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1. Pulmonary artery to aorta ratio is associated with cardiac structure and functional changes in mild-to-moderate COPD

Author

Cuttica MJ, Bhatt SP, Rosenberg SR, Beussink L, Shah SJ, Smith LJ, Dransfield MT, and Kalhan R

Subjects
COPD, diastolic dysfunction, pulmonary artery, Diseases of the respiratory system, RC705-779
Abstract

Michael J Cuttica,1 Surya P Bhatt,2 Sharon R Rosenberg,1 Lauren Beussink,3 Sanjiv J Shah,3 Lewis J Smith,1 Mark T Dransfield,2 Ravi Kalhan1 1Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, 2Division of Pulmonary, Allergy & Critical Care Medicine, University of Alabama-Birmingham, Birmingham, AL, 3Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Background: The ratio of the diameter of the pulmonary artery (PA) to the diameter of the aorta (PA:A) on computed tomography (CT) imaging is associated with both COPD exacerbation and pulmonary hypertension. The mechanisms of PA enlargement in COPD are poorly understood. Methods: In this retrospective, single center study we evaluated pulmonary function, CT scans, right heart catheterizations, and echocardiography in 88 subjects with mild-to-moderately severe COPD. A sensitivity analysis was performed in 43 subjects in whom CT scan and echocardiogram were performed within 50 days of each other. To evaluate the association between PA:A ratio and echocardiographic parameters and hemodynamics, we performed simple correlations and multivariable linear regression analysis adjusting for lung function, age, sex, race, and diastolic function. Results: All subjects had preserved left ventricular (LV) systolic function (LV ejection fraction 62.7%±5.5%). Among them, 56.8% had evidence of diastolic dysfunction. There was no association between PA:A ratio and the presence of diastolic dysfunction. In a multivariable model, PA:A ratio was associated with right ventricular (RV) chamber size (β=0.015; P

Published
2017

2. PAI‐1 gain‐of‐function genotype, factors increasing PAI‐1 levels, and airway obstruction: The GALA II Cohort

Author

Sherenian, MG, Cho, SH, Levin, A, Min, J‐Y, Oh, SS, Hu, D, Galanter, J, Sen, S, Huntsman, S, Eng, C, Rodriguez‐Santana, JR, Serebrisky, D, Avila, PC, Kalhan, R, Smith, LJ, Borrell, LN, Seibold, MA, Williams, L Keoki, Burchard, EG, and Kumar, R

Subjects
Biomedical and Clinical Sciences, Immunology, Lung, Genetics, Prevention, Clinical Research, Asthma, Aetiology, 2.1 Biological and endogenous factors, Respiratory, Adolescent, Adult, Airway Obstruction, Alleles, Asthma, Occupational, Child, Cohort Studies, Ethnicity, Female, Gain of Function Mutation, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Male, Odds Ratio, Plasminogen Activator Inhibitor 1, Polymorphism, Single Nucleotide, Respiratory Function Tests, Young Adult, asthma, epidemiology, PAI-1, pediatrics, Nutrition and Dietetics, Public Health and Health Services, Allergy
Abstract

BackgroundPAI-1 gain-of-function variants promote airway fibrosis and are associated with asthma and with worse lung function in subjects with asthma.ObjectiveWe sought to determine whether the association of a gain-of-function polymorphism in plasminogen activator inhibitor-1 (PAI-1) with airway obstruction is modified by asthma status, and whether any genotype effect persists after accounting for common exposures that increase PAI-1 level.MethodsWe studied 2070 Latino children (8-21y) with genotypic and pulmonary function data from the GALA II cohort. We estimated the relationship of the PAI-1 risk allele with FEV1/FVC by multivariate linear regression, stratified by asthma status. We examined the association of the polymorphism with asthma and airway obstruction within asthmatics via multivariate logistic regression. We replicated associations in the SAPPHIRE cohort of African Americans (n=1056). Secondary analysis included the effect of the at-risk polymorphism on postbronchodilator lung function.ResultsThere was an interaction between asthma status and the PAI-1 polymorphism on FEV1 /FVC (P=.03). The gain-of-function variants, genotypes (AA/AG), were associated with lower FEV1 /FVC in subjects with asthma (β=-1.25, CI: -2.14,-0.35, P=.006), but not in controls. Subjects with asthma and the AA/AG genotypes had a 5% decrease in FEV1 /FVC (P

Published
2017

3. Legacy ExtraGalactic UV Survey with The Hubble Space Telescope: Stellar Cluster Catalogs and First Insights Into Cluster Formation and Evolution in NGC 628∗ ∗ Based on observations obtained with the NASA/ESA Hubble Space Telescope, at the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., under NASA contract NAS 5-26555.

