk in Chinese subjects. Between 2007 and 2009, 250 newly diagnosed, histologically confirmed ccRCC cases and 299 sex-, age-matched healthy controls provided complete information including consumption of tea and alcohol, smoking, occupational exposure, body mass index (BMI), hypertension, diabetes, and urolithiasis by face-to-face interview in Shanghai. Genetic polymorphisms of cytochrome P450 mono-oxygenase (CYP1A1: 6235T>C, 4889A>G, and 4887C>A), glutathione S-transferase (GSTP1: 342A>G), and N-acetyltransferase (NAT2: 481C>T, 590G>A, and 857G>A) were identified by PCR-RFLP and DNA sequencing. Adjusted odds ratio (AOR) and 95% confidence interval (CI) were derived through multivariate logistic regression. Green tea intake (≥500 ml/d) was inversely associated with ccRCC risk, with an AOR of 0.34 (95% CI 0.21-0.55). BMI (≥25 kg/m(2)), hypertension, and urolithiasis were independently associated with an increased risk of ccRCC, with AOR (95% CI) of 2.10 (1.32-3.34), 2.49 (1.57-3.93), and 3.33 (1.12-9.89), respectively. No association was observed between smoking, alcohol consumption, or occupational exposure with ccRCC risk. The polymorphisms and their interactions with the environmental exposures were mostly not associated with ccRCC risk. BMI (≥25 kg/m(2)), hypertension, and urolithiasis are independently associated with an increased risk, whereas green tea intake (≥500 ml/d) is independently associated with a decreased risk of ccRCC. The polymorphisms of the xenobiotic-metabolizing enzymes are weakly associated with ccRCC risk in Chinese subjects. Copyright © 2011 Elsevier Ltd. All rights reserved.

Using Classical Population Genetics Tools with Heterochroneous Data: Time Matters!

PubMed Central

Depaulis, Frantz; Orlando, Ludovic; Hänni, Catherine

2009-01-01

Background New polymorphism datasets from heterochroneous data have arisen thanks to recent advances in experimental and microbial molecular evolution, and the sequencing of ancient DNA (aDNA). However, classical tools for population genetics analyses do not take into account heterochrony between subsets, despite potential bias on neutrality and population structure tests. Here, we characterize the extent of such possible biases using serial coalescent simulations. Methodology/Principal Findings We first use a coalescent framework to generate datasets assuming no or different levels of heterochrony and contrast most classical population genetic statistics. We show that even weak levels of heterochrony (∼10% of the average depth of a standard population tree) affect the distribution of polymorphism substantially, leading to overestimate the level of polymorphism θ, to star like trees, with an excess of rare mutations and a deficit of linkage disequilibrium, which are the hallmark of e.g. population expansion (possibly after a drastic bottleneck). Substantial departures of the tests are detected in the opposite direction for more heterochroneous and equilibrated datasets, with balanced trees mimicking in particular population contraction, balancing selection, and population differentiation. We therefore introduce simple corrections to classical estimators of polymorphism and of the genetic distance between populations, in order to remove heterochrony-driven bias. Finally, we show that these effects do occur on real aDNA datasets, taking advantage of the currently available sequence data for Cave Bears (Ursus spelaeus), for which large mtDNA haplotypes have been reported over a substantial time period (22–130 thousand years ago (KYA)). Conclusions/Significance Considering serial sampling changed the conclusion of several tests, indicating that neglecting heterochrony could provide significant support for false past history of populations and inappropriate conservation decisions. We therefore argue for systematically considering heterochroneous models when analyzing heterochroneous samples covering a large time scale. PMID:19440242

Association between Hcy levels and the CBS844ins68 and MTHFR C677T polymorphisms with essential hypertension.

PubMed

Cai, Weijuan; Yin, Liang; Yang, Fang; Zhang, Lei; Cheng, Jiang

2014-11-01

The aim of the present study was to investigate the association between the homocysteine (Hcy) levels and polymorphisms of the CBS844ins68 and MTHFR C677T genes in essential hypertension (EH). The effects of the MTHFR C677T and CBS844ins68 haploid genotypes and the combined genotypes on EH and levels of Hcy were further explored. The polymorphisms of CBS844ins68 and MTHFR C677T genes in 200 EH and 200 normal tensive (NT) patients were detected using polymerase chain reaction-restriction fragment length polymorphism and analysis of the distribution of genotypes. An automated biochemical analyzer was used to measure the plasma Hcy levels and the clinical biochemistry data. The plasma Hcy levels in EH were significantly higher than those of the NT group (P<0.05). There were no significant differences (P>0.05) between males and females. Two genotypes, deletion/deletion (DD) and deletion/insertion (DI), of the CBS844ins68 polymorphism were found in two groups with no clear differences in two genotypes and allele frequency distribution (P>0.05). There were significant differences in the three genotype frequencies (χ 2 =6.658, χ 2 =4.410, P<0.05) for MTHFR C677T locus genotypes CC, CT and TT. The Hcy levels in genotypes DD and DI had no significant differences (P>0.05) and the CT and TT types were significantly higher compared to the CC genotype (P<0.05). The CC/DD combined genotype in the two groups was significantly different (P<0.05), and the odds ratio (OR), 0.569 showed that the CC/DD genotype may be a protective factor of hypertension. In the two groups, the Hcy levels for combined genotypes CC/DD, CT/DD, TT/DD and TT/DI were significantly different (P<0.05). The SHEsis software analysis linkage disequilibrium coefficient=0.216, indicates that there is probably a weak linkage for MTHFR C677T and CBS844ins68 . Haplotype analysis suggested that the C-D haplotype was negatively correlated with EH (OR, 0.727) and that there was a positive correlation between T-D haplotype and EH (OR, 1.376). MTHFR C677T and CBS844ins68 polymorphisms were present in the populations studied and the CBS844ins68 homozygous mutation was not present. Therefore, there is a correlation between the polymorphisms of the MTHFR C677T gene and EH, and allele T may be one of the predisposing factors. MTHFR C677T and CBS844ins68 may exist with a certain linkage and the T-D haplotype may be a risk factor for EH.

Association between Hcy levels and the CBS844ins68 and MTHFR C677T polymorphisms with essential hypertension

PubMed Central

CAI, WEIJUAN; YIN, LIANG; YANG, FANG; ZHANG, LEI; CHENG, JIANG

2014-01-01

The aim of the present study was to investigate the association between the homocysteine (Hcy) levels and polymorphisms of the CBS844ins68 and MTHFR C677T genes in essential hypertension (EH). The effects of the MTHFR C677T and CBS844ins68 haploid genotypes and the combined genotypes on EH and levels of Hcy were further explored. The polymorphisms of CBS844ins68 and MTHFR C677T genes in 200 EH and 200 normal tensive (NT) patients were detected using polymerase chain reaction-restriction fragment length polymorphism and analysis of the distribution of genotypes. An automated biochemical analyzer was used to measure the plasma Hcy levels and the clinical biochemistry data. The plasma Hcy levels in EH were significantly higher than those of the NT group (P<0.05). There were no significant differences (P>0.05) between males and females. Two genotypes, deletion/deletion (DD) and deletion/insertion (DI), of the CBS844ins68 polymorphism were found in two groups with no clear differences in two genotypes and allele frequency distribution (P>0.05). There were significant differences in the three genotype frequencies (χ2=6.658, χ2=4.410, P<0.05) for MTHFR C677T locus genotypes CC, CT and TT. The Hcy levels in genotypes DD and DI had no significant differences (P>0.05) and the CT and TT types were significantly higher compared to the CC genotype (P<0.05). The CC/DD combined genotype in the two groups was significantly different (P<0.05), and the odds ratio (OR), 0.569 showed that the CC/DD genotype may be a protective factor of hypertension. In the two groups, the Hcy levels for combined genotypes CC/DD, CT/DD, TT/DD and TT/DI were significantly different (P<0.05). The SHEsis software analysis linkage disequilibrium coefficient=0.216, indicates that there is probably a weak linkage for MTHFR C677T and CBS844ins68. Haplotype analysis suggested that the C-D haplotype was negatively correlated with EH (OR, 0.727) and that there was a positive correlation between T-D haplotype and EH (OR, 1.376). MTHFR C677T and CBS844ins68 polymorphisms were present in the populations studied and the CBS844ins68 homozygous mutation was not present. Therefore, there is a correlation between the polymorphisms of the MTHFR C677T gene and EH, and allele T may be one of the predisposing factors. MTHFR C677T and CBS844ins68 may exist with a certain linkage and the T-D haplotype may be a risk factor for EH. PMID:25279160

Spatial characterization of the edge barrier in wide superconducting films

NASA Astrophysics Data System (ADS)

Sivakov, A. G.; Turutanov, O. G.; Kolinko, A. E.; Pokhila, A. S.

2018-03-01

The current-induced destruction of superconductivity is discussed in wide superconducting thin films, whose width is greater than the magnetic field penetration depth, in weak magnetic fields. Particular attention is paid to the role of the boundary potential barrier (the Bin-Livingston barrier) in critical state formation and detection of the edge responsible for this critical state with different mutual orientations of external perpendicular magnetic field and transport current. Critical and resistive states of the film were visualized using the space-resolving low-temperature laser scanning microscopy (LTLSM) method, which enables detection of critical current-determining areas on the film edges. Based on these observations, a simple technique was developed for investigation of the critical state separately at each film edge, and for the estimation of residual magnetic fields in cryostats. The proposed method only requires recording of the current-voltage characteristics of the film in a weak magnetic field, thus circumventing the need for complex LTLSM techniques. Information thus obtained is particularly important for interpretation of studies of superconducting film single-photon light emission detectors.

Oxidation of the Ru(0001) surface covered by weakly bound, ultrathin silicate films

DOE PAGES

Emmez, Emre; Anibal Boscoboinik, J.; Tenney, Samuel; ...

2015-06-30

Bilayer silicate films grown on metal substrates are weakly bound to the metal surfaces, which allows ambient gas molecules to intercalate the oxide/metal interface. In this work, we studied the interaction of oxygen with Ru(0001) supported ultrathin silicate and aluminosilicate films at elevated O 2 pressures (10 -5–10 mbar) and temperatures (450–923 K). The results show that the silicate films stay essentially intact under these conditions, and oxygen in the film does not exchange with oxygen in the ambient. O 2 molecules readily penetrate the film and dissociate on the underlying Ru surface underneath. Also, the silicate layer does howevermore » strongly passivate the Ru surface towards RuO 2(110) oxide formation that readily occurs on bare Ru(0001) under the same conditions. Lastly, the results indicate considerable spatial effects for oxidation reactions on metal surfaces in the confined space at the interface. Moreover, the aluminosilicate films completely suppress the Ru oxidation, providing some rationale for using crystalline aluminosilicates in anti-corrosion coatings.« less

Propagation of electromagnetic waves in a weak collisional and fully ionized dusty plasma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jia, Jieshu; Yuan, Chengxun, E-mail: yuancx@hit.edu.cn; Gao, Ruilin

2016-04-15

The propagation properties of electromagnetic (EM) waves in fully ionized dusty plasmas is the subject of this study. The dielectric relationships for EM waves propagating in a fully ionized dusty plasma was derived from the Boltzmann distribution law, taking into consideration the collision and charging effects of the dust grains. The propagation properties of the EM waves in a dusty plasma were numerically calculated and studied. The study results indicated that the dusty grains with an increased radius and charge were more likely to impede the penetration of EM waves. Dust grains with large radii and high charge cause themore » attenuation of the EM wave in the dusty plasma. The different density of the dust in the plasma appeared to have no obvious effect on the transmission of the EM waves. The propagation of the EM waves in a weakly ionized dusty plasma varies from that in a fully ionized dusty plasma. The results are helpful to analyze the effects of dust in dusty plasmas and also provide a theoretical basis for future studies.« less

Not an Oxymoron: Some X-ray Binary Pulsars with Enormous Spinup Rates Reveal Weak Magnetic Fields

NASA Astrophysics Data System (ADS)

Christodoulou, D. M.; Laycock, S. G. T.; Kazanas, D.

2018-05-01

Three high-mass X-ray binaries have been discovered recently exhibiting enormous spinup rates. Conventional accretion theory predicts extremely high surface dipolar magnetic fields that we believe are unphysical. Instead, we propose quite the opposite scenario: some of these pulsars exhibit weak magnetic fields, so much so that their magnetospheres are crushed by the weight of inflowing matter. The enormous spinup rate is achieved before inflowing matter reaches the pulsar's surface as the penetrating inner disk transfers its excess angular momentum to the receding magnetosphere which, in turn, applies a powerful spinup torque to the pulsar. This mechanism also works in reverse: it spins a pulsar down when the magnetosphere expands beyond corotation and finds itself rotating faster than the accretion disk which then exerts a powerful retarding torque to the magnetic field and to the pulsar itself. The above scenaria cannot be accommodated within the context of neutron-star accretion processes occurring near spin equilibrium, thus they constitute a step toward a new theory of extreme (far from equilibrium) accretion phenomena.

Ionically Paired Layer-by-Layer Hydrogels: Water and Polyelectrolyte Uptake Controlled by Deposition Time

DOE PAGES

Selin, Victor; Ankner, John Francis; Sukhishvili, Svetlana

2018-01-11

Despite intense recent interest in weakly bound nonlinear (“exponential”) multilayers, the underlying structure-property relationships of these films are still poorly understood. This study explores the effect of time used for deposition of individual layers of nonlinearly growing layer-by-layer (LbL) films composed of poly(methacrylic acid) (PMAA) and quaternized poly-2-(dimethylamino)ethyl methacrylate (QPC) on film internal structure, swelling, and stability in salt solution, as well as the rate of penetration of invading polyelectrolyte chains. Thicknesses of dry and swollen films were measured by spectroscopic ellipsometry, film internal structure—by neutron reflectometry (NR), and degree of PMAA ionization—by Fourier-transform infrared spectroscopy (FTIR). The results suggestmore » that longer deposition times resulted in thicker films with higher degrees of swelling (up to swelling ratio as high as 4 compared to dry film thickness) and stronger film intermixing. The stronger intermixed films were more swollen in water, exhibited lower stability in salt solutions, and supported a faster penetration rate of invading polyelectrolyte chains. These results can be useful in designing polyelectrolyte nanoassemblies for biomedical applications, such as drug delivery coatings for medical implants or tissue engineering matrices.« less

Ionically Paired Layer-by-Layer Hydrogels: Water and Polyelectrolyte Uptake Controlled by Deposition Time

DOE Office of Scientific and Technical Information (OSTI.GOV)

Selin, Victor; Ankner, John Francis; Sukhishvili, Svetlana

Despite intense recent interest in weakly bound nonlinear (“exponential”) multilayers, the underlying structure-property relationships of these films are still poorly understood. This study explores the effect of time used for deposition of individual layers of nonlinearly growing layer-by-layer (LbL) films composed of poly(methacrylic acid) (PMAA) and quaternized poly-2-(dimethylamino)ethyl methacrylate (QPC) on film internal structure, swelling, and stability in salt solution, as well as the rate of penetration of invading polyelectrolyte chains. Thicknesses of dry and swollen films were measured by spectroscopic ellipsometry, film internal structure—by neutron reflectometry (NR), and degree of PMAA ionization—by Fourier-transform infrared spectroscopy (FTIR). The results suggestmore » that longer deposition times resulted in thicker films with higher degrees of swelling (up to swelling ratio as high as 4 compared to dry film thickness) and stronger film intermixing. The stronger intermixed films were more swollen in water, exhibited lower stability in salt solutions, and supported a faster penetration rate of invading polyelectrolyte chains. These results can be useful in designing polyelectrolyte nanoassemblies for biomedical applications, such as drug delivery coatings for medical implants or tissue engineering matrices.« less

Ground Penetrating Radar Investigation of Sinter Deposits at Old Faithful Geyser and Immediately Adjacent Hydrothermal Features, Yellowstone National Park, Wyoming, USA

NASA Astrophysics Data System (ADS)

Foley, D.; Lynne, B. Y.; Jaworowski, C.; Heasler, H.; Smith, G.; Smith, I.

2015-12-01

Ground Penetrating Radar (GPR) was used to evaluate the characteristics of the shallow subsurface siliceous sinter deposits around Old Faithful Geyser. Zones of fractures, areas of subsurface alteration and pre-eruption hydrologic changes at Old Faithful Geyser and surrounding hydrothermal mounds were observed. Despite being viewed directly by about 3,000,000 people a year, shallow subsurface geologic and hydrologic conditions on and near Old Faithful Geyser are poorly characterized. GPR transects of 5754 ft (1754m) show strong horizontal to sub-horizontal reflections, which are interpreted as 2.5 to 4.5 meters of sinter. Some discontinuities in reflections are interpreted as fractures in the sinter, some of which line up with known hydrothermal features and some of which have little to no surface expression. Zones with moderate and weak amplitude reflections are interpreted as sinter that has been hydrothermally altered. Temporal changes from stronger to weaker reflections are correlated with the eruption cycle of Old Faithful Geyser, and are interpreted as post-eruption draining of shallow fractures, followed by pre-eruption fracture filling with liquid or vapor thermal fluids.

When Does Frequency-Independent Selection Maintain Genetic Variation?

PubMed

Novak, Sebastian; Barton, Nicholas H

2017-10-01

Frequency-independent selection is generally considered as a force that acts to reduce the genetic variation in evolving populations, yet rigorous arguments for this idea are scarce. When selection fluctuates in time, it is unclear whether frequency-independent selection may maintain genetic polymorphism without invoking additional mechanisms. We show that constant frequency-independent selection with arbitrary epistasis on a well-mixed haploid population eliminates genetic variation if we assume linkage equilibrium between alleles. To this end, we introduce the notion of frequency-independent selection at the level of alleles, which is sufficient to prove our claim and contains the notion of frequency-independent selection on haploids. When selection and recombination are weak but of the same order, there may be strong linkage disequilibrium; numerical calculations show that stable equilibria are highly unlikely. Using the example of a diallelic two-locus model, we then demonstrate that frequency-independent selection that fluctuates in time can maintain stable polymorphism if linkage disequilibrium changes its sign periodically. We put our findings in the context of results from the existing literature and point out those scenarios in which the possible role of frequency-independent selection in maintaining genetic variation remains unclear. Copyright © 2017 by the Genetics Society of America.

Association of lipoprotein lipase polymorphism rs2197089 with serum lipid concentrations and LPL gene expression.

PubMed

Mo, Xingbo; Liu, Xuehui; Wang, Laiyuan; Lu, Xiangfeng; Chen, Shufeng; Li, Hongfan; Huang, Jianfeng; Chen, Jichun; Cao, Jie; Li, Jianxin; Tang, Yida; Gu, Dongfeng

2013-03-01

Many single-nucleotide polymorphisms (SNPs) have been reported to be associated with lipid concentrations in recent genome-wide association studies. The aim of this study was to validate the associations of rs2197089 in the lipoprotein lipase (LPL) gene with serum lipid concentrations and gene expression levels in the Chinese Han population and examine the potential interactions. A total of 9339 participants were recruited and genotyped for rs2197089. Gene expression levels of LPL in blood cells of 309 participants were evaluated by real-time PCR. We observed significant associations between rs2197089 and decreased triglycerides (TG) (P=0.0006), but not high-density lipoprotein cholesterol (HDL-C) concentration (P=0.0881). However, weak evidence of interaction between cigarette smoking and rs2197089 was detected (P=0.0362). In smokers, significant association between rs2197089 and increased HDL-C concentration was found (P=0.0068). Participants with the minor allele A had higher expression levels of LPL (P=0.0243). The results of our study indicated that rs2197089 was significantly associated with TG but it was associated with HDL-C only in smokers. This SNP seemed to have influence on the expression level of LPL.

Prenatal exposure to drinking-water chlorination by-products, cytochrome P450 gene polymorphisms and small-for-gestational-age neonates.

PubMed

Bonou, Samuella G; Levallois, Patrick; Giguère, Yves; Rodriguez, Manuel; Bureau, Alexandre

2017-10-01

Genetic susceptibility may modulate chlorination by-products (CBPs) effects on fetal growth, especially genes coding for the cytochrome P450 involved in the metabolism of CBPs and steroidogenesis. In a case-control study of 1432 mother-child pairs, we assessed the association between maternal and child single nucleotide polymorphisms (SNPs) within CYP1A2, CYP2A6, CYP2D6 and CYP17A1 genes and small-for-gestational-age neonates (SGA<10th percentile) as well as interaction between these SNPs and maternal exposure to trihalomethanes or haloacetic acids (HAAs) during the third trimester of pregnancy. Interactions were found between mother and neonate carrying CYP17A1 rs4919687A and rs743572G alleles and maternal exposure to total trihalomethanes or five regulated HAAs species. However, these interactions became non statistically significant after correction for multiple testing. There is some evidence, albeit weak, of a potential effect modification of the association between CBPs and SGA by SNPs in CYP17A1 gene. Further studies are needed to validate these observations. Copyright © 2017 Elsevier Inc. All rights reserved.

Phonon dispersions, band structures, and dielectric functions of BeO and BeS polymorphs

NASA Astrophysics Data System (ADS)

Wang, Ke-Long; Gao, Shang-Peng

2018-07-01

Structures, phonon dispersions, electronic structures, and dielectric functions of beryllium oxide (BeO) and beryllium sulfide (BeS) polymorphs are investigated by density functional theory and many-body perturbation theory. Phonon calculations indicate that both wurtzite (w-) and zincblende (zb-) structures are dynamically stable for BeO and BeS, whereas rocksalt (rs-) structures for both BeO and BeS have imaginary phonon frequencies and thus are dynamically unstable at zero pressure. Band structures for the 4 dynamically stable phases show that only w-BeO has a direct band gap. Both the one-shot G0W0 and quasiparticle self-consistent GW methods are used to correct band energies at high symmetry k-points. Bethe-Salpeter equation (BSE), which considers Coulomb correlated electron-hole pairs, is employed to deal with the computation of macroscopic dielectric functions. It is shown that BSE calculation, employing scissors operator derived by self-consistent GW method, can give dielectric functions agreeing very well with experimental measurement of w-BeO. Weak anisotropic characters can be observed for w-BeO and w-BeS. Both zb-BeS and w-BeS show high optical transition probabilities within a narrow ultraviolet energy range.

Genetic contributions to the association between adult height and testicular germ cell tumors.

PubMed

Cook, Michael B; Chia, Victoria M; Berndt, Sonja I; Graubard, Barry I; Chanock, Stephen J; Rubertone, Mark V; Erickson, Ralph L; Hayes, Richard B; McGlynn, Katherine A

2011-06-01

Previously, we have shown that increasing adult height is associated with increased risk of testicular germ-cell tumor (TGCT). Recently, a number of single nucleotide polymorphisms (SNPs) have been found to be related to height. We examined whether these SNPs were associated with TGCT and whether they explained the relationship between height and TGCT. We genotyped 15 height-related SNPs in the US Servicemen's Testicular Tumor Environmental and Endocrine Determinants (STEED) case-control study. DNA was extracted from buccal cell samples and Taqman assays were used to type the selected SNPs. We used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs). There were 561 cases and 676 controls for analysis. Two SNPs were found to be associated with risk of TGCT, rs6060373 (CC vs TT, OR = 1.51, 95% CI: 1.06-2.15) and rs143384 (CC vs TT, OR = 1.53, 95% CI: 1.09-2.15). rs6060373 is an intronic polymorphism of ubiquinol-cytochrome c reductase complex chaperone (UQCC), and rs143384 is a 5'UTR polymorphism of growth differentiation factor 5 (GDF5). No individual SNP attenuated the association between height and TGCT. Adjustment for all SNPs previously associated with adult height reduced the associations between adult height and TGCT by ~8.5%, although the P-value indicated only weak evidence that this difference was important (P = 0.26). This novel analysis provides tentative evidence that SNPs which are associated with adult height may also share an association with risk of TGCT.

Recent divergence, intercontinental dispersal and shared polymorphism are shaping the genetic structure of amphi-Atlantic peatmoss populations.

PubMed

Szövényi, P; Terracciano, S; Ricca, M; Giordano, S; Shaw, A J

2008-12-01

Several lines of evidence suggest that recent long-distance dispersal may have been important in the evolution of intercontinental distribution ranges of bryophytes. However, the absolute rate of intercontinental migration and its relative role in the development of certain distribution ranges is still poorly understood. To this end, the genetic structure of intercontinental populations of six peatmoss species showing an amphi-Atlantic distribution was investigated using microsatellite markers. Methods relying on the coalescent were applied (IM and MIGRATE) to understand the evolution of this distribution pattern in peatmosses. Intercontinental populations of the six peatmoss species were weakly albeit significantly differentiated (average F(ST) = 0.104). This suggests that the North Atlantic Ocean is acting as a barrier to gene flow even in bryophytes adapted to long-range dispersal. The im analysis suggested a relatively recent split of intercontinental populations dating back to the last two glacial periods (9000-289,000 years ago). In contrast to previous hypotheses, analyses indicated that both ongoing migration and ancestral polymorphism are important in explaining the intercontinental genetic similarity of peatmoss populations, but their relative contribution varies with species. Migration rates were significantly asymmetric towards America suggesting differential extinction of genotypes on the two continents or invasion of the American continent by European lineages. These results indicate that low genetic divergence of amphi-Atlantic populations is a general pattern across numerous flowering plants and bryophytes. However, in bryophytes, ongoing intercontinental gene flow and retained shared ancestral polymorphism must both be considered to explain the genetic similarity of intercontinental populations.

Distinct Trajectories of Massive Recent Gene Gains and Losses in Populations of a Microbial Eukaryotic Pathogen

PubMed Central

Hartmann, Fanny E.; Croll, Daniel

2017-01-01

Abstract Differences in gene content are a significant source of variability within species and have an impact on phenotypic traits. However, little is known about the mechanisms responsible for the most recent gene gains and losses. We screened the genomes of 123 worldwide isolates of the major pathogen of wheat Zymoseptoria tritici for robust evidence of gene copy number variation. Based on orthology relationships in three closely related fungi, we identified 599 gene gains and 1,024 gene losses that have not yet reached fixation within the focal species. Our analyses of gene gains and losses segregating in populations showed that gene copy number variation arose preferentially in subtelomeres and in proximity to transposable elements. Recently lost genes were enriched in virulence factors and secondary metabolite gene clusters. In contrast, recently gained genes encoded mostly secreted protein lacking a conserved domain. We analyzed the frequency spectrum at loci segregating a gene presence–absence polymorphism in four worldwide populations. Recent gene losses showed a significant excess in low-frequency variants compared with genome-wide single nucleotide polymorphism, which is indicative of strong negative selection against gene losses. Recent gene gains were either under weak negative selection or neutral. We found evidence for strong divergent selection among populations at individual loci segregating a gene presence–absence polymorphism. Hence, gene gains and losses likely contributed to local adaptation. Our study shows that microbial eukaryotes harbor extensive copy number variation within populations and that functional differences among recently gained and lost genes led to distinct evolutionary trajectories. PMID:28981698

Quantile-Specific Penetrance of Genes Affecting Lipoproteins, Adiposity and Height

PubMed Central

Williams, Paul T.

2012-01-01

Quantile-dependent penetrance is proposed to occur when the phenotypic expression of a SNP depends upon the population percentile of the phenotype. To illustrate the phenomenon, quantiles of height, body mass index (BMI), and plasma lipids and lipoproteins were compared to genetic risk scores (GRS) derived from single nucleotide polymorphisms (SNP)s having established genome-wide significance: 180 SNPs for height, 32 for BMI, 37 for low-density lipoprotein (LDL)-cholesterol, 47 for high-density lipoprotein (HDL)-cholesterol, 52 for total cholesterol, and 31 for triglycerides in 1930 subjects. Both phenotypes and GRSs were adjusted for sex, age, study, and smoking status. Quantile regression showed that the slope of the genotype-phenotype relationships increased with the percentile of BMI (P = 0.002), LDL-cholesterol (P = 3×10−8), HDL-cholesterol (P = 5×10−6), total cholesterol (P = 2.5×10−6), and triglyceride distribution (P = 7.5×10−6), but not height (P = 0.09). Compared to a GRS's phenotypic effect at the 10th population percentile, its effect at the 90th percentile was 4.2-fold greater for BMI, 4.9-fold greater for LDL-cholesterol, 1.9-fold greater for HDL-cholesterol, 3.1-fold greater for total cholesterol, and 3.3-fold greater for triglycerides. Moreover, the effect of the rs1558902 (FTO) risk allele was 6.7-fold greater at the 90th than the 10th percentile of the BMI distribution, and that of the rs3764261 (CETP) risk allele was 2.4-fold greater at the 90th than the 10th percentile of the HDL-cholesterol distribution. Conceptually, it maybe useful to distinguish environmental effects on the phenotype that in turn alters a gene's phenotypic expression (quantile-dependent penetrance) from environmental effects affecting the gene's phenotypic expression directly (gene-environment interaction). PMID:22235250

Progress in terahertz nondestructive testing: A review

NASA Astrophysics Data System (ADS)

Zhong, Shuncong

2018-05-01

Terahertz (THz) waves, whose frequencies range between microwave and infrared, are part of the electromagnetic spectrum. A gap exists in THz literature because investigating THz waves is difficult due to the weak characteristics of the waves and the lack of suitable THz sources and detectors. Recently, THz nondestructive testing (NDT) technology has become an interesting topic. This review outlines several typical THz devices and systems and engineering applications of THz NDT techniques in composite materials, thermal barrier coatings, car paint films, marine protective coatings, and pharmaceutical tablet coatings. THz imaging has higher resolution but lower penetration than ultrasound imaging. This review presents the significance and advantages provided by the emerging THz NDT technique.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Khan, Mojammel A.; Karki, A. B.; Samanta, T.

Here, we report the electronic structure, synthesis, and measurements of the magnetic, transport, and thermal properties of the polycrystalline noncentrosymmetric compound Re 6Zr . We observed a bulk superconducting transition at temperature T c ~ 6.7 K, and measured the resistivity, heat capacity, thermal conductivity, and the London penetration depth below the transition, as well as performed doping and pressure studies. From these measurements we extracted the critical field and the superconducting parameters of Re 6Zr. Lastly, our measurements indicate a relatively weak to moderate contribution from a triplet component to the order parameter, and favor a full superconducting gap,more » although we cannot exclude the existence of point nodes based on our data.« less

Morphology and fracture of enamel.

PubMed

Myoung, Sangwon; Lee, James; Constantino, Paul; Lucas, Peter; Chai, Herzl; Lawn, Brian

2009-08-25

This study examines the inter-relation between enamel morphology and crack resistance by sectioning extracted human molars after loading to fracture. Cracks appear to initiate from tufts, hypocalcified defects at the enamel-dentin junction, and grow longitudinally around the enamel coat to produce failure. Microindentation corner cracks placed next to the tufts in the sections deflect along the tuft interfaces and occasionally penetrate into the adjacent enamel. Although they constitute weak interfaces, the tufts are nevertheless filled with organic matter, and appear to be stabilized against easy extension by self-healing, as well as by mutual stress-shielding and decussation, accounting at least in part for the capacity of tooth enamel to survive high functional forces.

Interaction of capsaicinoids with cell membrane models does not correlate with pungency of peppers

NASA Astrophysics Data System (ADS)

Geraldo, Vananélia P. N.; Ziglio, Analine C.; Gonçalves, Débora; Oliveira, Osvaldo N.

2017-04-01

Mixed monolayers were prepared using phospholipids in order to mimic cell membranes and fractions of capsaicinoids (extracted from Malagueta, Caps-M, and Bhut Jolokia, Caps-B, peppers). According to their surface-pressure isotherms and polarization-modulated infrared reflection absorption spectra (PM-IRRAS), weak molecular-level interactions were observed between Caps and phospholipids. Both Caps-M and Caps-B penetrated into the alkyl tail region of the monolayer, interacted with the phosphate group of the phospholipids and affected hydration of their Cdbnd O groups. Since the physiological activity of Caps is not governed solely by interaction with cell membranes, it should require participation of a neuronal membrane receptor, e.g. vanilloid receptor (TRPV1).

Moxifloxacin: Clinically compatible contrast agent for multiphoton imaging

NASA Astrophysics Data System (ADS)

Wang, Taejun; Jang, Won Hyuk; Lee, Seunghun; Yoon, Calvin J.; Lee, Jun Ho; Kim, Bumju; Hwang, Sekyu; Hong, Chun-Pyo; Yoon, Yeoreum; Lee, Gilgu; Le, Viet-Hoan; Bok, Seoyeon; Ahn, G.-One; Lee, Jaewook; Gho, Yong Song; Chung, Euiheon; Kim, Sungjee; Jang, Myoung Ho; Myung, Seung-Jae; Kim, Myoung Joon; So, Peter T. C.; Kim, Ki Hean

2016-06-01

Multiphoton microscopy (MPM) is a nonlinear fluorescence microscopic technique widely used for cellular imaging of thick tissues and live animals in biological studies. However, MPM application to human tissues is limited by weak endogenous fluorescence in tissue and cytotoxicity of exogenous probes. Herein, we describe the applications of moxifloxacin, an FDA-approved antibiotic, as a cell-labeling agent for MPM. Moxifloxacin has bright intrinsic multiphoton fluorescence, good tissue penetration and high intracellular concentration. MPM with moxifloxacin was demonstrated in various cell lines, and animal tissues of cornea, skin, small intestine and bladder. Clinical application is promising since imaging based on moxifloxacin labeling could be 10 times faster than imaging based on endogenous fluorescence.

[Type I Chiari malformation associated with cerebellar atrophy. Case report].

PubMed

Moscote-Salazar, Luis Rafael; Calderón-Miranda, Willem Guillermo; Alvis-Miranda, Hernando Raphael; Lee-Aguirre, Ángel; Alcalá-Cerra, Gabriel

2017-01-01

Chiari malformation is characterized by caudal displacement of the cerebellar tonsils that penetrate into the spinal canal through the foramen magnum, achieving reach the atlas or axis. trunk and any drop of the fourth ventricle is observed. Typically is seen in young adults. In some cases scoliosis and Syringomyelic cavities may occur. The authors present (as far as they know) the first case in the literature with long term follow-up, of a caucasian woman with an unusual form of cerebellar atrophy and Chiari Type I malformation, suffering from weakness in his upper and lower extremities with rapidly progression. The patient was successfully treated with suboccipital decompression and C1 laminectomy.

Investigating the association between polymorphisms in connective tissue growth factor and susceptibility to colon carcinoma.

PubMed

Ahmad, Abrar; Askari, Shlear; Befekadu, Rahel; Hahn-Strömberg, Victoria

2015-04-01

There have been numerous studies on the gene expression of connective tissue growth factor (CTGF) in colorectal cancer, however very few have investigated polymorphisms in this gene. The present study aimed to determine whether single nucleotide polymorphisms (SNPs) in the CTGF gene are associated with a higher susceptibility to colon cancer and/or an invasive tumor growth pattern. The CTGF gene was genotyped for seven SNPs (rs6918698, rs1931002, rs9493150, rs12526196, rs12527705, rs9399005 and rs12527379) by pyrosequencing. Formalin‑fixed paraffin‑embedded tissue samples (n=112) from patients diagnosed with colon carcinoma, and an equal number of blood samples from healthy controls, were selected for genomic DNA extraction. The complexity index was measured using images of tumor samples (n=64) stained for cytokeratin‑8. The images were analyzed and correlated with the identified CTGF SNPs and clinicopathological parameters of the patients, including age, gender, tumor penetration, lymph node metastasis, systemic metastasis, differentiation and localization of tumor. It was demonstrated that the frequency of the SNP rs6918698 GG genotype was significantly associated (P=0.05) with an increased risk of colon cancer, as compared with the GC and CC genotypes. The other six SNPs (rs1931002, rs9493150, rs12526196, rs12527705, rs9399005 and rs12527379) exhibited no significant difference in the genotype and allele frequencies between patients diagnosed with colon carcinoma and the normal healthy population. A trend was observed between genotype variation at rs6918698 and the complexity index (P=0.052). The complexity index and genotypes for any of the studied SNPs were not significantly correlated with clinical or pathological parameters of the patients. These results indicate that the rs6918698 GG genotype is associated with an increased risk of developing colon carcinoma, and genetic variations at the rs6918698 are associated with the growth pattern of the tumor. The present results may facilitate the identification of potential biomarkers of the disease in addition to drug targets.

Interactions between propagating rifts and pre-existing linear rheological heterogeneities: insights from 3D analogue experiments of rotational extension

NASA Astrophysics Data System (ADS)

Molnar, Nicolas; Cruden, Alexander

2017-04-01

Propagating rifts are a natural consequence of lithospheric plates that diverge with respect to each other about a pole of rotation. This process of "unzipping" is common in the geological record, but how rifts interact with pre-existing structures (i.e., with a non-homogeneous lithosphere) as they propagate is poorly understood. Here we report on a series of lithospheric-scale three-dimensional analogue experiments of rotational extension with in-built, variably oriented linear weak zones in the lithospheric mantle, designed to investigate the role that inherited structural or thermal weaknesses play in the localisation of strain and rifting. Surface strain and dynamic topography in the analogue models are quantified by high-resolution particle imaging velocimetry and digital photogrammetry, which allows us to characterise the spatio-temporal evolution of deformation as a function of the orientation of the linear heterogeneities in great detail. The results show that the presence of a linear zone of weakness oriented at low angles with respect to the rift axis (i.e., favourably oriented) produces strain localisation in narrow domains, which enhances the "unzipping" process prior to continental break up. Strong strain partitioning is observed when the linear heterogeneity is oriented at high angles with respect to the rift axis (i.e., unfavourably oriented). In these experiments, early sub-parallel V-shaped basins propagate towards the pole of rotation until they are abandoned and strain is transferred entirely to structures developed in the vicinity of the strongly oblique weak lithosphere zone boundary. The modelling also provides insights on how propagating rift branches that penetrate the weak linear zone boundary are aborted when strain is relayed onto structures that develop in rheologically weaker areas. The experimental results are summarised in terms of their evolution, patterns of strain localisation, and dynamic topography as a function of the lithospheric heterogeneity obliquity angle, and compared to ancient and modern examples in nature.

Ginzburg-Landau expansion in strongly disordered attractive Anderson-Hubbard model

NASA Astrophysics Data System (ADS)

Kuchinskii, E. Z.; Kuleeva, N. A.; Sadovskii, M. V.

2017-07-01

We have studied disordering effects on the coefficients of Ginzburg-Landau expansion in powers of superconducting order parameter in the attractive Anderson-Hubbard model within the generalized DMFT+Σ approximation. We consider the wide region of attractive potentials U from the weak coupling region, where superconductivity is described by BCS model, to the strong coupling region, where the superconducting transition is related with Bose-Einstein condensation (BEC) of compact Cooper pairs formed at temperatures essentially larger than the temperature of superconducting transition, and a wide range of disorder—from weak to strong, where the system is in the vicinity of Anderson transition. In the case of semielliptic bare density of states, disorder's influence upon the coefficients A and B of the square and the fourth power of the order parameter is universal for any value of electron correlation and is related only to the general disorder widening of the bare band (generalized Anderson theorem). Such universality is absent for the gradient term expansion coefficient C. In the usual theory of "dirty" superconductors, the C coefficient drops with the growth of disorder. In the limit of strong disorder in BCS limit, the coefficient C is very sensitive to the effects of Anderson localization, which lead to its further drop with disorder growth up to the region of the Anderson insulator. In the region of BCS-BEC crossover and in BEC limit, the coefficient C and all related physical properties are weakly dependent on disorder. In particular, this leads to relatively weak disorder dependence of both penetration depth and coherence lengths, as well as of related slope of the upper critical magnetic field at superconducting transition, in the region of very strong coupling.

STK15 polymorphisms and association with risk of invasive ovarian cancer.

PubMed

Dicioccio, Richard A; Song, Honglin; Waterfall, Christy; Kimura, Makoto T; Nagase, Hiroki; McGuire, Valerie; Hogdall, Estrid; Shah, Mitul N; Luben, Robert N; Easton, Douglas F; Jacobs, Ian J; Ponder, Bruce A J; Whittemore, Alice S; Gayther, Simon A; Pharoah, Paul D P; Kruger-Kjaer, Susan

2004-10-01

STK15 is a putative oncogene that codes for a centrosome-associated, serine/threonine kinase, the normal function of which is to ensure accurate segregation of chromosomes during mitosis. Amplification of STK15 has been reported in ovarian tumors, suggesting a role in ovarian cancer pathology. STK15 is polymorphic with two single nucleotide substitutions (449t/a and 527g/a) in evolutionarily conserved regions causing amino acid changes (F31I and V57I). Two other nucleotide substitutions (287c/g and 1891g/c) of unknown significance are in 5' and 3' untranslated regions (UTR), respectively. To learn more about the involvement of STK15 in ovarian cancer, we genotyped and haplotyped these polymorphisms in three population-based ovarian cancer case-control studies from the United Kingdom, United States, and Denmark with 1,821 combined cases and 2,467 combined controls and calculated risks for developing ovarian cancer. Genotypes of individual polymorphisms in control groups of the United Kingdom, United States, and Denmark conformed to Hardy-Weinberg equilibrium. In combined cases and combined controls, rare allele frequencies were 0.23 and 0.21 for I31, 0.16 and 0.17 for I57, 0.08 and 0.07 for 5' UTR g, and 0.25 and 0.24 for 3' UTR c, respectively. Using FF common homozygotes of F31I as comparator, there was increased ovarian cancer risk to FI heterozygotes (odds ratio, 1.18; 95% confidence interval, 1.01-1.36), II homozygotes (odds ratio, 1.25; 95% confidence interval, 0.89-1.75), and I31 allele carriers (odds ratio, 1.17; 95% confidence interval, 1.02-1.35) in the combined group data. For either V57I, 5' UTR C/G, or 3' UTR G/C, all genotypic ovarian cancer risks were essentially in unity relative to their respective common homozygotes, VV, cc, or gg. Haplotype analysis of combined group data revealed seven haplotypes with frequencies between 0.02 and 0.5, with c-F-V-g the most common. None of the haplotype-specific risks significantly differed from unity relative to c-F-V-g. These results suggest a model of dominant inheritance of ovarian cancer risk by the I31 allele of F31I and that the I31 allele may be a common ovarian cancer susceptibility allele of low penetrance.