Author

Adamo, A, Ryon, JE, Messa, M, Kim, H, Grasha, K, Cook, DO, Calzetti, D, Lee, JC, Whitmore, BC, Elmegreen, BG, Ubeda, L, Smith, LJ, Bright, SN, Runnholm, A, Andrews, JE, Fumagalli, M, Gouliermis, DA, Kahre, L, Nair, P, Thilker, D, Walterbos, R, Wofford, A, Aloisi, A, Ashworth, G, Brown, TM, Chandar, R, Christian, C, Cignoni, M, Clayton, GC, Dale, DA, de Mink, SE, Dobbs, C, Elmegreen, DM, Evans, AS, Gallagher, JS, Grebel, EK, Herrero, A, Hunter, DA, Johnson, KE, Kennicutt, RC, Krumholz, MR, Lennon, D, Levay, K, Martin, C, Nota, A, Östlin, G, Pellerin, A, Prieto, J, Regan, MW, Sabbi, E, Sacchi, E, Schaerer, D, Schiminovich, D, Shabani, F, Tosi, M, Van Dyk, SD, and Zackrisson, E

Subjects
galaxies: individual, galaxies: star clusters: general, galaxies: star formation, stars: formation, Astronomical and Space Sciences, Atomic, Molecular, Nuclear, Particle and Plasma Physics, Physical Chemistry (incl. Structural), Astronomy & Astrophysics
Published
2017

4. P177 129Xe MRI phenotyping and longitudinal change in patients with asthma and/or COPD and normal pulmonary function tests

Author

Marshall, H, primary, Smith, LJ, additional, Biancardi, A, additional, Collier, GJ, additional, Chan, HF, additional, Capener, D, additional, Bray, J, additional, Jakymelen, D, additional, Saunders, L, additional, Astley, J, additional, Tahir, BA, additional, Munro, R, additional, Rodgers, O, additional, Ball, J, additional, Hughes, PJC, additional, Rajaram, S, additional, Swift, AJ, additional, Stewart, NJ, additional, Norquay, G, additional, Brook, ML, additional, Armstrong, L, additional, Hardaker, L, additional, Hughes, R, additional, and Wild, JM, additional

Published
2023
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5. P176 Bronchodilator response discordance in patients with asthma and/or COPD assessed by 129Xe-MRI and spirometry

Author

Smith, LJ, primary, Marshall, H, additional, Biancardi, A, additional, Collier, GJ, additional, Chan, HF, additional, Capener, D, additional, Bray, J, additional, Jakymelen, D, additional, Saunders, L, additional, Astley, J, additional, Tahir, BA, additional, Munro, R, additional, Rodgers, O, additional, Ball, J, additional, Hughes, PJC, additional, Rajaram, S, additional, Swift, AJ, additional, Stewart, NJ, additional, Norquay, G, additional, Brook, ML, additional, Armstrong, L, additional, Hardaker, L, additional, Hughes, R, additional, and Wild, JM, additional

Published
2023
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6. Pathways and transformations of dissolved methane and dissolved inorganic carbon in Arctic tundra watersheds: Evidence from analysis of stable isotopes

Author

Throckmorton, HM, Heikoop, JM, Newman, BD, Altmann, GL, Conrad, MS, Muss, JD, Perkins, GB, Smith, LJ, Torn, MS, Wullschleger, SD, and Wilson, CJ

Subjects
Meteorology & Atmospheric Sciences, Atmospheric Sciences, Geochemistry, Oceanography
Abstract

Arctic soils contain a large pool of terrestrial C and are of interest due to their potential for releasing significant carbon dioxide (CO2) and methane (CH4) to the atmosphere. Due to substantial landscape heterogeneity, predicting ecosystem-scale CH4 and CO2 production is challenging. This study assessed dissolved inorganic carbon (DIC = Σ (total) dissolved CO2) and CH4 in watershed drainages in Barrow, Alaska as critical convergent zones of regional geochemistry, substrates, and nutrients. In July and September of 2013, surface waters and saturated subsurface pore waters were collected from 17 drainages. Based on simultaneous DIC and CH4 cycling, we synthesized isotopic and geochemical methods to develop a subsurface CH4 and DIC balance by estimating mechanisms of CH4 and DIC production and transport pathways and oxidation of subsurface CH4. We observed a shift from acetoclastic (July) toward hydrogenotropic (September) methanogenesis at sites located toward the end of major freshwater drainages, adjacent to salty estuarine waters, suggesting an interesting landscape-scale effect on CH4 production mechanism. The majority of subsurface CH4 was transported upward by plant-mediated transport and ebullition, predominantly bypassing the potential for CH4 oxidation. Thus, surprisingly, CH4 oxidation only consumed approximately 2.51 ± 0.82% (July) and 0.79 ± 0.79% (September) of CH4 produced at the frost table, contributing to