Etude de la Generation des Ultrasons Par Laser dans un Materiau Composite

NASA Astrophysics Data System (ADS)

Dubois, Marc

Laser generation of ultrasound is not a new subject. Many authors have proposed mathematical models of the thermoelastic process of generation of acoustic waves. However, none of those models, up to now, could take simultaneously the effects of the thermal conduction, the optical penetration, the anisotropy of the material and any time and surface profiles of the laser excitation into account. The model presented in this work takes all these parameters into consideration in the case of an infinite orthotropic plate. The mathematical approach used allows to obtain an analytical solution of the mechanical displacement field in the Laplace and two-dimensional (2-D) Fourier spaces. Numerical inverse Laplace and 2-D Fourier transformations bring the mechanical displacement field back into the normal spaces. The use of direct numerical transformations enables to consider almost any time and spatial distributions of the generation laser beam. The acoustic displacements calculated by this model have been compared to experimental displacements measured with a wide band optical detection system. The features of this system allow the quantitative measurement of the parallel and normal displacements to the surface of the sample. Hence, the calculated normal and parallel displacements have been compared to those experimentally measured at various locations on aluminum, glass and polymer samples. In all cases, the agreement between the calculated and experimentally measured displacements was good. The semi-analytical model having proved its validity, it has been used, in addition to a completely analytical one-dimensional model, to study the effects of the optical penetration and the laser pulse duration on the longitudinal acoustic wave generated. This study has established that a short enough laser pulse and a large irradiation with regard to the sample thickness allows to determine quantitatively, from the full width at half maximum of the acoustic pulse, the optical penetration depth at the wavelength of the generation laser inside the material. This semi-analytical model has also permitted to analyze the effects of the optical penetration on the directivity patterns of the longitudinal and shear waves generated by a thermoelastic source. This study has clearly shown that the optical penetration modifies significantly the longitudinal wave directivity pattern, but has only weak effects on the shear wave one. (Abstract shortened by UMI.).

AFLP analysis of Cynodon dactylon (L.) Pers. var. dactylon genetic variation.

PubMed

Wu, Y Q; Taliaferro, C M; Bai, G H; Anderson, M P

2004-08-01

Cynodon dactylon (L.) Pers. var. dactylon (common bermudagrass) is geographically widely distributed between about lat 45 degrees N and lat 45 degrees S, penetrating to about lat 53 degrees N in Europe. The extensive variation of morphological and adaptive characteristics of the taxon is substantially documented, but information is lacking on DNA molecular variation in geographically disparate forms. Accordingly, this study was conducted to assess molecular genetic variation and genetic relatedness among 28 C. dactylon var. dactylon accessions originating from 11 countries on 4 continents (Africa, Asia, Australia, and Europe). A fluorescence-labeled amplified fragment length polymorphism (AFLP) DNA profiling method was used to detect the genetic diversity and relatedness. On the basis of 443 polymorphic AFLP fragments from 8 primer combinations, the accessions were grouped into clusters and subclusters associating with their geographic origins. Genetic similarity coefficients (SC) for the 28 accessions ranged from 0.53 to 0.98. Accessions originating from Africa, Australia, Asia, and Europe formed major groupings as indicated by cluster and principal coordinate analysis. Accessions from Australia and Asia, though separately clustered, were relatively closely related and most distantly related to accessions of European origin. African accessions formed two distant clusters and had the greatest variation in genetic relatedness relative to accessions from other geographic regions. Sampling the full extent of genetic variation in C. dactylon var. dactylon would require extensive germplasm collection in the major geographic regions of its distributional range.

Evaluation of germline sequence variants of GFRA1, GFRA2, and GFRA3 genes in a cohort of Spanish patients with sporadic medullary thyroid cancer.

PubMed

Borrego, Salud; Fernández, Raquel M; Dziema, Heather; Japón, Miguel A; Marcos, Irene; Eng, Charis; Antiñolo, Guillermo

2002-11-01

The etiology of sporadic medullary thyroid carcinoma (sMTC) remains elusive. While germline gain-of-function mutations in the RET proto-oncogene cause hereditary MTC, somatic RET mutations have been described in a variable number of sMTC. So far, S836S of RET, is the only variant whose association with sMTC has been found in several European cohorts. Because RET variants seem to be associated with MTC, it is plausible that variants in genes encoding for RET coreceptors may play a role in the pathogenesis of sMTC. Recently, we described two possible low penetrance susceptibility alleles in the gene encoding RET coreceptor GFRalpha1, -193C > G and 537T > C, in a German series of sMTC. In this study, we have genotyped nine polymorphisms within GFRA1-3 genes for 51 Spanish sMTC, and 100 normal controls. Our results show that no statistical signification was found when Spanish sMTC patients were compared to controls. Taken together with the observations in the German sMTC series, the present findings suggest that GFRA1-193C > G and 537T > C could be in linkage disequilibrium with other loci responsible for the disease with a founder effect in Germany. Alternatively, the combined observations might also suggest that, if indeed the polymorphisms are functional, the effect is small.

The rs10993994 risk allele for prostate cancer results in clinically relevant changes in microseminoprotein-beta expression in tissue and urine.

PubMed

Whitaker, Hayley C; Kote-Jarai, Zsofia; Ross-Adams, Helen; Warren, Anne Y; Burge, Johanna; George, Anne; Bancroft, Elizabeth; Jhavar, Sameer; Leongamornlert, Daniel; Tymrakiewicz, Malgorzata; Saunders, Edward; Page, Elizabeth; Mitra, Anita; Mitchell, Gillian; Lindeman, Geoffrey J; Evans, D Gareth; Blanco, Ignacio; Mercer, Catherine; Rubinstein, Wendy S; Clowes, Virginia; Douglas, Fiona; Hodgson, Shirley; Walker, Lisa; Donaldson, Alan; Izatt, Louise; Dorkins, Huw; Male, Alison; Tucker, Kathy; Stapleton, Alan; Lam, Jimmy; Kirk, Judy; Lilja, Hans; Easton, Douglas; Cooper, Colin; Eeles, Rosalind; Neal, David E

2010-10-13

Microseminoprotein-beta (MSMB) regulates apoptosis and using genome-wide association studies the rs10993994 single nucleotide polymorphism in the MSMB promoter has been linked to an increased risk of developing prostate cancer. The promoter location of the risk allele, and its ability to reduce promoter activity, suggested that the rs10993994 risk allele could result in lowered MSMB in benign tissue leading to increased prostate cancer risk. MSMB expression in benign and malignant prostate tissue was examined using immunohistochemistry and compared with the rs10993994 genotype. Urinary MSMB concentrations were determined by ELISA and correlated with urinary PSA, the presence or absence of cancer, rs10993994 genotype and age of onset. MSMB levels in prostate tissue and urine were greatly reduced with tumourigenesis. Urinary MSMB was better than urinary PSA at differentiating men with prostate cancer at all Gleason grades. The high risk allele was associated with heterogeneity of MSMB staining and loss of MSMB in both tissue and urine in benign prostate. These data show that some high risk alleles discovered using genome-wide association studies produce phenotypic effects with potential clinical utility. We provide the first link between a low penetrance polymorphism for prostate cancer and a potential test in human tissue and bodily fluids. There is potential to develop tissue and urinary MSMB for a biomarker of prostate cancer risk, diagnosis and disease monitoring.

The rs10993994 Risk Allele for Prostate Cancer Results in Clinically Relevant Changes in Microseminoprotein-Beta Expression in Tissue and Urine

PubMed Central

Whitaker, Hayley C.; Warren, Anne Y.; Burge, Johanna; George, Anne; Bancroft, Elizabeth; Jhavar, Sameer; Leongamornlert, Daniel; Tymrakiewicz, Malgorzata; Saunders, Edward; Page, Elizabeth; Mitra, Anita; Mitchell, Gillian; Lindeman, Geoffrey J.; Evans, D. Gareth; Blanco, Ignacio; Mercer, Catherine; Rubinstein, Wendy S.; Clowes, Virginia; Douglas, Fiona; Hodgson, Shirley; Walker, Lisa; Donaldson, Alan; Izatt, Louise; Dorkins, Huw; Male, Alison; Tucker, Kathy; Stapleton, Alan; Lam, Jimmy; Kirk, Judy; Lilja, Hans; Easton, Douglas; Cooper, Colin; Eeles, Rosalind; Neal, David E.

2010-01-01

Background Microseminoprotein-beta (MSMB) regulates apoptosis and using genome-wide association studies the rs10993994 single nucleotide polymorphism in the MSMB promoter has been linked to an increased risk of developing prostate cancer. The promoter location of the risk allele, and its ability to reduce promoter activity, suggested that the rs10993994 risk allele could result in lowered MSMB in benign tissue leading to increased prostate cancer risk. Methodology/Principal Findings MSMB expression in benign and malignant prostate tissue was examined using immunohistochemistry and compared with the rs10993994 genotype. Urinary MSMB concentrations were determined by ELISA and correlated with urinary PSA, the presence or absence of cancer, rs10993994 genotype and age of onset. MSMB levels in prostate tissue and urine were greatly reduced with tumourigenesis. Urinary MSMB was better than urinary PSA at differentiating men with prostate cancer at all Gleason grades. The high risk allele was associated with heterogeneity of MSMB staining and loss of MSMB in both tissue and urine in benign prostate. Conclusions These data show that some high risk alleles discovered using genome-wide association studies produce phenotypic effects with potential clinical utility. We provide the first link between a low penetrance polymorphism for prostate cancer and a potential test in human tissue and bodily fluids. There is potential to develop tissue and urinary MSMB for a biomarker of prostate cancer risk, diagnosis and disease monitoring. PMID:20967219

A Laboratory Impact Study of Simulated Edgeworth-Kuiper Belt Objects

NASA Astrophysics Data System (ADS)

Ryan, Eileen V.; Davis, Donald R.; Giblin, Ian

1999-11-01

This paper reports on a series of laboratory impact experiments designed to provide basic data on how simulated Edgeworth-Kuiper belt objects (EKOs) fragment in an impact event. In September-October 1997 we carried out 20 low-velocity airgun shots at the Ames Vertical Gun Range into porous and homogeneous ice spheres using aluminum, fractured ice, and solid ice projectiles. We found that the porous ice targets behaved as strongly as solid ice in collision. Energy is apparently well dissipated by the void spaces within the target, such that these fragile ice structures respond as if they were strong in impacts. Therefore, it would appear that if EKOs are porous, they are not collisionally weak. Also, our data show that collisional outcomes for low-velocity impacts into ice targets depend on the type of projectile used as well as the properties of the target. We observed that the degree of fragmentation for a given type of target increases as the strength of the projectile increases. Aluminum projectiles are far more damaging to the target at the same collisional energy than are solid ice projectiles, which, in turn, are more damaging than fractured ice projectiles. One possible explanation for this behavior is the variable depth of penetration of the projectile for the different cases—stronger projectiles penetrate more deeply and couple more energy into the target than do weak projectiles. Based on this, if we assume that there has not been significant heating or differentiation in the Edgeworth-Kuiper (E-K) belt, the most applicable impact strength for the low-velocity E-K belt collisions is likely to be that derived from similar target/projectile materials impacting each other. The laboratory data from this analysis indicate that a value for impact strength>5×10 5 erg/cm 3 is appropriate for porous ice targets impacted with solid/porous ice projectiles.

A global perspective on hepatitis B‐related single nucleotide polymorphisms and evolution during human migration

PubMed Central

Jeng, Wen‐Juei; Lin, Chun‐Yen

2017-01-01

Genome‐wide association studies have indicated that human leukocyte antigen (HLA)‐DP and HLA‐DQ play roles in persistent hepatitis B virus (HBV) infection in Asia. To understand the evolution of HBV‐related single nucleotide polymorphisms (SNPs) and to correlate these SNPs with chronic HBV infection among different populations, we conducted a global perspective study on hepatitis‐related SNPs. We selected 12 HBV‐related SNPs on the HLA locus and two HBV and three hepatitis C virus immune‐related SNPs for analysis. Five nasopharyngeal carcinoma‐related SNPs served as controls. All SNP data worldwide from 26 populations were downloaded from 1,000 genomes. We found a dramatic difference in the allele frequency in most of the HBV‐ and HLA‐related SNPs in East Asia compared to the other continents. A sharp change in allele frequency in 8 of 12 SNPs was found between Bengali populations in Bangladesh and Chinese Dai populations in Xishuangbanna, China (P < 0.001); these areas represent the junction of South and East Asia. For the immune‐related SNPs, significant changes were found after leaving Africa. Most of these genes shifted from higher expression genotypes in Africa to lower expression genotypes in either Europe or South Asia (P < 0.001). During this two‐stage adaptation, immunity adjusted toward a weak immune response, which could have been a survival strategy during human migration to East Asia. The prevalence of chronic HBV infection in Africa is as high as in Asia; however, the HBV‐related SNP genotypes are not present in Africa, and so the genetic mechanism of chronic HBV infection in Africa needs further exploration. Conclusion: Two stages of genetic changes toward a weak immune response occurred when humans migrated out of Africa. These changes could be a survival strategy for avoiding cytokine storms and surviving in new environments. (Hepatology Communications 2017;1:1005–1013) PMID:29404438

Incidence of Dysphagia and Serial Videofluoroscopic Swallow Study Findings After Anterior Cervical Discectomy and Fusion: A Prospective Study.

PubMed

Min, Yusun; Kim, Won-Seok; Kang, Sung Shik; Choi, Jin Man; Yeom, Jin S; Paik, Nam-Jong

2016-05-01

Prospective study. To prospectively assess the incidence of dysphagia and to present the serial changes of each finding in the videofluoroscopic swallow study (VFSS) after anterior cervical discectomy and fusion (ACDF). The reported incidence of dysphagia after ACDF has varied widely, and the serial changes of dysphagia using VFSS have not been clearly determined yet. Data of 47 patients preoperatively and at 1 week and 1 month postoperatively were used for the analyses. The Bazaz dysphagia score and VFSS were checked preoperatively and at 1 week and 1 month postoperatively. The presence of aspiration or penetration, amount of vallecular and pyriform sinus residues, functional dysphagia scale, temporal parameters of oral transit time, pharyngeal transit time, and pharyngeal delay time (PDT) were evaluated from the VFSS data. Incidences of dysphagia measured by the Bazaz dysphagia score were 83.0% at 1 week and 59.6% at 1 month after ACDF. Although the incidence of aspiration was 4.3% and the incidence of penetration was 36.2% at 1 week and 25.5% at 1 month after surgery, none of the patients had aspiration pneumonia. The number of patients with vallecular and pyriform sinus residues significantly increased after ACDF. Further, there were no statistically significant changes at all time points in terms of oral transit time, pharyngeal transit time, and pharyngeal delay time. Dysphagia is common until 1 month after ACDF. Although the incidence of aspiration or penetration in VFSS after ACDF was high, no patient had aspiration pneumonia, which may be because of the intact neurological swallowing mechanism. The typical pattern of dysphagia after ACDF included vallecular and pyriform sinuses filled with postswallow residue, which may result from soft tissue edema and weak constriction of pharyngeal muscles after ACDF.

Determination of silver in personal care nanoproducts and effects on dermal exposure

NASA Astrophysics Data System (ADS)

Wasukan, Nootcharin; Srisung, Sujittra; Kulthong, Kornphimol; Boonrungsiman, Suwimon; Maniratanachote, Rawiwan

2015-11-01

Silver (Ag) is one of the widely used nanomaterials in cosmetics, personal care, and household products. This research aimed to investigate the Ag concentration contained in 20 commercial nanoproducts using a simple and reliable procedure. The exposure and adverse effects of a single topical application of Ag on the skin were also evaluated. Herein, we demonstrated that the technique of wet acid digestion, extraction and detection of Ag with graphite furnace absorption spectrometry were effective for any and all nanoproduct matrices. The Ag morphology was characterized by scanning and transmission electron microscopy equipped with energy-dispersive x-ray spectroscopy. Penetration of Ag was evaluated using a polyethersulfone (PES) membrane through a Franz cell and reconstructed human epidermis (RhE) tissue. A skin irritation test was performed on RhE, an acceptable in vitro model which was in compliance with OECD test guideline 439. The results showed that the initial Ag concentration in the tested nanoproducts ranged between 0.0058 and 94 µg/g. However, particulate Ag was only found in two products, both of a liquid formulation. Silver penetration through a PES membrane (0.12-53 % by weight) was weakly correlated with the initial Ag concentration in each sample, but more so to the product formulation. The liquid products demonstrated the highest percent of average Ag penetration, followed by the semi-solid and solid formulations, respectively. In contrast, neither any Ag diffusion from these products into the RhE tissue nor any irritation or toxicity was detected. This study suggests a screening method to evaluate the Ag level in products and their potential adverse effects on the skin that could be incorporated as a part of risk assessment for nanotechnology products.

Multipoint Observations of Energetic Particle Injections and Substorm Activity During a Conjunction Between Magnetospheric Multiscale (MMS) and Van Allen Probes

NASA Astrophysics Data System (ADS)

Turner, D. L.; Fennell, J. F.; Blake, J. B.; Claudepierre, S. G.; Clemmons, J. H.; Jaynes, A. N.; Leonard, T.; Baker, D. N.; Cohen, I. J.; Gkioulidou, M.; Ukhorskiy, A. Y.; Mauk, B. H.; Gabrielse, C.; Angelopoulos, V.; Strangeway, R. J.; Kletzing, C. A.; Le Contel, O.; Spence, H. E.; Torbert, R. B.; Burch, J. L.; Reeves, G. D.

2017-11-01

This study examines multipoint observations during a conjunction between Magnetospheric Multiscale (MMS) and Van Allen Probes on 7 April 2016 in which a series of energetic particle injections occurred. With complementary data from Time History of Events and Macroscale Interactions during Substorms, Geotail, and Los Alamos National Laboratory spacecraft in geosynchronous orbit (16 spacecraft in total), we develop new insights on the nature of energetic particle injections associated with substorm activity. Despite this case involving only weak substorm activity (maximum AE <300 nT) during quiet geomagnetic conditions in steady, below-average solar wind, a complex series of at least six different electron injections was observed throughout the system. Intriguingly, only one corresponding ion injection was clearly observed. All ion and electron injections were observed at <600 keV only. MMS reveals detailed substructure within the largest electron injection. A relationship between injected electrons with energy <60 keV and enhanced whistler mode chorus wave activity is also established from Van Allen Probes and MMS. Drift mapping using a simplified magnetic field model provides estimates of the dispersionless injection boundary locations as a function of universal time, magnetic local time, and L shell. The analysis reveals that at least five electron injections, which were localized in magnetic local time, preceded a larger injection of both electrons and ions across nearly the entire nightside of the magnetosphere near geosynchronous orbit. The larger ion and electron injection did not penetrate to L < 6.6, but several of the smaller electron injections penetrated to L < 6.6. Due to the discrepancy between the number, penetration depth, and complexity of electron versus ion injections, this event presents challenges to the current conceptual models of energetic particle injections.

Self-penetration--a structural compromise between single networks and interpenetration: magnetic properties and crystal structures of

PubMed

Jensen; Price; Batten; Moubaraki; Murray

2000-09-01

The three-dimensional coordination polymers [Mn(dca)2(H2O)] (1) and [M(dca)(tcm)], M =Co (2), Ni (3), Cu (4), dca =dicyanamide, N(CN)2-, tcm = tricyanomethanide, C(CN)3-, have isomorphous structures. In 1 half the dca ligands coordinate directly (through all three nitrogen atoms) to three Mn atoms (all metal atoms are six-coordinate), while the other half coordinate to two Mn atoms (through the nitrile nitrogens) and hydrogen bond to water molecules coordinated to a third Mn atom (through the amide nitrogen). This dca. H2O structural moiety is disordered over a mirror plane, and is replaced by the structurally equivalent tcm ligand in compounds 2-4. The resulting structures display a new self-penetrating 3,6-connected (2:1) network topology that can be related to, but is different from, the rutile net. The self-penetrating [M(dca)(tcm)] network can be viewed as a structural compromise between the two interpenetrating rutile-like networks of [M(tcm)2] and the single rutile-like network of alpha-[M(dca)2]. The temperature and field dependence of the DC and AC magnetic susceptibilities and magnetisations has been measured for complexes 1-4. Compounds 1-3 exhibit long-range magnetic order with critical temperatures of 6.3 K for 1, 3.5 K for 2 and 8.0 K for 3. The Cu11 compound 4 does not order and is essentially a paramagnet. Hysteresis measurements of coercive field and remnant magnetisation show that 1, 2 and 3 are soft magnets, 1 being a canted-spin antiferromagnet (weak ferromagnet), while 2 and 3 are ferromagnets that display some unusual features in their high-field magnetisation isotherms in comparison to their related alpha-[M(dca)2] phases.

Multipoint Observations of Energetic Particle Injections and Substorm Activity During a Conjunction Between Magnetospheric Multiscale (MMS) and Van Allen Probes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Turner, Drew L.; Fennell, J. F.; Blake, J. B.

Here, this study examines multipoint observations during a conjunction between Magnetospheric Multiscale (MMS) and Van Allen Probes on 7 April 2016 in which a series of energetic particle injections occurred. With complementary data from Time History of Events and Macroscale Interactions during Substorms, Geotail, and Los Alamos National Laboratory spacecraft in geosynchronous orbit (16 spacecraft in total), we develop new insights on the nature of energetic particle injections associated with substorm activity. Despite this case involving only weak substorm activity (maximum AE <300 nT) during quiet geomagnetic conditions in steady, below-average solar wind, a complex series of at least sixmore » different electron injections was observed throughout the system. Intriguingly, only one corresponding ion injection was clearly observed. All ion and electron injections were observed at <600 keV only. MMS reveals detailed substructure within the largest electron injection. A relationship between injected electrons with energy <60 keV and enhanced whistler mode chorus wave activity is also established from Van Allen Probes and MMS. Drift mapping using a simplified magnetic field model provides estimates of the dispersionless injection boundary locations as a function of universal time, magnetic local time, and L shell. The analysis reveals that at least five electron injections, which were localized in magnetic local time, preceded a larger injection of both electrons and ions across nearly the entire nightside of the magnetosphere near geosynchronous orbit. The larger ion and electron injection did not penetrate to L < 6.6, but several of the smaller electron injections penetrated to L < 6.6. Due to the discrepancy between the number, penetration depth, and complexity of electron versus ion injections, this event presents challenges to the current conceptual models of energetic particle injections.« less

Multipoint Observations of Energetic Particle Injections and Substorm Activity During a Conjunction Between Magnetospheric Multiscale (MMS) and Van Allen Probes

DOE PAGES

Turner, Drew L.; Fennell, J. F.; Blake, J. B.; ...

2017-09-25

Here, this study examines multipoint observations during a conjunction between Magnetospheric Multiscale (MMS) and Van Allen Probes on 7 April 2016 in which a series of energetic particle injections occurred. With complementary data from Time History of Events and Macroscale Interactions during Substorms, Geotail, and Los Alamos National Laboratory spacecraft in geosynchronous orbit (16 spacecraft in total), we develop new insights on the nature of energetic particle injections associated with substorm activity. Despite this case involving only weak substorm activity (maximum AE <300 nT) during quiet geomagnetic conditions in steady, below-average solar wind, a complex series of at least sixmore » different electron injections was observed throughout the system. Intriguingly, only one corresponding ion injection was clearly observed. All ion and electron injections were observed at <600 keV only. MMS reveals detailed substructure within the largest electron injection. A relationship between injected electrons with energy <60 keV and enhanced whistler mode chorus wave activity is also established from Van Allen Probes and MMS. Drift mapping using a simplified magnetic field model provides estimates of the dispersionless injection boundary locations as a function of universal time, magnetic local time, and L shell. The analysis reveals that at least five electron injections, which were localized in magnetic local time, preceded a larger injection of both electrons and ions across nearly the entire nightside of the magnetosphere near geosynchronous orbit. The larger ion and electron injection did not penetrate to L < 6.6, but several of the smaller electron injections penetrated to L < 6.6. Due to the discrepancy between the number, penetration depth, and complexity of electron versus ion injections, this event presents challenges to the current conceptual models of energetic particle injections.« less

Polymorphisms in the serotonin transporter and monoamine oxidase A genes and their relationship to personality traits measured by the Temperament and Character Inventory and NEO Five-Factor Inventory in healthy volunteers.

PubMed

Samochowiec, Jerzy; Syrek, Szymon; Michał, Parus; Ryzewska-Wódecka, Aneta; Samochowiec, Agnieszka; Horodnicki, Jan; Zakrzewska, Marzena; Kucharska-Mazur, Jolanta

2004-01-01

The associations between 5-HTT-linked polymorphic region (5-HTT-LPR), monoamine oxidase A (MAOA)-LPR and the dimensions of temperament evaluated using the Temperament and Character Inventory (TCI) and NEO Five-Factor Inventory (NEO-FFI) were studied. One hundred healthy volunteers (without psychiatric disorders) were recruited to represent a cross-section of the population of Szczecin (Poland) in terms of sex, age and education. No associations between 5-HTT-LPR and the TCI harm avoidance dimension and between 5-HTT-LPR and the NEO-FFI neuroticism dimension were found. Males carrying the 3-VNTR MAOA gene variant (209 bp) had significantly lower values on the NEO-FFI openness dimension (p = 0.039) and obtained higher scores on the subdimension 3 of the TCI reward dependence (RD3), i.e. attachment vs. detachment (p = 0.005). Individuals carrying the 'short' variant of 5-HTT-LPR had lower values on the reward dependence dimension and the RD4 subdimension (dependence vs. independence) than individuals not carrying the 'short' variant (p = 0.039 and p = 0.011, respectively). Females carrying the 'short' variant had lower values on NS1 (exploratory excitability vs. stoic rigidity) and RD4 (dependence vs. independence) than those not carrying the variant (p = 0.042 and 0.043, respectively). The obtained level of significance with respect to the observed associations between 5-HTT-LPR and the reward dependence scales and subscales and between 5-HTT-LPR and the NS1 subscale are too weak for further interpretation. Our results do not confirm the hypothesis that there is a simple correlation between single gene polymorphisms and a personality trait measured by the TCI and NEO-FFI scales.

Effect of genetic polymorphism on the inhibition of dopamine formation from p-tyramine catalyzed by brain cytochrome P450 2D6.

PubMed

Niwa, Toshiro; Shizuku, Marina; Yamano, Kaori

2017-04-15

The inhibitory effects of steroid hormones, including glucocorticoids such as cortisol, and related compounds on dopamine formation from p-tyramine, catalyzed by cytochrome P450 (CYP) 2D6.2 (Arg296Cys, Ser486Thr) and CYP2D6.10 (Pro34Ser, Ser486Thr) were compared with the effects of those catalyzed by CYP2D6.1 (wild type), to investigate the effect of a CYP2D6 polymorphism on neuroactive amine metabolism in the brain. Inhibition constants (K i ) or 50% inhibitory concentrations of six steroid hormones (cortisol, cortisone, corticosterone, dehydroepiandrosterone, progesterone, and pregnenolone) and quinidine and quinine-typical potent inhibitors of the human CYP2D6 and rat CYP2D subfamily, respectively-toward dopamine formation catalyzed by CYP2D6.1, CYP2D6.2, and CYP2D6.10 expressed in recombinant Escherichia coli were compared. Although most steroid hormones had no or minor inhibitory effects on the dopamine formation by all CYP2D6 variants, progesterone inhibited the metabolism and K i value against CYP2D6.10 was approximately twice that for CYP2D6.1 and CYP2D6.2. Quinidine exhibited stronger inhibition than quinine; however, these two compounds inhibited the CYP2D6.10-mediated reaction more weakly than the CYP2D6.1 and CYP2D6.2 reactions. These results suggest that CYP2D6 polymorphism would affect drug interaction through dopamine formation in the brain. Copyright © 2017 Elsevier Inc. All rights reserved.

Genetic variation maintained in multilocus models of additive quantitative traits under stabilizing selection.

PubMed Central

Bürger, R; Gimelfarb, A

1999-01-01

Stabilizing selection for an intermediate optimum is generally considered to deplete genetic variation in quantitative traits. However, conflicting results from various types of models have been obtained. While classical analyses assuming a large number of independent additive loci with individually small effects indicated that no genetic variation is preserved under stabilizing selection, several analyses of two-locus models showed the contrary. We perform a complete analysis of a generalization of Wright's two-locus quadratic-optimum model and investigate numerically the ability of quadratic stabilizing selection to maintain genetic variation in additive quantitative traits controlled by up to five loci. A statistical approach is employed by choosing randomly 4000 parameter sets (allelic effects, recombination rates, and strength of selection) for a given number of loci. For each parameter set we iterate the recursion equations that describe the dynamics of gamete frequencies starting from 20 randomly chosen initial conditions until an equilibrium is reached, record the quantities of interest, and calculate their corresponding mean values. As the number of loci increases from two to five, the fraction of the genome expected to be polymorphic declines surprisingly rapidly, and the loci that are polymorphic increasingly are those with small effects on the trait. As a result, the genetic variance expected to be maintained under stabilizing selection decreases very rapidly with increased number of loci. The equilibrium structure expected under stabilizing selection on an additive trait differs markedly from that expected under selection with no constraints on genotypic fitness values. The expected genetic variance, the expected polymorphic fraction of the genome, as well as other quantities of interest, are only weakly dependent on the selection intensity and the level of recombination. PMID:10353920

Distinct Trajectories of Massive Recent Gene Gains and Losses in Populations of a Microbial Eukaryotic Pathogen.

PubMed

Hartmann, Fanny E; Croll, Daniel

2017-11-01

Differences in gene content are a significant source of variability within species and have an impact on phenotypic traits. However, little is known about the mechanisms responsible for the most recent gene gains and losses. We screened the genomes of 123 worldwide isolates of the major pathogen of wheat Zymoseptoria tritici for robust evidence of gene copy number variation. Based on orthology relationships in three closely related fungi, we identified 599 gene gains and 1,024 gene losses that have not yet reached fixation within the focal species. Our analyses of gene gains and losses segregating in populations showed that gene copy number variation arose preferentially in subtelomeres and in proximity to transposable elements. Recently lost genes were enriched in virulence factors and secondary metabolite gene clusters. In contrast, recently gained genes encoded mostly secreted protein lacking a conserved domain. We analyzed the frequency spectrum at loci segregating a gene presence-absence polymorphism in four worldwide populations. Recent gene losses showed a significant excess in low-frequency variants compared with genome-wide single nucleotide polymorphism, which is indicative of strong negative selection against gene losses. Recent gene gains were either under weak negative selection or neutral. We found evidence for strong divergent selection among populations at individual loci segregating a gene presence-absence polymorphism. Hence, gene gains and losses likely contributed to local adaptation. Our study shows that microbial eukaryotes harbor extensive copy number variation within populations and that functional differences among recently gained and lost genes led to distinct evolutionary trajectories. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Assessment of cumulative evidence for the association between glutathione S-transferase polymorphisms and lung cancer: application of the Venice interim guidelines.

PubMed

Langevin, Scott M; Ioannidis, John P A; Vineis, Paolo; Taioli, Emanuela

2010-10-01

There is an overwhelming abundance of genetic association studies available in the literature, which can often be collectively difficult to interpret. To address this issue, the Venice interim guidelines were established for determining the credibility of the cumulative evidence. The objective of this report is to evaluate the literature on the association of common glutathione S-transferase (GST) variants (GSTM1 null, GSTT1 null and GSTP1 Ile105Val polymorphism) and lung cancer, and to assess the credibility of the associations using the newly proposed cumulative evidence guidelines. Information from the literature was enriched with an updated meta-analysis and a pooled analysis using data from the Genetic Susceptibility to Environmental Carcinogens database. There was a significant association between GSTM1 null and lung cancer for the meta-analysis (meta odds ratio=1.17, 95% confidence interval: 1.10-1.25) and pooled analysis (adjusted odds ratio=1.10, 95% confidence interval: 1.04-1.16), although substantial heterogeneity was present. No overall association between lung cancer and GSTT1 null or GSTP1 Ile105Val was found. When the Venice criteria was applied, cumulative evidence for all associations were considered 'weak', with the exception of East Asian carriers of the G allele of GSTP1 Ile105Val, which was graded as 'moderate' evidence. Despite the large amounts of studies, and several statistically significant summary estimates produced by meta-analyses, the application of the Venice criteria suggests extensive heterogeneity and susceptibility to bias for the studies on association of common genetic polymorphisms, such as with GST variants and lung cancer.

Identification of Candidate Single-Nucleotide Polymorphisms in NRXN1 Related to Antipsychotic Treatment Response in Patients with Schizophrenia

PubMed Central

Jenkins, Aaron; Apud, José A; Zhang, Fengyu; Decot, Heather; Weinberger, Daniel R; Law, Amanda J

2014-01-01

Neurexins are presynaptic neuronal adhesion molecules that interact with postsynaptic neuroligins to form an inter-synaptic complex required for synaptic specification and efficient neurotransmission. Deletions and point mutations in the neurexin 1 (NRXN1) gene are associated with a broad spectrum of neuropsychiatric and neurodevelopmental disorders, including autism, intellectual disability, epilepsy, developmental delay, and schizophrenia. Recently, small nucleotide polymorphisms in NRXN1 have been associated with antipsychotic drug response in patients with schizophrenia. Based on previous suggestive evidence of an impact on clozapine response in patients with schizophrenia, we conducted an association study of NRXN1 polymorphisms (rs12467557 and rs10490162) with antipsychotic treatment response in 54 patients with schizophrenia in a double blind, placebo-controlled NIMH inpatient crossover trial and examined for association with risk for schizophrenia in independent case-control and family-based clinical cohorts. Pharmacogenetic analysis in the placebo controlled trial revealed significant association of rs12467557and rs10490162 with drug response, whereby individuals homozygous for the A allele, at either SNP, showed significant improvement in positive symptoms, general psychopathology, thought disturbance, and negative symptoms, whereas patients carrying the G allele showed no overall response. Although we did not find evidence of the same NRXN1 SNPs being associated with results of the NIMH sponsored CATIE trial, other SNPs showed weakly positive signals. The family and case-control analyses for schizophrenia risk were negative. Our results provide confirmatory evidence of genetically determined differences in drug response in patients with schizophrenia related to NRXN1 variation. Furthermore, these findings potentially implicate NRXN1 in the therapeutic actions of antipsychotic drugs. PMID:24633560

TOLLIP gene variant is associated with Plasmodium vivax malaria in the Brazilian Amazon.

PubMed

Brasil, Larissa W; Barbosa, Laila R A; de Araujo, Felipe J; da Costa, Allyson G; da Silva, Luan D O; Pinheiro, Suzana K; de Almeida, Anne C G; Kuhn, Andrea; Vitor-Silva, Sheila; de Melo, Gisely C; Monteiro, Wuelton M; de Lacerda, Marcus V G; Ramasawmy, Rajendranath

2017-03-13

Toll-interacting protein is a negative regulator in the TLR signaling cascade, particularly by impeding the TLR2 and, TLR4 pathway. Recently, TOLLIP was shown to regulate human TLR signaling pathways. Two common TOLLIP polymorphisms (rs5743899 and rs3750920) were reported to be influencing IL-6, TNF and IL-10 expression. In this study, TOLLIP variants were investigated to their relation to Plasmodium vivax malaria in the Brazilian Amazon. This cohort study was performed in the municipalities of Careiro and, Manaus, in Western Brazilian Amazon. A total of 319 patients with P. vivax malaria and, 263 healthy controls with no previous history of malaria were included in the study. Genomic DNA was extracted from blood collected on filter paper, using the QIAamp ® DNA Mini Kit, according to the manufacturer's suggested protocol. The rs5743899 and rs3750920 polymorphisms of the TOLLIP gene were typed by PCR-RFLP. Homozygous individuals for the rs3750920 T allele gene had twice the risk of developing malaria when compared to individuals homozygous for the C allele (OR 2.0 [95% CI 1.23-3.07]; p = 0.004). In the dominant model, carriers the C allele indicates protection to malaria, carriers of the C allele were compared to individuals with the T allele, and the difference is highly significant (OR 0.52 [95% CI 0.37-0.76]; p = 0.0006). The linkage disequilibrium between the two polymorphisms was weak (r 2  = 0.037; D' = 0.27). These findings suggest that genes involved in the TLRs-pathway may be involved in malaria susceptibility. The association of the TOLLIP rs3750920 T allele with susceptibility to malaria further provides evidence that genetic variations in immune response genes may predispose individuals to malaria.

Complex superconductivity in the noncentrosymmetric compound Re 6Zr

DOE PAGES

Khan, Mojammel A.; Karki, A. B.; Samanta, T.; ...

2016-10-24

Here, we report the electronic structure, synthesis, and measurements of the magnetic, transport, and thermal properties of the polycrystalline noncentrosymmetric compound Re 6Zr . We observed a bulk superconducting transition at temperature T c ~ 6.7 K, and measured the resistivity, heat capacity, thermal conductivity, and the London penetration depth below the transition, as well as performed doping and pressure studies. From these measurements we extracted the critical field and the superconducting parameters of Re 6Zr. Lastly, our measurements indicate a relatively weak to moderate contribution from a triplet component to the order parameter, and favor a full superconducting gap,more » although we cannot exclude the existence of point nodes based on our data.« less

Wireless Sensors Grouping Proofs for Medical Care and Ambient Assisted-Living Deployment

PubMed Central

Trček, Denis

2016-01-01

Internet of Things (IoT) devices are rapidly penetrating e-health and assisted living domains, and an increasing proportion among them goes on the account of computationally-weak devices, where security and privacy provisioning alone are demanding tasks, not to mention grouping proofs. This paper, therefore, gives an extensive analysis of such proofs and states lessons learnt to avoid possible pitfalls in future designs. It sticks with prudent engineering techniques in this field and deploys in a novel way the so called non-deterministic principle to provide not only grouping proofs, but (among other) also privacy. The developed solution is analyzed by means of a tangible metric and it is shown to be lightweight, and formally for security. PMID:26729131

Electric dipole moment of magnetoexciton in concentric quantum rings

NASA Astrophysics Data System (ADS)

García, L. F.; Mikhailov, I. D.; Revinova, S. Yu

2017-12-01

We study properties of exciton in a weakly coupled concentric quantum rings, penetrated by an axially directed magnetic flux and subjected to an electric field in the ring’s plane. To this end, we adopt a simple model of quasi-one-dimensional rotator, for which the wave functions and the corresponding energies we found by using the double Fourier series expansion method. Revealed multiple intersections of the energy levels provide conditions for abrupt changes of the radial and the angular quantum numbers, making possible the tunnelling of carriers between rings and allowing the formation of a permanent large dipole moment. We show that the electric and magnetic polarizability of concentric quantum rings with a trapped exciton are very sensible to external electric and magnetic fields.

An unusual presentation of Brown-Sequard syndrome.

PubMed

Herr, R D; Barrett, J

1987-11-01

We report the case of a man with Brown-Sequard syndrome following a fall in which he sustained fractures of the thoracic and lumbosacral spine. Despite characteristic neurological findings, the diagnosis was delayed due to the absence of history of penetrating spinal trauma and incorrect attribution of unilateral-like weakness and numbness to lumbosacral trauma. A directed history and examination revealed that the patient was stabbed in the back with a penknife while leaving a bus and stepped down onto a paralyzed leg, which collapsed beneath him. The patient was given an antibiotic, underwent a negative peritoneal lavage, and had myelography and nerve conduction velocity confirmatory for Brown-Sequard syndrome. With rehabilitation he became ambulatory with a cane one month after the stabbing.

Extent and character of early tertiary penetrative deformation, Sonora, Northwest Mexico

NASA Technical Reports Server (NTRS)

Anderson, T. H.

1985-01-01

Reconnaissance field work has led to the recognition of extensive Early Tertiary gneiss and schist which are distinguished by weakly developed to highly conspicous northeast to east-trending stretching lineation commonly accompanied by low-dipping foliation. This structural fabric has been imposed on Precambrian to Paleogene rocks. Regionally, minimum ages of deformation are based upon interpreted U-Pb isotopic ages from suites of cogenetic zircon from the Paleogene orthogneiss. Locally, the interpreted ages indicate that ductile deformation continued as late as Oligocene (Anderson and others, 1980; Silver and Anderson, 1984). The consistency of the deformational style is such that, although considerable variation in intensity exists, the fabric can be recognized and correlated in rocks away from the Paleogene orthogneiss.

Wireless Sensors Grouping Proofs for Medical Care and Ambient Assisted-Living Deployment.