Published
2015

7. Legacy extragalactic UV survey (LEGUS) with the hubble space telescope. I. Survey description

Author

Calzetti, D, Lee, JC, Sabbi, E, Adamo, A, Smith, LJ, Andrews, JE, Ubeda, L, Bright, SN, Thilker, D, Aloisi, A, Brown, TM, Chandar, R, Christian, C, Cignoni, M, Clayton, GC, Da Silva, R, De Mink, SE, Dobbs, C, Elmegreen, BG, Elmegreen, DM, Evans, AS, Fumagalli, M, Gallagher, JS, Gouliermis, DA, Grebel, EK, Herrero, A, Hunter, DA, Johnson, KE, Kennicutt, RC, Kim, H, Krumholz, MR, Lennon, D, Levay, K, Martin, C, Nair, P, Nota, A, Östlin, G, Pellerin, A, Prieto, J, Regan, MW, Ryon, JE, Schaerer, D, Schiminovich, D, Tosi, M, Van Dyk, SD, Walterbos, R, Whitmore, BC, and Wofford, A

Abstract

© 2015. The American Astronomical Society. All rights reserved. The Legacy ExtraGalactic UV Survey (LEGUS) is a Cycle 21 Treasury program on the Hubble Space Telescope aimed at the investigation of star formation and its relation with galactic environment in nearby galaxies, from the scales of individual stars to those of ∼kiloparsec-size clustered structures. Five-band imaging from the nearultraviolet to the I band with the Wide-Field Camera 3 (WFC3), plus parallel optical imaging with the Advanced Camera for Surveys (ACS), is being collected for selected pointings of 50 galaxies within the local 12 Mpc. The filters used for the observations with the WFC3 are F275W (λ2704 A˚), F336W(λ3355 A˚), F438W(λ4325 A˚), F555W(λ5308 A˚), and F814W(ë8024 A˚); the parallel observations with the ACS use the filters F435W (λ4328 A˚), F606W(λ5921 A˚), and F814W(λ8057 A˚). The multiband images are yielding accurate recent (≲50 Myr) star formation histories from resolved massive stars and the extinction-corrected ages and masses of star clusters and associations. The extensive inventories of massive stars and clustered systems will be used to investigate the spatial and temporal evolution of star formation within galaxies. This will, in turn, inform theories of galaxy evolution and improve the understanding of the physical underpinning of the gas-star formation relation and the nature of star formation at high redshift. This paper describes the survey, its goals and observational strategy, and the initial scientific results. Because LEGUS will provide a reference survey and a foundation for future observations with the James Webb Space Telescope and with ALMA, a large number of data products are planned for delivery to the community.

Published
2015

8. Genome-wide association analysis identifies six new loci associated with forced vital capacity

Author

Loth, DW, Artigas, MS, Gharib, SA, Wain, LV, Franceschini, N, Koch, B, Pottinger, TD, Smith, AV, Duan, Q, Oldmeadow, C, Lee, MK, Strachan, DP, James, AL, Huffman, JE, Vitart, V, Ramasamy, A, Wareham, NJ, Kaprio, J, Wang, XQ, Trochet, H, Kähönen, M, Flexeder, C, Albrecht, E, Lopez, LM, De Jong, K, Thyagarajan, B, Alves, AC, Enroth, S, Omenaas, E, Joshi, PK, Fall, T, Viñuela, A, Launer, LJ, Loehr, LR, Fornage, M, Li, G, Wilk, JB, Tang, W, Manichaikul, A, Lahousse, L, Harris, TB, North, KE, Rudnicka, AR, Hui, J, Gu, X, Lumley, T, Wright, AF, Hastie, ND, Campbell, S, Kumar, R, Pin, I, Scott, RA, Pietiläinen, KH, Surakka, I, Liu, Y, Holliday, EG, Schulz, H, Heinrich, J, Davies, G, Vonk, JM, Wojczynski, M, Pouta, A, Johansson, A, Wild, SH, Ingelsson, E, Rivadeneira, F, Völzke, H, Hysi, PG, Eiriksdottir, G, Morrison, AC, Rotter, JI, Gao, W, Postma, DS, White, WB, Rich, SS, Hofman, A, Aspelund, T, Couper, D, Smith, LJ, Psaty, BM, Lohman, K, Burchard, EG, Uitterlinden, AG, Garcia, M, Joubert, BR, McArdle, WL, Musk, AB, Hansel, N, Heckbert, SR, Zgaga, L, Van Meurs, JBJ, Navarro, P, Rudan, I, Oh, YM, Redline, S, Jarvis, DL, Zhao, JH, Rantanen, T, O'Connor, GT, and Ripatti, S

Subjects
Developmental Biology, Medical and Health Sciences, Biological Sciences
Abstract

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10-8) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.© 2014 Nature America, Inc. All rights reserved.

Published
2014

9. Dynamical mass of a star cluster in M83: a test of fibre-fed multi-object spectroscopy

Author

Moll, SL, de Grijs, R, Anders, P, Crowther, PA, Larsen, SS, Smith, LJ, and Zwart, SF Portegies

Subjects
Astrophysics
Abstract

(Abridged) Aims: We obtained VLT/FLAMES+UVES high-resolution, fibre-fed spectroscopy (FFS) of five young massive clusters in M83 (NGC 5236). This forms the basis of a pilot study testing the feasibility of using FFS to measure the velocity dispersions of several clusters simultaneously, in order to determine their dynamical masses; Methods: We adopted two methods for determining the velocity dispersion of the star clusters: cross-correlating the cluster spectrum with the template spectra and minimising a chi^2 value between the cluster spectrum and the broadened template spectra. Cluster 805 in M83 was chosen as a control to test the reliability of the method, through a comparison with the results obtained from a standard echelle VLT/UVES spectrum obtained by Larsen & Richtler; Results: We find no dependence of the velocity dispersions measured for a cluster on the choice of red giant versus red supergiant templates, nor on the method adopted. We measure a velocity dispersion of sigma_los = 10.2+/-1.1 km/s for cluster 805 from our FFS. Our FLAMES+UVES velocity dispersion measurement gives M_vir = (6.6+/-1.7)e5 M_sun, consistent with previous results. This is a factor of ~3 greater than the cluster's photometric mass, indicating a lack of virial equilibrium. However, based on its effective star formation efficiency, the cluster is likely to virialise, and may survive for a Hubble time, in the absence of external disruptive forces; Conclusions: We find that reliable velocity dispersions can be determined from FFS. The advantages of observing several clusters simultaneously outweighs the difficulty of accurate galaxy background subtraction, providing that the targets are chosen to provide sufficient S/N ratios, and are much brighter than the galaxy background., Comment: 10 pages, 4 figures, accepted by A&A

Published
2008
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14. CLusters in the UV as EngineS (CLUES). I. Survey Presentation and FUV Spectral Analysis of the Stellar Light

Author

Sirressi, M, Adamo, A, Hayes, M, Osborne, S, Hernandez, S, Chisholm, J, Messa, M, Smith, L, Aloisi, A, Wofford, A, Fox, A, Mizener, A, Usher, C, Bik, A, Calzetti, D, Sabbi, E, Schinnerer, E, Ostlin, G, Grasha, K, Cignoni, M, Fumagalli, M, Smith, LJ, Fox, AJ, Sirressi, M, Adamo, A, Hayes, M, Osborne, S, Hernandez, S, Chisholm, J, Messa, M, Smith, L, Aloisi, A, Wofford, A, Fox, A, Mizener, A, Usher, C, Bik, A, Calzetti, D, Sabbi, E, Schinnerer, E, Ostlin, G, Grasha, K, Cignoni, M, Fumagalli, M, Smith, LJ, and Fox, AJ