PubMed

Trček, Denis

2016-01-02

Internet of Things (IoT) devices are rapidly penetrating e-health and assisted living domains, and an increasing proportion among them goes on the account of computationally-weak devices, where security and privacy provisioning alone are demanding tasks, not to mention grouping proofs. This paper, therefore, gives an extensive analysis of such proofs and states lessons learnt to avoid possible pitfalls in future designs. It sticks with prudent engineering techniques in this field and deploys in a novel way the so called non-deterministic principle to provide not only grouping proofs, but (among other) also privacy. The developed solution is analyzed by means of a tangible metric and it is shown to be lightweight, and formally for security.

Myotilinopathy in a family with late onset myopathy.

PubMed

Pénisson-Besnier, Isabelle; Talvinen, Kati; Dumez, Catherine; Vihola, Anna; Dubas, Frédéric; Fardeau, Michel; Hackman, Peter; Carpen, Olli; Udd, Bjarne

2006-07-01

Mutations in titin are well known cause of late onset autosomal dominant distal myopathy. Mutations in another sarcomeric protein, myotilin, were first identified in two families with dominant limb girdle muscular phenotype. Recently, however, myotilin mutations have been associated with more distal phenotypes in patients with late onset myofibrillar myopathy. We report here a multigenerational French family in which gene sequencing identified a S60F myotilin mutation in all patients with full penetrance despite very late onset. The family was originally reported as a distal myopathy but intrafamilial variability was remarkable with proximal or distal muscle weakness or both. Extended morphological characteristics of muscle biopsy findings in myotilinopathy indicate that immunohistochemistry may be important for selection of molecular genetic approach in myofibrillar myopathy.

Imaging of biophoton emission from electrostimulated skin acupuncture point jg4: effect of light enhancers.

PubMed

Slawinski, Janusz; Gorski, Zbigniew

2008-05-01

Using an ultrasensitive CCD camera, an extremely low light intensity from the acupuncture-sensitive point JG4 at the left hand was recorded. As the intensity of the light was very weak and the time of electrostimulation exceeded the recommended period, the quality of biophoton images was poor. Chemiluminescent and fluorescent hydrophilic, hydrophobic and amphyphilic molecular probes were used to: (i) ensure penetration of probes into skin, (ii) enhance the intensity of BP emission, (iii) shorten time and (iv) obtain information about mechanisms of biophotons generation in EAP-sensitive points and channels. The results obtained partially fulfilled expectations and indicate on the necessity to elaborate special techniques of probes deposition on the skin.

Er:YAG laser pulse for small-dose splashback-free microjet transdermal drug delivery.

PubMed

Park, Mi-ae; Jang, Hun-jae; Sirotkin, Fedir V; Yoh, Jack J

2012-09-15

The microjet injector system accelerates drugs and delivers them without a needle, which is shown to overcome the weaknesses of existing jet injectors. A significant increase in the delivered dose of drugs is reported with multiple pulses of laser beam at lower laser energy than was previously used in a Nd:YAG system. The new injection scheme uses the beam wavelength best absorbable by water at a longer pulse mode for elongated microjet penetration into a skin target. A 2.9 μm Er:YAG laser at 250 μs pulse duration is used for fluorescent staining of guinea pig skin and for injection controllability study. Hydrodynamic theory confirms the nozzle exit jet velocity obtained by the present microjet system.

The erosion of sexual dimorphism: challenges to religion and religious ethics.

PubMed

Gudorf, C E

2001-01-01

Late modernity has been witnessing the erosion of the dimorphic sexual paradigm that, in both strong and weak forms, has characterized human history as we know it. Recent discoveries in biology and the social sciences have combined with altered patterns in human sexual behavior to raise critical new questions about the inherited paradigm. Religions of the West whose sacred texts, mythologies, and codes of behavior assume that maleness and femaleness are exclusive and complementary types of sexuality-each of which determines sexual identity, reproductive role, social role, and the sex of one's partner-increasingly must grapple with both theoretical evidence for and experiential evidence of polymorphous human sexuality. Inherited categories of dimorphic sexuality not only are challenged but become less and less intelligible.

The concentration of the global alcohol industry and its penetration in the African region.

PubMed

Jernigan, David H; Babor, Thomas F

2015-04-01

To describe the penetration and expansion of the global alcohol industry into the African region, as a context for exploring the implications for public health. Source materials for this study came primarily from market research and the business press. This was supplemented by industry sources (from websites, company annual reports), World Health Organization reports and the scientific literature. Drinking in Africa is characterized by high rates of abstention and a high prevalence of heavy episodic consumption among those who drink. Much of the region is currently experiencing a rapid rise in consumption. Rising populations and income and the rapid pace of urbanization make Africa very attractive to the global alcohol industry, and industry leaders have identified Africa as a key area for growth. The shift from collaboration to competition in Africa among the global alcohol companies has prompted increasing alcohol production, promotion, new product development, pricing schemes and stakeholder lobbying. Beer consumption has increased across most of the continent, and global brewers view themselves as legitimate players at the alcohol policy table. Weak alcohol policy environments may be compromised further in terms of public health protections by alcohol industry opposition to effective measures such as marketing regulations, availability controls and taxation. © 2014 Society for the Study of Addiction.

Seismotectonic implications of sand blows in the southern Mississippi Embayment

USGS Publications Warehouse

Cox, R.T.; Hill, A.A.; Larsen, D.; Holzer, T.; Forman, S.L.; Noce, T.; Gardner, C.; Morat, J.

2007-01-01

We explore seismically-induced sand blows from the southern Mississippi Embayment and their implications in resolving the question of near or distal epicentral source region. This was accomplished using aerial photography, field excavations, and cone penetration tests. Our analysis shows that three sand blow fields exhibit a distinct chronology of strong ground motion for the southern embayment: (1) The Ashley County, Arkansas sand blow field, near the Arkansas/Louisiana state border, experienced four Holocene sand venting episodes; (2) to the north, the Desha County field experienced at least three episodes of liquefaction; and (3) the Lincoln-Jefferson Counties field experienced at least one episode. Cone penetration tests (CPT) conducted in and between the sand blow fields suggest that the fields may not be distal liquefaction associated with New Madrid seismic zone earthquakes but rather are likely associated with strong earthquakes on local faults. This conclusion is consistent with the differences in timing of the southern embayment sand venting episodes and those in the New Madrid seismic zone. These results suggest that active tectonism and strong seismicity in intraplate North America may not be localized at isolated weak spots, but rather widespread on fault systems that are favorably oriented for slip in the contemporary stress field. ?? 2006 Elsevier B.V. All rights reserved.

Land- and sea-surface impacts on local coastal breezes

NASA Astrophysics Data System (ADS)

Veron, D. E.; Hughes, C.; Gilchrist, J.; Lodise, J.; Goldman, W.

2014-12-01

The state of Delaware has seen significant increases in population along the coastline in the past three decades. With this increase in population have come changes to the land surface, as forest and farmland has been converted to residential and commercial purposes, causing changes in the surface roughness, temperature, and land-atmosphere fluxes. There is also a semi-permanent upwelling center in the spring and summer outside the Delaware Bay mouth that significantly changes the structure of the sea surface temperature both inside and outside the Bay. Through a series of high resolution modeling and observational studies, we have determined that in cases of strong synoptic forcing, the impact of the land-surface on the boundary layer properties can be advected offshore, creating a false coastline and modifying the location and timing of the sea breeze circulation. In cases of weak synoptic forcing, the influence of the upwelling and the tidal circulation of the Delaware Bay waters can greatly change the location, strength, and penetration of the sea breeze. Understanding the importance of local variability in the surface-atmosphere interactions on the sea breeze can lead to improved prediction of sea breeze onset, penetration, and duration which is important for monitoring air quality and developing offshore wind power production.

Ground penetrating radar detection of subsnow slush on ice-covered lakes in interior Alaska

NASA Astrophysics Data System (ADS)

Gusmeroli, A.; Grosse, G.

2012-12-01

Lakes are abundant throughout the pan-Arctic region. For many of these lakes ice cover lasts for up to two thirds of the year. The frozen cover allows human access to these lakes, which are therefore used for many subsistence and recreational activities, including water harvesting, fishing, and skiing. Safe traveling condition onto lakes may be compromised, however, when, after significant snowfall, the weight of the snow acts on the ice and causes liquid water to spill through weak spots and overflow at the snow-ice interface. Since visual detection of subsnow slush is almost impossible our understanding on overflow processes is still very limited and geophysical methods that allow water and slush detection are desirable. In this study we demonstrate that a commercially available, lightweight 1 GHz, ground penetrating radar system can detect and map extent and intensity of overflow. The strength of radar reflections from wet snow-ice interfaces are at least twice as much in strength than returns from dry snow-ice interface. The presence of overflow also affects the quality of radar returns from the base of the lake ice. During dry conditions we were able to profile ice thickness of up to 1 m, conversely, we did not retrieve any ice-water returns in areas affected by overflow.

Differential diagnosis of an unusual shoulder articular lesion in an ancient domestic dog (Canis lupus familiaris L., 1758).

PubMed

Lawler, D F; Rubin, D A; Evans, R H; Hildebolt, C F; Smith, K E; Widga, C; Martin, T J; Siegel, M; Sackman, J E; Smith, G K; Patel, T K

2013-12-01

A proximal humeral articular surface from an ancient domestic dog deliberate burial was examined during survey of small mammal bones from a prehistoric early Late Woodland archeological site. An unusual lesion on the caudolateral articular surface prompted micro-computed tomography to define detailed structure. Results indicate cortical or immature woven bone arising subchondrally, replacing normal trabeculae, extending through a breach in the cortical surface, and having sharp transition with surrounding normal bone. Organized bone within the lesion indicates that the dog lived for months-to-years following insult. Differential diagnoses initially included: sharp penetrating trauma; intrinsic or extrinsic blunt fracturing force; osteochondrosis or complication of an osteochondral lesion; unusual osteoarthritis; and neoplasia. Computed tomography ruled out normal or unusual osteoarthritis, and neoplasia. The nature and small size of the lesion, relatively small size of the dog, and lack of evidence for complicating infection, suggest against sharp penetrating trauma as a sole cause. The most plausible differential diagnoses include: uncommon fracture-producing force in a companion animal, and blunt intrinsic or extrinsic force causing fracture at a weak point, such as an early osteochondral lesion, that was obliterated by healing. Combined gross examination, micro-computed tomography, and archeological-anthropological influences facilitated refinement of differential diagnosis. Copyright © 2013 Elsevier Inc. All rights reserved.

Concomitant presentation of Anderson-Tawil syndrome and myasthenia gravis in an adult patient: A case report.

PubMed

Fan, Rui; Ji, Ruirui; Zou, Wenxin; Wang, Guoliang; Wang, Hu; Penney, Daniel James; Luo, Jin Jun; Fan, Yuxin

2016-10-01

Andersen-Tawil syndrome (ATS) is an autosomal dominant, multisystem channelopathy characterized by periodic paralysis, ventricular arrhythmias and distinctive dysmorphic facial or skeletal features. The disorder displays marked intrafamilial variability and incomplete penetrance. Myasthenia gravis (MG) is an autoimmune disorder that demonstrates progressive fatigability, in which the nicotinic acetylcholine receptor (AChR) at neuromuscular junctions is the primary autoantigen. The present study reports a rare case of a 31-year-old woman with a history of morbid obesity and periodic weakness, who presented with hemodynamic instability, cardiogenic shock and facial anomalies. Laboratory results revealed hypokalemia and an elevated anti-AChR antibody expression levels. Electrocardiography demonstrated prolonged QT-interval, ST-elevation, and subsequent third-degree atrioventricular block. Neurological examination revealed bilateral ptosis, horizontal diplopia, dysarthria and generalized weakness. No mutations in the potassium channel inwardly rectifying subfamily J member 2 gene were detected in the present case. The patient was treated with oral potassium supplementation and an acetylcholinesterase inhibitor (pyridostigmine), after which the symptoms were improved. To the best of our knowledge, the present case report was the first to describe concomitant presentation of both ATS and MG, which represents a diagnostic and therapeutic challenge.

Generalization of the Hartree-Fock approach to collision processes

NASA Astrophysics Data System (ADS)

Hahn, Yukap

1997-06-01

The conventional Hartree and Hartree-Fock approaches for bound states are generalized to treat atomic collision processes. All the single-particle orbitals, for both bound and scattering states, are determined simultaneously by requiring full self-consistency. This generalization is achieved by introducing two Ansäauttze: (a) the weak asymptotic boundary condition, which maintains the correct scattering energy and target orbitals with correct number of nodes, and (b) square integrable amputated scattering functions to generate self-consistent field (SCF) potentials for the target orbitals. The exact initial target and final-state asymptotic wave functions are not required and thus need not be specified a priori, as they are determined simultaneously by the SCF iterations. To check the asymptotic behavior of the solution, the theory is applied to elastic electron-hydrogen scattering at low energies. The solution is found to be stable and the weak asymptotic condition is sufficient to produce the correct scattering amplitudes. The SCF potential for the target orbital shows the strong penetration by the projectile electron during the collision, but the exchange term tends to restore the original form. Potential applicabilities of this extension are discussed, including the treatment of ionization and shake-off processes.

Visualizing weakly bound surface Fermi arcs and their correspondence to bulk Weyl fermions

PubMed Central

Batabyal, Rajib; Morali, Noam; Avraham, Nurit; Sun, Yan; Schmidt, Marcus; Felser, Claudia; Stern, Ady; Yan, Binghai; Beidenkopf, Haim

2016-01-01

Fermi arcs are the surface manifestation of the topological nature of Weyl semimetals, enforced by the bulk-boundary correspondence with the bulk Weyl nodes. The surface of tantalum arsenide, similar to that of other members of the Weyl semimetal class, hosts nontopological bands that obscure the exploration of this correspondence. We use the spatial structure of the Fermi arc wave function, probed by scanning tunneling microscopy, as a spectroscopic tool to distinguish and characterize the surface Fermi arc bands. We find that, as opposed to nontopological states, the Fermi arc wave function is weakly affected by the surface potential: it spreads rather uniformly within the unit cell and penetrates deeper into the bulk. Fermi arcs reside predominantly on tantalum sites, from which the topological bulk bands are derived. Furthermore, we identify a correspondence between the Fermi arc dispersion and the energy and momentum of the bulk Weyl nodes that classify this material as topological. We obtain these results by introducing an analysis based on the role the Bloch wave function has in shaping quantum electronic interference patterns. It thus carries broader applicability to the study of other electronic systems and other physical processes. PMID:27551687

Strong Purifying Selection at Synonymous Sites in D. melanogaster

PubMed Central

Lawrie, David S.; Messer, Philipp W.; Hershberg, Ruth; Petrov, Dmitri A.

2013-01-01

Synonymous sites are generally assumed to be subject to weak selective constraint. For this reason, they are often neglected as a possible source of important functional variation. We use site frequency spectra from deep population sequencing data to show that, contrary to this expectation, 22% of four-fold synonymous (4D) sites in Drosophila melanogaster evolve under very strong selective constraint while few, if any, appear to be under weak constraint. Linking polymorphism with divergence data, we further find that the fraction of synonymous sites exposed to strong purifying selection is higher for those positions that show slower evolution on the Drosophila phylogeny. The function underlying the inferred strong constraint appears to be separate from splicing enhancers, nucleosome positioning, and the translational optimization generating canonical codon bias. The fraction of synonymous sites under strong constraint within a gene correlates well with gene expression, particularly in the mid-late embryo, pupae, and adult developmental stages. Genes enriched in strongly constrained synonymous sites tend to be particularly functionally important and are often involved in key developmental pathways. Given that the observed widespread constraint acting on synonymous sites is likely not limited to Drosophila, the role of synonymous sites in genetic disease and adaptation should be reevaluated. PMID:23737754

Multiple testing and power calculations in genetic association studies.

PubMed

So, Hon-Cheong; Sham, Pak C

2011-01-01

Modern genetic association studies typically involve multiple single-nucleotide polymorphisms (SNPs) and/or multiple genes. With the development of high-throughput genotyping technologies and the reduction in genotyping cost, investigators can now assay up to a million SNPs for direct or indirect association with disease phenotypes. In addition, some studies involve multiple disease or related phenotypes and use multiple methods of statistical analysis. The combination of multiple genetic loci, multiple phenotypes, and multiple methods of evaluating associations between genotype and phenotype means that modern genetic studies often involve the testing of an enormous number of hypotheses. When multiple hypothesis tests are performed in a study, there is a risk of inflation of the type I error rate (i.e., the chance of falsely claiming an association when there is none). Several methods for multiple-testing correction are in popular use, and they all have strengths and weaknesses. Because no single method is universally adopted or always appropriate, it is important to understand the principles, strengths, and weaknesses of the methods so that they can be applied appropriately in practice. In this article, we review the three principle methods for multiple-testing correction and provide guidance for calculating statistical power.

The c.64_80del SMIM1 allele is segregating in the Hutterite population.

PubMed

Coghlan, Gail; Zelinski, Teresa

2016-04-01

The high-incidence red blood cell (RBC) antigen Vel is coded by SMIM1 (small-membrane molecule 1 gene), where a homozygous 17 base pair deletion underlies the majority of Vel- phenotypes. Because anti-Vel has been reported to cause severe hemolytic transfusion reactions and periodically hemolytic disease of the newborn and fetus, identification of individuals negative for Vel is clinically important. RBCs from the members of a large three-generation Hutterite family were serologically determined to be Vel+(w) . Genomic DNA from these family members was polymerase chain reaction amplified and analyzed for SMIM1 polymorphisms by either Sanger sequencing or restriction fragment length polymorphisms. SMIM1 genotyping was also conducted on DNA from an additional 104 Hutterites. All family members whose RBCs weakly expressed the Vel antigen were found to be heterozygous for the c.64_80del mutation in SMIM1. Of the 104 additional Hutterite samples, four were found to be heterozygous for the same SMIM1 mutation. After emigrating to the United States and Canada, the Hutterite population has expanded dramatically. Alleles that initially entered the population have been maintained within the population. The c.64_80del null allele of SMIM1 is one such allele, thus having implications for transfusion medicine and child or maternal health. © 2015 AABB.

Identification of TNIP1 Polymorphisms by High Resolution Melting Analysis with Unlabelled Probe: Association with Systemic Lupus Erythematosus

PubMed Central

Zhang, Jie; Chen, Yuewen; Shao, Yong; Wu, Qi; Guan, Ming; Zhang, Wei; Wan, Jun; Yu, Bo

2012-01-01

Background. TNFα-induced protein 3 (TNFAIP3) interacting with protein 1 (TNIP1) acts as a negative regulator of NF-κB and plays an important role in maintaining the homeostasis of immune system. A recent genome-wide association study (GWAS) showed that the polymorphism of TNIP1 was associated with the disease risk of SLE in Caucasian. In this study, we investigated whether the association of TNIP1 with SLE was replicated in Chinese population. Methods. The association of TNIP1 SNP rs7708392 (G/C) was determined by high resolution melting (HRM) analysis with unlabeled probe in 285 SLE patients and 336 healthy controls. Results. A new SNP rs79937737 located on 5 bp upstream of rs7708392 was discovered during the HRM analysis. No association of rs7708392 or rs79937737 with the disease risk of SLE was found. Furthermore, rs7708392 and rs79937737 were in weak linkage disequilibrium (LD). Hypotypes analysis of the two SNPs also showed no association with SLE in Chinese population. Conclusions. High resolution melting analysis with unlabeled probes proves to be a powerful and efficient genotyping method for identifying and screening SNPs. No association of rs7708392 or rs79937737 with the disease risk of SLE was observed in Chinese population. PMID:22852072

Size and symmetry of the superconducting gap in the f.c.c. Cs3C60 polymorph close to the metal-Mott insulator boundary.

PubMed

Potočnik, Anton; Krajnc, Andraž; Jeglič, Peter; Takabayashi, Yasuhiro; Ganin, Alexey Y; Prassides, Kosmas; Rosseinsky, Matthew J; Arčon, Denis

2014-03-03

The alkali fullerides, A(3)C(60) (A = alkali metal) are molecular superconductors that undergo a transition to a magnetic Mott-insulating state at large lattice parameters. However, although the size and the symmetry of the superconducting gap, Δ, are both crucial for the understanding of the pairing mechanism, they are currently unknown for superconducting fullerides close to the correlation-driven magnetic insulator. Here we report a comprehensive nuclear magnetic resonance (NMR) study of face-centred-cubic (f.c.c.) Cs(3)C(60) polymorph, which can be tuned continuously through the bandwidth-controlled Mott insulator-metal/superconductor transition by pressure. When superconductivity emerges from the insulating state at large interfullerene separations upon compression, we observe an isotropic (s-wave) Δ with a large gap-to-superconducting transition temperature ratio, 2Δ0/k(B)T(c) = 5.3(2) [Δ0 = Δ(0 K)]. 2Δ0/k(B)T(c) decreases continuously upon pressurization until it approaches a value of ~3.5, characteristic of weak-coupling BCS theory of superconductivity despite the dome-shaped dependence of Tc on interfullerene separation. The results indicate the importance of the electronic correlations for the pairing interaction as the metal/superconductor-insulator boundary is approached.

Polymorphisms of steroid 5-alpha-reductase type I (SRD5A1) gene are associated to peripheral arterial disease.

PubMed

Signorelli, S S; Barresi, V; Musso, N; Anzaldi, M; Croce, E; Fiore, V; Condorelli, D F

2008-12-01

Although animal studies support the hypothesis that androgenic biological actions may affect experimental atherosclerosis progression, evidence for a relationship between androgen effects and peripheral arterial disease (PAD), a common clinical form of atherosclerosis, is weak or contradictory. Testosterone, the main androgen hormone, is converted in a 5alpha-reduced form by enzymatic activities in the target cells and some specific actions are mediated by such metabolites. Steroid 5-alpha reductase isoenzymes (SRD5A1 and SRD5A2) catalyze the conversion to the bioactive potent androgen dihydrotestosterone and other reduced metabolites and represent relevant regulators of local hormonal actions. In the present study we tested for the association of selected single nucleotide polymorphisms (SNP) of SRD5A1 and SRD5A2 with symptomatic PAD patients. Two different SNP in the SRD5A1 were significantly associated which the PAD phenotype (p<0.03, odds ratio 1.73), while no association was found between PAD phenotypes and SRD5A2. Since the examined SRDA1 gene variant was previously associated with a low enzymatic activity, we suggest that a decreased local enzymatic conversion of testosterone may contribute to PAD genetic susceptibility.

Size and symmetry of the superconducting gap in the f.c.c. Cs3C60 polymorph close to the metal-Mott insulator boundary

PubMed Central

Potočnik, Anton; Krajnc, Andraž; Jeglič, Peter; Takabayashi, Yasuhiro; Ganin, Alexey Y.; Prassides, Kosmas; Rosseinsky, Matthew J.; Arčon, Denis

2014-01-01

The alkali fullerides, A3C60 (A = alkali metal) are molecular superconductors that undergo a transition to a magnetic Mott-insulating state at large lattice parameters. However, although the size and the symmetry of the superconducting gap, Δ, are both crucial for the understanding of the pairing mechanism, they are currently unknown for superconducting fullerides close to the correlation-driven magnetic insulator. Here we report a comprehensive nuclear magnetic resonance (NMR) study of face-centred-cubic (f.c.c.) Cs3C60 polymorph, which can be tuned continuously through the bandwidth-controlled Mott insulator-metal/superconductor transition by pressure. When superconductivity emerges from the insulating state at large interfullerene separations upon compression, we observe an isotropic (s-wave) Δ with a large gap-to-superconducting transition temperature ratio, 2Δ0/kBTc = 5.3(2) [Δ0 = Δ(0 K)]. 2Δ0/kBTc decreases continuously upon pressurization until it approaches a value of ~3.5, characteristic of weak-coupling BCS theory of superconductivity despite the dome-shaped dependence of Tc on interfullerene separation. The results indicate the importance of the electronic correlations for the pairing interaction as the metal/superconductor-insulator boundary is approached. PMID:24584087

An APOE-independent cis-eSNP on chromosome 19q13.32 influences tau levels and late-onset Alzheimer's disease risk.

PubMed

Rao, Shuquan; Ghani, Mahdi; Guo, Zhiyun; Deming, Yuetiva; Wang, Kesheng; Sims, Rebecca; Mao, Canquan; Yao, Yao; Cruchaga, Carlos; Stephan, Dietrich A; Rogaeva, Ekaterina

2018-06-01

Although multiple susceptibility loci for late-onset Alzheimer's disease (LOAD) have been identified, a large portion of the genetic risk for this disease remains unexplained. LOAD risk may be associated with single-nucleotide polymorphisms responsible for changes in gene expression (eSNPs). To detect eSNPs associated with LOAD, we integrated data from LOAD genome-wide association studies and expression quantitative trait loci using Sherlock (a Bayesian statistical method). We identified a cis-regulatory eSNP (rs2927438) located on chromosome 19q13.32, for which subsequent analyses confirmed the association with both LOAD risk and the expression level of several nearby genes. Importantly, rs2927438 may represent an APOE-independent LOAD eSNP according to the weak linkage disequilibrium of rs2927438 with the 2 polymorphisms (rs7412 and rs429358) defining the APOE-ε2, -ε3, and -ε4 alleles. Furthermore, rs2927438 does not influence chromatin interaction events at the APOE locus or cis-regulation of APOE expression. Further exploratory analysis revealed that rs2927438 is significantly associated with tau levels in the cerebrospinal fluid. Our findings suggest that rs2927438 may confer APOE-independent risk for LOAD. Copyright © 2017 Elsevier Inc. All rights reserved.

Heme Oxygenase-1 and 2 Common Genetic Variants and Risk for Restless Legs Syndrome

PubMed Central

García-Martín, Elena; Jiménez-Jiménez, Félix Javier; Alonso-Navarro, Hortensia; Martínez, Carmen; Zurdo, Martín; Turpín-Fenoll, Laura; Millán-Pascual, Jorge; Adeva-Bartolomé, Teresa; Cubo, Esther; Navacerrada, Francisco; Rojo-Sebastián, Ana; Rubio, Lluisa; Ortega-Cubero, Sara; Pastor, Pau; Calleja, Marisol; Plaza-Nieto, José Francisco; Pilo-de-la-Fuente, Belén; Arroyo-Solera, Margarita; García-Albea, Esteban; Agúndez, José A.G.

2015-01-01

Abstract Several neurochemical, neuropathological, neuroimaging, and experimental data, suggest that iron deficiency plays an important role in the pathophysiology of restless legs syndrome (RLS). Heme-oxygenases (HMOX) are an important defensive mechanism against oxidative stress, mainly through the degradation of heme to biliverdin, free iron, and carbon monoxide. We analyzed whether HMOX1 and HMOX2 genes are related with the risk to develop RLS. We analyzed the distribution of genotypes and allelic frequencies of the HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363, and HMOX2 rs1051308 SNPs, as well as the presence of Copy number variations (CNVs) of these genes in 205 subjects RLS and 445 healthy controls. The frequencies of rs2071746TT genotype and rs2071746T allelic variant were significantly lower in RLS patients than that in controls, although the other 3 studied SNPs did not differ between RLS patients and controls. None of the studied polymorphisms influenced the disease onset, severity of RLS, family history of RLS, serum ferritin levels, or response to dopaminergic agonist, clonazepam or GABAergic drugs. The present study suggests a weak association between HMOX1 rs2071746 polymorphism and the risk to develop RLS in the Spanish population. PMID:26313808

Heme Oxygenase-1 and 2 Common Genetic Variants and Risk for Restless Legs Syndrome.

PubMed

García-Martín, Elena; Jiménez-Jiménez, Félix Javier; Alonso-Navarro, Hortensia; Martínez, Carmen; Zurdo, Martín; Turpín-Fenoll, Laura; Millán-Pascual, Jorge; Adeva-Bartolomé, Teresa; Cubo, Esther; Navacerrada, Francisco; Rojo-Sebastián, Ana; Rubio, Lluisa; Ortega-Cubero, Sara; Pastor, Pau; Calleja, Marisol; Plaza-Nieto, José Francisco; Pilo-de-la-Fuente, Belén; Arroyo-Solera, Margarita; García-Albea, Esteban; Agúndez, José A G

2015-08-01

Several neurochemical, neuropathological, neuroimaging, and experimental data, suggest that iron deficiency plays an important role in the pathophysiology of restless legs syndrome (RLS). Heme-oxygenases (HMOX) are an important defensive mechanism against oxidative stress, mainly through the degradation of heme to biliverdin, free iron, and carbon monoxide. We analyzed whether HMOX1 and HMOX2 genes are related with the risk to develop RLS.We analyzed the distribution of genotypes and allelic frequencies of the HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363, and HMOX2 rs1051308 SNPs, as well as the presence of Copy number variations (CNVs) of these genes in 205 subjects RLS and 445 healthy controls.The frequencies of rs2071746TT genotype and rs2071746T allelic variant were significantly lower in RLS patients than that in controls, although the other 3 studied SNPs did not differ between RLS patients and controls. None of the studied polymorphisms influenced the disease onset, severity of RLS, family history of RLS, serum ferritin levels, or response to dopaminergic agonist, clonazepam or GABAergic drugs.The present study suggests a weak association between HMOX1 rs2071746 polymorphism and the risk to develop RLS in the Spanish population.

Magnetic Field Effects and Electromagnetic Wave Propagation in Highly Collisional Plasmas.

NASA Astrophysics Data System (ADS)

Bozeman, Steven Paul

The homogeneity and size of radio frequency (RF) and microwave driven plasmas are often limited by insufficient penetration of the electromagnetic radiation. To investigate increasing the skin depth of the radiation, we consider the propagation of electromagnetic waves in a weakly ionized plasma immersed in a steady magnetic field where the dominant collision processes are electron-neutral and ion-neutral collisions. Retaining both the electron and ion dynamics, we have adapted the theory for cold collisionless plasmas to include the effects of these collisions and obtained the dispersion relation at arbitrary frequency omega for plane waves propagating at arbitrary angles with respect to the magnetic field. We discuss in particular the cases of magnetic field enhanced wave penetration for parallel and perpendicular propagation, examining the experimental parameters which lead to electromagnetic wave propagation beyond the collisional skin depth. Our theory predicts that the most favorable scaling of skin depth with magnetic field occurs for waves propagating nearly parallel to B and for omega << Omega_{rm e} where Omega_{rm e} is the electron cyclotron frequency. The scaling is less favorable for propagation perpendicular to B, but the skin depth does increase for this case as well. Still, to achieve optimal wave penetration, we find that one must design the plasma configuration and antenna geometry so that one generates primarily the appropriate angles of propagation. We have measured plasma wave amplitudes and phases using an RF magnetic probe and densities using Stark line broadening. These measurements were performed in inductively coupled plasmas (ICP's) driven with a standard helical coil, a reverse turn (Stix) coil, and a flat spiral coil. Density measurements were also made in a microwave generated plasma. The RF magnetic probe measurements of wave propagation in a conventional ICP with wave propagation approximately perpendicular to B show an increase in skin depth with magnetic field and a damping of the effect of B with pressure. The flat coil geometry which launches waves more nearly parallel to B allows enhanced wave penetration at higher pressures than the standard helical coil.

Linkage analysis of juvenile myoclonic epilepsy and microsatellite loci spanning 61 cM of human chromosome 6p in 19 nuclear pedigrees provides no evidence for a susceptibility locus in this region

DOE Office of Scientific and Technical Information (OSTI.GOV)

Elmslie, F.V.; Williamson, M.P.; Rees, M.

1996-09-01

Linkage analysis in separately ascertained families of probands with juvenile myoclonic epilepsy (JME) has previously provided evidence both for and against the existence of a locus (designated {open_quotes}EJM1{close_quotes}), on chromosome 6p, predisposing to a trait defined as either clinical JME, its associated electroencephalographic abnormality, or idiopathic generalized epilepsy. Linkage analysis was performed in 19 families in which a proband and at least one first- or two second-degree relatives have clinical JME. Family members were typed for seven highly polymorphic microsatellite markers on chromosome 6p: D6S260, D6S276, D6S291, D6S271, D6S465, D6S257, and D6S254. Pairwise and multipoint linkage analysis was carried outmore » under the assumptions of autosomal dominant inheritance at 70% and 50% penetrance and autosomal recessive inheritance at 70% and 50% penetrance. No significant evidence in favor of linkage to the clinical trait of JME was obtained for any locus. The region formally excluded (LOD score <-2) by using multipoint analysis varies depending on the assumptions made concerning inheritance parameters and the proportion of linked families, {alpha} - that is, the degree of locus heterogeneity. Further analysis either classifying all unaffected individuals as unknown or excluding a subset of four families in which pyknoleptic absence seizures were present in one or more individuals did not alter these conclusions. 24 refs., 4 figs., 1 tab.« less

Comparison of Family History and SNPs for Predicting Risk of Complex Disease

PubMed Central

Do, Chuong B.; Hinds, David A.; Francke, Uta; Eriksson, Nicholas

2012-01-01

The clinical utility of family history and genetic tests is generally well understood for simple Mendelian disorders and rare subforms of complex diseases that are directly attributable to highly penetrant genetic variants. However, little is presently known regarding the performance of these methods in situations where disease susceptibility depends on the cumulative contribution of multiple genetic factors of moderate or low penetrance. Using quantitative genetic theory, we develop a model for studying the predictive ability of family history and single nucleotide polymorphism (SNP)–based methods for assessing risk of polygenic disorders. We show that family history is most useful for highly common, heritable conditions (e.g., coronary artery disease), where it explains roughly 20%–30% of disease heritability, on par with the most successful SNP models based on associations discovered to date. In contrast, we find that for diseases of moderate or low frequency (e.g., Crohn disease) family history accounts for less than 4% of disease heritability, substantially lagging behind SNPs in almost all cases. These results indicate that, for a broad range of diseases, already identified SNP associations may be better predictors of risk than their family history–based counterparts, despite the large fraction of missing heritability that remains to be explained. Our model illustrates the difficulty of using either family history or SNPs for standalone disease prediction. On the other hand, we show that, unlike family history, SNP–based tests can reveal extreme likelihood ratios for a relatively large percentage of individuals, thus providing potentially valuable adjunctive evidence in a differential diagnosis. PMID:23071447

Novel loci interacting epistatically with bone morphogenetic protein receptor 2 cause familial pulmonary arterial hypertension.

PubMed

Rodriguez-Murillo, Laura; Subaran, Ryan; Stewart, William C L; Pramanik, Sreemanta; Marathe, Sudhir; Barst, Robyn J; Chung, Wendy K; Greenberg, David A

2010-02-01

Familial pulmonary arterial hypertension (FPAH) is a rare, autosomal-dominant, inherited disease with low penetrance. Mutations in the bone morphogenetic protein receptor 2 (BMPR2) have been identified in at least 70% of FPAH patients. However, the lifetime penetrance of these BMPR2 mutations is 10% to 20%, suggesting that genetic and/or environmental modifiers are required for disease expression. Our goal in this study was to identify genetic loci that may influence FPAH expression in BMPR2 mutation carriers. We performed a genome-wide linkage scan in 15 FPAH families segregating for BMPR2 mutations. We used a dense single-nucleotide polymorphism (SNP) array and a novel multi-scan linkage procedure that provides increased power and precision for the localization of linked loci. We observed linkage evidence in four regions: 3q22 ([median log of the odds (LOD) = 3.43]), 3p12 (median LOD) = 2.35), 2p22 (median LOD = 2.21), and 13q21 (median LOD = 2.09). When used in conjunction with the non-parametric bootstrap, our approach yields high-resolution to identify candidate gene regions containing putative BMPR2-interacting genes. Imputation of the disease model by LOD-score maximization indicates that the 3q22 locus alone predicts most FPAH cases in BMPR2 mutation carriers, providing strong evidence that BMPR2 and the 3q22 locus interact epistatically. Our findings suggest that genotypes at loci in the newly identified regions, especially at 3q22, could improve FPAH risk prediction in FPAH families. We also suggest other targets for therapeutic intervention.

Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.

PubMed

El Khattabi, Laïla; Guimiot, Fabien; Pipiras, Eva; Andrieux, Joris; Baumann, Clarisse; Bouquillon, Sonia; Delezoide, Anne-Lise; Delobel, Bruno; Demurger, Florence; Dessuant, Hélène; Drunat, Séverine; Dubourg, Christelle; Dupont, Céline; Faivre, Laurence; Holder-Espinasse, Muriel; Jaillard, Sylvie; Journel, Hubert; Lyonnet, Stanislas; Malan, Valérie; Masurel, Alice; Marle, Nathalie; Missirian, Chantal; Moerman, Alexandre; Moncla, Anne; Odent, Sylvie; Palumbo, Orazio; Palumbo, Pietro; Ravel, Aimé; Romana, Serge; Tabet, Anne-Claude; Valduga, Mylène; Vermelle, Marie; Carella, Massimo; Dupont, Jean-Michel; Verloes, Alain; Benzacken, Brigitte; Delahaye, Andrée

2015-08-01

6q16 deletions have been described in patients with a Prader-Willi-like (PWS-like) phenotype. Recent studies have shown that certain rare single-minded 1 (SIM1) loss-of-function variants were associated with a high intra-familial risk for obesity with or without features of PWS-like syndrome. Although SIM1 seems to have a key role in the phenotype of patients carrying 6q16 deletions, some data support a contribution of other genes, such as GRIK2, to explain associated behavioural problems. We describe 15 new patients in whom de novo 6q16 deletions were characterised by comparative genomic hybridisation or single-nucleotide polymorphism (SNP) array analysis, including the first patient with fetopathological data. This fetus showed dysmorphic facial features, cerebellar and cerebral migration defects with neuronal heterotopias, and fusion of brain nuclei. The size of the deletion in the 14 living patients ranged from 1.73 to 7.84 Mb, and the fetus had the largest deletion (14 Mb). Genotype-phenotype correlations confirmed the major role for SIM1 haploinsufficiency in obesity and the PWS-like phenotype. Nevertheless, only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency. This study in the largest series reported to date confirms that the PWS-like phenotype is strongly linked to 6q16.2q16.3 deletions and varies considerably in its clinical expression. The possible involvement of other genes in the 6q16.2q16.3-deletion phenotype is discussed.

Identification of IRF6 gene variants in three families with Van der Woude syndrome.

PubMed

Tan, Ene-Choo; Lim, Eileen Chew-Ping; Yap, Shiao-Hui; Lee, Seng-Teik; Cheng, Joanne; Por, Yong-Chen; Yeow, Vincent

2008-06-01

Van der Woude syndrome is the most common cause of syndromic orofacial clefting. It is characterised by the presence of lip pits, cleft lip and/or cleft palate. It is transmitted in an autosomal dominant manner, with high penetrance and variable expressivity. Several mutations in the interferon regulatory factor 6 (IRF6) gene have been found in VWS families, suggesting that this gene is the primary locus. We screened for mutations in this gene in three families in our population. There was a recurrent nonsense mutation within exon 9 of the gene for a Malay family consisting of five affected members with different presentations. We also found a co-segregating rare polymorphism which would result in a non-synonymous change 23 bases downstream of the nonsense mutation. This polymorphism was present in <1% of the Malay subjects screened, but was not found among the Chinese and Indians in our population. For another family, a 396C-->T mutation (R45W in the DNA-binding domain) was found in the proband, although the possibility of a genetic defect elsewhere could not be excluded because his mother and twin sister (both unaffected) also had this variant. In the third case with complete absence of family history, a de novo deletion spanning the whole IRF6 gene was detected in the child with VWS. This case of haploinsufficiency caused disruption of orofacial development but not other organ systems as the child has no other medical or developmental abnormalities despite the deletion of at least five other genes.

Association of single nucleotide polymorphisms in pro-inflammatory cytokine and toll-like receptor genes with pediatric hematogenous osteomyelitis.

PubMed

Osman, A E; Mubasher, M; ElSheikh, N E; AlHarthi, H; AlZahrani, M S; Ahmed, N; ElGhazali, G; Bradley, B A; Fadil, A-S A

2016-05-23

Hematogenous osteomyelitis (HO) is a bone infection wherein bacteria penetrate to the bone through the blood stream. Several single nucleotide polymorphisms (SNPs) have been associated with susceptibility to infectious diseases. In this study, we investigated the contribution of SNPs in interleukin (IL)-1B1 (rs16944), IL1A (rs1800587), IL1B (rs1143634), toll-like receptor (TLR)-2 (rs3804099), TLR4 (rs4986790), TLR4 (rs4986791), IL1R (rs2234650), tumor necrosis factor (TNF)-α (rs1800629), TNF (rs361525), and IL1RN (rs315952) towards the development of HO in Saudi patients and compared to healthy controls. Fifty-two patients diagnosed with HO and 103 healthy individuals were genotyped. The frequencies of genotypes GG (rs16944) and AA (rs16944) were lower and higher in patients [odds ratio (OR) = 0.34, Pc = 0.05] and controls (OR = 1.33, Pc = 0.05), respectively, suggesting that SNPs at this locus could alter HO susceptibility. In addition, the patients and controls exhibited lower and higher frequencies of the alleles G (rs16944) (OR = 0.43, Pc = 0.007) and A (rs16944) (OR = 2.32, Pc = 0.007), respectively. The expression of alleles C (rs3804099) and T (rs3804099) were higher in patients (OR = 2.05, Pc = 0.04) and controls (OR = 0.49, Pc = 0.04), respectively. In conclusion, SNPs at rs16944 and rs3804099 were found to be associated with HO in the Saudi population.

A brief history of Alzheimer's disease gene discovery.