Abstract

The CLusters in the Uv as EngineS (CLUES) survey is a Cosmic Origins Spectrograph (COS) campaign aimed at acquiring the 1130-1770 angstrom rest-frame spectroscopy of very young (<20 Myr) and massive (>10(4) M (circle dot)) star clusters in galaxies that are part of the Hubble treasury program Legacy ExtraGalactic UV Survey. In this first paper of a series, we describe the CLUES sample consisting of 20 young star clusters and report their physical properties as derived by both multiwavelength photometry and far-UV (FUV) spectroscopy with Hubble Space Telescope. Thanks to the synergy of the two different data sets, we build a coherent picture of the diverse stellar populations found in each region (with sizes of 40-160 pc). We associate the FUV-brightest stellar population to the central targeted star cluster and the other modeled population to the diffuse stars that are included in the COS aperture. We observe better agreement between photometric and spectroscopic ages for star clusters younger than 5 Myr. For clusters older than 5 Myr, photometry and spectroscopy measurements deviate, with the latter producing older ages, due to the degeneracy of photometric models. FUV spectroscopy enables us to better constrain the stellar metallicities, a parameter that optical colors are insensitive to. Finally, the derived E(B - V) are quite similar, with a tendency for FUV spectroscopy to favor solutions with higher extinctions. The recovered masses are in agreement within a factor of 2 for all of the clusters.

Published
2022

16. P136 The relationship between symptoms and functional physiological outcomes in survivors of severe COVID-19 pneumonia

Author

Zamani, P, primary, Mehrotra, S, additional, Griffin, D, additional, D’Cruz, RF, additional, Mathew, S, additional, Byrne, A, additional, Choudhury, M, additional, Fleming, T, additional, Cho, P, additional, Walder, D, additional, Madula, R, additional, Smith, LJ, additional, Macedo, P, additional, Norton, S, additional, Birring, S, additional, Patel, A, additional, Patel, I, additional, Perrin, F, additional, Waller, M, additional, and Jolley, CJ, additional

Published
2021
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18. P135 Clinical, functional and psychological characteristics of survivors of severe COVID-19 pneumonia: a comparison of outcomes from the first and second waves

Author

Griffin, D, primary, D’Cruz, RF, additional, Mehrotra, S, additional, Zamani, P, additional, Perrin, F, additional, Byrne, A, additional, Matthew, S, additional, Choudhury, M, additional, Smith, LJ, additional, Madula, R, additional, Cho, P, additional, Patrick, T, additional, Walder, D, additional, Periselneris, J, additional, Kavanagh, J, additional, Lee, K, additional, McNulty, W, additional, Macedo, P, additional, Warwick, G, additional, Heitmann, A, additional, Lyall, R, additional, Galloway, J, additional, Norton, S, additional, Birring, S, additional, Patel, A, additional, Patel, I, additional, Waller, M, additional, and Jolley, CJ, additional

Published
2021
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20. Germline mutation in POLR2A: a heterogeneous, multi-systemic developmental disorder characterized by transcriptional dysregulation.

Author

Hansen, AW, Arora, P, Khayat, MM, Smith, LJ, Lewis, AM, Rossetti, LZ, Jayaseelan, J, Cristian, I, Haynes, D, DiTroia, S, Meeks, N, Delgado, MR, Rosenfeld, JA, Pais, L, White, SM, Meng, Q, Pehlivan, D, Liu, P, Gingras, M-C, Wangler, MF, Muzny, DM, Lupski, JR, Kaplan, CD, Gibbs, RA, Hansen, AW, Arora, P, Khayat, MM, Smith, LJ, Lewis, AM, Rossetti, LZ, Jayaseelan, J, Cristian, I, Haynes, D, DiTroia, S, Meeks, N, Delgado, MR, Rosenfeld, JA, Pais, L, White, SM, Meng, Q, Pehlivan, D, Liu, P, Gingras, M-C, Wangler, MF, Muzny, DM, Lupski, JR, Kaplan, CD, and Gibbs, RA

Abstract

De novo germline variation in POLR2A was recently reported to associate with a neurodevelopmental disorder. We report twelve individuals harboring putatively pathogenic de novo or inherited variants in POLR2A, detail their phenotypes, and map all known variants to the domain structure of POLR2A and crystal structure of RNA polymerase II. Affected individuals were ascertained from a local data lake, pediatric genetics clinic, and an online community of families of affected individuals. These include six affected by de novo missense variants (including one previously reported individual), four clinical laboratory samples affected by missense variation with unknown inheritance-with yeast functional assays further supporting altered function-one affected by a de novo in-frame deletion, and one affected by a C-terminal frameshift variant inherited from a largely asymptomatic mother. Recurrently observed phenotypes include ataxia, joint hypermobility, short stature, skin abnormalities, congenital cardiac abnormalities, immune system abnormalities, hip dysplasia, and short Achilles tendons. We report a significantly higher occurrence of epilepsy (8/12, 66.7%) than previously reported (3/15, 20%) (p value = 0.014196; chi-square test) and a lower occurrence of hypotonia (8/12, 66.7%) than previously reported (14/15, 93.3%) (p value = 0.076309). POLR2A-related developmental disorders likely represent a spectrum of related, multi-systemic developmental disorders, driven by distinct mechanisms, converging at a single locus.