PubMed

Tanzi, Rudolph E

2013-01-01

The rich and colorful history of gene discovery in Alzheimer's disease (AD) over the past three decades is as complex and heterogeneous as the disease, itself. Twin and family studies indicate that genetic factors are estimated to play a role in at least 80% of AD cases. The inheritance of AD exhibits a dichotomous pattern. On one hand, rare mutations inAPP, PSEN1, and PSEN2 are fully penetrant for early-onset (<60 years) familial AD, which represents <5% of AD. On the other hand, common gene polymorphisms, such as the 4 and 2 variants of the APOE gene, influence susceptibility for common (>95%) late-onset AD. These four genes account for 30-50% of the inheritability of AD. Genome-wide association studies have recently led to the identification of additional highly confirmed AD candidate genes. Here, I review the past, present, and future of attempts to elucidate the complex and heterogeneous genetic underpinnings of AD along with some of the unique events that made these discoveries possible.

Towards identification of an epilepsy gene in a large family with idiopathic generalized epilepsy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Roussear, M.; Lopes-Cendes, I.; Berkovic, S.F.

1994-09-01

To identify the disease gene in a large, multiplex family segregating an autosomal dominant form of idiopathic generalized epilepsy (IGE). The IGEs have been recognized for several decades as being genetically determined. However, large pedigrees with a clear Mendelian inheritance are not commonly available. This, and the presence of locus heterogeneity have been obstacles to the identification of linkage in several IGE syndromes. We have identified a large IGE kindred with fifty-eight living individuals, including 26 affecteds, showing a clear autosomal dominant inheritance with incomplete penetrance. Forty-fur informative individuals, including 23 affecteds, were selected for the linkage studies. We havemore » chosen 200 polymorphic microsatellite markers, about 20 cM apart, throughout the human autosomes as a genome-search linkage strategy. To date, 47 markers, representing 30% of the human genome, have been excluded for linkage in the Australian kindred. As our study progresses, we will report up-to-date results.« less

Cardiac Channelopathies and Sudden Death: Recent Clinical and Genetic Advances.

PubMed

Fernández-Falgueras, Anna; Sarquella-Brugada, Georgia; Brugada, Josep; Brugada, Ramon; Campuzano, Oscar

2017-01-29

Sudden cardiac death poses a unique challenge to clinicians because it may be the only symptom of an inherited heart condition. Indeed, inherited heart diseases can cause sudden cardiac death in older and younger individuals. Two groups of familial diseases are responsible for sudden cardiac death: cardiomyopathies (mainly hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic cardiomyopathy) and channelopathies (mainly long QT syndrome, Brugada syndrome, short QT syndrome, and catecholaminergic polymorphic ventricular tachycardia). This review focuses on cardiac channelopathies, which are characterized by lethal arrhythmias in the structurally normal heart, incomplete penetrance, and variable expressivity. Arrhythmias in these diseases result from pathogenic variants in genes encoding cardiac ion channels or associated proteins. Due to a lack of gross structural changes in the heart, channelopathies are often considered as potential causes of death in otherwise unexplained forensic autopsies. The asymptomatic nature of channelopathies is cause for concern in family members who may be carrying genetic risk factors, making the identification of these genetic factors of significant clinical importance.

Corticotropin releasing factor: a key role in the neurobiology of addiction.

PubMed

Zorrilla, Eric P; Logrip, Marian L; Koob, George F

2014-04-01

Drug addiction is a chronically relapsing disorder characterized by loss of control over intake and dysregulation of stress-related brain emotional systems. Since the discovery by Wylie Vale and his colleagues of corticotropin-releasing factor (CRF) and the structurally-related urocortins, CRF systems have emerged as mediators of the body's response to stress. Relatedly, CRF systems have a prominent role in driving addiction via actions in the central extended amygdala, producing anxiety-like behavior, reward deficits, excessive, compulsive-like drug self-administration and stress-induced reinstatement of drug seeking. CRF neuron activation in the medial prefrontal cortex may also contribute to the loss of control. Polymorphisms in CRF system molecules are associated with drug use phenotypes in humans, often in interaction with stress history. Drug discovery efforts have yielded brain-penetrant CRF1 antagonists with activity in preclinical models of addiction. The results support the hypothesis that brain CRF-CRF1 systems contribute to the etiology and maintenance of addiction. Copyright © 2014 Elsevier Inc. All rights reserved.

Corticotropin Releasing Factor: A Key Role in the Neurobiology of Addiction

PubMed Central

Zorrilla, Eric P.; Logrip, Marian L.; Koob, George F.

2014-01-01

Drug addiction is a chronically relapsing disorder characterized by loss of control over intake and dysregulation of stress-related brain emotional systems. Since the discovery by Wylie Vale and his colleagues of corticotropin-releasing factor (CRF) and the structurally-related urocortins, CRF systems have emerged as mediators of the body’s response to stress. Relatedly, CRF systems have a prominent role in driving addiction via actions in the central extended amygdala, producing anxiety-like behavior, reward deficits, excessive, compulsive-like drug self-administration and stress-induced reinstatement of drug seeking. CRF neuron activation in the medial prefrontal cortex may also contribute to the loss of control. Polymorphisms in CRF system molecules are associated with drug use phenotypes in humans, often in interaction with stress history. Drug discovery efforts have yielded brain-penetrant CRF1 antagonists with activity in preclinical models of addiction.. The results support the hypothesis that brain CRF-CRF1 systems contribute to the etiology and maintenance of addiction. PMID:24456850

Melanocortin 1 Receptor: Structure, Function, and Regulation

PubMed Central

Wolf Horrell, Erin M.; Boulanger, Mary C.; D’Orazio, John A.

2016-01-01

The melanocortin 1 receptor (MC1R) is a melanocytic Gs protein coupled receptor that regulates skin pigmentation, UV responses, and melanoma risk. It is a highly polymorphic gene, and loss of function correlates with a fair, UV-sensitive, and melanoma-prone phenotype due to defective epidermal melanization and sub-optimal DNA repair. MC1R signaling, achieved through adenylyl cyclase activation and generation of the second messenger cAMP, is hormonally controlled by the positive agonist melanocortin, the negative agonist agouti signaling protein, and the neutral antagonist β-defensin 3. Activation of cAMP signaling up-regulates melanin production and deposition in the epidermis which functions to limit UV penetration into the skin and enhances nucleotide excision repair (NER), the genomic stability pathway responsible for clearing UV photolesions from DNA to avoid mutagenesis. Herein we review MC1R structure and function and summarize our laboratory’s findings on the molecular mechanisms by which MC1R signaling impacts NER. PMID:27303435

Detection of the mtDNA 14484 mutation on an African-specific haplotype: Implications about its role in causing Leber hereditary optic neuropathy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Torroni, A.; Petrozzi, M.; Terracina, M.

1996-07-01

Leber hereditary optic neuropathy (LHON) is a maternally transmitted disease whose primary clinical manifestation is acute or subacute bilateral loss of central vision leading to central scotoma and blindness. To date, LHON has been associated with 18 mtDNA missense mutations, even though, for many of these mutations, it remains unclear whether they cause the disease, contribute to the pathology, or are nonpathogenic mtDNA polymorphisms. On the basis of numerous criteria, which include the specificity for LHON, the frequency in the general population, and the penetrance within affected pedigrees, the detection of associated defects in the respiratory chain, mutations at threemore » nucleotide positions (nps), 11778 (G{r_arrow}A), 3460 (G{r_arrow}A), and 14484 (T{r_arrow}C) have been classified as high-risk and primary LHON mutations. Overall, these three mutations encompass {ge}90% of the LHON cases. 29 refs., 1 fig.« less

Glutathione-S-transferase M1, T1 and P1 polymorphisms, and breast cancer risk, in BRCA1/2 mutation carriers

PubMed Central

Kadouri, L; Kote-Jarai, Z; Hubert, A; Baras, M; Abeliovich, D; Hamburger, T; Peretz, T; Eeles, R A

2008-01-01

Variation in penetrance estimates for BRCA1/2 carriers suggests that other environmental and genetic factors may modify cancer risk in carriers. The GSTM1, T1 and P1 isoenzymes are involved in metabolism of environmental carcinogens. The GSTM1 and GSTT1 gene is absent in a substantial proportion of the population. In GSTP1, a single-nucleotide polymorphism that translates to Ile112Val was associated with lower activity. We studied the effect of these polymorphisms on breast cancer (BC) risk in BRCA1/2 carriers. A population of 320 BRCA1/2 carriers were genotyped; of them 262 were carriers of one of the three Ashkenazi founder mutations. Two hundred and eleven were affected with BC (20 also with ovarian cancer (OC)) and 109 were unaffected with BC (39 of them had OC). Risk analyses were conducted using Cox proportional hazard models adjusted for origin (Ashkenazi vs non-Ashkenazi). We found an estimated BC HR of 0.89 (95% CI 0.65–1.12, P=0.25) and 1.11 (95% CI 0.81–1.52, P=0.53) for the null alleles of GSTM1 and GSTT1, respectively. For GSTP1, HR for BC was 1.36 (95% CI 1.02–1.81, P=0.04) for individuals with Ile/Val, and 2.00 (95% CI 1.18–3.38) for carriers of the Val/Val genotype (P=0.01). An HR of 3.20 (95% CI 1.26–8.09, P=0.01), and younger age at BC onset (P=0.2), were found among Val/Val, BRCA2 carriers, but not among BRCA1 carriers. In conclusion, our results indicate significantly elevated risk for BC in carriers of BRCA2 mutations with GSTP1-Val allele with dosage effect, as implicated by higher risk in homozygous Val carriers. The GSTM1- and GSTT1-null allele did not seem to have a major effect. PMID:18542066

Observation of organized structure in turbulent flow within and above a forest canopy

NASA Technical Reports Server (NTRS)

Gao, W.; Shaw, R. H.; Paw u, K. T.

1989-01-01

Data obtained with seven triaxial sonic anemometer/thermometers and three Lyman-alpha hygrometers at an experimental site in Ontario, Canada reveal the coherent occurrence of ramp patterns of temperature and humidity at several levels within and above the deciduous forest considered. The ramps appear most clearly in the middle and upper portion of the forest, and near the top of the forest they are composed of a weak ejecting motion transporting warm and/or moist air out of the forest, followed by strong sweeps of cool and/or dry air penetrating into the canopy. In the middle and upper parts of the canopy, the sweeps are found to conduct a large proportion of the overall transfer between the forest and the lower atmosphere, with a lesser contribution from ejections.

International cometary explorer encounter with giacobini-zinner: magnetic field observations.

PubMed

Smith, E J; Tsurutani, B T; Slvain, J A; Jones, D E; Siscoe, G L; Mendis, D A

1986-04-18

The vector helium magnetometer on the International Cometary Explorer observed the magnetic fields induced by the interaction of comet Giacobini-Zinner with the solar wind. A magnetic tail was penetrated approximately 7800 kilometers downstream from the comet and was found to be 10(4) kilometers wide. It consisted of two lobes, containing oppositely directed fields with strengths up to 60 nanoteslas, separated by a plasma sheet approximately 10(3)kilometers thick containing a thin current sheet. The magnetotail was enclosed in an extended ionosheath characterized by intense hydromagnetic turbulene and interplanetary fields draped around the comet. A distant bow wave, which may or may not have been a bow shock, was observed at both edges of the ionosheath. Weak turbulence was observed well upstream of the bow wave.

Optimized optical clearing method for imaging central nervous system

NASA Astrophysics Data System (ADS)

Yu, Tingting; Qi, Yisong; Gong, Hui; Luo, Qingming; Zhu, Dan

2015-03-01

The development of various optical clearing methods provides a great potential for imaging entire central nervous system by combining with multiple-labelling and microscopic imaging techniques. These methods had made certain clearing contributions with respective weaknesses, including tissue deformation, fluorescence quenching, execution complexity and antibody penetration limitation that makes immunostaining of tissue blocks difficult. The passive clarity technique (PACT) bypasses those problems and clears the samples with simple implementation, excellent transparency with fine fluorescence retention, but the passive tissue clearing method needs too long time. In this study, we not only accelerate the clearing speed of brain blocks but also preserve GFP fluorescence well by screening an optimal clearing temperature. The selection of proper temperature will make PACT more applicable, which evidently broaden the application range of this method.

Fully gapped superconductivity in single crystals of noncentrosymmetric Re6Zr with broken time-reversal symmetry

NASA Astrophysics Data System (ADS)

Pang, G. M.; Nie, Z. Y.; Wang, A.; Singh, D.; Xie, W.; Jiang, W. B.; Chen, Y.; Singh, R. P.; Smidman, M.; Yuan, H. Q.

2018-06-01

The noncentrosymmetric superconductor Re6Zr has attracted much interest due to the observation of broken time-reversal symmetry in the superconducting state. Here we report an investigation of the superconducting gap structure of Re6Zr single crystals by measuring the magnetic penetration depth shift Δ λ (T ) and electronic specific heat Ce(T ) . Δ λ (T ) exhibits an exponential temperature dependence behavior for T ≪Tc , which indicates a fully open superconducting gap. Our analysis shows that a single gap s -wave model is sufficient to describe both the superfluid density ρs(T ) and Ce(T ) results, with a fitted gap magnitude larger than the weak coupling BCS value, providing evidence for fully gapped superconductivity in Re6Zr with moderate coupling.

Semi-analytical study of the tokamak pedestal density profile in a single-null diverted plasma with puffing-recycling gas sources

NASA Astrophysics Data System (ADS)

Shi, Bingren

2010-10-01

The tokamak pedestal density structure is generally studied using a diffusion-dominant model. Recent investigations (Stacey and Groebner 2009 Phys. Plasmas 16 102504) from first principle based physics have shown a plausible existence of large inward convection in the pedestal region. The diffusion-convection equation with rapidly varying convection and diffusion coefficients in the near edge region and model puffing-recycling neutral particles is studied in this paper. A peculiar property of its solution for the existence of the large convection case is that the pedestal width of the density profile, qualitatively different from the diffusion-dominant case, depends mainly on the width of the inward convection and only weakly on the neutral penetration length and its injection position.

Endoscopic Options for Gastroesophageal Reflux: Where Are We Now and What Does the Future Hold?

PubMed

Triadafilopoulos, George

2016-09-01

Early in the twenty-first century, novel endoscopic techniques were introduced for the management of gastroesophageal reflux disease, providing minimally invasive ways to eliminate pharmacologic acid inhibition and avoid the need for anti-reflux surgery. These techniques do not significantly alter the anatomy of the gastroesophageal junction, minimizing short- and long-term adverse effects, such as dysphagia and bloating. After extensive clinical testing, many endoscopic therapies were abandoned due to either lack of durable efficacy or unfavorable safety profile. Today, only four such therapies remain clinically available, each with variable levels of clinical validation and market penetration. This review will provide an assessment of these endoscopic therapies, highlighting their respective strengths and weaknesses and their present and future applicability to patients with gastroesophageal reflux disease.

Dielectric response of a nondegenerate electron gas in semiconductor nanocrystallites

NASA Astrophysics Data System (ADS)

van Faassen, E.

1998-12-01

We investigate the low-frequency dielectric response of a dilute electron gas in a small spherical semiconductor particle. The flow of the electrons is described by hydrodynamic equations which incorporate the electrostatic interactions between the electrons in a self-consistent fashion. In the low-frequency regime, the dielectric loss is small and proportional to the frequency, despite substantial field penetration into the semiconductor. The loss remains small even for high doping levels due to effective cancellation between field-induced drift and diffusion. The model is used to estimate the complex dielectric constant of a system of weakly conducting nanosized semiconductor particles. The most prominent manifestation of spatial dispersion is that photoinduced changes in the real and imaginary parts of the dielectric constant are positive and of comparable magnitude.

Molecular characterization of the Fy(a-b-) phenotype in a Polish family.

PubMed

Karolak, Ewa; Grodecka, Magdalena; Suchanowska, Anna; Klausa, Elżbieta; Bochenek, Stanisława; Majorczyk, Edyta; Czerwiński, Marcin; Waśniowska, Kazimiera

2013-10-01

The Fy(a-b-) phenotype, very rare in Caucasians and defined by the homozygous FY(*)B-33 allele, is associated with the -33T>C mutation in the promoter region of the FY gene. The allele FY(*)X is correlated with weak expression of Fy(b) antigen due to 265C>T and 298G>A mutations in FY(*)B allele. The purpose of this study was molecular characterization of Fy blood group antigens in Fy(a-b-) members of a Polish family. High-resolution melting analysis was performed to detect single nucleotide polymorphisms in amplified fragments of the FY gene. The Fy(a-b-) phenotype in three siblings of the Polish family was caused by the FY(*)X/FY(*)B-33 genotype. Copyright © 2013 Elsevier Ltd. All rights reserved.

The long, the short and the weak: the origin of gamma-ray bursts.

PubMed

Piran, Tsvi; Bromberg, Omer; Nakar, Ehud; Sari, Re'em

2013-06-13

The origin of gamma-ray bursts (GRBs) is one of the most interesting puzzles in recent astronomy. During the last decade a consensus has formed that long GRBs (LGRBs) arise from the collapse of massive stars, and that short GRBs (SGRBs) have a different origin, most likely neutron star mergers. A key ingredient of the collapsar model that explains how the collapse of massive stars produces a GRB is the emergence of a relativistic jet that penetrates the stellar envelope. The condition that the emerging jet penetrates the envelope imposes strong constraints on the system. Using these constraints we show the following. (i) Low-luminosity GRBs (llGRBs), a subpopulation of GRBs with very low luminosities (and other peculiar properties: single-peaked, smooth and soft), cannot be formed by collapsars. llGRBs must have a different origin (most likely a shock breakout). (ii) On the other hand, regular LGRBs must be formed by collapsars. (iii) While for BATSE the dividing line between collapsars and non-collapsars is indeed at approximately 2 s, the dividing line is different for other GRB detectors. In particular, most Swift bursts longer than 0.8 s are of a collapsar origin. This last result requires a revision of many conclusions concerning the origin of Swift SGRBs, which were based on the commonly used 2 s limit.

Ionization of short polymethacrylic acid: titration, DLS, and model calculations.

PubMed

Pohlmeier, A; Haber-Pohlmeier, S

2004-05-15

In this work the charging of polymethacrylic acid in excess electrolyte solution is investigated experimentally by titration and dynamic light scattering. The results are analyzed by a penetrable sphere model, which employs the Poisson-Boltzmann equation for the description of electrostatic interactions and takes into account specific binding of H+ and Na+. The evaluation of the DLS data yields two relaxation modes. The slow mode is present only at finite degrees of charging and is therefore caused by collective diffusion. The fast mode, which corresponds to diffusion coefficients in the range from (1.1 to 1.5) x 10(-10) m2 s(-1), is present over the whole pH range. This reflects the diffusional dynamics of the polyion itself and allows the calculation of hydrodynamic radii for equivalent spheres (RH). These increase from 1.5 nm at pH 2.14 up to 1.8 nm for a degree of deprotonation alpha=0.47 at pH 5.86. With a further increase of pH the radii slightly decrease to 1.6 nm. Setting the radius of the penetrable sphere equal to RH, we can successfully model the overall charging curve with logK0H=4.85 and logK0Na=-0.6. This means that weak complexes of the type COO---Na are formed, which reduce the effective charge inside the polyelectrolyte coil.

External vibration multi-directional ultrasound shearwave elastography (EVMUSE): application in liver fibrosis staging.

PubMed

Zhao, Heng; Song, Pengfei; Meixner, Duane D; Kinnick, Randall R; Callstrom, Matthew R; Sanchez, William; Urban, Matthew W; Manduca, Armando; Greenleaf, James F; Chen, Shigao

2014-11-01

Shear wave speed can be used to assess tissue elasticity, which is associated with tissue health. Ultrasound shear wave elastography techniques based on measuring the propagation speed of the shear waves induced by acoustic radiation force are becoming promising alternatives to biopsy in liver fibrosis staging. However, shear waves generated by such methods are typically very weak. Therefore, the penetration may become problematic, especially for overweight or obese patients. In this study, we developed a new method called external vibration multi-directional ultrasound shearwave elastography (EVMUSE), in which external vibration from a loudspeaker was used to generate a multi-directional shear wave field. A directional filter was then applied to separate the complex shear wave field into several shear wave fields propagating in different directions. A 2-D shear wave speed map was reconstructed from each individual shear wave field, and a final 2-D shear wave speed map was constructed by compounding these individual wave speed maps. The method was validated using two homogeneous phantoms and one multi-purpose tissue-mimicking phantom. Ten patients undergoing liver magnetic resonance elastography (MRE) were also studied with EVMUSE to compare results between the two methods. Phantom results showed EVMUSE was able to quantify tissue elasticity accurately with good penetration. In vivo EVMUSE results were well correlated with MRE results, indicating the promise of using EVMUSE for liver fibrosis staging.

The radial electric field as a measure for field penetration of resonant magnetic perturbations

DOE PAGES

Mordijck, Saskia; Moyer, Richard A.; Ferraro, Nathaniel M.; ...

2014-06-18

In this study, we introduce a new indirect method for identifying the radial extent of the stochastic layer due to applying resonant magnetic perturbations (RMPs) in H-mode plasmas by measuring the spin-up of the plasma near the separatrix. This spin-up is a predicted consequence of enhanced loss of electrons due to magnetic stochastization. We find that in DIII-D H-mode plasmas with n = 3 RMPs applied for edge localized mode (ELM) suppression, the stochastic layer is limited to the outer 5% region in normalized magnetic flux, Ψ N. This is in contrast to vacuum modeling predictions where this layer canmore » penetrate up to 20% in Ψ N. Theoretical predictions of a stochastic red radial electric field, E r component exceed the experimental measurements by about a factor 3 close to the separatrix, suggesting that the outer region of the plasma is weakly stochastic. Linear response calculations with M3D-C1, a resistive two-fluid model, show that in this outer 5% region, plasma response often reduces the resonant magnetic field components by 67% or more in comparison with vacuum calculations. These results for DIII-D are in reasonable agreement with results from the MAST tokamak, where the magnetic field perturbation from vacuum field calculations needed to be reduced by 75% for agreement with experimental measurements of the x-point lobe structures.« less

External Vibration Multi-directional Ultrasound Shearwave Elastography (EVMUSE): Application in Liver Fibrosis Staging

PubMed Central

Zhao, Heng; Song, Pengfei; Meixner, Duane D.; Kinnick, Randall R.; Callstrom, Matthew R.; Sanchez, William; Urban, Matthew W.; Manduca, Armando; Greenleaf, James F.

2014-01-01

Shear wave speed can be used to assess tissue elasticity, which is associated with tissue health. Ultrasound shear wave elastography techniques based on measuring the propagation speed of the shear waves induced by acoustic radiation force are becoming promising alternatives to biopsy in liver fibrosis staging. However, shear waves generated by such methods are typically very weak. Therefore, the penetration may become problematic, especially for overweight or obese patients. In this study, we developed a new method called External Vibration Multi-directional Ultrasound Shearwave Elastography (EVMUSE), in which external vibration from a loudspeaker was used to generate a multi-directional shear wave field. A directional filter was then applied to separate the complex shear wave field into several shear wave fields propagating in different directions. A two-dimensional (2D) shear wave speed map was reconstructed from each individual shear wave field, and a final 2D shear wave speed map was constructed by compounding these individual wave speed maps. The method was validated using two homogeneous phantoms and one multi-purpose tissue-mimicking phantom. Ten patients undergoing liver Magnetic Resonance Elastography (MRE) were also studied with EVMUSE to compare results between the two methods. Phantom results showed EVMUSE was able to quantify tissue elasticity accurately with good penetration. In vivo EVMUSE results were well correlated with MRE results, indicating the promise of using EVMUSE for liver fibrosis staging. PMID:25020066

Detection of mosaicism for the polymorphic variants in the 5'-UTR of hOGG1 by cloning and sequence analysis and pyrosequencing.

PubMed

Cao, Lili; Li, Tianfeng; Zhu, Yanbei; Zhou, Wei; Guo, Wenwen; Cai, Zhenming; Xie, Yuan; He, Xuan; Li, Xinxiu; Zhu, Dalong; Wang, Yaping

2013-04-01

Mosaicism refers to the presence of genetically distinct cell lines within an organism or a tissue. Somatic mosaicism exists in distinct populations of somatic cells and commonly arises as a result of somatic mutations, mainly in early embryonic development. SNPs are important markers that distinguish between different individuals in heterogeneous biological samples and contribute greatly to disease risk association studies. In this work, we investigated the relationship between the functional variants in the 5'-UTR of the hOGG1 gene and the risk of type 2 diabetes. Upon detection of the polymorphisms c.-53G>C, c.-23A>G, and c.-18G>T in the hOGG1 gene, we found that mosaicism was present in 3/28 (10.71%), 7/51 (13.73%), and 1/44 (2.27%) patients respectively, who were carriers of these single nucleotide variations, by cloning and sequence analysis and pyrosequencing. Statistical analysis showed that the frequency of the variation c.-23A>G in the hOGG1 5'-UTR in type 2 diabetic patients was significantly higher than that in healthy controls. However, sequencing of the mutant alleles in mosaic individuals showed weak peaks that may affect detection of the SNPs and impair association-based investigations. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Morphological and Genetic Analysis of Four Color Morphs of Bean Leaf Beetle.

PubMed

Tiroesele, Bamphitlhi; Skoda, Steven R; Hunt, Thomas E; Lee, Donald J; Ullah, Muhammad Irfan; Molina-Ochoa, Jaime; Foster, John E

2018-03-01

Bean leaf beetle (BLB), Cerotoma trifurcata (Forster; Coleoptera: Chrysomelidae), exhibits considerable color variation but little is known about the underlying genetic structure and gene flow among color phenotypes. Genetic and morphological variation among four color phenotypes-green with spots (G+S), green without spots (G-S), red with spots (R+S) and red without spots (R-S)-were analyzed using amplified fragment length polymorphisms (AFLP) and morphometrics, respectively. AFLP generated 175 markers that showed ≥80% polymorphism. Analysis of molecular variance (AMOVA) indicated that genetic variation was greatest within phenotypes (82.6-84.0%); gene flow among the four phenotypes was relatively high (Nm = 3.82). The dendrogram and STRUCTURE analysis indicated some population divergence of G-S from the other phenotypes. Morphological parameters were similar among phenotypes except that R+S showed significant differences in weight and body-length. Canonical variables 1 and 2, based on average morphometric characters, accounted for 98% of the total variation; some divergence was indicated between G+S and R+S from each other and from the G-S/R-S BLB color morphs. The pattern of genetic variation indicated potential divergence of G-S and G+S from each other and from R-S and R+S. Although these results indicate that the four different color morphs are not genetically or reproductively isolated, there is some genetic differentiation/structure and morphological dissimilarity suggesting weak/incomplete isolation.

Genetic diversity of the forage peanut in the Jequitinhonha, São Francisco, and Paranã River valleys of Brazil.

PubMed

Azêvedo, H S F S; Sousa, A C B; Martins, K; Oliveira, J C; Yomura, R B T; Silva, L M; Valls, J F M; Assis, G M L; Campos, T

2016-09-09

Arachis pintoi and A. repens are legumes with a high forage value that are used to feed ruminants in consortium systems. Not only do they increase the persistence and quality of pastures, they are also used for ornamental and green cover. The objective of this study was to analyze microsatellite markers in order to access the genetic diversity of 65 forage peanut germplasm accessions in the section Caulorrhizae of the genus Arachis in the Jequitinhonha, São Francisco and Paranã River valleys of Brazil. Fifty-seven accessions of A. pintoi and eight of A. repens were analyzed using 17 microsatellites, and the observed heterozygosity (H O ), expected heterozygosity (H E ), number of alleles per locus, discriminatory power, and polymorphism information content were all estimated. Ten loci (58.8%) were polymorphic, and 125 alleles were found in total. The H E ranged from 0.30 to 0.94, and H O values ranged from 0.03 to 0.88. By using Bayesian analysis, the accessions were genetically differentiated into three gene pools. Neither the unweighted pair group method with arithmetic mean nor a neighbor-joining analysis clustered samples into species, origin, or collection area. These results reveal a very weak genetic structure that does not form defined clusters, and that there is a high degree of similarity between the two species.

Stabilization of Wide Band-Gap p-Type Wurtzite MnTe Thin Films on Amorphous Substrates

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zakutayev, Andriy A; Siol, Sebastian; Han, Yanbing

An important challenge in the development of optoelectronic devices for energy conversion applications is the search for suitable p-type contact materials. For example, p-type MnTe would be a promising alternative back contact to due to their chemical compatibility, but at normal conditions it has too narrow band gap due to octahedrally coordinated nickeline (NC) structure. The tetrahedrally coordinated wurtzite (WZ) polymorph of MnTe has not been reported, but it is especially interesting due to its predicted wider band gap, and because of better structural compatibility with CdTe and related II-VI semiconductor materials. Here, we report on the stabilization of WZ-MnTemore » thin films on amorphous indium zinc oxide (a-IZO) substrates relevant to photovoltaic applications. Optical spectroscopy of the WZ-MnTe films shows a wide direct band gap of Eg = 2.7 eV, while PES measurements reveal weak p-type doping with the Fermi level 0.6 eV above the valence band maximum. The results of electron microscopy and photoelectron spectroscopy (PES) measurements indicate that the WZ-MnTe is stabilized due to interdiffusion at the interface with IZO. The results of this work introduce a substrate stabilized WZ-MnTe polymorph as a potential p-type contact material candidate for future applications in CdTe devices for solar energy conversion and other optoelectronic technologies.« less

Solid-state characterization of nevirapine.

PubMed

Sarkar, Mahua; Perumal, O P; Panchagnula, R

2008-09-01

The purpose of this investigation is to characterize nevirapine from commercial samples and samples crystallized from different solvents under various conditions. The solid-state behavior of nevirapine samples was investigated using a variety of complementary techniques such as microscopy (optical, polarized, hot stage microscopy), differential scanning calorimeter, thermogravimetric analysis, Fourier transform infrared spectroscopy and powder X-ray diffractometry. The commercial samples of nevirapine had the same polymorphic crystalline form with an anhedral crystal habit. Intrinsic dissolution of nevirapine was similar for both the commercial batches. Powder dissolution showed pH dependency, with maximum dissolution in acidic pH and there was no significant effect of particle size. The samples recrystallized from different solvent systems with varying polarity yielded different crystal habits. Stirring and degrees of supersaturation influenced the size and shape of the crystals. The recrystallized samples did not produce any new polymorphic form, but weak solvates with varying crystal habit were produced. Recrystallized samples showed differences in the x-ray diffractograms. However, all the samples had the same internal crystal lattice as revealed from their similar melting points and heat of fusion. The intrinsic dissolution rate of recrystallized samples was lower than the commercial sample. It was found that the compression pressure resulted in desolvation and partial conversion of the crystal form. After compression, the recrystallized samples showed similar x-ray diffractograms to the commercial sample. Amorphous form showed slightly higher aqueous solubility than the commercial crystalline form.

Experimental Effects on IR Reflectance Spectra: Particle Size and Morphology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beiswenger, Toya N.; Myers, Tanya L.; Brauer, Carolyn S.

For geologic and extraterrestrial samples it is known that both particle size and morphology can have strong effects on the species’ infrared reflectance spectra. Due to such effects, the reflectance spectra cannot be predicted from the absorption coefficients alone. This is because reflectance is both a surface as well as a bulk phenomenon, incorporating both dispersion as well as absorption effects. The same spectral features can even be observed as either a maximum or minimum. The complex effects depend on particle size and preparation, as well as the relative amplitudes of the optical constants n and k, i.e. the realmore » and imaginary components of the complex refractive index. While somewhat oversimplified, upward-going amplitude in the reflectance spectrum usually result from surface scattering, i.e. rays that have been reflected from the surface without penetration, whereas downward-going peaks are due to either absorption or volume scattering, i.e. rays that have penetrated or refracted into the sample interior and are not reflected. While the effects are well known, we report seminal measurements of reflectance along with quantified particle size of the samples, the sizing obtained from optical microscopy measurements. The size measurements are correlated with the reflectance spectra in the 1.3 – 16 micron range for various bulk materials that have a combination of strong and weak absorption bands in order to understand the effects on the spectral features as a function of the mean grain size of the sample. We report results for both sodium sulfate Na2SO4 as well as ammonium sulfate (NH4)2SO4; the optical constants have been measured for (NH4)2SO4. To go a step further from the field to the laboratory we explore our understanding of particle size effects on reflectance spectra in the field using standoff detection. This has helped identify weaknesses and strengths in detection using standoff distances of up 160 meters away from the Target. The studies have shown that particle size has an enormous influence on the measured reflectance spectra of such materials; successful identification requires sufficient, representative reflectance data to include the particle sizes of interest.« less

Forecasting of Hourly Photovoltaic Energy in Canarian Electrical System

NASA Astrophysics Data System (ADS)

Henriquez, D.; Castaño, C.; Nebot, R.; Piernavieja, G.; Rodriguez, A.

2010-09-01

The Canarian Archipelago face similar problems as most insular region lacking of endogenous conventional energy resources and not connected to continental electrical grids. A consequence of the "insular fact" is the existence of isolated electrical systems that are very difficult to interconnect due to the considerable sea depths between the islands. Currently, the Canary Islands have six isolated electrical systems, only one utility generating most of the electricity (burning fuel), a recently arrived TSO (REE) and still a low implementation of Renewable Energy Resources (RES). The low level of RES deployment is a consequence of two main facts: the weakness of the stand-alone grids (from 12 MW in El Hierro up to only 1 GW in Gran Canaria) and the lack of space to install RES systems (more than 50% of the land protected due to environmental reasons). To increase the penetration of renewable energy generation, like solar or wind energy, is necessary to develop tools to manage them. The penetration of non manageable sources into weak grids like the Canarian ones causes a big problem to the grid operator. There are currently 104 MW of PV connected to the islands grids (Dec. 2009) and additional 150 MW under licensing. This power presents a serious challenge for the operation and stability of the electrical system. ITC, together with the local TSO (Red Eléctrica de España, REE) started in 2008 and R&D project to develop a PV energy prediction tool for the six Canarian Insular electrical systems. The objective is to supply reliable information for hourly forecast of the generation dispatch programme and to predict daily solar radiation patterns, in order to help program spinning reserves. ITC has approached the task of weather forecasting using different numerical model (MM5 and WRF) in combination with MSG (Meteosat Second Generation) images. From the online data recorded at several monitored PV plants and meteorological stations, PV nominal power and energy produced by every plant in Canary Islands are estimated using a series of theoretical and statistical energy models.

Assessing pathogenicity for novel mutation/sequence variants: the value of healthy older individuals.

PubMed

Zatz, Mayana; Pavanello, Rita de Cassia M; Lourenço, Naila Cristina V; Cerqueira, Antonia; Lazar, Monize; Vainzof, Mariz

2012-12-01

Improvement in DNA technology is increasingly revealing unexpected/unknown mutations in healthy persons and generating anxiety due to their still unknown health consequences. We report a 44-year-old healthy father of a 10-year-old daughter with bilateral coloboma and hearing loss, but without muscle weakness, in whom a whole-genome CGH revealed a deletion of exons 38-44 in the dystrophin gene. This mutation was inherited from her asymptomatic father, who was further clinically and molecularly evaluated for prognosis and genetic counseling (GC). This deletion was never identified by us in 982 Duchenne/Becker patients. To assess whether the present case represents a rare case of non-penetrance, and aiming to obtain more information for prognosis and GC, we suggested that healthy older relatives submit their DNA for analysis, to which several complied. Mutation analysis revealed that his mother, brother, and 56-year-old maternal uncle also carry the 38-44 deletion, suggesting it an unlikely cause of muscle weakness. Genome sequencing will disclose mutations and variants whose health impact are still unknown, raising important problems in interpreting results, defining prognosis, and discussing GC. We suggest that, in addition to family history, keeping the DNA of older relatives could be very informative, in particular for those interested in having their genome sequenced.

Beam-Plasma Interaction and Instabilities in a 2D Yukawa Plasma

NASA Astrophysics Data System (ADS)

Kyrkos, S.; Kalman, G.; Rosenberg, M.

2008-11-01

In a complex plasma, penetrating charged particle beams may lead to beam-plasma instabilities. When either the plasma, the beam, or both, are strongly interacting [1], the features of the instability are different from those in a weakly coupled plasma. We consider the case when a 2D dusty plasma forms a lattice, and the beam is moving in the lattice plane. Both the grains and the beam particles interact through a Yukawa potential; the beam particles are weakly coupled to each other and to the lattice. The system develops both a longitudinal and a transverse instability. Based on the phonon spectrum of a 2D hexagonal Yukawa lattice [2], we determine and compare the transverse and longitudinal growth rates. As a function of the wavenumber, the growth rates exhibit remarkable gaps, where no instability is excited. The gap locations are governed by the ratio of the lattice and the beam plasma frequencies. The behavior of the growth rates also depends on the direction of the beam and on the relationship between the beam speed and the longitudinal and transverse sound speeds. [1] GJ Kalman, M Rosenberg, JPA 36, 5963 (2003). [2] T Sullivan, GJ Kalman, S Kyrkos, P Bakshi, M Rosenberg, Z Donko, JPA 39, 4607 (2006).

Simulations of Low-q Disruptions in the Compact Toroidal Hybrid Experiment

NASA Astrophysics Data System (ADS)

Howell, E. C.; Hanson, J. D.; Ennis, D. A.; Hartwell, G. J.; Maurer, D. A.

2017-10-01

Resistive MHD simulations of low-q disruptions in the Compact Toroidal Hybrid Device (CTH) are performed using the NIMROD code. CTH is a current-carrying stellarator used to study the effects of 3D shaping on MHD stability. Experimentally, it is observed that the application of 3D vacuum fields allows CTH to operate with edge safety factor less than 2.0. However, these low-q discharges often disrupt after peak current if the applied 3D fields are too weak. Nonlinear simulations are initialized using model VMEC equilibria representative of low-q discharges with weak vacuum transform. Initially a series of symmetry preserving island chains are excited at the q=6/5, 7/5, 8/5, and 9/5 rational surfaces. These island chains act as transport barriers preventing stochastic magnetic fields in the edge from penetrating into the core. As the simulation progresses, predominately m/n=3/2 and 4/3 instabilities are destabilized. As these instabilities grow to large amplitude they destroy the symmetry preserving islands leading to large regions of stochastic fields. A current spike and loss of core thermal confinement occurs when the innermost island chain (6/5) is destroyed. Work Supported by US-DOE Grant #DE-FG02-03ER54692.

Genetics of autoimmune thyroid disease in the Lebanese population.

PubMed

Farra, C; Awwad, J; Fadlallah, A; Sebaly, G; Hage, G; Souaid, M; Ashkar, H; Medlej, R; Gannageh, M H; Halaby, G

2012-10-01

This study aims to investigate the association of human leukocyte antigen (HLA) class II genes and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) with autoimmune thyroid diseases in the Lebanese population. A total of 128 patients with autoimmune thyroid disease (55 with Graves' disease (GD) and 73 with Hashimoto's thyroiditis (HT)) were typed for HLA DQA1 (0301 and 0501) and DQB1 (0201, 0302, and 0303) and for 49A/G CTLA-4 using PCR-based sequence-specific priming methods. A total of 186 matched controls were typed for the same alleles and compared to the diseased population. Results showed no significant differences in HLA DQB1*0201 or DQB1*0301 allelic frequencies or CTLA-4 polymorphisms between patients and controls. For GD, there was a weak association with HLA DQB1*0302 [34.6% (19 of 55) vs. 21.5% (40 of 186), P = 0.048, odds ratio (OR) = 1.926, confidence interval (CI) = 0.999-3.715] and HLA DQB1*0302-DQA1*0501 haplotype [56.36% (31 of 55) vs. 40.8% (76 of 186), P = 0.042, OR = 1.870, CI = 1.018-3.433]. For HT, the frequencies of DQB1*0302-DQA1*0501 haplotype [28.8% (21of 73) vs. 14.5% (27 of 186), P = 0.008, OR = 2.378, CI = 1.241-4.558] and DQB1*0302-DQA1*0301 haplotype [60.2% (44 of 73) vs. 38.7% (72 of 186), P = 0.002, OR = 2.402, CI = 1.381-4.180] were significantly higher in patients. On the other hand, weak association was found between HT and DQA1*0301 allele [32.9% (24 of 73) vs. 20.9% (39 of 186), P = 0.044, OR = 1.846, CI = 1.011-3.373]. Findings show that DQB1*0302-DQA1*0501 and DQB1*0302-DQA1*0301 haplotypes may play a role in the pathogenesis of HT in the Lebanese population. For the 49A/G CTLA-4 polymorphism, no significant difference was found between patients and controls.

A new case of limb girdle muscular dystrophy 2G in a Greek patient, founder effect and review of the literature.