Published
2021

21. The severe epilepsy syndromes of infancy: A population-based study

Author

Howell, KB, Freeman, JL, Mackay, MT, Fahey, MC, Archer, J, Berkovic, SF, Chan, E, Dabscheck, G, Eggers, S, Hayman, M, Holberton, J, Hunt, RW, Jacobs, SE, Kornberg, AJ, Leventer, RJ, Mandelstam, S, McMahon, JM, Mefford, HC, Panetta, J, Riseley, J, Rodriguez-Casero, V, Ryan, MM, Schneider, AL, Smith, LJ, Stark, Z, Wong, F, Yiu, EM, Scheffer, IE, Harvey, AS, Howell, KB, Freeman, JL, Mackay, MT, Fahey, MC, Archer, J, Berkovic, SF, Chan, E, Dabscheck, G, Eggers, S, Hayman, M, Holberton, J, Hunt, RW, Jacobs, SE, Kornberg, AJ, Leventer, RJ, Mandelstam, S, McMahon, JM, Mefford, HC, Panetta, J, Riseley, J, Rodriguez-Casero, V, Ryan, MM, Schneider, AL, Smith, LJ, Stark, Z, Wong, F, Yiu, EM, Scheffer, IE, and Harvey, AS

Abstract

OBJECTIVE: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes. METHODS: A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined. RESULTS: Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS-like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS-like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe-profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe-profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS-like," or "unifocal epilepsy" had severe-profound delay, and only two of 64 (3%) were deceased. SIGNIFICANCE: Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initi

Published
2021

22. A passive, objective and implicit measure of recognition memory in Alzheimer’s Disease using Fastball memory assessment

Author

Coulthard E, Smith Lj, milton a, and Stothart G

Subjects
Text mining, business.industry, Computer science, Measure (physics), Artificial intelligence, Disease, business, Machine learning, computer.software_genre, computer, Recognition memory
Abstract

Earlier diagnosis of Alzheimer’s disease (AD) requires biomarkers sensitive to the structural and functional changes associated with the disease. While considerable progress has been made in the development of structural biomarkers, functional biomarkers of early cognitive change are still needed. We present Fastball, a new EEG method for the passive, objective and implicit measurement of recognition memory, that requires no behavioural response or comprehension of the task. Younger adults (aged M=24 SD=6), older adults (aged M=74 SD=4) and AD patients aged M=79 SD=10), (n=20 per group) completed the Fastball task, lasting just under three minutes. The task required the passive viewing of rapidly presented images and assessed their spontaneous ability to differentiate between images on the basis of previous exposure, i.e. old/new. Participants were not instructed to attend to previously seen images and provided no behavioural response. Following the Fastball task, they completed a cued recall task to measure their explicit recognition of previously seen stimuli. AD patients showed significantly impaired recognition memory compared to healthy older adult controls in the Fastball task (p

Published
2020

23. S125 Quantitative CT and hyperpolarised 129-xenon diffusion-weighted MRI in interstitial lung disease

Author

Eaden, JA, primary, Chan, H-F, additional, Hughes, PJC, additional, Weatherly, ND, additional, Austin, M, additional, Smith, LJ, additional, Lithgow, J, additional, Rajaram, S, additional, Swift, AJ, additional, Renshaw, SA, additional, Karwoski, RA, additional, Bartholmai, BJ, additional, Leonard, CT, additional, Skeoch, S, additional, Chaudhuri, N, additional, Parker, GJM, additional, Bianchi, SM, additional, and Wild, JM, additional

Published
2019
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24. Abstracts

Author

Hurtado, Cristina, Bradley, John, Burns, Andrew R., Bradley, John, Karkouti, Keyvan, Hurtado, Cristina, Burns, Andrew R., Bradley, John, Anderson, Rob, Abrahamson, Simon D., Mazer, C. David, Hung, O. R., Comeau, L., Fisher, Joseph A., Tessler, Janet, Rucker, Joshua, Mathicu, Alix, Murray-Foster, Sara, Tz-Chong Chou, Chi-Yuan Li, Tsuda, Takako, Tabuchi, Akihiko, Sasano, Hiroshi, Kiriyama, Masanobu, Okada, Akinori, Hayano, Junichiro, Takeuchi, Akinori, Katsuya, Hirotada, Tousignant, Claude P., Mazer, C. David, Tousignant, Claude P., Mazer, C. David, Ling, Elizabeth, Arellano, Ramiro, Dowd, N., Karski, J., Cheng, D., Carroll-Munro, J., Rose, D. K., Mazer, C. O., Cohen, M. M., Wigglesworth, D., McKay, William P. S., Teskey, Robert J., Militzer, Julio, Kember, Guy, Blanchet, Travis, Gregson, Peter H., Howells, Steven R., Robblee, James A., Breen, Terrance W., Dierenfield, Laura, McNeil, Tacie, Breen, Terrance W., McNeil, Tacie, Dierenfield, Laura, Nicholson, Donna J., Kowalski, Stephen E., Hamilton, G. Andrew, Meyers, Michael P., Serrette, Carl, Duke, Peter C., Custeau, Ingrid, Martin, Rend, Larabée, Sonia, Pirlet, Martine, Pilote, Madeleine, Tetrault, Jean-Pierre, Tsui, Ban C. H., Gupta, Sunil, Finucane, Brendan, Weisbrod, Mitchell J., Chan, Vincent W. S., Kaszas, Z., Dragomir, C., Cohen, M. R., Gandhi, M., Clanachan, A. S., Finegan, B. A., Isaac, Lisa, Splinter, William M., Hall, L. A., Gould, H. M., Rhine, E. J., Bergeron, Lyne, Girard, Michel, Drolet, Pierre, Truong, Hong Hanh Le, Boucher, Carl, Vézina, Daniel, Lessard, Martin R., Gourdeau, Marie, Trépanier, Claude A., Yang, Theresa, Breen, Terrance W., Macarthur, Alison, Chouinard, P., Fugère, F., Ruel, M., Tarkkila, Pekka, Silvasti, Marja, Tuominen, Marjatta, Svartling, Nils, Rosenberg, Per H., Bond, David M., Rudan, John F., Adams, Michael A., Tsang, Brian K., Keahey, Wanda, Gagliese, Lucia, Jackson, Marla, Ritvo, Paul, Wowk, Adarose, Sandler, Alan N., Katz, Joel, Laffey, J. G., Boylan, J. F., Badner, Neal H., Komar, Wendy E., Bond, David M., Cherry, R. A., Spadafora, S. M., Butler, R. J., McHardy, Fiona, Fortier, Joanne, Chung, Frances, Marshall, Scott, Krishnathas, Ananthan, Wong, Jean, Chung, Frances, Ritchie, Ewan, McHardy, Fiona, Marshall, Scott, Fortier, Joanne, Meikle, Andrew, Avery, Nicole, van Vlymen, Janet, Parlow, Joel L., Sinclair, David, Chung, Frances, Mezei, Gabor, Jin, Fengling, Chung, Frances, Norris, Andrew, Ganeshram, Tharini, MacLeod, Bernard A., Azmudéh, Aliréza, Franciosi, Luigi G., Ries, Craig R., Schwarz, Stephan K. W., McKay, William PS, Gregson, Peter H., McKay, Benjamin W. S., Blanchet, Travis, Meuret, Pascal, Bonhomme, Vincent, Plourde, Gilles, Fiset, Pierre, Backman, Stevens B., Vesely, Alex, Takeuchi, Akinori, Sommer, Leeor, Rucker, Joshua, Greenwald, Joel, Lavine, Elana, Iscoe, Steve, Volgyesi, George, Fedorko, Ludwik, Fisher, Joseph, Lobato, Emilio B., Sulek, Cheri A., Davies, Laurie K., Gearen, Peter F., Bellemare, François, Donati, François, Couture, Jacques, Joo, Hwan S., Rose, D. K., Kapoor, Sunil, Shayan, Shahriar, Karkouti, Keyvan, LeDez, Kenneth M., Au, Jim, Tucker, John H., Redmond, Edwin B., Gadag, V., Penney, Catherine, Hare, Gregory M. T., Lee, Timothy