PubMed

Brusa, Roberta; Magri, Francesca; Papadimitriou, Dimitra; Govoni, Alessandra; Del Bo, Roberto; Ciscato, Patrizia; Savarese, Marco; Cinnante, Claudia; Walter, Maggie C; Abicht, Angela; Bulst, Stefanie; Corti, Stefania; Moggio, Maurizio; Bresolin, Nereo; Nigro, Vincenzo; Comi, Giacomo Pietro

2018-04-13

Limb girdle muscular dystrophy (LGMD) type 2G is a rare form of muscle disease, described only in a few patients worldwide, caused by mutations in TCAP gene, encoding the protein telethonin. It is characterised by proximal limb muscle weakness associated with distal involvement of lower limbs, starting in the first or second decade of life. We describe the case of a 37-year-old woman of Greek origin, affected by disto-proximal lower limb weakness. No cardiac or respiratory involvement was detected. Muscle biopsy showed myopathic changes with type I fibre hypotrophy, cytoplasmic vacuoles, lipid overload, multiple central nuclei and fibre splittings; ultrastructural examination showed metabolic abnormalities. Next generation sequencing analysis detected a homozygous frameshift mutation in the TCAP gene (c.90_91del), previously described in one Turkish family. Immunostaining and Western blot analysis showed complete absence of telethonin. Interestingly, Single Nucleotide Polymorphism analysis of the 10 Mb genomic region containing the TCAP gene showed a shared homozygous haplotype of both the Greek and the Turkish patients, thus suggesting a possible founder effect of TCAP gene c.90_91del mutation in this part of the Mediterranean area. Copyright © 2018 Elsevier B.V. All rights reserved.

Slab Penetration vs. Slab Stagnation: Mantle Reflectors as an Indicator

NASA Astrophysics Data System (ADS)

Okeler, A.; Gu, Y. J.; Schultz, R.; Contenti, S. M.

2011-12-01

Subducting oceanic lithosphere along convergent margins may stagnate near the base of the upper mantle or penetrate into the lower mantle. These dynamic processes cause extensive thermal and compositional variations, which can be observed in terms of impedance contrast (reflectivity) and topography of mantle transition zone (MTZ) discontinuities, i.e., 410- and 660-km discontinuities. In this study, we utilize ~ 15000 surface-reflected shear waves (SS) and their precursory arrivals (S410S and S660S) to analyze subduction related deformations on mantle reflectivity structure. We apply pre-stack, time-to-depth migration technique to SS precursors, and move weak underside reflections using PREM-predicted travel-time curves. Common Mid-point gathers are formed to investigate structure under the western Pacific, south America, and Mediterranean convergent boundaries. In general, mantle reflectivity structures are consistent with previous seismic tomography models. In regions of slab penetration (e.g., southern Kurile arc, Aegean Sea), our results show 1) a substantial decrease in S660S amplitude, and 2) strong lower mantle reflector(s) at ~ 900 km depth. These reflective structures are supported by zones of high P and S velocities extending into the lower mantle. Our 1-D synthetic simulations suggest that the decreasing S660S amplitudes are, at least partially, associated with shear wave defocusing due to changes in reflector depth (by ±20 km) within averaging bin. Assuming a ~500 km wide averaging area, a dipping reflector with 6-8 % slope can reduce the amplitude of a SS precursor by ~50%. On the other hand, broad depressions with strong impedance contrast at the base of the MTZ characterize the regions of slab stagnation, such as beneath the Tyrrhenian Sea and northeastern China. For the latter region, substantial topography on the 660-km discontinuity west of the Wadati-Benioff zone suggests that the stagnant part of the Pacific plate across Honshu arc is not nearly as flat as previously suggested.

Dysphagia in Duchenne muscular dystrophy: practical recommendations to guide management.

PubMed

Toussaint, Michel; Davidson, Zoe; Bouvoie, Veronique; Evenepoel, Nathalie; Haan, Jurn; Soudon, Philippe

2016-10-01

Duchenne muscular dystrophy (DMD) is a rapidly progressive neuromuscular disorder causing weakness of the skeletal, respiratory, cardiac and oropharyngeal muscles with up to one third of young men reporting difficulty swallowing (dysphagia). Recent studies on dysphagia in DMD clarify the pathophysiology of swallowing disorders and offer new tools for its assessment but little guidance is available for its management. This paper aims to provide a step-by-step algorithm to facilitate clinical decisions regarding dysphagia management in this patient population. This algorithm is based on 30 years of clinical experience with DMD in a specialised Centre for Neuromuscular Disorders (Inkendaal Rehabilitation Hospital, Belgium) and is supported by literature where available. Dysphagia can worsen the condition of ageing patients with DMD. Apart from the difficulties of chewing and oral fragmentation of the food bolus, dysphagia is rather a consequence of an impairment in the pharyngeal phase of swallowing. By contrast with central neurologic disorders, dysphagia in DMD accompanies solid rather than liquid intake. Symptoms of dysphagia may not be clinically evident; however laryngeal food penetration, accumulation of food residue in the pharynx and/or true laryngeal food aspiration may occur. The prevalence of these issues in DMD is likely underestimated. There is little guidance available for clinicians to manage dysphagia and improve feeding for young men with DMD. This report aims to provide a clinical algorithm to facilitate the diagnosis of dysphagia, to identify the symptoms and to propose practical recommendations to treat dysphagia in the adult DMD population. Implications for Rehabilitation Little guidance is available for the management of dysphagia in Duchenne dystrophy. Food can penetrate the vestibule, accumulate as residue or cause aspiration. We propose recommendations and an algorithm to guide management of dysphagia. Penetration/residue accumulation: prohibit solid food and promote intake of fluids. Aspiration: if cough augmentation techniques are ineffective, consider tracheostomy.

Dysphagia in Duchenne muscular dystrophy: practical recommendations to guide management

PubMed Central

Toussaint, Michel; Davidson, Zoe; Bouvoie, Veronique; Evenepoel, Nathalie; Haan, Jurn; Soudon, Philippe

2016-01-01

Abstract Purpose: Duchenne muscular dystrophy (DMD) is a rapidly progressive neuromuscular disorder causing weakness of the skeletal, respiratory, cardiac and oropharyngeal muscles with up to one third of young men reporting difficulty swallowing (dysphagia). Recent studies on dysphagia in DMD clarify the pathophysiology of swallowing disorders and offer new tools for its assessment but little guidance is available for its management. This paper aims to provide a step-by-step algorithm to facilitate clinical decisions regarding dysphagia management in this patient population. Methods: This algorithm is based on 30 years of clinical experience with DMD in a specialised Centre for Neuromuscular Disorders (Inkendaal Rehabilitation Hospital, Belgium) and is supported by literature where available. Results: Dysphagia can worsen the condition of ageing patients with DMD. Apart from the difficulties of chewing and oral fragmentation of the food bolus, dysphagia is rather a consequence of an impairment in the pharyngeal phase of swallowing. By contrast with central neurologic disorders, dysphagia in DMD accompanies solid rather than liquid intake. Symptoms of dysphagia may not be clinically evident; however laryngeal food penetration, accumulation of food residue in the pharynx and/or true laryngeal food aspiration may occur. The prevalence of these issues in DMD is likely underestimated. Conclusions: There is little guidance available for clinicians to manage dysphagia and improve feeding for young men with DMD. This report aims to provide a clinical algorithm to facilitate the diagnosis of dysphagia, to identify the symptoms and to propose practical recommendations to treat dysphagia in the adult DMD population.Implications for RehabilitationLittle guidance is available for the management of dysphagia in Duchenne dystrophy.Food can penetrate the vestibule, accumulate as residue or cause aspiration.We propose recommendations and an algorithm to guide management of dysphagia.Penetration/residue accumulation: prohibit solid food and promote intake of fluids.Aspiration: if cough augmentation techniques are ineffective, consider tracheostomy. PMID:26728920

The Caenorhabditis elegans SH2 domain-containing protein tyrosine phosphatase PTP-2 participates in signal transduction during oogenesis and vulval development

PubMed Central

Gutch, Michael J.; Flint, Andrew J.; Keller, James; Tonks, Nicholas K.; Hengartner, Michael O.

1998-01-01

Src homology-2 (SH2) domain-containing protein tyrosine phosphatases (SHPs) have been identified as either positive or negative regulators of signaling events downstream of receptor protein tyrosine kinases (R-PTKs). We describe here our characterization of ptp-2, a Caenorhabditis elegans gene that encodes a 668-amino-acid SHP. We isolated a recessive ptp-2 loss-of-function allele, op194, that lacks the conserved protein tyrosine phosphatase catalytic domain by screening for transposon-mediated deletion mutations. Homozygous ptp-2(op194) hermaphrodites exhibit a completely penetrant zygotic semisterile/maternal effect lethal phenotype, characterized by the presence of abnormally large oocytes in the zygotic semisterile animals. These phenotypes indicate that PTP-2 activity is essential for proper oogenesis. Gain-of-function let-60 ras alleles rescued the defects associated with ptp-2(op194), suggesting that LET-60 Ras acts downstream of, or in parallel to, PTP-2 during oogenesis. Although ptp-2 function is not required for normal vulval development, ptp-2(op194) altered significantly the vulval phenotypes caused by mutations in several genes of the inductive signaling pathway. The penetrance of the multivulva phenotype caused by loss-of-function mutations in lin-15, and gain-of-function mutations in let-23 or let-60 ras, was reduced by ptp-2(op194). Moreover, ptp-2(op194) increased the penetrance of the vulvaless phenotype conferred by a weak loss-of-function sem-5 allele. Taken together, our genetic data positions PTP-2 activity downstream of LET-23 in the vulval induction signaling pathway. Although PTP-2 functions to transmit a requisite signal during oogenesis, PTP-2 function during C. elegans vulval cell differentiation appears to be directed at regulating the overall strength of the inductive signal, which may contribute to the quantitative differences in signaling required for the proper specification of the 1°, 2°, and 3° vulval cell fates. PMID:9472025

Initial experience with dual-lumen balloon catheter injection for preoperative Onyx embolization of skull base paragangliomas.

PubMed

Ladner, Travis R; He, Lucy; Davis, Brandon J; Yang, George L; Wanna, George B; Mocco, J

2016-06-01

OBJECT Paragangliomas are highly vascular head and neck tumors for which preoperative embolization is often considered to facilitate resection. The authors evaluated their initial experience using a dual-lumen balloon to facilitate preoperative embolization in 5 consecutive patients who underwent preoperative transarterial Onyx embolization assisted by the Scepter dual-lumen balloon catheter between 2012 and 2014. OBJECT The authors reviewed the demographic and clinical records of 5 patients who underwent Scepter-assisted Onyx embolization of a paraganglioma followed by resection between 2012 and 2014. Descriptive statistics of clinical outcomes were assessed. RESULTS Five patients (4 with a jugular and 1 with a vagal paraganglioma) were identified. Three paragangliomas were embolized in a single session, and each of the other 2 were completed in 3 staged sessions. The mean volume of Onyx used was 14.3 ml (range 6-30 ml). Twenty-seven vessels were selectively catheterized for embolization. All patients required selective embolization via multiple vessels. Two patients required sacrifice of parent vessels (1 petrocavernous internal carotid artery and 1 vertebral artery) after successful balloon test occlusion. One patient underwent embolization with Onyx-18 alone, 2 with Onyx-34 alone, and 1 with Onyx-18 and -34. In each case, migration of Onyx was achieved within the tumor parenchyma. The mean time between embolization and resection was 3.8 days (range 1-8 days). Gross-total resection was achieved in 3 (60%) patients, and the other 2 patients had minimal residual tumor. The mean estimated blood loss during the resections was 556 ml (range 200-850 ml). The mean postoperative hematocrit level change was -17.3%. Two patients required blood transfusions. One patient, who underwent extensive tumor penetration with Onyx, developed a temporary partial cranial nerve VII palsy that resolved to House-Brackmann Grade I (out of VI) at the 6-month follow-up. One patient experienced improvement in existing facial nerve weakness after embolization. CONCLUSIONS Scepter catheter-based Onyx embolization seems to be safe and effective. It was associated with excellent distal tumor vasculature penetration and holds promise as an adjunct to conventional transarterial Onyx embolization of paragangliomas. However, the ease of tumor penetration should encourage caution in practitioners who may be able to effect comparable improvement in blood loss with more conservative proximal Onyx penetration.

Role of GLI2 in hypopituitarism phenotype.

PubMed

Arnhold, Ivo J P; França, Marcela M; Carvalho, Luciani R; Mendonca, Berenice B; Jorge, Alexander A L

2015-06-01

GLI2 is a zinc-finger transcription factor involved in the Sonic Hedgehog pathway. Gli2 mutant mice have hypoplastic anterior and absent posterior pituitary glands. We reviewed the literature for patients with hypopituitarism and alterations in GLI2. Twenty-five patients (16 families) had heterozygous truncating mutations, and the phenotype frequently included GH deficiency, a small anterior pituitary lobe and an ectopic/undescended posterior pituitary lobe on magnetic resonance imaging and postaxial polydactyly. The inheritance pattern was autosomal dominant with incomplete penetrance and variable expressivity. The mutation was frequently inherited from an asymptomatic parent. Eleven patients had heterozygous non-synonymous GLI2 variants that were classified as variants of unknown significance, because they were either absent from or had a frequency lower than 0.001 in the databases. In these patients, the posterior pituitary was also ectopic, but none had polydactyly. A third group of variants found in patients with hypopituitarism were considered benign because their frequency was ≥ 0.001 in the databases. GLI2 is a large and polymorphic gene, and sequencing may identify variants whose interpretation may be difficult. Incomplete penetrance implies in the participation of other genetic and/or environmental factors. An interaction between Gli2 mutations and prenatal ethanol exposure has been demonstrated in mice dysmorphology. In conclusion, a relatively high frequency of GLI2 mutations and variants were identified in patients with congenital GH deficiency without other brain defects, and most of these patients presented with combined pituitary hormone deficiency and an ectopic posterior pituitary lobe. Future studies may clarify the relative role and frequency of GLI2 alterations in the aetiology of hypopituitarism. © 2015 Society for Endocrinology.

Prefrontal cortex lesions and MAO-A modulate aggression in penetrating traumatic brain injury

PubMed Central

Pardini, M.; Krueger, F.; Hodgkinson, C.; Raymont, V.; Ferrier, C.; Goldman, D.; Strenziok, M.; Guida, S.

2011-01-01

Objective: This study investigates the interaction between brain lesion location and monoamine oxidase A (MAO-A) in the genesis of aggression in patients with penetrating traumatic brain injury (PTBI). Methods: We enrolled 155 patients with PTBI and 42 controls drawn from the Vietnam Head Injury Study registry. Patients with PTBI were divided according to lesion localization (prefrontal cortex [PFC] vs non-PFC) and were genotyped for the MAO-A polymorphism linked to low and high transcriptional activity. Aggression was assessed with the aggression/agitation subscale of the Neuropsychiatric Inventory (NPI-a). Results: Patients with the highest levels of aggression preferentially presented lesions in PFC territories. A significant interaction between MAO-A transcriptional activity and lesion localization on aggression was revealed. In the control group, carriers of the low-activity allele demonstrated higher aggression than high-activity allele carriers. In the PFC lesion group, no significant differences in aggression were observed between carriers of the 2 MAO-A alleles, whereas in the non-PFC lesion group higher aggression was observed in the high-activity allele than in the low-activity allele carriers. Higher NPI-a scores were linked to more severe childhood psychological traumatic experiences and posttraumatic stress disorder symptomatology in the control and non-PFC lesion groups but not in the PFC lesion group. Conclusions: Lesion location and MAO-A genotype interact in mediating aggression in PTBI. Importantly, PFC integrity is necessary for modulation of aggressive behaviors by genetic susceptibilities and traumatic experiences. Potentially, lesion localization and MAO-A genotype data could be combined to develop risk-stratification algorithms and individualized treatments for aggression in PTBI. PMID:21422455

Genomewide Linkage Scan for Split–Hand/Foot Malformation with Long-Bone Deficiency in a Large Arab Family Identifies Two Novel Susceptibility Loci on Chromosomes 1q42.2-q43 and 6q14.1

PubMed Central

Naveed, Mohammed; Nath, Swapan K.; Gaines, Mathew; Al-Ali, Mahmoud T.; Al-Khaja, Najib; Hutchings, David; Golla, Jeffrey; Deutsch, Samuel; Bottani, Armand; Antonarakis, Stylianos E.; Ratnamala, Uppala; Radhakrishna, Uppala

2007-01-01

Split–hand/foot malformation with long-bone deficiency (SHFLD) is a rare, severe limb deformity characterized by tibia aplasia with or without split-hand/split-foot deformity. Identification of genetic susceptibility loci for SHFLD has been unsuccessful because of its rare incidence, variable phenotypic expression and associated anomalies, and uncertain inheritance pattern. SHFLD is usually inherited as an autosomal dominant trait with reduced penetrance, although recessive inheritance has also been postulated. We conducted a genomewide linkage analysis, using a 10K SNP array in a large consanguineous family (UR078) from the United Arab Emirates (UAE) who had disease transmission consistent with an autosomal dominant inheritance pattern. The study identified two novel SHFLD susceptibility loci at 1q42.2-q43 (nonparametric linkage [NPL] 9.8, P=.000065) and 6q14.1 (NPL 7.12, P=.000897). These results were also supported by multipoint parametric linkage analysis. Maximum multipoint LOD scores of 3.20 and 3.78 were detected for genomic locations 1q42.2-43 and 6q14.1, respectively, with the use of an autosomal dominant mode of inheritance with reduced penetrance. Haplotype analysis with informative crossovers enabled mapping of the SHFLD loci to a region of ∼18.38 cM (8.4 Mb) between single-nucleotide polymorphisms rs1124110 and rs535043 on 1q42.2-q43 and to a region of ∼1.96 cM (4.1 Mb) between rs623155 and rs1547251 on 6q14.1. The study identified two novel loci for the SHFLD phenotype in this UAE family. PMID:17160898

SERT Ileu425Val in autism, Asperger syndrome and obsessive-compulsive disorder.

PubMed

Wendland, Jens R; DeGuzman, Theresa B; McMahon, Francis; Rudnick, Gary; Detera-Wadleigh, Sevilla D; Murphy, Dennis L

2008-02-01

SERT I425V, an uncommon missense single nucleotide polymorphism producing a gain-of-function of the serotonin transporter (SERT), was originally found to segregate with a primarily obsessive-compulsive disorder (OCD) but complexly comorbid phenotype in two unrelated families. As two individuals with SERT I425V and OCD also had Asperger syndrome (AS), an autism spectrum disorder, and as other rare SERT variants have recently shown significant associations with autism, we set out to extend our original OCD study by genotyping additional autism/AS and OCD samples. Case-control association study of SERT I425V in 210 AS/autism probands and 215 controls, plus 335 OCD probands and their family members. SERT I425V was not found in any of the individuals with AS/autism, OCD alone or OCD comorbid with AS and other disorders, or in controls. This results in new estimates of SERT I425V having a 1.5% prevalence in 530 individuals with OCD from five unrelated families genotyped by us and by one other group and a 0.23% frequency in four control populations totaling 1300 individuals, yielding a continuing significant OCD-control difference (Fisher's exact test corrected for family coefficient of identity P=0.004, odds ratio=6.54). As several other uncommon, less well quantitated genetic variations occur with an OCD phenotype, including chromosomal anomalies and some other rare gene variants (SGCE, GCH1 and SLITRK1), a tentative conclusion is that OCD resembles other complex disorders in being etiologically heterogeneous and in having both highly penetrant familial subtypes associated with rare alleles or chromosomal anomalies, as well as having a more common, polygenetic form that may involve polymorphisms in such genes as BDNF, COMT, GRIN2beta, TPH2, HTR2A and SLC1A1.

COMT Val(158)Met genotype determines the direction of cognitive effects produced by catechol-O-methyltransferase inhibition.

PubMed

Farrell, Sarah M; Tunbridge, Elizabeth M; Braeutigam, Sven; Harrison, Paul J

2012-03-15

Catechol-O-methyltransferase (COMT) metabolizes dopamine. The COMT Val(158)Met polymorphism influences its activity, and multiple neural correlates of this genotype on dopaminergic phenotypes, especially working memory, have been reported. COMT activity can also be regulated pharmacologically by COMT inhibitors. The inverted-U relationship between cortical dopamine signaling and working memory predicts that the effects of COMT inhibition will differ according to COMT genotype. Thirty-four COMT Met(158)Met (Met-COMT) and 33 COMT Val(158)Val (Val-COMT) men were given a single 200-mg dose of the brain-penetrant COMT inhibitor tolcapone or placebo in a randomized, double-blind, between-subjects design. They completed the N-back task of working memory and a gambling task. In the placebo group, Met-COMT subjects outperformed Val-COMT subjects on the 2- back, and they were more risk averse. Tolcapone had opposite effects in the two genotype groups: it worsened N-back performance in Met-COMT subjects but enhanced it in Val-COMT subjects. Tolcapone made Met-COMT subjects less risk averse but Val-COMT subjects more so. In both tasks, tolcapone reversed the baseline genotype differences. Depending on genotype, COMT inhibition can enhance or impair working memory and increase or decrease risky decision making. To our knowledge, the data are the clearest demonstration to date that the direction of effect of a drug can be influenced by a polymorphism in its target gene. The results support the inverted-U model of dopamine function. The findings are of translational relevance, because COMT inhibitors are used in the adjunctive treatment of Parkinson's disease and are under evaluation in schizophrenia and other disorders. Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Personal Genomic Testing for Cancer Risk: Results From the Impact of Personal Genomics Study.

PubMed

Gray, Stacy W; Gollust, Sarah E; Carere, Deanna Alexis; Chen, Clara A; Cronin, Angel; Kalia, Sarah S; Rana, Huma Q; Ruffin, Mack T; Wang, Catharine; Roberts, J Scott; Green, Robert C

2017-02-20

Purpose Significant concerns exist regarding the potential for unwarranted behavior changes and the overuse of health care resources in response to direct-to-consumer personal genomic testing (PGT). However, little is known about customers' behaviors after PGT. Methods Longitudinal surveys were given to new customers of 23andMe (Mountain View, CA) and Pathway Genomics (San Diego, CA). Survey data were linked to individual-level PGT results through a secure data transfer process. Results Of the 1,042 customers who completed baseline and 6-month surveys (response rate, 71.2%), 762 had complete cancer-related data and were analyzed. Most customers reported that learning about their genetic risk of cancers was a motivation for testing (colorectal, 88%; prostate, 95%; breast, 94%). No customers tested positive for pathogenic mutations in highly penetrant cancer susceptibility genes. A minority of individuals received elevated single nucleotide polymorphism-based PGT cancer risk estimates (colorectal, 24%; prostate, 24%; breast, 12%). At 6 months, customers who received elevated PGT cancer risk estimates were not significantly more likely to change their diet, exercise, or advanced planning behaviors or engage in cancer screening, compared with individuals at average or reduced risk. Men who received elevated PGT prostate cancer risk estimates changed their vitamin and supplement use more than those at average or reduced risk (22% v 7.6%, respectively; adjusted odds ratio, 3.41; 95% CI, 1.44 to 8.18). Predictors of 6-month behavior include baseline behavior (exercise, vitamin or supplement use, and screening), worse health status (diet and vitamin or supplement use), and older age (advanced planning, screening). Conclusion Most adults receiving elevated direct-to-consumer PGT single nucleotide polymorphism-based cancer risk estimates did not significantly change their diet, exercise, advanced care planning, or cancer screening behaviors.

Personal Genomic Testing for Cancer Risk: Results From the Impact of Personal Genomics Study

PubMed Central

Gollust, Sarah E.; Carere, Deanna Alexis; Chen, Clara A.; Cronin, Angel; Kalia, Sarah S.; Rana, Huma Q.; Ruffin, Mack T.; Wang, Catharine; Roberts, J. Scott; Green, Robert C.

2017-01-01

Purpose Significant concerns exist regarding the potential for unwarranted behavior changes and the overuse of health care resources in response to direct-to-consumer personal genomic testing (PGT). However, little is known about customers’ behaviors after PGT. Methods Longitudinal surveys were given to new customers of 23andMe (Mountain View, CA) and Pathway Genomics (San Diego, CA). Survey data were linked to individual-level PGT results through a secure data transfer process. Results Of the 1,042 customers who completed baseline and 6-month surveys (response rate, 71.2%), 762 had complete cancer-related data and were analyzed. Most customers reported that learning about their genetic risk of cancers was a motivation for testing (colorectal, 88%; prostate, 95%; breast, 94%). No customers tested positive for pathogenic mutations in highly penetrant cancer susceptibility genes. A minority of individuals received elevated single nucleotide polymorphism-based PGT cancer risk estimates (colorectal, 24%; prostate, 24%; breast, 12%). At 6 months, customers who received elevated PGT cancer risk estimates were not significantly more likely to change their diet, exercise, or advanced planning behaviors or engage in cancer screening, compared with individuals at average or reduced risk. Men who received elevated PGT prostate cancer risk estimates changed their vitamin and supplement use more than those at average or reduced risk (22% v 7.6%, respectively; adjusted odds ratio, 3.41; 95% CI, 1.44 to 8.18). Predictors of 6-month behavior include baseline behavior (exercise, vitamin or supplement use, and screening), worse health status (diet and vitamin or supplement use), and older age (advanced planning, screening). Conclusion Most adults receiving elevated direct-to-consumer PGT single nucleotide polymorphism-based cancer risk estimates did not significantly change their diet, exercise, advanced care planning, or cancer screening behaviors. PMID:27937091

Beauveria keratitis and biopesticides: case histories and a random amplification of polymorphic DNA comparison.

PubMed

Pariseau, Brett; Nehls, Sarah; Ogawa, Gregory S H; Sutton, Deanna A; Wickes, Brian L; Romanelli, Anna M

2010-02-01

The purposes of this study were to describe 2 contact lens-associated Beauveria keratitis cases and to compare the isolates of 3 contact lens-associated Beauveria keratitis cases with Beauveria-based biopesticides using random amplification of polymorphic DNA (RAPD). A 55-year-old diabetic woman from New Mexico and a 31-year-old healthy woman from southern Wisconsin developed soft contact lens-related corneal ulcers unresponsive to topical moxifloxacin and prednisolone acetate drops. Their corneal cultures grew B. bassiana. These isolates, an isolate from a third soft contact lens-related Beauveria keratitis case, and Beauveria-based biopesticides sold in the United States were analyzed using morphological features, DNA sequencing, and RAPD. A PubMed, Cochrane Library, OVID, UpToDate, and Google search using the term "Beauveria" found only 9 reported Beauveria keratitis infections. Patient 1 responded to topical natamycin, ketoconazole, and 200 mg oral ketoconazole twice daily before developing a secondary bacterial infection requiring penetrating keratoplasty. After subsequent cataract surgery, the best-corrected visual acuity was 20/20. Patient 2 was treated with topical natamycin, topical amphotericin, and 200 mg oral voriconazole twice daily for 1 month with residual scarring and a best-corrected visual acuity of 20/25. RAPD showed that all isolates were unrelated. Although earlier reported Beauveria keratitis cases occurred after corneal injury in patients who did not wear contact lenses, 3 recent patients wore soft contact lenses and denied trauma, mirroring a changing trend in microbial keratitis. RAPD analysis showed that the Beauveria isolates were unrelated to one another and to Beauveria-based biopesticides. In Patient 2, oral voriconazole worked well.

Polymorphisms in peptidylarginine deiminase associate with rheumatoid arthritis in diverse Asian populations: evidence from MyEIRA study and meta-analysis

PubMed Central

2012-01-01

Introduction The majority of our knowledge regarding disease-related mechanisms of uncontrolled citrullination and anti-citrullinated protein antibody development in rheumatoid arthritis (RA) was investigated in Caucasian populations. However, peptidylarginine deiminase (PADI) type 4 gene polymorphisms are associated with RA in East Asian populations and weak or no association was found in Caucasian populations. This study explores the association between the PADI4 polymorphisms and RA risk in a multiethnic population residing in South East Asia with the goal of elucidating generalizability of association in non-Caucasian populations. Methods A total of 320 SNPs from the PADI locus (including PADI1, PADI2, PADI3, PADI4 and PADI6 genes) were genotyped in 1,238 RA cases and 1,571 control subjects from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA) case-control study. Additionally, we conducted meta-analysis of our data together with the previously published studies of RA from East Asian populations. Results The overall odds ratio (ORoverall) for the PADI4 (rs2240340) allelic model was 1.11 (95% confidence interval (CI) = 1.00 to 1.23, P = 0.04) and for the genotypic model was 1.20 (95% CI = 1.01 to 1.44, P = 0.04). Haplotype analysis for four selected PADI4 SNPs revealed a significant association of one with susceptibility (P = 0.001) and of another with a protective effect (P = 0.02). The RA susceptibility was further confirmed when combined meta-analysis was performed using these data together with data from five previously published studies from Asia comprising 5,192 RA cases and 4,317 control subjects (ORoverall = 1.23 (95% CI = 1.16 to 1.31, Pheterogeneity = 0.08) and 1.31 (95% CI = 1.20 to 1.44, Pheterogeneity = 0.32) in allele and genotype-based models, respectively). In addition, we also detected a novel association of PADI2 genetic variant rs1005753 with RA (ORoverall = 0.87 (95% CI = 0.77 to 0.99)). Conclusion Our study demonstrates an association between PADI4 and RA in the multiethnic population from South East Asia and suggests additional association with a PADI2 gene. The study thus provides further support for the notion that polymorphisms in genes for enzymes responsible for citrullination contribute to RA development in multiple populations of Asian descent. PMID:23164236

SRB frustrum 'smiley' cracking phenomenon study

NASA Technical Reports Server (NTRS)

Cruse, Thomas A.

1993-01-01

The thermal protection system installed on the SRB frustrums incurs the formation of debonds between the MSA-2 TPS material and the substrate. The debonds can lead to surface penetrating cracks, called 'smileys' near sealed fasteners and other surface discontinuities. The study concluded that the 'smileys' were caused as the result of stress risers caused by excess fastener sealant (PR-1422) and weakly bonded surfaces. Once the debond occurs, 'smileys' form when the debond area is sufficiently large. The loading for the debond and 'smiley' formation is seen to be depressurization at the vacuum conditions near the end of powered boost. The porous nature of the MSA-2 material covered by a vapor barrier paint provides internal pressure loading of the MSA-2 material. Recommendations for eliminating the problem include elimination of excess PR-1422 sealant and improved attention to bonding surface preparation.

A line-imaging velocity interferometer technique for shock diagnostics without x-ray preheat limitation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang Feng; Peng Xiaoshi; Liu Shenye

2011-10-15

A study was conducted with a line-imaging velocity interferometer on sandwich targets at the Shen Guang-III prototype laser facility in China, with the goal of eliminating the preheat effect. A sandwich target structure was used to reduce the x-ray preheat limitation (radiation temperature {approx}170 eV) in a radiative drive shock experiment. With a thick ablator, the preheat effect appeared before the shock arrived at the window. After adding a shield layer of high-Z material on the ablator, x-rays which penetrated the ablator were so weak that the blank-out effect could not be measured. This experiment indicates that the sandwich targetmore » may provide a valuable technique in experiments such as equation of state and shock timing for inertial confinement fusion studies.« less

Effect of Oryzalin and 1,1-Dimethylpiperidinium Chloride on Cotton and Tomato Roots Infected with the Root-knot Nematode, Meloidogyne incognita

PubMed Central

Orum, T. V.; Bartels, P. G.; McClure, M. A.

1979-01-01

Oryzalin (3,5-dinitro-N4,N4-dipropyl-sulfanilamide) and BAS 083 (l,l-dimethylpiperdinium chloride) reduced root-knot infection in tomato roots when respectively applied as a soil drench at 20 ppm and 10,000 ppm. Oryzalin reduced knot counts with various intervals between treatment and inoculation. BAS 083 reduced knot counts only when applied before inoculation. Oryzalin was shown not to be a contact nematicide, and BAS 083 was only a weak one. Neither compound reduced penetration by infective larvae. Postinfection reduction in knot counts by Oryzalin and BAS 083 resulted, in part, from activation of natural defense mechanisms of the host. Giant-cell development in cotton roots inoculated with nematodes was inhibited by Oryzalin. Lateral root development was inhibited by BAS 083. PMID:19305533

Modelling disorder in 3,3' -dimethoxybensil, C[subscript 16]H[subscript 14]O[subscript 4

DOE Office of Scientific and Technical Information (OSTI.GOV)

Goossens, Darren J.; Welberry, T.Richard; Heerdegen, Aidan P.

2008-06-18

This work is part of an extended study of benzil (C{sub 14}H{sub 10}O{sub 2}) and some of its derivatives which aims to understand the role of molecular flexibility in crystal packing and polymorphism. Significant steps have been made in modelling the structured thermal diffuse scattering from 3,3'-dimethoxybenzil, C{sub 16}H{sub 1}4O{sub 4}. It appears that the structure can be considered as a stack of layers of molecules in which interactions are strongest within the layers. The layers interact weakly along the a direction but more strongly along c, so shearing of the planes relative to each other is energetically likely. Themore » molecule must be treated as flexible for a good model to be found.« less

A marine dynamic penetrometer for the determination of sea floor geotechnical properties

NASA Astrophysics Data System (ADS)

Stephan, S.; Kaul, N. E.; Villinger, H. W.

2013-12-01

We present a seafloor lance penetration monitoring system: the Lance Insertion Retardation Meter (LIRmeter). The device can be used to infer geotechnical seafloor properties, such as bearing capacity by monitoring the deceleration of a free-fall penetrating lance. The deceleration record can be furthermore used to estimate mean grain size and mud content of the sea floor as well as total penetration depth. The LIRmeter is contained in a pressure vessel (440 x 110 mm) and equipped with accelerometers of different sensitivities to (i) determine sea floor resistance during penetration and (ii) to generate a depth axis. Typically, measurements are carried out in a pogo style fashion to allow a rapid measurement progress during field campaigns. The LIRmeter is intended to determine sea floor properties on the sole basis of deceleration measurements in order to achieve a mechanically and electronically robust system. Data is sampled at a resolution of 16 bit and at a rate of typically 500 Hz for each channel. The device can either be installed in any type of lance i.e. marine heat flow probes, gravity corers, piston corers or can be used in combination with a purpose built lance as a standalone instrument. It has a usable length of four meters, a total weight of 280 kg in air and can be operated up to full ocean depth (6000m). The bearing capacity of the sea floor is a critical factor for marine engineering projects such as burial of marine cables, pipeline laying and foundations. Knowledge of the mud content can provide constraints for the estimation of hydraulic conductivity. The identification of weak zones along a slope can moreover provide vital information for risk assessment studies. Traditionally, frame based, quasi static Cone Penetration Tests (CPT) or sampling methods like gravity coring are used to conduct these types of investigation. In comparison to established but time consuming and rather costly methods, the LIRmeter is intended (i) for near surface investigations and/or (ii) to complement and connect conventional but isolated CPT measurements in a very efficient and rapid way. We show results from measurements in the North Sea, as well as results of laboratory experiments. During sea trials, the LIRmeter was equipped with an additional CPT sensor, which delivered data for cone (tip) resistance, sleeve friction and pore pressure, thus allowing a direct comparison between results of the acceleration measurements and results from conventional CPT sensors. The laboratory measurements were also carried out using both acceleration and tip resistance sensors. Resulting values show a very good agreement between tip resistance calculated from deceleration data and tip resistance from direct laboratory and field measurements. The influence of sediment type (mainly mud content) will be discussed within the context of laboratory measurements.

Leber's hereditary optic neuropathy is associated with mitochondrial ND1 T3394C mutation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liang, Min; Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou, Zhejiang 325003; Guan, Minqiang

2009-06-05

We report here the clinical, genetic and molecular characterization of four Chinese families with Leber's hereditary optic neuropathy (LHON). There were variable severity and age-of-onset in visual impairment among these families. Strikingly, there were extremely low penetrances of visual impairment in these Chinese families. Sequence analysis of complete mitochondrial genomes in these pedigrees showed the homoplasmic T3394C (Y30H) mutation, which localized at a highly conserved tyrosine at position 30 of ND1, and distinct sets of mtDNA polymorphisms belonging to haplogroups D4b and M9a. The occurrence of T3394C mutation in these several genetically unrelated subjects affected by visual impairment strongly indicatesmore » that this mutation is involved in the pathogenesis of visual impairment. However, there was the absence of functionally significant mtDNA mutations in these four Chinese pedigrees carrying the T3394C mutation. Therefore, nuclear modifier gene(s) or environmental factor(s) may play a role in the phenotypic expression of the LHON-associated T3394C mutation.« less

Utilizing Structures of CYP2D6 and BACE1 Complexes To Reduce Risk of Drug–Drug Interactions with a Novel Series of Centrally Efficacious BACE1 Inhibitors

PubMed Central

2016-01-01

In recent years, the first generation of β-secretase (BACE1) inhibitors advanced into clinical development for the treatment of Alzheimer’s disease (AD). However, the alignment of drug-like properties and selectivity remains a major challenge. Herein, we describe the discovery of a novel class of potent, low clearance, CNS penetrant BACE1 inhibitors represented by thioamidine 5. Further profiling suggested that a high fraction of the metabolism (>95%) was due to CYP2D6, increasing the potential risk for victim-based drug–drug interactions (DDI) and variable exposure in the clinic due to the polymorphic nature of this enzyme. To guide future design, we solved crystal structures of CYP2D6 complexes with substrate 5 and its corresponding metabolic product pyrazole 6, which provided insight into the binding mode and movements between substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal structures, we designed and synthesized analogues with reduced risk for DDI, central efficacy, and improved hERG therapeutic margins. PMID:25781223

Mitochondrial tRNA(Thr) A15951G mutation may not be associated with Leber's Hereditary Optic Neuropathy.

PubMed

Zhang, Xi; Yu, Shuaishuai; Tu, Yunhai; Huang, Wenjie

2016-07-01

Mutation in mitochondrial DNA (mtDNA) has been found to play an important role in the pathogenesis of Leber's Hereditary Optic Neuropathy (LHON). Three primary mutations, the ND4 G11778A, ND6 T14484C, and ND1 G3460A, have been found to account more than 90% of LHON patients in many families worldwide. In addition to the mutations in genes encoding the respiratory chain complex I, reports concerning the mt-tRNA gene mutations associated with LHON have increased, some pathogenic mutations caused the failure in mt-tRNA metabolism, thereby worsened the mitochondrial dysfunction that is responsible for LHON. Recently, the A15951G mutation in mt-tRNA(Thr) gene has been reported to be a "modified" factor in increasing the penetrance and expressivity of LHON-associated ND4 G11778A mutation in three Chinese families. However, evolutionary conservation analysis of this mutation suggested a poor conservation index and the pathogenicity scoring system showed that this mutation was a neutral polymorphism.

Avidin as a Model for Charge Driven Transport into Cartilage and Drug Delivery for treating Early Stage Post-traumatic Osteoarthritis

PubMed Central

Bajpayee, Ambika G.; Wong, Cliff R.; Bawendi, Moungi G.; Frank, Eliot H.; Grodzinsky, Alan J.

2013-01-01

Local drug delivery into cartilage remains a challenge due to its dense extracellular matrix of negatively charged proteoglycans enmeshed within a collagen fibril network. The high negative fixed charge density of cartilage offers the unique opportunity to utilize electrostatic interactions to augment transport, binding and retention of drug carriers. With the goal of developing particle-based drug delivery mechanisms for treating post-traumatic osteoarthritis, our objectives were, first, to determine the size range of a variety of solutes that could penetrate and diffuse through normal cartilage and enzymatically treated cartilage to mimic early stages of OA, and second, to investigate the effects of electrostatic interactions on particle partitioning, uptake and binding within cartilage using the highly positively charged protein, Avidin, as a model. Results showed that solutes having a hydrodynamic diameter ≤ 10 nm can penetrate into the full thickness of cartilage explants while larger sized solutes were trapped in the tissue’s superficial zone. Avidin had a 400-fold higher uptake than its neutral same-sized counterpart, NeutrAvidin, and >90% of the absorbed Avidin remained within cartilage explants for at least 15 days. We report reversible, weak binding (KD ~150 μM) of Avidin to intratissue sites in cartilage. The large effective binding site density (NT ~ 2920 μM) within cartilage matrix facilitates Avidin’s retention, making its structure suitable for particle based drug delivery into cartilage. PMID:24120044

Preparation of dual-stimuli-responsive liposomes using methacrylate-based copolymers with pH and temperature sensitivities for precisely controlled release.

PubMed

Sugimoto, Takumi; Yamazaki, Naoko; Hayashi, Takaaki; Yuba, Eiji; Harada, Atsushi; Kotaka, Aki; Shinde, Chiharu; Kumei, Takayuki; Sumida, Yasushi; Fukushima, Mitsuhiro; Munekata, Yuki; Maruyama, Keiichi; Kono, Kenji

2017-07-01

Dual-signal-sensitive copolymers were synthesized by copolymerization of methoxy diethylene glycol methacrylate, methacrylic acid, and lauroxy tetraethylene glycol methacrylate, which respectively provide temperature sensitivity, pH sensitivity, and anchoring to liposome surfaces. These novel copolymers, with water solubility that differs depending on temperature and pH, are soluble in water under neutral pH and low-temperature conditions, but they become water-insoluble and form aggregates under acidic pH and high-temperature conditions. Liposomes modified with these copolymers exhibited enhanced content release at weakly acidic pH with increasing temperature, although no temperature-dependent content release was observed in neutral conditions. Interaction between the copolymers and the lipid monolayer at the air-water interface revealed that the copolymer chains penetrate more deeply into the monolayer with increasing temperature at acidic pH than at neutral pH, where the penetration of copolymer chains was moderate and temperature-independent at neutral pH. Interaction of the copolymer-modified liposomes with HeLa cells demonstrated that the copolymer-modified liposomes were adsorbed quickly and efficiently onto the cell surface and that they were internalized more gradually than the unmodified liposomes through endocytosis. Furthermore, the copolymer-modified liposomes enhanced the content release in endosomes with increasing temperature, but no such temperature-dependent enhancement of content release was observed for unmodified liposomes. Copyright © 2017 Elsevier B.V. All rights reserved.

The utility of ground-penetrating radar and its time-dependence in the discovery of clandestine burials.

PubMed

Salsarola, Dominic; Poppa, Pasquale; Amadasi, Alberto; Mazzarelli, Debora; Gibelli, Daniele; Zanotti, Emma; Porta, Davide; Cattaneo, Cristina

2015-08-01

In the field of forensic investigation burial is a relatively common method of hiding a corpse. The location of clandestine graves is, however, a particularly difficult task in which multiple forensic disciplines such as anthropology, botany or archaeology can provide valuable assistance. The use of GPR (ground-penetrating radar) has recently been introduced as a method in the detection of these graves, but what is the true potential of this tool in an operative search scenario? In this study a total of 11 pig carcasses were buried in two wooded areas, each presenting a similar soil composition. The animals were subsequently exhumed at regular intervals, ranging from 2 to 111 weeks, using systematic GPR analysis of the burial sites and archaeological recovery of the subjects that were then autopsied. GPR proved to be useful in recognizing anomalies at the chosen depths of burial and appeared to be dependent on the state of decay of the samples, producing only slight anomalous readings in the presence of skeletal remains: at 92 weeks from burial the difference in signal was weak and at 111 weeks GPR survey offered no helpful information as to burial location. The experiment, in this particular context, determined the technique as being successful in the presence of recent burials, highlighting the need for a multidisciplinary approach in the operative search for buried human remains. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Nitrification in the Upper Mississippi River: Patterns, controls, and contribution to the NO3- budget

USGS Publications Warehouse

Strauss, E.A.; Richardson, W.B.; Bartsch, L.A.; Cavanaugh, J.C.; Bruesewitz, D.A.; Imker, H.; Heinz, J.A.; Soballe, D.M.

2004-01-01

We measured nitrification rates in sediment samples collected from a variety of aquatic habitats in Navigation Pool 8 of the Upper Mississippi River (UMR) 7 times between May 2000 and October 2001. We also conducted nutrient-enrichment experiments and analyzed vertical profiles of sediment to determine factors regulating nitrification. Nitrification rates were relatively high compared to other ecosystems (ranging from 0-8.25 ??g N cm-2 h-1) and exhibited significant temporal and spatial patterns. Nitrification rates were greatest during the summer and spring compared to autumn and winter (ANOVA, p < 0.05) and were greater in contiguous backwater and impounded habitats compared to main and side-channel habitats (p < 0.05). Regression analysis indicated that nitrification rates were weakly (r 2 = 0.18, p < 0.0001) related to temperature and exchangeable NH4+ of the sediment. However, nutrient-enrichment experiments showed that NH4+ availability did not limit nitrification in 3 sediment types with variable organic matter. Vertical profiles of sediment cores demonstrated that oxygen concentration and nitrification had similar patterns suggesting that nitrification may be limited by oxygen penetration into sediments. We conclude that temperature and sediment NH4+ can be useful for predicting broad-scale temporal and spatial nitrification patterns, respectively, but oxygen penetration into the sediments likely regulates nitrification rates in much of the UMR. Overall, we estimated that nitrification produces 6982 mt N/y of NO3- or 7% of the total annual NO3- budget.

Genome-wide association screens for Achilles tendon and ACL tears and tendinopathy

PubMed Central

Roos, Thomas R.; Roos, Andrew K.; Kleimeyer, John P.; Ahmed, Marwa A.; Goodlin, Gabrielle T.; Fredericson, Michael; Ioannidis, John P. A.; Avins, Andrew L.; Dragoo, Jason L.

2017-01-01

Achilles tendinopathy or rupture and anterior cruciate ligament (ACL) rupture are substantial injuries affecting athletes, associated with delayed recovery or inability to return to competition. To identify genetic markers that might be used to predict risk for these injuries, we performed genome-wide association screens for these injuries using data from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort consisting of 102,979 individuals. We did not find any single nucleotide polymorphisms (SNPs) associated with either of these injuries with a p-value that was genome-wide significant (p<5x10-8). We found, however, four and three polymorphisms with p-values that were borderline significant (p<10−6) for Achilles tendon injury and ACL rupture, respectively. We then tested SNPs previously reported to be associated with either Achilles tendon injury or ACL rupture. None showed an association in our cohort with a false discovery rate of less than 5%. We obtained, however, moderate to weak evidence for replication in one case; specifically, rs4919510 in MIR608 had a p-value of 5.1x10-3 for association with Achilles tendon injury, corresponding to a 7% chance of false replication. Finally, we tested 2855 SNPs in 90 candidate genes for musculoskeletal injury, but did not find any that showed a significant association below a false discovery rate of 5%. We provide data containing summary statistics for the entire genome, which will be useful for future genetic studies on these injuries. PMID:28358823

Association Genetics of Wood Physical Traits in the Conifer White Spruce and Relationships With Gene Expression

PubMed Central

Beaulieu, Jean; Doerksen, Trevor; Boyle, Brian; Clément, Sébastien; Deslauriers, Marie; Beauseigle, Stéphanie; Blais, Sylvie; Poulin, Pier-Luc; Lenz, Patrick; Caron, Sébastien; Rigault, Philippe; Bicho, Paul; Bousquet, Jean; MacKay, John

2011-01-01

Marker-assisted selection holds promise for highly influencing tree breeding, especially for wood traits, by considerably reducing breeding cycles and increasing selection accuracy. In this study, we used a candidate gene approach to test for associations between 944 single-nucleotide polymorphism markers from 549 candidate genes and 25 wood quality traits in white spruce. A mixed-linear model approach, including a weak but nonsignificant population structure, was implemented for each marker–trait combination. Relatedness among individuals was controlled using a kinship matrix estimated either from the known half-sib structure or from the markers. Both additive and dominance effect models were tested. Between 8 and 21 single-nucleotide polymorphisms (SNPs) were found to be significantly associated (P ≤ 0.01) with each of earlywood, latewood, or total wood traits. After controlling for multiple testing (Q ≤ 0.10), 13 SNPs were still significant across as many genes belonging to different families, each accounting for between 3 and 5% of the phenotypic variance in 10 wood characters. Transcript accumulation was determined for genes containing SNPs associated with these traits. Significantly different transcript levels (P ≤ 0.05) were found among the SNP genotypes of a 1-aminocyclopropane-1-carboxylate oxidase, a β-tonoplast intrinsic protein, and a long-chain acyl-CoA synthetase 9. These results should contribute toward the development of efficient marker-assisted selection in an economically important tree species. PMID:21385726

Genetic Polymorphisms Associated with Rubella Virus-Specific Cellular Immunity Following MMR Vaccination

PubMed Central

Kennedy, Richard B.; Ovsyannikova, Inna G.; Haralambieva, Iana H.; Lambert, Nathaniel D.; Pankratz, V. Shane; Poland, Gregory A.

2014-01-01

Rubella virus causes a relatively benign disease in most cases, although infection during pregnancy can result in serious birth defects. An effective vaccine has been available since the early 1970s and outbreaks typically do not occur among highly vaccinated (≥2 doses) populations. Nevertheless, considerable inter-individual variation in immune response to rubella immunization does exist, with single dose seroconversion rates ~95%. Understanding the mechanisms behind this variability may provide important insights into rubella immunity. In the current study, we examined associations between single nucleotide polymorphisms (SNPs) in selected cytokine, cytokine receptor, and innate/antiviral genes and immune responses following rubella vaccination in order to understand genetic influences on vaccine response. Our approach consisted of a discovery cohort of 887 subjects ages 11–22 at the time of enrollment and a replication cohort of 542 older adolescents and young adults (ages 18–40). Our data indicate that SNPs near the butyrophilin genes (BTN3A3/BTN2A1) and cytokine receptors (IL10RB/IFNAR1) are associated with variations in IFNγ secretion and that multiple SNPs in the PVR gene, as well as SNPs located in the ADAR gene, exhibit significant associations with rubella virus-specific IL-6 secretion. This information may be useful, not only in furthering our understanding immune responses to rubella vaccine, but also in identifying key pathways for targeted adjuvant use to boost immunity in those with weak or absent immunity following vaccination. PMID:25098560

IL2RA/CD25 Gene Polymorphisms: Uneven Association with Multiple Sclerosis (MS) and Type 1 Diabetes (T1D)

PubMed Central

Alcina, Antonio; Fedetz, María; Ndagire, Dorothy; Fernández, Oscar; Leyva, Laura; Guerrero, Miguel; Abad-Grau, María M.; Arnal, Carmen; Delgado, Concepción; Lucas, Miguel; Izquierdo, Guillermo; Matesanz, Fuencisla

2009-01-01

Background IL-2 receptor (IL2R) alpha is the specific component of the high affinity IL2R system involved in the immune response and in the control of autoimmunity. Methods and Results Here we perform a replication and fine mapping of the IL2RA gene region analyzing 3 SNPs previously associated with multiple sclerosis (MS) and 5 SNPs associated with type 1 diabetes (T1D) in a collection of 798 MS patients and 927 matched Caucasian controls from the south of Spain. We observed association with MS in 6 of 8 SNPs. The rs1570538, at the 3′- UTR extreme of the gene, previously reported to have a weak association with MS, is replicated here (P = 0.032). The most associated T1D SNP (rs41295061) was not associated with MS in the present study. However, the rs35285258, belonging to another independent group of SNPs associated with T1D, showed the maximal association in this study but different risk allele. We replicated the association of only one (rs2104286) of the two IL2RA SNPs identified in the recently performed genome-wide association study of MS. Conclusions These findings confirm and extend the association of this gene with MS and reveal a genetic heterogeneity of the associated polymorphisms and risk alleles between MS and T1D suggesting different immunopathological roles of IL2RA in these two diseases. PMID:19125193

Variability of the caprine whey protein genes and their association with milk yield, composition and renneting properties in the Sarda breed: 2. The BLG gene.

PubMed

Dettori, Maria Luisa; Pazzola, Michele; Pira, Emanuela; Puggioni, Ornella; Vacca, Giuseppe Massimo

2015-11-01

The variability of the promoter region and the 3'UTR (exon-7) of the BLG gene, encoding the β-lactoglobulin, was investigated by sequencing in 263 lactating Sarda goats in order to assess its association with milk traits. Milk traits included: milk yield, fat, total protein and lactose content, pH, daily fat and protein yield (DFPY), freezing point, milk energy, somatic cell count, total microbial mesophilic count, rennet coagulation time (RCT), curd firming rate (k20) and curd firmness (a30). A total of 7 polymorphic sites were detected and the sequence analysed was given accession number KM817769. Only three SNPs (c.-381C>T, c.-323C>T and c.*420C>A) had minor allele frequency higher than 0.05. The effects of farm, stage of lactation and the interaction farm × stage of lactation significantly influenced all the milk traits (P T and c.*420C>A (P T (P < 0.001). The c.-381TT homozygous goats showed lower pH, RCT and k20 than c.-381CT (P < 0.05). In conclusion the polymorphism of the goat BLG gene did not affect the total protein content of the Sarda goat milk, and only weakly influenced RCT and k20. On the other hand, an interesting effect on milk yields and DFPY emerged in two SNPs. This information might be useful in dairy goat breeding programs.

Genetic polymorphisms associated with rubella virus-specific cellular immunity following MMR vaccination.

PubMed

Kennedy, Richard B; Ovsyannikova, Inna G; Haralambieva, Iana H; Lambert, Nathaniel D; Pankratz, V Shane; Poland, Gregory A

2014-11-01

Rubella virus causes a relatively benign disease in most cases, although infection during pregnancy can result in serious birth defects. An effective vaccine has been available since the early 1970s and outbreaks typically do not occur among highly vaccinated (≥2 doses) populations. Nevertheless, considerable inter-individual variation in immune response to rubella immunization does exist, with single-dose seroconversion rates ~95 %. Understanding the mechanisms behind this variability may provide important insights into rubella immunity. In the current study, we examined associations between single nucleotide polymorphisms (SNPs) in selected cytokine, cytokine receptor, and innate/antiviral genes and immune responses following rubella vaccination in order to understand genetic influences on vaccine response. Our approach consisted of a discovery cohort of 887 subjects aged 11-22 at the time of enrollment and a replication cohort of 542 older adolescents and young adults (age 18-40). Our data indicate that SNPs near the butyrophilin genes (BTN3A3/BTN2A1) and cytokine receptors (IL10RB/IFNAR1) are associated with variations in IFNγ secretion and that multiple SNPs in the PVR gene, as well as SNPs located in the ADAR gene, exhibit significant associations with rubella virus-specific IL-6 secretion. This information may be useful, not only in furthering our understanding immune responses to rubella vaccine, but also in identifying key pathways for targeted adjuvant use to boost immunity in those with weak or absent immunity following vaccination.

Large-scale variation in subsurface stream biofilms: a cross-regional comparison of metabolic function and community similarity.

PubMed

Findlay, S; Sinsabaugh, R L

2006-10-01

We examined bacterial metabolic activity and community similarity in shallow subsurface stream sediments distributed across three regions of the eastern United States to assess whether there were parallel changes in functional and structural attributes at this large scale. Bacterial growth, oxygen consumption, and a suite of extracellular enzyme activities were assayed to describe functional variability. Community similarity was assessed using randomly amplified polymorphic DNA (RAPD) patterns. There were significant differences in streamwater chemistry, metabolic activity, and bacterial growth among regions with, for instance, twofold higher bacterial production in streams near Baltimore, MD, compared to Hubbard Brook, NH. Five of eight extracellular enzymes showed significant differences among regions. Cluster analyses of individual streams by metabolic variables showed clear groups with significant differences in representation of sites from different regions among groups. Clustering of sites based on randomly amplified polymorphic DNA banding resulted in groups with generally less internal similarity although there were still differences in distribution of regional sites. There was a marginally significant (p = 0.09) association between patterns based on functional and structural variables. There were statistically significant but weak (r2 approximately 30%) associations between landcover and measures of both structure and function. These patterns imply a large-scale organization of biofilm communities and this structure may be imposed by factor(s) such as landcover and covariates such as nutrient concentrations, which are known to also cause differences in macrobiota of stream ecosystems.

Intramandibular glands in different castes of leaf-cutting ant, Atta laevigata (Fr. Smith, 1858) (Formicidae: Attini).

PubMed

Martins, Luiza Carla Barbosa; Della Lucia, Terezinha Maria Castro; Gonçalves, Wagner Gonzaga; Delabie, Jacques Hubert Charles; Zanuncio, José Cola; Serrão, José Eduardo

2015-07-01

Intramandibular glands have been poorly studied in polymorphic ants, where the differences between castes were unsufficiently scrutinized. Leaf-cutting ants possess one of the most complex systems of communication and labor division, which is polymorphic well as age polyethism, and makes them an ideal model for the study of intramandibular glands. This study has investigated the occurrence of intramandibular glands in female castes and subcastes of Atta laevigata. The mandibles of the queen, medium, and minor workers, and soldiers were submitted to histological, histochemical, ultrastructural, and morphometric analyses. The class-3 gland cells and the epidermal gland with a reservoir were found in all the castes. The queens and soldiers showed a higher number of class-3 gland cells, distributed within the mandible as well as a greater gland size in comparison to the workers. The histochemical tests, periodic acid-Schiff (PAS), mercury-bromophenol, and Nile blue, were similar for the class-3 gland cells and epidermal glands with a reservoir. However, the tests evidenced differences between the castes, with carbohydrates strongly positive in all of them, whereas neutral lipids were found in the queen and soldiers. The protein was weakly positive in the queen, whereas in the soldier, medium, and minor workers these reactions were strongly positive in the intramandibular glands. Our findings in A. laevigata suggest that intramandibular glands are directly involved in labor division and consequently in chemical communication between the castes. © 2015 Wiley Periodicals, Inc.

Association of Polymorphisms in CYBA, SOD1, and CAT Genes with Type 1 Diabetes and Diabetic Peripheral Neuropathy in Children and Adolescents.

PubMed

Snahnicanova, Zuzana; Mendelova, Andrea; Grendar, Marian; Holubekova, Veronika; Kostkova, Martina; Pozorciakova, Katarina; Jancinová, Maria; Kasubova, Ivana; Vojtkova, Jarmila; Durdik, Peter; Lasabova, Zora; Ciljakova, Miriam; Banovcin, Peter

2018-06-20

The aim of our study was to investigate possible associations between three SNPs: rs4673 in the CYBA gene; rs1041740 in the SOD1 gene; and rs1001179 in the CAT gene, and type 1 diabetes (T1D) or diabetic peripheral neuropathy (DPN) in T1D patients. Allelic variants of the selected SNPs were determined by allelic discrimination assays in 114 T1D patients enrolled in the study group and in 90 healthy individuals from a control group. Associations between each of the three SNPs were tested in subgroups of T1D patients divided according to the presence of DPN. The TT genotype of rs4673 in the CYBA gene was associated with DPN in T1D patients (OR 4.997, 95% CI 1.403-19.083, p = 0.016). Weak significance was observed for a protective effect of the TT genotype of rs1041740 in the SOD1 gene relative to T1D development (OR 0.318, 95% CI 0.092-0.959, p = 0.056). There was no significant association between the CAT gene SNP rs1001179 and T1D or DPN. We showed a strong association of the CYBA polymorphism rs4673 with DPN in Slovak children and adolescents with T1D. Further studies are necessary to assess the relationship between rs1041740, and T1D or DPN.

LORETA indicates frequency-specific suppressions of current sources within the cerebrums of blindfolded subjects from patterns of blue light flashes applied over the skull.

PubMed

Karbowski, Lukasz M; Saroka, Kevin S; Murugan, Nirosha J; Persinger, Michael A

2015-10-01

An array of eight cloistered (completely covered) 470-nm LEDs was attached to the right caudal scalp of subjects while each sat blindfolded within a darkened chamber. The LEDs were activated by a computer-generated complex (frequency-modulated) temporal pattern that, when applied as weak magnetic fields, has elicited sensed presences and changes in LORETA (low-resolution electromagnetic tomography) configurations. Serial 5-min on to 5-min off presentations of the blue light (10,000lx) resulted in suppression of gamma activity within the right cuneus (including the extrastriate area), beta activity within the left angular and right superior temporal regions, and alpha power within the right parahippocampal region. The effect required about 5min to emerge followed by a transient asymptote for about 15 to 20min when diminished current source density was evident even during no light conditions. Subjective experiences, as measured by our standard exit questionnaire, reflected sensations similar to those reported when the pattern was presented as a weak magnetic field. Given previous evidence that photon flux density of this magnitude can penetrate the skull, these results suggest that properly configured LEDs that generate physiologically patterned light sequences might be employed as noninvasive methods to explore the dynamic characteristics of cerebral activity in epileptic and nonepileptic brains. Copyright © 2015 Elsevier Inc. All rights reserved.

Hot spot generation in energetic materials created by long-wavelength infrared radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Ming-Wei; You, Sizhu; Suslick, Kenneth S.

Hot spots produced by long-wavelength infrared (LWIR) radiation in an energetic material, crystalline RDX (1,3,5-trinitroperhydro-1,3,5-triazine), were studied by thermal-imaging microscopy. The LWIR source was a CO{sub 2} laser operating in the 28-30 THz range. Hot spot generation was studied using relatively low intensity (∼100 W cm{sup −2}), long-duration (450 ms) LWIR pulses. The hot spots could be produced repeatedly in individual RDX crystals, to investigate the fundamental mechanisms of hot spot generation by LWIR, since the peak hot-spot temperatures were kept to ∼30 K above ambient. Hot spots were generated preferentially beneath RDX crystal planes making oblique angles with the LWIR beam. Surprisingly,more » hot spots were more prominent when the LWIR wavelength was tuned to be weakly absorbed (absorption depth ∼30 μm) than when the LWIR wavelength was strongly absorbed (absorption depth ∼5 μm). This unexpected effect was explained using a model that accounts for LWIR refraction and RDX thermal conduction. The weakly absorbed LWIR is slightly focused underneath the oblique crystal planes, and it penetrates the RDX crystals more deeply, increasing the likelihood of irradiating RDX defect inclusions that are able to strongly absorb or internally focus the LWIR beam.« less

[Professor WU Zhongchao's experience of penetration needling].

PubMed

Zhang, Ning; Wang, Bing; Zhou, Yu

2016-08-12

Professor WU Zhongchao has unique application of penetration needling in clinical treatment. Professor WU applies penetration needling along meridians, and the methods of penetration needling include self-meridian penetration, exterior-interior meridian penetration, identical-name meridian penetration, different meridian penetration. The meridian differentiation is performed according to different TCM syndromes, locations and natures of diseases and acupoint nature, so as to make a comprehensive assessment. The qi movement during acupuncture is focused. In addition, attention is paid on anatomy and long-needle penetration; the sequence and direction of acupuncture is essential, and the reinforcing and reducing methods have great originality, presented with holding, waiting, pressing and vibrating. Based on classical acupoint, the acupoint of penetration needling is flexible, forming unique combination of acupoints.

Weak hydrogen bonding interactions influence slip system activity and compaction behavior of pharmaceutical powders.

PubMed

Khomane, Kailas S; Bansal, Arvind K

2013-12-01

Markedly different mechanical behavior of powders of polymorphs, cocrystals, hydrate/anhydrate pairs, or structurally similar molecules has been attributed to the presence of active slip planes system in their crystal structures. Presence of slip planes in the crystal lattice allows easier slip under the applied compaction pressure. This allows greater plastic deformation of the powder and results into increased interparticulate bonding area and greater tensile strength of the compacts. Thus, based on this crystallographic feature, tableting performance of the active pharmaceutical ingredients can be predicted. Recently, we encountered a case where larger numbers of CH···O type interactions across the proposed slip planes hinder the slip and thus resist plastic deformation of the powder under the applied compaction pressure. Hence, attention must be given to these types of interactions while identifying slip planes by visualization method. Generally, slip planes are visualized as flat layers often strengthened by a two-dimensional hydrogen-bonding network within the layers or planes. No hydrogen bonding should exist between these layers to consider them as slip planes. Moreover, one should also check the presence of CH···O type interactions across these planes. Mercury software provides an option for visualization of these weak hydrogen bonding interactions. Hence, caution must be exercised while selecting appropriate solid form based on this crystallographic feature. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association.

[Thyrotoxic hypokalemic periodic paralysis, an endocrine emergency: clinical and genetic features in 25 patients].

PubMed

Silva, Magnus R Dias da; Chiamolera, Maria Izabel; Kasamatsu, Teresa S; Cerutti, Janete M; Maciel, Rui M B

2004-02-01

Thyrotoxic hypokalemic periodic paralysis (THPP) is a medical emergency characterized by acute attacks of weakness, hypokalemia, and thyrotoxicosis that resolve with the treatment of hyperthyroidism. Attacks are transient, self-limited, associated with hypokalemia and resemble those of familial hypokalemic periodic paralysis (FHPP), an autosomal dominant neurological channelopathy. This study reviews the clinical features and genetic findings of THPP in 25 Brazilian patients. Most patients had weight loss, taquicardia, goiter, tremor, and ophthalmopathy. Most often attacks arose during the night and recovered spontaneously but some patients evolved to total quadriplegia, and few experienced cardiac arrhythmias. All patients had suppressed TSH and elevated T4 and most had positive anti-thyroid antibodies, indicating autoimmunity thyrotoxic etiology. Potassium was low in all patients during the crisis. Prophylactic potassium therapy has not been shown to prevent attacks; however it was useful for curbing the paralysis during the crisis. We identified the mutation R83H in the KCNE3 gene in one sporadic case, and M58V in the KCNE4 gene in one case with family history. Furthermore, we identified other genetic polymorphisms in the CACNA1S, SCN4A, KCNE1, KCNE2, KCNE1L, KCNJ2, KCNJ8 e KCNJ11 genes. We conclude that THPP is the most common treatable cause of acquired periodic paralysis; therefore, it must be included in the differential diagnosis of acute muscle weakness.

Theory of activated penetrant diffusion in viscous fluids and colloidal suspensions

NASA Astrophysics Data System (ADS)

Zhang, Rui; Schweizer, Kenneth S.

2015-10-01

We heuristically formulate a microscopic, force level, self-consistent nonlinear Langevin equation theory for activated barrier hopping and non-hydrodynamic diffusion of a hard sphere penetrant in very dense hard sphere fluid matrices. Penetrant dynamics is controlled by a rich competition between force relaxation due to penetrant self-motion and collective matrix structural (alpha) relaxation. In the absence of penetrant-matrix attraction, three activated dynamical regimes are predicted as a function of penetrant-matrix size ratio which are physically distinguished by penetrant jump distance and the nature of matrix motion required to facilitate its hopping. The penetrant diffusion constant decreases the fastest with size ratio for relatively small penetrants where the matrix effectively acts as a vibrating amorphous solid. Increasing penetrant-matrix attraction strength reduces penetrant diffusivity due to physical bonding. For size ratios approaching unity, a distinct dynamical regime emerges associated with strong slaving of penetrant hopping to matrix structural relaxation. A crossover regime at intermediate penetrant-matrix size ratio connects the two limiting behaviors for hard penetrants, but essentially disappears if there are strong attractions with the matrix. Activated penetrant diffusivity decreases strongly with matrix volume fraction in a manner that intensifies as the size ratio increases. We propose and implement a quasi-universal approach for activated diffusion of a rigid atomic/molecular penetrant in a supercooled liquid based on a mapping between the hard sphere system and thermal liquids. Calculations for specific systems agree reasonably well with experiments over a wide range of temperature, covering more than 10 orders of magnitude of variation of the penetrant diffusion constant.

Theory of activated penetrant diffusion in viscous fluids and colloidal suspensions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Rui; Schweizer, Kenneth S., E-mail: kschweiz@illinois.edu

2015-10-14

We heuristically formulate a microscopic, force level, self-consistent nonlinear Langevin equation theory for activated barrier hopping and non-hydrodynamic diffusion of a hard sphere penetrant in very dense hard sphere fluid matrices. Penetrant dynamics is controlled by a rich competition between force relaxation due to penetrant self-motion and collective matrix structural (alpha) relaxation. In the absence of penetrant-matrix attraction, three activated dynamical regimes are predicted as a function of penetrant-matrix size ratio which are physically distinguished by penetrant jump distance and the nature of matrix motion required to facilitate its hopping. The penetrant diffusion constant decreases the fastest with size ratiomore » for relatively small penetrants where the matrix effectively acts as a vibrating amorphous solid. Increasing penetrant-matrix attraction strength reduces penetrant diffusivity due to physical bonding. For size ratios approaching unity, a distinct dynamical regime emerges associated with strong slaving of penetrant hopping to matrix structural relaxation. A crossover regime at intermediate penetrant-matrix size ratio connects the two limiting behaviors for hard penetrants, but essentially disappears if there are strong attractions with the matrix. Activated penetrant diffusivity decreases strongly with matrix volume fraction in a manner that intensifies as the size ratio increases. We propose and implement a quasi-universal approach for activated diffusion of a rigid atomic/molecular penetrant in a supercooled liquid based on a mapping between the hard sphere system and thermal liquids. Calculations for specific systems agree reasonably well with experiments over a wide range of temperature, covering more than 10 orders of magnitude of variation of the penetrant diffusion constant.« less

Evolutionary Determinants of Morphological Polymorphism in Colonial Animals.

PubMed

Simpson, Carl; Jackson, Jeremy B C; Herrera-Cubilla, Amalia

2017-07-01

Colonial animals commonly exhibit morphologically polymorphic modular units that are phenotypically distinct and specialize in specific functional tasks. But how and why these polymorphic modules have evolved is poorly understood. Across colonial invertebrates, there is wide variation in the degree of polymorphism, from none in colonial ascidians to extreme polymorphism in siphonophores, such as the Portuguese man-of-war. Bryozoa are a phylum of exclusively colonial invertebrates that uniquely exhibit almost the entire range of polymorphism, from monomorphic species to others that rival siphonophores in their polymorphic complexity. Previous approaches to understanding the evolution of polymorphism have been based on analyses of (1) the functional role of polymorphs or (2) presumed evolutionary costs and benefits based on evolutionary theory that postulates polymorphism should be evolutionarily sustainable only in more stable environments because polymorphism commonly leads to the loss of feeding and sexual competence. Here we use bryozoans from opposite shores of the Isthmus of Panama to revisit the environmental hypothesis by comparison of faunas from distinct oceanographic provinces that differ greatly in environmental variability, and we then examine the correlations between the extent of polymorphism in relation to patterns of ecological succession and variation in life histories. We find no support for the environmental hypothesis. Distributions of the incidence of polymorphism in the oceanographically unstable Eastern Pacific are indistinguishable from those in the more stable Caribbean. In contrast, the temporal position of species in a successional sequence is collinear with the degree of polymorphism because species with fewer types of polymorphs are competitively replaced by species with higher numbers of polymorphs on the same substrata. Competitively dominant species also exhibit patterns of growth that increase their competitive ability. The association between degrees of polymorphism and variations in life histories is fundamental to understanding of the macroevolution of polymorphism.

Photoswitchable non-fluorescent thermochromic dye-nanoparticle hybrid probes.

PubMed

Harrington, Walter N; Haji, Mwafaq R; Galanzha, Ekaterina I; Nedosekin, Dmitry A; Nima, Zeid A; Watanabe, Fumiya; Ghosh, Anindya; Biris, Alexandru S; Zharov, Vladimir P

2016-11-08

Photoswitchable fluorescent proteins with controllable light-dark states and spectral shifts in emission in response to light have led to breakthroughs in the study of cell biology. Nevertheless, conventional photoswitching is not applicable for weakly fluorescent proteins and requires UV light with low depth penetration in bio-tissue. Here we introduce a novel concept of photoswitchable hybrid probes consisting of thermochromic dye and absorbing nanoparticles, in which temperature-sensitive light-dark states and spectral shifts in absorption can be switched through controllable photothermal heating of doped nanoparticles. The proof-of-concept is demonstrated through the use of two different types of temperature-sensitive dyes doped with magnetic nanoparticles and reversibly photoswitched by a near-infrared laser. Photoacoustic imaging revealed the high contrast of these probes, which is sufficient for their visualization in cells and deep tissue. Our results suggest that these new photoswitchable multicolour probes can be used for multimodal cellular diagnostics and potentially for magnetic and photothermal therapy.

Failure Analysis of Alumina Reinforced Aluminum Microtruss and Tube Composites

NASA Astrophysics Data System (ADS)

Chien, Hsueh Fen (Karen)

The energy absorption capacity of cellular materials can be dramatically increased by applying a structural coating. This thesis examined the failure mechanisms of alumina reinforced 3003 aluminum alloy microtrusses and tubes. Alumina coatings were produced by hard anodizing and by plasma electrolytic oxidation (PEO). The relatively thin and discontinuous oxide coating at the hinge acted as a localized weak spot which triggered a chain reaction of failure, including oxide fracture, oxide spallation, oxide penetration to the aluminum core and severe local plastic deformation of the core. For the PEO microtrusses, delamination occurred within the oxide coating resulting in a global strut buckling failure mode. A new failure mode for the anodized tubes was observed: (i) axisymmetric folding of the aluminum core, (ii) longitudinal fracture, and (iii) alumina pulverization. Overall, the alumina coating enhanced the buckling resistance of the composites, while the aluminum core supported the oxide during the damage propagation.

Photoswitchable non-fluorescent thermochromic dye-nanoparticle hybrid probes

NASA Astrophysics Data System (ADS)

Harrington, Walter N.; Haji, Mwafaq R.; Galanzha, Ekaterina I.; Nedosekin, Dmitry A.; Nima, Zeid A.; Watanabe, Fumiya; Ghosh, Anindya; Biris, Alexandru S.; Zharov, Vladimir P.

2016-11-01

Photoswitchable fluorescent proteins with controllable light-dark states and spectral shifts in emission in response to light have led to breakthroughs in the study of cell biology. Nevertheless, conventional photoswitching is not applicable for weakly fluorescent proteins and requires UV light with low depth penetration in bio-tissue. Here we introduce a novel concept of photoswitchable hybrid probes consisting of thermochromic dye and absorbing nanoparticles, in which temperature-sensitive light-dark states and spectral shifts in absorption can be switched through controllable photothermal heating of doped nanoparticles. The proof-of-concept is demonstrated through the use of two different types of temperature-sensitive dyes doped with magnetic nanoparticles and reversibly photoswitched by a near-infrared laser. Photoacoustic imaging revealed the high contrast of these probes, which is sufficient for their visualization in cells and deep tissue. Our results suggest that these new photoswitchable multicolour probes can be used for multimodal cellular diagnostics and potentially for magnetic and photothermal therapy.

AC magnetic-field response of the ferromagnetic superconductor UGe2 with different magnetized states

NASA Astrophysics Data System (ADS)

Tanaka, Hiroyuki; Yamaguchi, Akira; Kawasaki, Ikuto; Sumiyama, Akihiko; Motoyama, Gaku; Yamamura, Tomoo

2018-01-01

We have performed parallel measurements of dc-magnetization and ac-magnetic susceptibility for a ferromagnetic superconductor, UGe2, in the ferromagnetic-superconducting phase. dc-magnetization measurements revealed that adequate demagnetizing of the sample allows for the preparation of various magnetized states with different zero-field residual magnetization. We observed that these states exhibit varying ac superconducting response at large ac-field amplitudes. The amount of ac flux penetration is less in the demagnetized state involving many domain walls. This result seems to contradict the theory that considers the domain walls as weak links. Moreover, the ferromagnetic domain walls enforce the shielding capability of superconductivity. This observation sheds light on the role of the domain walls on superconductivity, which has been a controversial issue for several decades. Two possible scenarios are presented to explain the enhancement of the shielding capability by the domain walls.

A bacteriophage endolysin that eliminates intracellular streptococci.

PubMed

Shen, Yang; Barros, Marilia; Vennemann, Tarek; Gallagher, D Travis; Yin, Yizhou; Linden, Sara B; Heselpoth, Ryan D; Spencer, Dennis J; Donovan, David M; Moult, John; Fischetti, Vincent A; Heinrich, Frank; Lösche, Mathias; Nelson, Daniel C

2016-03-15

PlyC, a bacteriophage-encoded endolysin, lyses Streptococcus pyogenes (Spy) on contact. Here, we demonstrate that PlyC is a potent agent for controlling intracellular Spy that often underlies refractory infections. We show that the PlyC holoenzyme, mediated by its PlyCB subunit, crosses epithelial cell membranes and clears intracellular Spy in a dose-dependent manner. Quantitative studies using model membranes establish that PlyCB interacts strongly with phosphatidylserine (PS), whereas its interaction with other lipids is weak, suggesting specificity for PS as its cellular receptor. Neutron reflection further substantiates that PlyC penetrates bilayers above a PS threshold concentration. Crystallography and docking studies identify key residues that mediate PlyCB-PS interactions, which are validated by site-directed mutagenesis. This is the first report that a native endolysin can traverse epithelial membranes, thus substantiating the potential of PlyC as an antimicrobial for Spy in the extracellular and intracellular milieu and as a scaffold for engineering other functionalities.

Effects of antenna orientation on 3-D ground penetrating radar surveys: an archaeological perspective

NASA Astrophysics Data System (ADS)

Lualdi, Maurizio; Lombardi, Federico

2014-02-01

This paper investigates the impact that the GPR antenna orientation, or survey direction, has on migrated image resulting from 3-D georadar acquisitions carried out on heterogeneous and anisotropic subsurface. This feature is related to the directional dependency of wave propagation effects, such as dispersion, absorption, depolarization, and scattering phenomena. We provide a proof of this with two field examples, demonstrating that a 3-D survey performed along a single direction could bring weak results in terms of target detection and reconstruction. To overcome this risk, we show the improvements that the combination of GPR 3-D data acquired along different directions on the same area can obtain: an enhancement of target detection probability and the practical advantage for the end-user of looking through a single image. Further on, we develop a stacking scheme that employs a threshold associated with amplitude comparison to adaptively handle the combination of georadar data volumes.

Teaching Elementary Particle Physics, Part II

NASA Astrophysics Data System (ADS)

Hobson, Art

2011-03-01

In order to explain certain features of radioactive beta decay, Wolfgang Pauli suggested in 1930 that the nucleus emitted, in addition to a beta particle, another particle of an entirely new type. The hypothesized particle, dubbed the neutrino, would not be discovered experimentally for another 25 years. It's not easy to detect neutrinos, because they respond to neither the EM force nor the strong force. For example, the mean free path (average penetration distance before it interacts) of a typical beta-decay neutrino moving through solid lead is about 1.5 light years! Enrico Fermi argued that neutrinos indicated a new force was at work. During the 1930s, he quickly adapted ideas from the developing new theory of QED to this new force, dubbed the weak force. Fermi's theory was able to predict the half-lives of beta-emitting nuclei and the range of energies of the emitted beta particles.

Some aspects of the scientific significance of high energy gamma ray astrophysics

NASA Technical Reports Server (NTRS)

Fichtel, Carl E.

1991-01-01

The attraction of high energy gamma-ray astronomy lies in this radiation relating directly to those processes in astrophysical situations which deviate most from thermo-dynamic equilibrium. Some examples of these phenomena which are known to or expected to emit gamma rays are cosmic rays as they interact in intergalactic space, the high energy particles in the magnetic fields of neutron stars, the death of a black hole, the explosion and residual of a supernova, lumps of Weakly Interacting Massive Particles, energetic solar particles interacting near the sun, and very high energy particles in the extreme conditions associated with active galaxies. Although the intensities are known to be low as seen near the earth, a partially compensating characteristic is that the very penetrating nature of high energy gamma rays increases the probability that they can escape from their origin and reach the solar system.

Development and characteristics of Mechanical Porous Ambient Comet Simulants as comet surface analogs

NASA Astrophysics Data System (ADS)

Carey, Elizabeth M.; Peters, Gregory H.; Choukroun, Mathieu; Chu, Lauren; Carpenter, Emma; Cohen, Brooklin; Panossian, Lara; Zhou, Yu Meng; Sarkissian, Ani; Moreland, Scott; Shiraishi, Lori R.; Backes, Paul; Zacny, Kris; Green, Jacklyn R.; Raymond, Carol

2017-11-01

Comets are icy remnants of the Solar System formation, and as such contain some of the most primitive volatiles and organic materials. Sampling the surface of a comet is a high priority for the New Frontiers program. Planetary simulants are crucial to the development of adequate in situ instruments and sample acquisition systems. A high-fidelity comet surface simulant has been developed to support hardware design and development for one Comet Surface Sample Return tool, the BiBlade Comet Sampler. Mechanical Porous Ambient Comet Simulants (MPACS) can be manufactured to cover a wide range of desired physical properties, such as density and cone penetration resistance, and exhibit a brittle fracture mode. The structure of the MPACS materials is an aggregated composite structure of weakly-bonded grains of very small size (diameter ≤ 40 μm) that are most relevant to the structure of the surface of a comet nucleus.

Simultaneous quasi-one-dimensional propagation and tuning of upconversion luminescence through waveguide effect

PubMed Central

Gao, Dangli; Tian, Dongping; Zhang, Xiangyu; Gao, Wei

2016-01-01

Luminescence-based waveguide is widely investigated as a promising alternative to conquer the difficulties of efficiently coupling light into a waveguide. But applications have been still limited due to employing blue or ultraviolet light as excitation source with the lower penetration depth leading to a weak guided light. Here, we show a quasi-one-dimensional propagation of luminescence and then resulting in a strong luminescence output from the top end of a single NaYF4:Yb3+/Er3+ microtube under near infrared light excitation. The mechanism of upconversion propagation, based on the optical waveguide effect accompanied with energy migration, is proposed. The efficiency of luminescence output is highly dependent on the concentration of dopant ions, excitation power, morphology, and crystallinity of tube as an indirect evidence of the existence of the optical actived waveguide effect. These findings provide the possibility for the construction of upconversion fiber laser. PMID:26926491

Features of the accretion in the EX Hydrae system: Results of numerical simulation

NASA Astrophysics Data System (ADS)

Isakova, P. B.; Zhilkin, A. G.; Bisikalo, D. V.; Semena, A. N.; Revnivtsev, M. G.

2017-07-01

A two-dimensional numerical model in the axisymmetric approximation that describes the flow structure in the magnetosphere of the white dwarf in the EX Hya system has been developed. Results of simulations show that the accretion in EX Hya proceeds via accretion columns, which are not closed and have curtain-like shapes. The thickness of the accretion curtains depends only weakly on the thickness of the accretion disk. This thickness developed in the simulations does not agree with observations. It is concluded that the main reason for the formation of thick accretion curtains in the model is the assumption that the magnetic field penetrates fully into the plasma of the disk. An analysis based on simple estimates shows that a diamagnetic disk that fully or partially shields the magnetic field of the star may be a more attractive explanation for the observed features of the accretion in EX Hya.

Low-velocity ion stopping in a dense and low-temperature plasma target

NASA Astrophysics Data System (ADS)

Deutsch, Claude; Popoff, Romain

2007-07-01

We investigate the stopping specificities involved in the heating of thin foils irradiated by intense ion beams in the 0.3-3 MeV/amu energy range and in close vicinity of the Bragg peak. Considering a swiftly ionized target to eV temperatures before expansion while retaining solid-state density, a typical warm dense matter (WDM) situation thus arises. We stress low Vp stopping through ion diffusion in the given target plasma. This allows to include the case of a strongly magnetized target in a guiding center approximation. We also demonstrate that the ion projectile penetration depth in target is significantly affected by multiple scattering on target electrons. The given plasma target is taken weakly coupled with Maxwell electron either with no magnetic field ( B=0) or strongly magnetized ( B≠0). Dynamical coupling between ion projectiles energy losses and projectiles charge state will also be addressed.

Superconducting properties of Rh 9 In 4 S 4 single crystals

DOE PAGES

Kaluarachchi, Udhara S.; Lin, Qisheng; Xie, Weiwei; ...

2016-03-28

The synthesis and crystallographic, thermodynamic, and transport properties of single crystalline Rh 9In 4S 4 were studied. The resistivity, magnetization, and specific heat measurements all clearly indicate bulk superconductivity with a critical temperature, T c~2.25 K. The Sommerfeld coefficient γ and the Debye temperature (ΘD) were found to be 34 mJ mol –1 K –2 and 217 K, respectively. The observed specific heat jump, ΔC/γT c=1.66, is larger than the expected BCS weak coupling value of 1.43. Ginzburg-Landau (GL) ratio of the low-temperature GL-penetration depth, λ GL≈5750 Å, to the GL-coherence length, ξ GL≈94 Å, is large: κ ~60. However,more » we observed a peak effect in the resistivity measurement as a function of both temperature and magnetic field.« less

Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tomfohrde, J.; Barnes, R.; Bowcock, A.

1994-05-20

A gene involved in psoriasis susceptibility was localized to the distal region of human chromosomes 17q as a result of a genome-wide linkage analysis with polymorphic microsatellites and eight multiply affected psoriasis kindreds. In the family which showed the strongest evidence for linkage, the recombination fraction between a psoriasis susceptibility locus and D17S784 was 0.04 with a maximum two-point lod score of 5.33. There was also evidence for genetic heterogeneity and although none of the linked families showed any association with HLA-Cw6, two unlinked families showed weak levels of association. This study demonstrates that is some families, psoriasis susceptibility ismore » due to variation at a single major genetic locus other than the human lymphocyte antigen locus. 28 refs., 2 figs., 1 tab.« less

Conformational dimorphism of isochroman-1-ones in the solid state

NASA Astrophysics Data System (ADS)

Babjaková, Eva; Hanulíková, Barbora; Dastychová, Lenka; Kuřitka, Ivo; Nečas, Marek; Vícha, Robert

2014-12-01

Isochroman-1-one derivatives, which are relatives of coumarins, display a broad spectrum of biological activity; therefore, these derivatives attract the attention of chemists. A series of new isochroman-1-ones were prepared by the reaction of benzyl-derived Grignard reagents with acyl chlorides. All of the prepared compounds were characterized using single-crystal X-ray diffraction as well as FT-IR, NMR and MS techniques. Single crystal X-ray diffraction analysis revealed that the isochromanones can adopt two distinct conformations in the solid state. For one of the compounds, two polymorphs with unique forms crystallized separately under different temperatures. The packing of all of the examined crystals is stabilized via weak intramolecular C-H⋯π and/or C-H⋯O interactions. Although the closed conformer was predominantly found in the actual crystals, the open conformer is thermochemically more stable for all of the examined compounds according to DFT calculations.

Experimental and theoretical infrared spectra of famotidine and its interaction with ofloxacin

NASA Astrophysics Data System (ADS)

Sagdinc, Seda; Bayarı, Sevgi

2005-06-01

We present FTIR spectrum of B polymorphic forms of famotidine (fam) that is a powerful histamine H2-receptor antagonist used in the treatment of peptic ulcer. Molecular mechanics and semi empirical AM1, PM3, MNDO and MINDO3 methods have been used to study the molecular geometry, and the harmonic vibrational spectra with the purpose to assist the experimental assignments of famotidine. The calculated geometric parameters have been compared to the corresponding X-ray structure of famotidine and it is found that AM1 structure in agreement with the crystal data. We are also investigated the interaction of famotidine with ofloxacin which is a synthetic antimicrobial agent. The changes observed in the some bands (wavenumber, shape) of interacted compound indicated that there is a weak interaction between two molecules. PM3 calculations are also carried out to determine the possible molecular structure of the interacted compound.

Is erythropoietin gene a modifier factor in amyotrophic lateral sclerosis?

PubMed

Ghezzi, Serena; Del Bo, Roberto; Scarlato, Marina; Nardini, Martina; Carlesi, Cecilia; Prelle, Alessandro; Corti, Stefania; Mancuso, Michelangelo; Briani, Chiara; Siciliano, Gabriele; Murri, Luigi; Bresolin, Nereo; Comi, Giacomo Pietro

2009-05-01

To investigate the role of erythropoietin (EPO) as genetic determinant in the susceptibility to sporadic amyotrophic lateral sclerosis (SALS). We sequenced a 259-bp region spanning the 3'hypoxia-responsive element of the EPO gene in 222 Italian SALS patients and 204 healthy subjects, matched for age and ethnic origin. No potentially causative variation was detected in SALS subjects; in addition, two polymorphic variants (namely C3434T and G3544T) showed the same genotype and haplotype frequencies in patients and controls. Conversely, a weak but significant association between G3544T and age of disease onset was observed (p=0.04). Overall, our data argue against the hypothesis of EPO as a genetic risk factor for motor neuron dysfunction, at least in Italian population. However, further studies on larger cohort of patients are needed to confirm the evidence of EPO gene as modifier factor.

Genetic diversity of worldwide Jerusalem artichoke (Helianthus tuberosus) germplasm as revealed by RAPD markers.

PubMed

Wangsomnuk, P P; Khampa, S; Wangsomnuk, P; Jogloy, S; Mornkham, T; Ruttawat, B; Patanothai, A; Fu, Y B

2011-12-12

Jerusalem artichoke (Helianthus tuberosus) is a wild relative of the cultivated sunflower (H. annuus); it is an old tuber crop that has recently received renewed interest. We used RAPD markers to characterize 147 Jerusalem artichoke accessions from nine countries. Thirty RAPD primers were screened; 13 of them detected 357 reproducible RAPD bands, of which 337 were polymorphic. Various diversity analyses revealed several different patterns of RAPD variation. More than 93% of the RAPD variation was found within accessions of a country. Weak genetic differentiation was observed between wild and cultivated accessions. Six groups were detected in this germplasm set. Four ancestral groups were found for the Canadian germplasm. The most genetically distinct accessions were identified. These findings provide useful diversity information for understanding the Jerusalem artichoke gene pool, for conserving Jerusalem artichoke germplasm, and for choosing germplasm for genetic improvement.

Loparite, a rare-earth ore (Ce, Na, Sr, Ca)(Ti, Nb, Ta, Fe+3)O3

USGS Publications Warehouse

Hedrick, James B.; Sinha, Shyama P.; Kosynkin, Valery D.

1997-01-01

The mineral loparite (Ce, NA, Sr, Ca)(Ti, Nb, Ta, Fe+3)O3 is the principal ore of the light-group rare-earth elements (LREE) in Russia. The complex oxide has a perovskite (ABO3) structure with coupled substitutions, polymorphism, defect chemistry and a tendency to become metamict. The A site generally contains weakly bonded, easily exchanged cations of the LREE, Na and Ca. The B site generally contains smaller, highly charged cations of Ti, Nb or Fe+3. Mine production is from Russia's Kola Peninsula. Ore is beneficiated to produce a 95% loparite concentrate containing 30% rare-earth oxides. Loparite concentrate is refined by either a chlorination process or acid decomposition process to recover rare-earths, titanium, niobium and tantalum. Rare-earths are separated by solvent extraction and selective precipitation/dissolution. The concentrate is processed at plants in Russia, Estonia and Kazakstan.

The effect of welding parameters on penetration in GTA welds

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shirali, A.A.; Mills, K.C.

1993-07-01

The effect of various welding parameters on the penetration of GTA welds has been investigated. Increases in welding speed were found to reduce penetration; however, increases in welding current were observed to increase the penetration in high sulfur (HS) casts and decrease penetration in low sulfur (LS) steels. Plots of penetration as a function of increasing linear energy (the heat supplied per unit length of weld) revealed a similar trend with increased penetration in HS casts, but the penetration in LS casts was unaffected by increases in linear energy. These results support the Burgardt-Heiple proposition that changes in welding parametersmore » on penetration can be explained in terms of their effect, sequentially, on the temperature gradient and the Marangoni forces operating in the weld pool. Increases in arc length were found to decrease weld penetration regardless of the sulfur concentration of the steel, and the effects of electrode geometry and welding position on weld penetration were also investigated.« less

Identifying disease polymorphisms from case-control genetic association data.

PubMed

Park, L

2010-12-01

In case-control association studies, it is typical to observe several associated polymorphisms in a gene region. Often the most significantly associated polymorphism is considered to be the disease polymorphism; however, it is not clear whether it is the disease polymorphism or there is more than one disease polymorphism in the gene region. Currently, there is no method that can handle these problems based on the linkage disequilibrium (LD) relationship between polymorphisms. To distinguish real disease polymorphisms from markers in LD, a method that can detect disease polymorphisms in a gene region has been developed. Relying on the LD between polymorphisms in controls, the proposed method utilizes model-based likelihood ratio tests to find disease polymorphisms. This method shows reliable Type I and Type II error rates when sample sizes are large enough, and works better with re-sequenced data. Applying this method to fine mapping using re-sequencing or dense genotyping data would provide important information regarding the genetic architecture of complex traits.

Polymorphism in molecular solids: an extraordinary system of red, orange, and yellow crystals.

PubMed

Yu, Lian

2010-09-21

Diamond and graphite are polymorphs of each other: they have the same composition but different structures and properties. Many other substances exhibit polymorphism: inorganic and organic, natural and manmade. Polymorphs are encountered in studies of crystallization, phase transition, materials synthesis, and biomineralization and in the manufacture of specialty chemicals. Polymorphs can provide valuable insights into crystal packing and structure-property relationships. 5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile, known as ROY for its red, orange, and yellow crystals, has seven polymorphs with solved structures, the largest number in the Cambridge Structural Database. First synthesized by medicinal chemists, ROY has attracted attention from solid-state chemists because it demonstrates the remarkable diversity possible in organic solids. Many structures of ROY polymorphs and their thermodynamic properties are known, making ROY an important model system for testing computational models. Though not the most polymorphic substance on record, ROY is extraordinary in that many of its polymorphs can crystallize simultaneously from the same liquid and are kinetically stable under the same conditions. Studies of ROY polymorphs have revealed a new crystallization mechanism that invalidates the common view that nucleation defines the polymorph of crystallization. A slow-nucleating polymorph can still dominate the product if it grows rapidly and nucleates on another polymorph. Studies of ROY have also helped understand a new, surprisingly fast mode of crystal growth in organic liquids cooled to the glass transition temperature. This growth mode exists only for those polymorphs that have more isotropic, and perhaps more liquid-like, packing. The rich polymorphism of ROY results from a combination of favorable thermodynamics and kinetics. Not only must there be many polymorphs of comparable energies or free energies, many polymorphs must be kinetically stable and crystallize at comparable rates to be observed. This system demonstrates the unique insights that polymorphism provides into solid-state structures and properties, as well as the inadequacy of our current understanding of the phenomenon. Despite many studies of ROY, it is still impossible to predict the next molecule that is equally or more polymorphic. ROY is a lucky gift from medicinal chemists.

Immunogenetic biomarkers in inflammatory bowel diseases: role of the IBD3 region.

PubMed

Muro, Manuel; López-Hernández, Ruth; Mrowiec, Anna

2014-11-07

Many studies have demonstrated the linkage between the IBD3 region (6p21.1-23), an area which encompasses the famous human leukocyte antigen (HLA) complex, and Crohn's disease (CD) or ulcerative colitis (UC). IBD3 is the only region that meets genome-wide significance, and provides stronger evidence of the linkage than 16p13.1-16q12.2 (IBD1), the locus that contains the susceptibility gene CARD15. However, despite these findings, IBD3 susceptibility genes remain elusive and unclear due to the strong linkage disequilibrium, extensive polymorphism, and high gene density that characterize this area and also due to varying allele frequencies in populations around the world. This area presents an extremely high abundance of genes, including the classical and non-classical major histocompatibility complex (MHC) class I and II genes, and other genes, namely MHC class III genes tumor necrosis factor (TNF)-α and -β, and Hsp, whose proteins play key functions in immunological processes. To date, it is not clear which genes within the MHC family contribute to the IBD pathogenesis, although certain HLA alleles have been associated with IBD. Recent insights into the biological function of other genes encoded within the IBD3 region, such as the MHC class I chain-related (MIC) genes, have led investigators to a more comprehensive exploration of this region. MHC class I chain-related molecule A (MICA) is highly polymorphic and interacts with NKG2D, its receptor on the surface of NK, Tγδ and T CD8(+) cells. Increased expression of MICA in intestinal epithelial cells and increased expression of NKG2D in CD4(+) T cells (lamina propria) in patients with CD have also been reported. MICA alleles have also been associated with IBD, and a variation at amino acid position 129 of the α2-heavy chain domain seems to categorize MICA alleles into strong and weak binders of NKG2D receptor, thereby influencing the effector cells' function. In this regard, a relevant role of MICA-129-Val/Met single nucleotide polymorphism has recently been implicated in the pathogenesis of IBD. TNF-α and -β also play an important role in inflammatory response. In fact, IBD is commonly treated with TNF-α inhibitors. Additionally, polymorphisms of TNF-α gene are known to affect the gene expression level and particular TNF-α genotypes may influence the response of IBD patients treated with TNF-α inhibitors.

Polymorphism of the hydroxide perovskite Ga(OH)3 and possible proton-driven transformational behaviour

NASA Astrophysics Data System (ADS)

Welch, M. D.; Kleppe, A. K.

2016-07-01

The crystal structure of hydroxide perovskite Ga(OH)3, the mineral söhngeite, has been determined for a natural sample by single-crystal XRD in space group P42/ nmc to R 1 = 0.031, wR 2 = 0.071, GoF = 1.208, and for comparison also in space group P42/ n to R 1 = 0.031, wR 2 = 0.073, GoF = 1.076. Unit cell parameters are a = 7.4546(2) Å, c = 7.3915(2) Å, V = 410.75(2) Å3. The two structures are very similar and both have tilt system a + a + c -. The approximate positions of all H atoms in each structure have been refined. In the P42/ nmc structure all five H sites are half-occupied, whereas in the P42/ n structure four sites are half-occupied and one is fully occupied. The presence of five non-equivalent OH groups in söhngeite is confirmed by single-crystal Raman spectroscopy, but does not allow a choice between these two space groups to be made. There is only a single very weak violator of the c-glide of P42/ nmc and the two refined structures are essentially the same, but are significantly different from that of the original description in which orthorhombic space group Pmn21 was reported with corresponding tilt system a 0 a 0 c +. It is argued here that such a structure is very implausible for a hydroxide perovskite. On heating söhngeite to 423 K, transformation to a cubic structure with Imbar{3} symmetry ( a + a + a +) of the aristotype occurs. This cubic phase was recovered on cooling to 293 K without back-transformation to the tetragonal polymorph. As there is no continuous group/subgroup pathway from P42/ nmc (or P42/ n) to Imbar{3}, the transformation must be first-order, which is consistent with the large hysteresis observed. The change from the tetragonal to cubic structures involves a change in tilt system a + a + c - → a + a + a +, with a significant reconfiguration of hydrogen-bonding topology. The very different tilt systems and hydrogen-bonding configurations of the two polymorphs are responsible for hysteresis and metastable preservation of the cubic phase at 293 K. As the Ga(OH)6 octahedra of the low- and high- T polymorphs are very similar it is inferred that the transformation is driven by proton behaviour, presumably involving proton re-ordering.

Effect of compressibility on the hypervelocity penetration

NASA Astrophysics Data System (ADS)

Song, W. J.; Chen, X. W.; Chen, P.

2018-02-01

We further consider the effect of rod strength by employing the compressible penetration model to study the effect of compressibility on hypervelocity penetration. Meanwhile, we define different instances of penetration efficiency in various modified models and compare these penetration efficiencies to identify the effects of different factors in the compressible model. To systematically discuss the effect of compressibility in different metallic rod-target combinations, we construct three cases, i.e., the penetrations by the more compressible rod into the less compressible target, rod into the analogously compressible target, and the less compressible rod into the more compressible target. The effects of volumetric strain, internal energy, and strength on the penetration efficiency are analyzed simultaneously. It indicates that the compressibility of the rod and target increases the pressure at the rod/target interface. The more compressible rod/target has larger volumetric strain and higher internal energy. Both the larger volumetric strain and higher strength enhance the penetration or anti-penetration ability. On the other hand, the higher internal energy weakens the penetration or anti-penetration ability. The two trends conflict, but the volumetric strain dominates in the variation of the penetration efficiency, which would not approach the hydrodynamic limit if the rod and target are not analogously compressible. However, if the compressibility of the rod and target is analogous, it has little effect on the penetration efficiency.

Rivastigmine hydrogen tartrate polymorphs: Solid-state characterisation of transition and polymorphic conversion via milling

NASA Astrophysics Data System (ADS)

Amaro, Maria Inês; Simon, Alice; Cabral, Lúcio Mendes; de Sousa, Valéria Pereira; Healy, Anne Marie

2015-11-01

Rivastigmine (RHT) is an active pharmaceutical ingredient that is used for the treatment of mild to moderately severe dementia in Alzheimer's disease, and is known to present two polymorphic forms and to amorphise upon granulation. To date there is no information in the scientific or patent literature on polymorphic transition and stability. Hence, the aim of the current study was to gain a fundamental understanding of the polymorphic forms by (1) evaluating RHT thermodynamic stability (monotropy or enantiotropy) and (2) investigating the potential for polymorphic transformation upon milling. The two polymorphic and amorphous forms were characterised using X-ray powder diffractometry, thermal analyses, infra-red spectroscopy and water sorption analysis. The polymorphic transition was found to be spontaneous (ΔG0 < 0) and exothermic (ΔH0 < 0), indicative of a monotropic polymorph pair. The kinetic studies showed a fast initial polymorphic transition characterised by a heterogeneous nucleation, followed by a slow crystal growth. Ball milling can be used to promote the polymorphic transition and for the production of RHT amorphous form.

Low penetrance of autosomal dominant lateral temporal epilepsy in Italian families without LGI1 mutations.

PubMed

Michelucci, Roberto; Pasini, Elena; Malacrida, Sandro; Striano, Pasquale; Bonaventura, Carlo Di; Pulitano, Patrizia; Bisulli, Francesca; Egeo, Gabriella; Santulli, Lia; Sofia, Vito; Gambardella, Antonio; Elia, Maurizio; de Falco, Arturo; Neve, Angela la; Banfi, Paola; Coppola, Giangennaro; Avoni, Patrizia; Binelli, Simona; Boniver, Clementina; Pisano, Tiziana; Marchini, Marco; Dazzo, Emanuela; Fanciulli, Manuela; Bartolini, Yerma; Riguzzi, Patrizia; Volpi, Lilia; de Falco, Fabrizio A; Giallonardo, Anna Teresa; Mecarelli, Oriano; Striano, Salvatore; Tinuper, Paolo; Nobile, Carlo

2013-07-01

In relatively small series, autosomal dominant lateral temporal epilepsy (ADLTE) has been associated with leucine-rich, glioma-inactivated 1 (LGI1) mutations in about 50% of the families, this genetic heterogeneity being probably caused by differences in the clinical characteristics of the families. In this article we report the overall clinical and genetic spectrum of ADLTE in Italy with the aim to provide new insight into its nosology and genetic basis. In a collaborative study of the Commission of Genetics of the Italian League Against Epilepsy (LICE) encompassing a 10-year period (2000-2010), we collected 33 ADLTE families, selected on the basis of the following criteria: presence of at least two members concordant for unprovoked partial seizures with prominent auditory and or aphasic symptoms, absence of any known structural brain pathology or etiology, and normal neurologic examination. The clinical, neurophysiologic, and neuroradiologic findings of all patients were analyzed and a genealogic tree was built for each pedigree. The probands' DNA was tested for LGI1 mutations by direct sequencing and, if negative, were genotyped with single-nucleotide polymorphism (SNP) array to search for disease-linked copy-number variation CNV. The disease penetrance in mutated and nonmutated families was assessed as a proportion of obligate carriers who were affected. The 33 families included a total of 127 affected individuals (61 male, 66 female, 22 deceased). The age at onset ranged between 2 and 60 years (mean 18.7 years). Ninety-one patients (72%) had clear-cut focal (elementary, complex, or secondarily generalized) seizures, characterized by prominent auditory auras in 68% of the cases. Other symptoms included complex visual hallucinations, vertigo, and déjà vu. Aphasic seizures, associated or not with auditory features, were observed in 20% of the cases, whereas tonic-clonic seizures occurred in 86% of the overall series. Sudden noises could precipitate the seizures in about 20% of cases. Seizures, which usually occurred at a low frequency, were promptly controlled or markedly improved by antiepileptic treatment in the majority of patients. The interictal electroencephalography (EEG) studies showed the epileptiform temporal abnormalities in 62% of cases, with a slight predominance over the left region. Magnetic resonance imaging (MRI) or computerized tomography (CT) scans were negative. LGI1 mutations (missense in nine and a microdeletion in one) were found in only 10 families (30%). The patients belonging to the mutated and not mutated groups did not differ except for penetrance estimate, which was 61.3% and 35% in the two groups, respectively (chi-square, p = 0.017). In addition, the disease risk of members of families with mutations in LGI1 was three times higher than that of members of LGI1-negative families (odds ratio [OR] 2.94, confidence interval [CI] 1.2-7.21). A large number of ADLTE families has been collected over a 10-year period in Italy, showing a typical and homogeneous phenotype. LGI1 mutations have been found in only one third of families, clinically indistinguishable from nonmutated pedigrees. The estimate of penetrance and OR, however, demonstrates a significantly lower penetrance rate and relative disease risk in non-LGI1-mutated families compared with LGI1-mutated pedigrees, suggesting that a complex inheritance pattern may underlie a proportion of these families. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

Thermal, spectroscopic and structural characterization of isostructural phase transition in 4-hydroxybenzaldehyde

NASA Astrophysics Data System (ADS)

Panicker, Lata

2018-05-01

Polycrystalline samples of 4-hydroxybenzaldehyde (4-HOBAL) were investigated using differential scanning calorimeter (DSC), Raman spectroscopy and X-ray powder diffraction. The DSC data indicated that 4-HOBAL on heating undergoes a polymorphic transformation from polymorph I to polymorph II. The polymorph II formed remains metastable at ambient condition and transforms to polymorph I when annealed at ambient temperature for more than seven days. The structural information of polymorphs I and II obtained using its X-ray powder diffraction patterns indicated that 4-HOBAL undergoes an isostructural phase transition from polymorph I (monoclinic, P21/c) to polymorph II (monoclinic, P21/c). Raman data suggest that this structural change is associated with some change in its molecular interactions. Thus, in 4-HOBAL the polymorphic phase transformation (II to I) even though energetically favoured is kinetically hindered.

Signal variation and its morphological correlates in Paramormyrops kingsleyae provide insight into the evolution of electrogenic signal diversity in mormyrid electric fish.

PubMed

Gallant, Jason R; Arnegard, Matthew E; Sullivan, John P; Carlson, Bruce A; Hopkins, Carl D

2011-08-01

We describe patterns of geographic variation in electric signal waveforms among populations of the mormyrid electric fish species Paramormyrops kingsleyae. This analysis includes study of electric organs and electric organ discharge (EOD) signals from 553 specimens collected from 12 localities in Gabon, West-Central Africa from 1998 to 2009. We measured time, slope, and voltage values from nine defined EOD "landmarks" and determined peak spectral frequencies from each waveform; these data were subjected to principal components analysis. The majority of variation in EODs is explained by two factors: the first related to EOD duration, the second related to the magnitude of the weak head-negative pre-potential, P0. Both factors varied clinally across Gabon. EODs are shorter in eastern Gabon and longer in western Gabon. Peak P0 is slightly larger in northern Gabon and smaller in southern Gabon. P0 in the EOD is due to the presence of penetrating-stalked (Pa) electrocytes in the electric organ while absence is due to the presence of non-penetrating stalked electrocytes (NPp). Across Gabon, the majority of P. kingsleyae populations surveyed have only individuals with P0-present EODs and Pa electrocytes. We discovered two geographically distinct populations, isolated from others by barriers to migration, where all individuals have P0-absent EODs with NPp electrocytes. At two sites along a boundary between P0-absent and P0-present populations, P0-absent and P0-present individuals were found in sympatry; specimens collected there had electric organs of intermediate morphology. This pattern of geographic variation in EODs is considered in the context of current phylogenetic work. Multiple independent paedomorphic losses of penetrating stalked electrocytes have occurred within five Paramormyrops species and seven genera of mormyrids. We suggest that this key anatomical feature in EOD signal evolution may be under a simple mechanism of genetic control, and may be easily influenced by selection or drift throughout the evolutionary history of mormyrids.

Detection capability of a pulsed Ground Penetrating Radar utilizing an oscilloscope and Radargram Fusion Approach for optimal signal quality

NASA Astrophysics Data System (ADS)

Seyfried, Daniel; Schoebel, Joerg

2015-07-01

In scientific research pulsed radars often employ a digital oscilloscope as sampling unit. The sensitivity of an oscilloscope is determined in general by means of the number of digits of its analog-to-digital converter and the selected full scale vertical setting, i.e., the maximal voltage range displayed. Furthermore oversampling or averaging of the input signal may increase the effective number of digits, hence the sensitivity. Especially for Ground Penetrating Radar applications high sensitivity of the radar system is demanded since reflection amplitudes of buried objects are strongly attenuated in ground. Hence, in order to achieve high detection capability this parameter is one of the most crucial ones. In this paper we analyze the detection capability of our pulsed radar system utilizing a Rohde & Schwarz RTO 1024 oscilloscope as sampling unit for Ground Penetrating Radar applications, such as detection of pipes and cables in the ground. Also effects of averaging and low-noise amplification of the received signal prior to sampling are investigated by means of an appropriate laboratory setup. To underline our findings we then present real-world radar measurements performed on our GPR test site, where we have buried pipes and cables of different types and materials in different depths. The results illustrate the requirement for proper choice of the settings of the oscilloscope for optimal data recording. However, as we show, displaying both strong signal contributions due to e.g., antenna cross-talk and direct ground bounce reflection as well as weak reflections from objects buried deeper in ground requires opposing trends for the oscilloscope's settings. We therefore present our Radargram Fusion Approach. By means of this approach multiple radargrams recorded in parallel, each with an individual optimized setting for a certain type of contribution, can be fused in an appropriate way in order to finally achieve a single radargram which displays all contributions occurring originally at different strengths in an equalized and normalized way by means of appropriate digital signal post-processing.

Thermal, spectroscopic, and ab initio structural characterization of carprofen polymorphs.

PubMed

Bruni, Giovanna; Gozzo, Fabia; Capsoni, Doretta; Bini, Marcella; Macchi, Piero; Simoncic, Petra; Berbenni, Vittorio; Milanese, Chiara; Girella, Alessandro; Ferrari, Stefania; Marini, Amedeo

2011-06-01

Commercial and recrystallized polycrystalline samples of carprofen, a nonsteroidal anti-inflammatory drug, were studied by thermal, spectroscopic, and structural techniques. Our investigations demonstrated that recrystallized sample, stable at room temperature (RT), is a single polymorphic form of carprofen (polymorph I) that undergoes an isostructural polymorphic transformation by heating (polymorph II). Polymorph II remains then metastable at ambient conditions. Commercial sample is instead a mixture of polymorphs I and II. The thermodynamic relationships between the two polymorphs were determined through the construction of an energy/temperature diagram. The ab initio structural determination performed on synchrotron X-Ray powder diffraction patterns recorded at RT on both polymorphs allowed us to elucidate, for the first time, their crystal structure. Both crystallize in the monoclinic space group type P2(1) /c, and the unit cell similarity index and the volumetric isostructurality index indicate that the temperature-induced polymorphic transformation I → II is isostructural. Polymorphs I and II are conformational polymorphs, sharing a very similar hydrogen bond network, but with different conformation of the propanoic skeleton, which produces two different packing. The small conformational change agrees with the low value of transition enthalpy obtained by differential scanning calorimetry measurements and the small internal energy computed with density functional methods. Copyright © 2011 Wiley-Liss, Inc.

Impact of serotonin transporter gene polymorphism on brain activation by colorectal distention.

PubMed

Fukudo, S; Kanazawa, M; Mizuno, T; Hamaguchi, T; Kano, M; Watanabe, S; Sagami, Y; Shoji, T; Endo, Y; Hongo, M; Itoyama, Y; Yanai, K; Tashiro, M; Aoki, M

2009-09-01

Determining the gene that plays a key role in brain-gut interactions is a crucial step for clarifying the pathophysiology of irritable bowel syndrome (IBS). We previously reported that the 5-hydroxytryptamine transporter gene-linked polymorphic region (5-HTTLPR) is related to anxiety in subjects with IBS. The amygdala is more activated during fearful face recognition in individuals with the s allele of 5-HTTLPR. Here, we tested our hypothesis that 5-HTTLPR differentially activates brain regions with colorectal distention in humans. We enrolled 28 subjects without any organic disease. The study was approved by the Ethics Committee and all subjects gave written informed consent. DNA was extracted from the peripheral blood. The genotype of 5-HTTLPR was determined using polymerase chain reaction. Age, sex, diagnosis-matched individuals with the s/s genotype (n=14) and individuals with the l allele (genotypes l/s, l/l, l/extra-l, n=14) were compared. A barostat bag was inserted to the colorectum and was intermittently inflated with no (0 mm Hg), mild (20 mm Hg), or intense (40 mm Hg) stimulation on a random order. Radioactive H2[(15-)O] saline was injected at bag inflation and then positron emission tomography was performed. Changes in rCBF were analyzed using statistical parametric mapping. Individuals with the s/s genotype showed a significantly larger increase in rCBF by colorectal distention from 0 mm Hg to 40 mm Hg than individuals with the l allele. The significantly more activated brain regions in individuals with the s/s genotype were the left anterior cingulate cortex and right parahippocampal gyrus (p<0.0001). The increase in rCBF by colorectal distention of 20 mm Hg compared with 0 mm Hg was significantly larger in the left orbitofrontal cortex of individuals with the s/s genotype than that of individuals with the l allele (p<0.0001). These data suggest that individuals with a weak function of serotonin transporter respond to gut signals more in emotion-regulating brain regions. Functional gene polymorphism may partially predict the individual effect of a selective serotonin reuptake inhibitor on visceral pain.

Physical function is weakly associated with angiotensin-converting enzyme gene I/D polymorphism in elderly Japanese subjects.

PubMed

Yoshihara, A; Tobina, T; Yamaga, T; Ayabe, M; Yoshitake, Y; Kimura, Y; Shimada, M; Nishimuta, M; Nakagawa, N; Ohashi, M; Hanada, N; Tanaka, H; Kiyonaga, A; Miyazaki, H

2009-01-01

The turning point in the deterioration of physical function seems to occur between the ages of 70 and 80 years. In particular, muscle strength may decline even more in subjects older than 75. A recent study found that the angiotensin-converting enzyme (ACE) genotype also affects physiological left ventricular hypertrophy. A very limited number of papers have examined genetic differences in resistance and endurance forms of a single sporting discipline. The purpose of this study was to evaluate the relationship between ACE genotype and physical function by controlling the known confounding factors including dental status. We selected 431 subjects who were aged 76 years and did not require special care for their daily activities. We conducted a medical examination, followed by 5 physical function tests, as follows: (1) maximum hand grip strength, (2) maximal isometric knee extensor strength, (3) maximal stepping rate for 10 s, (4) one-leg standing time with eyes open and (5) 10-meter maximum walking speed. Subjects were genotyped for the ACE intron 16 Alu insertion. In addition, serum concentrations of total cholesterol, total protein, IgA and IgG were measured at a commercial laboratory. The Eichner index was used as an indicator of occlusal condition. Multiple linear regression analysis was performed to evaluate the relationship between the ACE gene insertion/deletion (I/D) polymorphism and physical function considering confounding factors. The ACE gene I/D polymorphism was positively associated with hand grip strength and 10-meter maximum walking speed. Betas of hand grip strength were 0.09 for I/D (p = 0.022) and 0.12 for insertion/insertion (I/I; p = 0.004). Betas of 10-meter walking speed were -0.11 for I/D (p = 0.093) and -0.14 for I/I (p = 0.039). Dental status such as Eichner index class C was significantly associated with one-leg standing time with eyes open (beta -0.11; p = 0.028). This study suggests that there is a significant relationship between ACE genotype and physical function. In particular, subjects with the ACE deletion/deletion genotype were associated with upper extremities. Copyright 2009 S. Karger AG, Basel.

High-velocity impact loading of thick GFRP blocks

NASA Astrophysics Data System (ADS)

Ernst, H.-J.; Merkel, Th.; Wolf, Th.; Hoog, K.

2003-09-01

In previous depth of penetration experiments with tungsten long rod projectiles was found that the ballistic resistance of a relatively thick-up to the penetrator length-glass fibre reinforced plastic block grows with increasing penetration depth. This penetration behaviour significantly differs from that of other inert armour materials. Until now, no significant difference between unconfined and totally confined GFRP configurations bas been found. Newest experiments with up to semi-infinite thick GFRP blocks show a change in the penetration process: For thicknesses significantly higher than the penetrator length the protective power may saturate. During the late penetration phase the shortening and deceleration of the projectile induce a change of penetration mechanism from erosion to rigid body penetration. Additionally, the projectile may break into several individually tumbling parts. Reflected tension waves and, probably, pyrolysis effects may cause increasing precursory damage. These effects together are likely to explain the reduction of the ballistic resistance increase during the late penetration phase. Based on these experimental results the published working hypothesis on the governing mechanism of the GFRP penetration behaviour had to be completed. A new approach based on a hyperbolic tangent function seems to satisfactorily describe the observed thickness dependent phenomena.

Delafloxacin: Place in Therapy and Review of Microbiologic, Clinical and Pharmacologic Properties.

PubMed

Jorgensen, Sarah C J; Mercuro, Nicholas J; Davis, Susan L; Rybak, Michael J

2018-03-31

Delafloxacin (formerly WQ-3034, ABT492, RX-3341) is a novel fluoroquinolone chemically distinct from currently marketed fluoroquinolones with the absence of a protonatable substituent conferring a weakly acidic character to the molecule. This property results in increased intracellular penetration and enhanced bactericidal activity under acidic conditions that characterize the infectious milieu at a number of sites. The enhanced potency and penetration in low pH environments contrast what has been observed for other zwitterionic fluoroquinolones, which tend to lose antibacterial potency under acidic conditions, and may be particularly advantageous against methicillin-resistant Staphylococcus aureus, for which the significance of the intracellular mode of survival is increasingly being recognized. Delafloxacin is also unique in its balanced target enzyme inhibition, a property that likely explains the very low frequencies of spontaneous mutations in vitro. Delafloxacin recently received US Food and Drug Administration approval for the treatment of acute bacterial skin and skin structure infections and is currently being evaluated in a phase 3 trial among patients with community-acquired pneumonia. In the current era of a heightened awareness pertaining to collateral ecologic damage, safety issues and antimicrobial stewardship principles, it is critical to describe the unique properties of delafloxacin and define its potential role in therapy. The purpose of this article is to review available data pertaining to delafloxacin's biochemistry, pharmacokinetic/pharmacodynamics characteristics, in vitro activity and potential for resistance selection as well as current progress in clinical trials to ultimately assist clinicians in selecting patients who will benefit most from the distinctive properties of this agent.

Swot analysis of using aerostats for surveillance in counter terrorism

NASA Astrophysics Data System (ADS)

Çetin, Hüseyin

2013-06-01

In today's conjuncture, the terrorist activities are the most compelling issue for the defence forces in maintaining homeland security. Especially, the terrorist elements that penetrate the homeland may give harm. This harm can be minimized by preventing the terrorist penetrations from homeland borders. In counter terrorism, having Intelligence, Surveillance and Reconnaissance (ISR) capability and using this capability by twenty four hours is deterrence for the terrorist groups. Aerostats emerge as the ideal platform which can provide this capability. Aerostats are unmanned and aerodynamically shaped balloons that are stayed in the air, fixed to the ground by steel cable(s). The aerostat is made of a large fabric envelope that is filled with nonflammable helium gas, which provides the lifting force. The cables also serve to supply the electrical power to the aerostat systems, and for data relay between the aerostat and the ground station. Aerostats are different from the other manned and Unmanned Aerial Vehicles (UAVs) because of aerostats' capabilities such as cost effectiveness, long endurance and high resolution image transmission. Especially having uninterrupted image transmission and surveillance capabilities is important to be advantageous in counter terrorism. In this article, a short definition of terrorism has been given and then the importance of ensuring the homeland border security has been emphasized in counter terrorism. In addition, the questions of "what are the technical capabilities, the usage areas and the purposes of aerostats?" will be introduced as a result of literature review. Finally the strengths and weaknesses of aerostats, opportunities and threats for the near future will be introduced by using "SWOT" analysis method.

Description of an α-cluster tail in 8Be and 20Ne: Delocalization of the α cluster by quantum penetration

NASA Astrophysics Data System (ADS)

Kanada-En'yo, Yoshiko

2014-10-01

We analyze the α-cluster wave functions in cluster states of ^8Be and ^{20}Ne by comparing the exact relative wave function obtained by the generator coordinate method (GCM) with various types of trial functions. For the trial functions, we adopt the fixed range shifted Gaussian of the Brink-Bloch (BB) wave function, the spherical Gaussian with the adjustable range parameter of the spherical Tohsaki-Horiuchi-Schuck-Röpke (sTHSR), the deformed Gaussian of the deformed THSR (dTHSR), and a function with the Yukawa tail (YT). The quality of the description of the exact wave function with a trial function is judged by the squared overlap between the trial function and the GCM wave function. A better result is obtained with the sTHSR wave function than the BB wave function, and further improvement can be made with the dTHSR wave function because these wave functions can describe the outer tail better. The YT wave function gives almost an equal quality to or even better quality than the dTHSR wave function, indicating that the outer tail of α-cluster states is characterized by the Yukawa-like tail rather than the Gaussian tail. In weakly bound α-cluster states with small α separation energy and the low centrifugal and Coulomb barriers, the outer tail part is the slowly damping function described well by the quantum penetration through the effective barrier. This outer tail characterizes the almost zero-energy free α gas behavior, i.e., the delocalization of the cluster.

INCURVATA2 Encodes the Catalytic Subunit of DNA Polymerase α and Interacts with Genes Involved in Chromatin-Mediated Cellular Memory in Arabidopsis thaliana

PubMed Central

Barrero, José María; González-Bayón, Rebeca; del Pozo, Juan Carlos; Ponce, María Rosa; Micol, José Luis

2007-01-01

Cell type–specific gene expression patterns are maintained by the stable inheritance of transcriptional states through mitosis, requiring the action of multiprotein complexes that remodel chromatin structure. Genetic and molecular interactions between chromatin remodeling factors and components of the DNA replication machinery have been identified in Schizosaccharomyces pombe, indicating that some epigenetic marks are replicated simultaneously to DNA with the participation of the DNA replication complexes. This model of epigenetic inheritance might be extended to the plant kingdom, as we report here with the positional cloning and characterization of INCURVATA2 (ICU2), which encodes the putative catalytic subunit of the DNA polymerase α of Arabidopsis thaliana. The strong icu2-2 and icu2-3 insertional alleles caused fully penetrant zygotic lethality when homozygous and incompletely penetrant gametophytic lethality, probably because of loss of DNA polymerase activity. The weak icu2-1 allele carried a point mutation and caused early flowering, leaf incurvature, and homeotic transformations of sepals into carpels and of petals into stamens. Further genetic analyses indicated that ICU2 interacts with TERMINAL FLOWER2, the ortholog of HETEROCHROMATIN PROTEIN1 of animals and yeasts, and with the Polycomb group (PcG) gene CURLY LEAF. Another PcG gene, EMBRYONIC FLOWER2, was found to be epistatic to ICU2. Quantitative RT-PCR analyses indicated that a number of regulatory genes were derepressed in the icu2-1 mutant, including genes associated with flowering time, floral meristem, and floral organ identity. PMID:17873092

Altering the Polymorphic Accessibility of Polycyclic Aromatic Hydrocarbons with Fluorination

DOE PAGES

Hiszpanski, Anna M.; Woll, Arthur R.; Kim, Bumjung; ...

2017-04-25

Here, substituting hydrogen with fluorine is an extensively employed strategy to improve the macroscopic properties of compounds for use in fields as diverse as pharmaceutics and optoelectronics. The role fluorine substitution plays on polymorphism—the ability of a compound to adopt more than one crystal structure—has not been previously studied. Yet, this understanding is important as different polymorphs of the same compound can result in drastically different bulk properties (e.g., solubility, absorptivity, and conductivity). Strategies to either promote or suppress the crystallization of particular polymorphs are thus desired. Here, we show that substituting hydrogen with fluorine affects the polymorphic behavior ofmore » contorted hexabenzocoronene (cHBC). A polycyclic aromatic hydrocarbon and molecular semiconductor, cHBC exhibits two polymorphs (i.e., P2 1/c crystal structure which we refer to as polymorph I and a triclinic crystal structure which we refer to as polymorph II) that are accessible through postdeposition processing of amorphous films. While the same two polymorphs remain accessible in fluorinated derivatives of cHBC, fluorination appears to favor the formation of polymorph I, with progressively smaller energy barrier for transformation from polymorph II to polymorph I with fluorination.« less

Altering the Polymorphic Accessibility of Polycyclic Aromatic Hydrocarbons with Fluorination

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hiszpanski, Anna M.; Woll, Arthur R.; Kim, Bumjung

Here, substituting hydrogen with fluorine is an extensively employed strategy to improve the macroscopic properties of compounds for use in fields as diverse as pharmaceutics and optoelectronics. The role fluorine substitution plays on polymorphism—the ability of a compound to adopt more than one crystal structure—has not been previously studied. Yet, this understanding is important as different polymorphs of the same compound can result in drastically different bulk properties (e.g., solubility, absorptivity, and conductivity). Strategies to either promote or suppress the crystallization of particular polymorphs are thus desired. Here, we show that substituting hydrogen with fluorine affects the polymorphic behavior ofmore » contorted hexabenzocoronene (cHBC). A polycyclic aromatic hydrocarbon and molecular semiconductor, cHBC exhibits two polymorphs (i.e., P2 1/c crystal structure which we refer to as polymorph I and a triclinic crystal structure which we refer to as polymorph II) that are accessible through postdeposition processing of amorphous films. While the same two polymorphs remain accessible in fluorinated derivatives of cHBC, fluorination appears to favor the formation of polymorph I, with progressively smaller energy barrier for transformation from polymorph II to polymorph I with fluorination.« less

Functionality of promoter microsatellites of arginine vasopressin receptor 1A (AVPR1A): implications for autism.

PubMed

Tansey, Katherine E; Hill, Matthew J; Cochrane, Lynne E; Gill, Michael; Anney, Richard Jl; Gallagher, Louise

2011-03-31

Arginine vasopressin (AVP) has been hypothesized to play a role in aetiology of autism based on a demonstrated involvement in the regulation of social behaviours. The arginine vasopressin receptor 1A gene (AVPR1A) is widely expressed in the brain and is considered to be a key receptor for regulation of social behaviour. Moreover, genetic variation at AVPR1A has been reported to be associated with autism. Evidence from non-human mammals implicates variation in the 5'-flanking region of AVPR1A in variable gene expression and social behaviour. We examined four tagging single nucleotide polymorphisms (SNPs) (rs3803107, rs1042615, rs3741865, rs11174815) and three microsatellites (RS3, RS1 and AVR) at the AVPR1A gene for association in an autism cohort from Ireland. Two 5'-flanking region polymorphisms in the human AVPR1A, RS3 and RS1, were also tested for their effect on relative promoter activity. The short alleles of RS1 and the SNP rs11174815 show weak association with autism in the Irish population (P = 0.036 and P = 0.008, respectively). Both RS1 and RS3 showed differences in relative promoter activity by length. Shorter repeat alleles of RS1 and RS3 decreased relative promoter activity in the human neuroblastoma cell line SH-SY5Y. These aligning results can be interpreted as a functional route for this association, namely that shorter alleles of RS1 lead to decreased AVPR1A transcription, which may proffer increased susceptibility to the autism phenotype.

Chromosomal Inversions, Natural Selection and Adaptation in the Malaria Vector Anopheles funestus

PubMed Central

Ayala, Diego; Fontaine, Michael C.; Cohuet, Anna; Fontenille, Didier; Vitalis, Renaud; Simard, Frédéric

2011-01-01

Chromosomal polymorphisms, such as inversions, are presumably involved in the rapid adaptation of populations to local environmental conditions. Reduced recombination between alternative arrangements in heterozygotes may protect sets of locally adapted genes, promoting ecological divergence and potentially leading to reproductive isolation and speciation. Through a comparative analysis of chromosomal inversions and microsatellite marker polymorphisms, we hereby present biological evidence that strengthens this view in the mosquito Anopheles funestus s.s, one of the most important and widespread malaria vectors in Africa. Specimens were collected across a wide range of geographical, ecological, and climatic conditions in Cameroon. We observed a sharp contrast between population structure measured at neutral microsatellite markers and at chromosomal inversions. Microsatellite data detected only a weak signal for population structuring among geographical zones (FST < 0.013, P < 0.01). By contrast, strong differentiation among ecological zones was revealed by chromosomal inversions (FST > 0.190, P < 0.01). Using standardized estimates of FST, we show that inversions behave at odds with neutral expectations strongly suggesting a role of environmental selection in shaping their distribution. We further demonstrate through canonical correspondence analysis that heterogeneity in eco-geographical variables measured at specimen sampling sites explained 89% of chromosomal variance in A. funestus. These results are in agreement with a role of chromosomal inversions in ecotypic adaptation in this species. We argue that this widespread mosquito represents an interesting model system for the study of chromosomal speciation mechanisms and should provide ample opportunity for comparative studies on the evolution of reproductive isolation and speciation in major human malaria vectors. PMID:20837604

Lack of association between the BIM deletion polymorphism and the risk of lung cancer with and without EGFR mutations.

PubMed

Ebi, Hiromichi; Oze, Isao; Nakagawa, Takayuki; Ito, Hidemi; Hosono, Satoyo; Matsuda, Fumihiko; Takahashi, Meiko; Takeuchi, Shinji; Sakao, Yukinori; Hida, Toyoaki; Faber, Anthony C; Tanaka, Hideo; Yatabe, Yasushi; Mitsudomi, Tetsuya; Yano, Seiji; Matsuo, Keitaro

2015-01-01

The BIM deletion polymorphism in intron 2 was found in a significant percent of the Asian population. Patients with epidermal growth factor receptor (EGFR) mutant lung cancers harboring this BIM polymorphism have shorter progression free survival and overall response rates to EGFR tyrosine kinase inhibitors. However, the association between the BIM deletion polymorphism and lung cancer risk is unknown. The BIM deletion polymorphism was screened by polymerase chain reaction in 765 lung cancer cases and 942 healthy individuals. Carriers possessing one allele of the BIM polymorphism were observed in 13.0% of control cases and 12.8% of lung cancer cases, similar to incidence rates reported earlier in healthy individuals. Homozygote for the BIM polymorphism was observed in four of 942 healthy controls and three of 765 lung cancer cases. The frequency of the BIM deletion polymorphism in lung cancer patients was not related to age, sex, smoking history, or family history of lung cancer. The BIM deletion polymorphism was found in 30 of 212 patients with EGFR wild type lung cancers and 16 of 120 patients with EGFR mutant lung cancers. The frequency of the BIM polymorphism is similar between cancers with wild type EGFR and mutated EGFR (p = 0.78). The BIM deletion polymorphism was not associated with lung cancer susceptibility. Furthermore, the BIM polymorphism is not associated with EGFR mutant lung cancer.

Interaction of trace elements and welding parameters on GTA weld shape. [Variation with penetration and tip angle

DOE Office of Scientific and Technical Information (OSTI.GOV)

Burgardt, P.; Heiple, C.R.

1985-01-01

Good penetration and poor penetration steels have different responses to changes in temperature distribution on the weld pool surface. Penetration of 304 SS was varied using S and Se dopants. The weld parameter investigated was the electrode tip angle. Results of bead-on-plate GTA welds show that there is a difference in response of weld pool shape to tip angle depending on penetration: Low penetration base metal showed no dependence, intermediate penetration steel showed a small linear decrease of weld depth-to-width ratio (d/w) with tip angle, while high penetration steel showed an increase of d/w up to a maximum at aboutmore » 50/sup 0/, followed by a decrease in d/w. (DLC)« less

Snow instability evaluation: calculating the skier-induced stress in a multi-layered snowpack

NASA Astrophysics Data System (ADS)

Monti, Fabiano; Gaume, Johan; van Herwijnen, Alec; Schweizer, Jürg

2016-03-01

The process of dry-snow slab avalanche formation can be divided into two phases: failure initiation and crack propagation. Several approaches tried to quantify slab avalanche release probability in terms of failure initiation based on shear stress and strength. Though it is known that both the properties of the weak layer and the slab play a major role in avalanche release, most previous approaches only considered slab properties in terms of slab depth, average density and skier penetration. For example, for the skier stability index, the additional stress (e.g. due to a skier) at the depth of the weak layer is calculated by assuming that the snow cover can be considered a semi-infinite, elastic, half-space. We suggest a new approach based on a simplification of the multi-layered elasticity theory in order to easily compute the additional stress due to a skier at the depth of the weak layer, taking into account the layering of the snow slab and the substratum. We first tested the proposed approach on simplified snow profiles, then on manually observed snow profiles including a stability test and, finally, on simulated snow profiles. Our simple approach reproduced the additional stress obtained by finite element simulations for the simplified profiles well - except that the sequence of layering in the slab cannot be replicated. Once implemented into the classical skier stability index and applied to manually observed snow profiles classified into different stability classes, the classification accuracy improved with the new approach. Finally, we implemented the refined skier stability index into the 1-D snow cover model SNOWPACK. The two study cases presented in this paper showed promising results even though further verification is still needed. In the future, we intend to implement the proposed approach for describing skier-induced stress within a multi-layered snowpack into more complex models which take into account not only failure initiation but also crack propagation.

Snow instability evaluation: calculating the skier-induced stress in a multi-layered snowpack

NASA Astrophysics Data System (ADS)

Monti, F.; Gaume, J.; van Herwijnen, A.; Schweizer, J.

2015-08-01

The process of dry-snow slab avalanche formation can be divided into two phases: failure initiation and crack propagation. Several approaches tried to quantify slab avalanche release probability in terms of failure initiation based on shear stress and strength. Though it is known that both the properties of the weak layer and the slab play a major role in avalanche release, most previous approaches only considered slab properties in terms of slab depth, average density and skier penetration. For example, for the skier stability index, the additional stress (e.g. due to a skier) at the depth of the weak layer is calculated by assuming that the snow cover can be considered a semi-infinite, elastic half-space. We suggest a new approach based on a simplification of the multi-layered elasticity theory in order to easily compute the additional stress due to a skier at the depth of the weak layer taking into account the layering of the snow slab and the substratum. We first tested the proposed approach on simplified snow profiles, then on manually observed snow profiles including a stability test and, finally, on simulated snow profiles. Our simple approach well reproduced the additional stress obtained by finite element simulations for the simplified profiles - except that the sequence of layering in the slab cannot be replicated. Once implemented into the classical skier stability index and applied to manually observed snow profiles classified into different stability classes, the classification accuracy improved with the new approach. Finally, we implemented the refined skier stability index into the 1-D snow cover model SNOWPACK. For the two study cases presented in this paper, this approach showed promising results even though further verification is still needed. In the future, we intend to implement the proposed approach for describing skier-induced stress within a multi-layered snowpack into more complex models which take into account not only failure initiation but also crack propagation.

Bacterial and dye penetration through interim restorations used during endodontic treatment of molar teeth.

PubMed

Chailertvanitkul, Pattama; Abbott, Paul V; Riley, Thomas V; Sooksuntisakoonchai, Namchai

2009-07-01

The purpose of this study was to investigate the association between dye and bacterial penetration through interim restorations used during endodontic treatment. Sixty-four extracted human teeth were used, with 2 teeth each as positive and negative controls. Endodontic access with a mesio-occluso-distal cavity was prepared. Palatal cusps of maxillary molars and buccal cusps of mandibular molars were removed. Cotton was placed over the canals and covered with Cavit. Thirty teeth were restored with Ketac Silver (KS) and 30 with KS reinforced with a stainless steel band (KSSB). Samples were submersed in India ink mixed with brain heart infusion broth containing Streptococcus gordonii. After 3 months of simulated chewing, structural integrity and dye and bacterial penetration were assessed. Positive controls had both dye and bacterial penetration. Negative controls had no dye or bacterial penetration. All KS restorations debonded, whereas 18 KSSB restorations (60%) debonded. KS restorations were 1.67 times more likely to debond than KSSB restorations (Fisher exact test). KS was 1.3 times more likely to have dye penetration than KSSB (Fisher exact test) and 3 times more likely to have bacterial penetration, although not statistically significant (chi(2) test). Overall, 88.3% of specimens had dye penetration, and 20% had bacterial penetration. This 68.3% difference indicated no association between dye and bacterial penetration (exact McNemar test). Stainless steel bands helped maintain structural integrity of KS restorations under masticatory function. Bands helped prevent dye penetration but not bacterial penetration. There was no association between dye and bacterial penetration.

Altered Tnnt3 characterizes selective weakness of fast fibers in mice overexpressing FSHD region gene 1 (FRG1)

PubMed Central

Sancisi, Valentina; Germinario, Elena; Esposito, Alessandra; Morini, Elisabetta; Peron, Samantha; Moggio, Maurizio; Tomelleri, Giuliano; Danieli-Betto, Daniela

2013-01-01

Facioscapulohumeral muscular dystrophy (FSHD), a common hereditary myopathy, is characterized by atrophy and weakness of selective muscle groups. FSHD is considered an autosomal dominant disease with incomplete penetrance and unpredictable variability of clinical expression within families. Mice overexpressing FRG1 (FSHD region gene 1), a candidate gene for this disease, develop a progressive myopathy with features of the human disorder. Here, we show that in FRG1-overexpressing mice, fast muscles, which are the most affected by the dystrophic process, display anomalous fast skeletal troponin T (fTnT) isoform, resulting from the aberrant splicing of the Tnnt3 mRNA that precedes the appearance of dystrophic signs. We determine that muscles of FRG1 mice develop less strength due to impaired contractile properties of fast-twitch fibers associated with an anomalous MyHC-actin ratio and a reduced sensitivity to Ca2+. We demonstrate that the decrease of Ca2+ sensitivity of fast-twitch fibers depends on the anomalous troponin complex and can be rescued by the substitution with the wild-type proteins. Finally, we find that the presence of aberrant splicing isoforms of TNNT3 characterizes dystrophic muscles in FSHD patients. Collectively, our results suggest that anomalous TNNT3 profile correlates with the muscle impairment in both humans and mice. On the basis of these results, we propose that aberrant fTnT represents a biological marker of muscle phenotype severity and disease progression. PMID:24305066

The influence of self-assembling supramolecular structures on the passive membrane transport of ion-paired molecules.

PubMed

Benaouda, F; Brown, M B; Shah, B; Martin, G P; Jones, S A

2012-12-15

Weak ion-ion interactions, such as those associated with ion-pair formation, are difficult to isolate and characterise in the liquid state, but they have the potential to alter significantly the physicochemical behaviour of molecules in solution. The aim of this work was to gain a better understanding of how ion-ion interactions influenced passive membrane transport. The test system was composed of propylene (PG) glycol, water and diclofenac diethylamine (DDEA). Infrared spectroscopy was employed to determine the nature of the DDEA ion-pair interactions and the drug-vehicle association. Passive transport was assessed using homogeneous synthetic membranes. Solution-state analysis demonstrated that the ion-pair was unperturbed by vehicle composition changes, but the solvent-DDEA interactions were modified. DDEA-PG/water hydrogen bonding influenced the ion-pair solubility (X(dev)) and the solvent interactions slowed transport rate in PG-rich vehicles (0.84±0.05 μg cm(-2) h(-1), at ln(X(dev))=0.57). In water-rich co-solvents, the presence of strong water structuring facilitated a significant increase (p<0.05) in transmembrane penetration rate (e.g. 4.33±0.92 μg cm(-2) h(-1), at ln(X(dev))=-0.13). The data demonstrates that weak ion-ion interactions can result in the embedding of polar entities within a stable solvent complex and spontaneous supramolecular assembly should be considered when interpreting transmembrane transport processes of ionic molecules. Copyright © 2012 Elsevier B.V. All rights reserved.

Weakly-Correlated Nature of Ferromagnetism in Nonsymmorphic CrO2 Revealed by Bulk-Sensitive Soft-X-Ray ARPES

NASA Astrophysics Data System (ADS)

Bisti, F.; Rogalev, V. A.; Karolak, M.; Paul, S.; Gupta, A.; Schmitt, T.; Güntherodt, G.; Eyert, V.; Sangiovanni, G.; Profeta, G.; Strocov, V. N.

2017-10-01

Chromium dioxide CrO2 belongs to a class of materials called ferromagnetic half-metals, whose peculiar aspect is that they act as a metal in one spin orientation and as a semiconductor or insulator in the opposite one. Despite numerous experimental and theoretical studies motivated by technologically important applications of this material in spintronics, its fundamental properties such as momentum-resolved electron dispersions and the Fermi surface have so far remained experimentally inaccessible because of metastability of its surface, which instantly reduces to amorphous Cr2O3 . In this work, we demonstrate that direct access to the native electronic structure of CrO2 can be achieved with soft-x-ray angle-resolved photoemission spectroscopy whose large probing depth penetrates through the Cr2O3 layer. For the first time, the electronic dispersions and Fermi surface of CrO2 are measured, which are fundamental prerequisites to solve the long debate on the nature of electronic correlations in this material. Since density functional theory augmented by a relatively weak local Coulomb repulsion gives an exhaustive description of our spectroscopic data, we rule out strong-coupling theories of CrO2 . Crucial for the correct interpretation of our experimental data in terms of the valence-band dispersions is the understanding of a nontrivial spectral response of CrO2 caused by interference effects in the photoemission process originating from the nonsymmorphic space group of the rutile crystal structure of CrO2 .

Oceanographic structure drives the assembly processes of microbial eukaryotic communities.

PubMed

Monier, Adam; Comte, Jérôme; Babin, Marcel; Forest, Alexandre; Matsuoka, Atsushi; Lovejoy, Connie

2015-03-17

Arctic Ocean microbial eukaryote phytoplankton form subsurface chlorophyll maximum (SCM), where much of the annual summer production occurs. This SCM is particularly persistent in the Western Arctic Ocean, which is strongly salinity stratified. The recent loss of multiyear sea ice and increased particulate-rich river discharge in the Arctic Ocean results in a greater volume of fresher water that may displace nutrient-rich saltier waters to deeper depths and decrease light penetration in areas affected by river discharge. Here, we surveyed microbial eukaryotic assemblages in the surface waters, and within and below the SCM. In most samples, we detected the pronounced SCM that usually occurs at the interface of the upper mixed layer and Pacific Summer Water (PSW). Poorly developed SCM was seen under two conditions, one above PSW and associated with a downwelling eddy, and the second in a region influenced by the Mackenzie River plume. Four phylogenetically distinct communities were identified: surface, pronounced SCM, weak SCM and a deeper community just below the SCM. Distance-decay relationships and phylogenetic structure suggested distinct ecological processes operating within these communities. In the pronounced SCM, picophytoplanktons were prevalent and community assembly was attributed to water mass history. In contrast, environmental filtering impacted the composition of the weak SCM communities, where heterotrophic Picozoa were more numerous. These results imply that displacement of Pacific waters to greater depth and increased terrigenous input may act as a control on SCM development and result in lower net summer primary production with a more heterotroph dominated eukaryotic microbial community.

A naturally occurring nucleotide polymorphism in the orf2/folc promoter is associated with Streptococcus suis virulence.

PubMed

de Greeff, Astrid; Buys, Herma; Wells, Jerry M; Smith, Hilde E

2014-11-12

Streptococcus suis is a major problem in the swine industry causing meningitis, arthritis and pericarditis in piglets. Pathogenesis of S. suis is poorly understood. We previously showed that introduction of a 3 kb genomic fragment from virulent serotype 2 strain 10 into a weakly virulent serotype 2 strain S735, generated a hypervirulent isolate. The 3 kb genomic fragment contained two complete open reading frames (ORF) in an operon-structure of which one ORF showed similarity to folylpolyglutamate synthetase, whereas the function of the second ORF could not be predicted based on database searches for protein similarity. In this study we demonstrate that introduction of orf2 from strain 10 into strain S735 is sufficient to dramatically increase the virulence of S735 in pigs. This increase in virulence could not be associated with changes in pro-inflammatory responses of porcine blood mononucleated cells in response to S. suis in vitro. Sequence analysis of the orf2-folC-operon of S. suis isolates 10 and S735 revealed an SNP in the -35 region of the putative promoter sequence of the operon, as well as several SNPs resulting in amino acid substitutions in the ORF2 protein. Transcript levels of orf2 and folC were significantly higher in the virulent strain 10 than in the weakly virulent strain S735 and in vitro mutagenesis of the orf2 promoter confirmed that this was due to a SNP in the predicted -35 region upstream of the orf2 promoter. In this study, we demonstrated that the stronger promoter was present in all virulent and highly virulent S. suis isolates included in our study. This highlights a correlation between high orf2 expression and virulence. Conversely, the weaker promoter was present in isolates known to be weakly pathogenic or non-pathogenic. In summary, we demonstrate the importance of orf2 in the virulence of S. suis.

Seroprevalence and molecular characterization of Chlamydia abortus in frozen fetal and placental tissues of aborting ewes in northeastern Algeria.

PubMed

Hireche, Sana; Ababneh, Mustafa Mohammed Kheir; Bouaziz, Omar; Boussena, Sabrina

2016-02-01

Enzootic abortion of ewes is one of the most serious health problems in sheep flocks worldwide. It has a significant economic impact because abortion, decrease in milk production and weak lambs. Besides, the bacteria is zoonotic. A cross-sectional study was conducted to determine the seroprevalence and risk factors associated with Chlamydia abortus infection in 552 ewes in Constantine using a C. abortus-specific indirect ELISA kit. Chlamydial DNA was investigated in ten ovine fetuses and eight placentas using PCR- restriction fragment length polymorphism (RFLP) and DNA sequencing. The study concluded that 7.2 % of ewes were seropositive and 33.3 % of sheep flocks had at least one seropositive ewe. Adjacent farmworker visits (OR = 7.667, 95 % CI (OR) = 2.307; 27.203) was defined as a risk factor. Deliveries of weak lambs (OR = 2.920, 95 % CI (OR) = 1.022; 8.342) and septicemia in lambs (OR = 9.971, 95 % CI (OR) = 2.383; 41.713) were significantly associated with chlamydial infection. PCR-RFLP analysis revealed positive signals to C. abortus in six fetuses and four placentas. Sequencing of the omp2 gene revealed that the Algerian strain is 96 % similar with C. abortus FAS strain. C. abortus plays a major role in abortion in northeastern Algeria. Appropriate control measures must be implemented to reduce economic losses and to avoid human contamination.

Phylogeographic pattern suggests a general northeastward dispersal in the distribution of Machilus pauhoi in South China

PubMed Central

Zhu, Qin; Liao, Bo-Yong; Li, Pei; Li, Jun-Cheng; Deng, Xiao-Mei; Chen, Xiao-Yang

2017-01-01

Machilus pauhoi Kanehira is an important timber species in China. A provenance trial was recently set up to evaluate the growth performance of trees from different localities, with the aim of designing seed transfer guidelines. Here, we tested twelve nuclear microsatellite markers derived from other species of the Lauraceae family and investigated population genetic structure in M. pauhoi. Both the number of observed alleles per locus (Na) and the polymorphic information content (PIC) significantly decreased against the latitude, but showed an insignificant decrease against the longitude. Heterozygosity (Ho) and gene diversity (h) exhibited a weak correlation with geographic location. Private alleles were present in multiple populations, and a moderate level of population genetic differentiation was detected (Gst = 0.1691). The joint pattern of genetic diversity (Na, PIC, Ho, and h) suggests that general northeastward dispersal led to the current distribution of M. pauhoi. Significant but weak effects of isolation-by-distance (IBD) occurred, implicating the mountain ranges as the major barrier to gene flow. Both STRUCTURE and hierarchical clustering analyses showed three distinct groups of populations related to the physical connectivity among mountain ranges. A priority in designing genetic conservation should be given to the populations at the southwest side of the species’ distribution. This conservation strategy can also be combined with the pattern of adaptive genetic variation from the provenance trial for comprehensive genetic resource management of native M. pauhoi. PMID:28886133

Fibrin sealant for closure of mucosal penetration at the cardia during peroral endoscopic myotomy: A retrospective study at a single center

PubMed Central

Zhang, Wen-Gang; Linghu, En-Qiang; Li, Hui-Kai

2017-01-01

AIM To assess the efficacy and safety of fibrin sealant for closure of mucosal penetration at the cardia during peroral endoscopic myotomy (POEM). METHODS Twenty-four patients who underwent POEM and experienced mucosal injury of the cardia during the procedure were retrospectively identified. Of the 24 patients, 21 had mucosal penetration and 3 had only slight mucosal damage without penetration. The 21 patients with mucosal penetration received fibrin sealant for closure at the site of penetration. Penetration-related characteristics, treatment, and recovery were reviewed for all 21 patients to assess the efficacy and safety of fibrin sealant for closure of mucosal penetration at the cardia. Clinical data, including general characteristics, procedure-related parameters, Eckardt scores, lower esophageal sphincter pressures (LESP), and esophagogastroduodenoscopy (EGD) results, were analyzed to determine their influence on treatment success after mucosal penetration during POEM. RESULTS All 21 patients had a solitary mucosal penetration in the cardia (12 in esophageal region of the cardia, 9 in the stomach region of the cardia, and 1 in both the esophageal and stomach regions). Twelve had a hole-like penetration and 9 had a linear penetration. For those with a hole-like penetration, the mean size was 0.14 cm2 (0.02-0.32 cm2). For those with a linear penetration, the median size was 0.37 cm (0.10-1.00 cm). Closure of the mucosal penetration using fibrin sealant was performed successfully in all 21 patients (two patients required 5 mL fibrin sealant, and the remaining 19 patients required 2.5 mL). Two patients had a nasogastric tube placed for five days after POEM; the remaining 19 patients were kept fasting for 3 d. All 21 patients were discharged after a median of 5 d (range: 5-7 d) postoperatively. During a median 42 mo (range: 9-62 mo) follow-up, all 21 patients with a mucosal penetration successfully healed without the occurrence of infection, ulcer, or esophagitis. Furthermore, the median LESP decreased from 31.9 mmHg (range: 21.9-67.1 mmHg) preoperatively to 20.3 mmHg (range: 6.0-41.0 mmHg) postoperatively (P < 0.05). The median preoperative and postoperative Eckardt scores were 5.0 (range; 4-10) and 1.0 (range: 0-4), respectively (P < 0.05). Of the 21 patients with mucosal penetration, symptom remission, which is defined as a postoperative Eckardt score ≤ 3, was achieved in 20 patients (95.2%) indicating that mucosal penetration did not influence the success of POEM treatment if closed successfully using fibrin sealant. CONCLUSION Fibrin sealant is safe and effective for closure of mucosal penetration during POEM. Mucosal penetrations do not appear to influence the treatment success of POEM if closed successfully using fibrin sealant. Additional studies regarding the feasibility, efficacy, and safety of fibrin sealant for closure of larger mucosal penetrations is warranted. PMID:28321165

Polymorphism at codon 36 of the p53 gene.

PubMed

Felix, C A; Brown, D L; Mitsudomi, T; Ikagaki, N; Wong, A; Wasserman, R; Womer, R B; Biegel, J A

1994-01-01

A polymorphism at codon 36 in exon 4 of the p53 gene was identified by single strand conformation polymorphism (SSCP) analysis and direct sequencing of genomic DNA PCR products. The polymorphic allele, present in the heterozygous state in genomic DNAs of four of 100 individuals (4%), changes the codon 36 CCG to CCA, eliminates a FinI restriction site and creates a BccI site. Including this polymorphism there are four known polymorphisms in the p53 coding sequence.

Rare genetic variants and the risk of cancer.

PubMed

Bodmer, Walter; Tomlinson, Ian

2010-06-01

There are good reasons to expect that common genetic variants do not explain all of the inherited risk of the common cancers, not least of these being the relatively low proportion of familial relative risk that common cancer SNPs currently explain. One promising source of the unexplained risk is rare, low-penetrance genetic variants, a class that ranges from low-frequency polymorphisms (allele frequency < 5%) through subpolymorphic variants (frequency 0.1-1.0%) to very low frequency or 'private' variants with frequencies of 0.1% or less. Examples of rare cancer variants include breast cancer susceptibility loci CHEK2, BRIP1 and PALB2. There are considerable challenges associated with the discovery and testing of rare predisposition alleles, many of which are illustrated by the issues associated with variants of unknown significance in the Mendelian cancer predisposition genes. However, whilst cost constraints remain, the technological barriers to rare variant discovery and large-scale genotyping no longer exist. If each individual carries many disease-causing rare variants, the so-called missing heritability of cancer might largely be explained. Whether or not rare variants do end up filling the heritability gap, it is imperative to look for them along side common variants.

A novel duplication polymorphism in the FANCA promoter and its association with breast and ovarian cancer.

PubMed

Thompson, Ella; Dragovic, Rebecca L; Stephenson, Sally-Anne; Eccles, Diana M; Campbell, Ian G; Dobrovic, Alexander

2005-04-29

The FANCA gene is one of the genes in which mutations lead to Fanconi anaemia, a rare autosomal recessive disorder characterised by congenital abnormalities, bone marrow failure, and predisposition to malignancy. FANCA is also a potential breast and ovarian cancer susceptibility gene. A novel allele was identified which has a tandem duplication of a 13 base pair sequence in the promoter region. We screened germline DNA from 352 breast cancer patients, 390 ovarian cancer patients and 256 normal controls to determine if the presence of either of these two alleles was associated with an increased risk of breast or ovarian cancer. The duplication allele had a frequency of 0.34 in the normal controls. There was a non-significant decrease in the frequency of the duplication allele in breast cancer patients. The frequency of the duplication allele was significantly decreased in ovarian cancer patients. However, when malignant and benign tumours were considered separately, the decrease was only significant in benign tumours. The allele with the tandem duplication does not appear to modify breast cancer risk but may act as a low penetrance protective allele for ovarian cancer.

A novel duplication polymorphism in the FANCA promoter and its association with breast and ovarian cancer

PubMed Central

Thompson, Ella; Dragovic, Rebecca L; Stephenson, Sally-Anne; Eccles, Diana M; Campbell, Ian G; Dobrovic, Alexander

2005-01-01

The FANCA gene is one of the genes in which mutations lead to Fanconi anaemia, a rare autosomal recessive disorder characterised by congenital abnormalities, bone marrow failure, and predisposition to malignancy. FANCA is also a potential breast and ovarian cancer susceptibility gene. A novel allele was identified which has a tandem duplication of a 13 base pair sequence in the promoter region. Methods We screened germline DNA from 352 breast cancer patients, 390 ovarian cancer patients and 256 normal controls to determine if the presence of either of these two alleles was associated with an increased risk of breast or ovarian cancer. Results The duplication allele had a frequency of 0.34 in the normal controls. There was a non-significant decrease in the frequency of the duplication allele in breast cancer patients. The frequency of the duplication allele was significantly decreased in ovarian cancer patients. However, when malignant and benign tumours were considered separately, the decrease was only significant in benign tumours. Conclusion The allele with the tandem duplication does not appear to modify breast cancer risk but may act as a low penetrance protective allele for ovarian cancer. PMID:15860134

Genetic Susceptibility to Lymphoma

PubMed Central

Skibola, Christine F.; Curry, John D.; Nieters, Alexandra

2010-01-01

BACKGROUND Genetic susceptibility studies of lymphoma may serve to identify at risk populations and to elucidate important disease mechanisms. METHODS This review considered all studies published through October 2006 on the contribution of genetic polymorphisms in the risk of lymphoma. RESULTS Numerous studies implicate the role of genetic variants that promote B-cell survival and growth with increased risk of lymphoma. Several reports including a large pooled study by InterLymph, an international consortium of non-Hodgkin lymphoma (NHL) case-control studies, found positive associations between variant alleles in TNF -308G>A and IL10 -3575T>A genes and risk of diffuse large B-cell lymphoma. Four studies reported positive associations between a GSTT1 deletion and risk of Hodgkin and non-Hodgkin lymphoma. Genetic studies of folate-metabolizing genes implicate folate in NHL risk, but further studies that include folate and alcohol assessments are needed. Links between NHL and genes involved in energy regulation and hormone production and metabolism may provide insights into novel mechanisms implicating neuro- and endocrine-immune cross-talk with lymphomagenesis, but will need replication in larger populations. CONCLUSIONS Numerous studies suggest that common genetic variants with low penetrance influence lymphoma risk, though replication studies will be needed to eliminate false positive associations. PMID:17606447

Genetic profile for five common variants associated with age-related macular degeneration in densely affected families: a novel analytic approach

PubMed Central

Sobrin, Lucia; Maller, Julian B; Neale, Benjamin M; Reynolds, Robyn C; Fagerness, Jesen A; Daly, Mark J; Seddon, Johanna M

2010-01-01

About 40% of the genetic variance of age-related macular degeneration (AMD) can be explained by a common variation at five common single-nucleotide polymorphisms (SNPs). We evaluated the degree to which these known variants explain the clustering of AMD in a group of densely affected families. We sought to determine whether the actual number of risk alleles at the five variants in densely affected families matched the expected number. Using data from 322 families with AMD, we used a simulation strategy to generate comparison groups of families and determined whether their genetic profile at the known AMD risk loci differed from the observed genetic profile, given the density of disease observed. Overall, the genotypic loads for the five SNPs in the families did not deviate significantly from the genotypic loads predicted by the simulation. However, for a subset of densely affected families, the mean genotypic load in the families was significantly lower than the expected load determined from the simulation. Given that these densely affected families may harbor rare, more penetrant variants for AMD, linkage analyses and resequencing targeting these families may be an effective approach to finding additional implicated genes. PMID:19844262

Exome Sequencing Identifies Potential Risk Variants for Mendelian Disorders at High Prevalence in Qatar

PubMed Central

Rodriguez-Flores, Juan L.; Fakhro, Khalid; Hackett, Neil R.; Salit, Jacqueline; Fuller, Jennifer; Agosto-Perez, Francisco; Gharbiah, Maey; Malek, Joel A.; Zirie, Mahmoud; Jayyousi, Amin; Badii, Ramin; Al-Marri, Ajayeb Al-Nabet; Chouchane, Lotfi; Stadler, Dora J.; Hunter-Zinck, Haley; Mezey, Jason G.; Crystal, Ronald G.

2013-01-01

Exome sequencing of families of related individuals has been highly successful in identifying genetic polymorphisms responsible for Mendelian disorders. Here, we demonstrate the value of the reverse approach, where we use exome sequencing of a sample of unrelated individuals to analyze allele frequencies of known causal mutations for Mendelian diseases. We sequenced the exomes of 100 individuals representing the three major genetic subgroups of the Qatari population (Q1 Bedouin, Q2 Persian-South Asian, Q3 African) and identified 37 variants in 33 genes with effects on 36 clinically significant Mendelian diseases. These include variants not present in 1000 Genomes and variants at high frequency when compared to 1000 Genomes populations. Several of these Mendelian variants were only segregating in one Qatari subpopulation, where the observed subpopulation specificity trends were confirmed in an independent population of 386 Qataris. Pre-marital genetic screening in Qatar tests for only 4 out of the 37, such that this study provides a set of Mendelian disease variants with potential impact on the epidemiological profile of the population that could be incorporated into the testing program if further experimental and clinical characterization confirms high penetrance. PMID:24123366

Utilizing Structures of CYP2D6 and BACE1 Complexes To Reduce Risk of Drug–Drug Interactions with a Novel Series of Centrally Efficacious BACE1 Inhibitors

DOE PAGES

Brodney, Michael A.; Beck, Elizabeth M.; Butler, Christopher R.; ...

2015-03-17

In recent years, the first generation of β-secretase (BACE1) inhibitors advanced into clinical development for the treatment of Alzheimer’s disease (AD). However, the alignment of drug-like properties and selectivity remains a major challenge. Here in this paper, we describe the discovery of a novel class of potent, low clearance, CNS penetrant BACE1 inhibitors represented by thioamidine 5. Further profiling suggested that a high fraction of the metabolism (>95%) was due to CYP2D6, increasing the potential risk for victim-based drug–drug interactions (DDI) and variable exposure in the clinic due to the polymorphic nature of this enzyme. To guide future design, wemore » solved crystal structures of CYP2D6 complexes with substrate 5 and its corresponding metabolic product pyrazole 6, which provided insight into the binding mode and movements between substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal structures, we designed and synthesized analogues with reduced risk for DDI, central efficacy, and improved hERG therapeutic margins.« less

Utilizing Structures of CYP2D6 and BACE1 Complexes To Reduce Risk of Drug–Drug Interactions with a Novel Series of Centrally Efficacious BACE1 Inhibitors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Brodney, Michael A.; Beck, Elizabeth M.; Butler, Christopher R.

In recent years, the first generation of β-secretase (BACE1) inhibitors advanced into clinical development for the treatment of Alzheimer’s disease (AD). However, the alignment of drug-like properties and selectivity remains a major challenge. Here in this paper, we describe the discovery of a novel class of potent, low clearance, CNS penetrant BACE1 inhibitors represented by thioamidine 5. Further profiling suggested that a high fraction of the metabolism (>95%) was due to CYP2D6, increasing the potential risk for victim-based drug–drug interactions (DDI) and variable exposure in the clinic due to the polymorphic nature of this enzyme. To guide future design, wemore » solved crystal structures of CYP2D6 complexes with substrate 5 and its corresponding metabolic product pyrazole 6, which provided insight into the binding mode and movements between substrate/inhibitor complexes. Guided by the BACE1 and CYP2D6 crystal structures, we designed and synthesized analogues with reduced risk for DDI, central efficacy, and improved hERG therapeutic margins.« less

A mechanism for exon skipping caused by nonsense or missense mutations in BRCA1 and other genes.

PubMed

Liu, H X; Cartegni, L; Zhang, M Q; Krainer, A R

2001-01-01

Point mutations can generate defective and sometimes harmful proteins. The nonsense-mediated mRNA decay (NMD) pathway minimizes the potential damage caused by nonsense mutations. In-frame nonsense codons located at a minimum distance upstream of the last exon-exon junction are recognized as premature termination codons (PTCs), targeting the mRNA for degradation. Some nonsense mutations cause skipping of one or more exons, presumably during pre-mRNA splicing in the nucleus; this phenomenon is termed nonsense-mediated altered splicing (NAS), and its underlying mechanism is unclear. By analyzing NAS in BRCA1, we show here that inappropriate exon skipping can be reproduced in vitro, and results from disruption of a splicing enhancer in the coding sequence. Enhancers can be disrupted by single nonsense, missense and translationally silent point mutations, without recognition of an open reading frame as such. These results argue against a nuclear reading-frame scanning mechanism for NAS. Coding-region single-nucleotide polymorphisms (cSNPs) within exonic splicing enhancers or silencers may affect the patterns or efficiency of mRNA splicing, which may in turn cause phenotypic variability and variable penetrance of mutations elsewhere in a gene.

Data and animal management software for large-scale phenotype screening.

PubMed

Ching, Keith A; Cooke, Michael P; Tarantino, Lisa M; Lapp, Hilmar

2006-04-01

The mouse N-ethyl-N-nitrosourea (ENU) mutagenesis program at the Genomics Institute of the Novartis Research Foundation (GNF) uses MouseTRACS to analyze phenotype screens and manage animal husbandry. MouseTRACS is a Web-based laboratory informatics system that electronically records and organizes mouse colony operations, prints cage cards, tracks inventory, manages requests, and reports Institutional Animal Care and Use Committee (IACUC) protocol usage. For efficient phenotype screening, MouseTRACS identifies mutants, visualizes data, and maps mutations. It displays and integrates phenotype and genotype data using likelihood odds ratio (LOD) plots of genetic linkage between genotype and phenotype. More detailed mapping intervals show individual single nucleotide polymorphism (SNP) markers in the context of phenotype. In addition, dynamically generated pedigree diagrams and inventory reports linked to screening results summarize the inheritance pattern and the degree of penetrance. MouseTRACS displays screening data in tables and uses standard charts such as box plots, histograms, scatter plots, and customized charts looking at clustered mice or cross pedigree comparisons. In summary, MouseTRACS enables the efficient screening, analysis, and management of thousands of animals to find mutant mice and identify novel gene functions. MouseTRACS is available under an open source license at http://www.mousetracs.sourceforge.net.

No Major Host Genetic Risk Factor Contributed to A(H1N1)2009 Influenza Severity

PubMed Central

Garcia-Etxebarria, Koldo; Bracho, María Alma; Galán, Juan Carlos; Pumarola, Tomàs; Castilla, Jesús; Ortiz de Lejarazu, Raúl; Rodríguez-Dominguez, Mario; Quintela, Inés; Bonet, Núria; Garcia-Garcerà, Marc; Domínguez, Angela; González-Candelas, Fernando; Calafell, Francesc

2015-01-01

While most patients affected by the influenza A(H1N1) pandemic experienced mild symptoms, a small fraction required hospitalization, often without concomitant factors that could explain such a severe course. We hypothesize that host genetic factors could contribute to aggravate the disease. To test this hypothesis, we compared the allele frequencies of 547,296 genome-wide single nucleotide polymorphisms (SNPs) between 49 severe and 107 mild confirmed influenza A cases, as well as against a general population sample of 549 individuals. When comparing severe vs. mild influenza A cases, only one SNP was close to the conventional p = 5×10−8. This SNP, rs28454025, sits in an intron of the GSK233 gene, which is involved in a neural development, but seems not to have any connections with immunological or inflammatory functions. Indirectly, a previous association reported with CD55 was replicated. Although sample sizes are low, we show that the statistical power in our design was sufficient to detect highly-penetrant, quasi-Mendelian genetic factors. Hence, and assuming that rs28454025 is likely to be a false positive, no major genetic factor was detected that could explain poor influenza A course. PMID:26379185