D. G., Hirsch, Gregory M., Yang, Fan, Troncy, Eric, Blaise, Gilbert, Naito, Yoshiyuki, Arisawa, Shoji, Ide, Masahiro, Nakano, Susumu, Yamazaki, Kazuo, Kawamura, Takae, Nara, Noriko, Wakusawa, Reiji, Inada, Katsuya, Hudson, Robert J., Singh, Karanbir, Harding, Gary A., Henderson, Blair T., Thomson, Ian R., Harding, Gary A., Hudson, Robert J., Thomson, Ian R., Thomson, Ian R., Singh, Karanbir, Hudson, Robert J., Wherrett, Christopher G., Miller, Donald R., Giachino, Alan A., Turek, Michelle A., Rody, Kelly, Vaghadia, H., Chan, V., Ganapathy, S., Lui, A., McKenna, J., Zimmer, K., Schwarz, Stephan K. W., MacLeod, Bernard A., Ries, Craig R., Franciosi, Luigi G., Regan, William D., Davidson, Ross G., Nevin, Krista, Escobedo, Sergio, Mitmaker, E., Tessler, M. J., Kardash, K., Kleiman, S. J., Rossignol, M., Kahn, L., Baxter, F., Dauphin, A., Goldsmith, C., Jackson, P., McChesney, J., Miller, J., Takeuchi, L., Young, E., Klubien, Kristine, Bandi, Edith, Carli, Franco, Dattilo, Kathleen, Tong, Doris, Bhandari, Mohit, Carli, Franco, Klubien, Kristine, Mazza, Louise, Wykes, Linda, Sommer, L. Z., Rucker, J., Veseley, A., Levene, E., Greenwald, Y., Volgyesi, G., Fedorko, L., Iscoe, S., Fisher, J. A., Tian, Guo-Feng, Baker, Andrew J., Reinders, F. X., Baker, A. J., Moulton, R. J., Brown, J. I. M., Schlichter, L., Troncy, Eric, Van Tulder, Laurence, Carignan, Stéphane, Prénovault, Julie, Collet, Jean-Paul, Shapiro, Stan, Guimond, Jean-Gilles, Blait, Louis, Ducruet, Thierry, Francœur, Martin, Charbonneau, Marc, Cousineau, Guy, Blaise, Gilbert, Wong, Daniel R., McCall, Michele, Walsh, Fergus, Kurian, Regina, Keith, Mary, Sole, Michael J., Jeejeebhoy, Kursheed N., Mazer, C. David, Whitten, E., Norman, P. H., Aucar, J. A., Coveler, L. A., Solgonick, Rodney M., Bastien, Y., Mazer, Bruce, Lihara, Koji, Orser, Beverley A., Tymianski, Michael, Finucane, Brendan T., Zaman, Nuzhat, Kashkari, Ibrahim, Tawfik, Soheir, Tarn, Yun K., Slinger, Peter D., McRae, Karen, Winton, Timothy, Sandier, Alan N., Zamora, J. E., Salpeter, Mary Jane, Bai, Donglin, MacDonald, John F., Orser, Beverley A., Mayson, Kelly, Gofton, Ed, Chambers, Keith, Belo, Susan E., Kay, J. Colin, Mazer, C. David, Hall, Sean R. R., Wang, Louie, Milne, Brian, Loomis, Chris, Tsang, Brian K., He, Zhi, Wougchanapai, Wichai, Ho, Ing K., Eichhorn, John H., Tsang, Brian K., Ma, Tangeng, Wongchanapai, Wichai, He, Zhi, Ho, Ing K., Eicnhorn, John H., Tsang, Brian K., Wongchanapai, Wichai, He, Zhi, Ho, Ing K., Eichhorn, John H., Murphy, Damian B., Murphy, M. B., Bonhomme, Vincent, Meuret, Pascal, Backman, Steven B., Plourde, Gilles, Fiset, Pierre, Stein, Reuben D., Backman, Steven B., Collier, Brian, Polosa, Canio, Li, Chi-Yuan, Chou, Tz-Chong, Wang, Jia-Yi, Fuller, John, Butler, Ronald, Spadafora, Salvatore, Donen, Neil, Brownell, Laurence, Donen, Neil, Brownell, Laurence, Shysh, Sandy, Carter, Keith, Eagle, Chris, Devito, Isabella, Halpern, Stephen, Devitt, J. Hugh, Yee, Doreen A., deLacy, John L., Oxorn, Donald C., Morris, Gary F., Yip, Raymond W., Gregoret-Quinn, M. G., Seal, R. F., Smith, LJ., Jones, A. B., Tang, C., Clanachan, A. S., Gallant, B. J., Nadwidny, L. A., Goresky, Gerald V., Cowtan, Tara, Bridge, Hilary S., Montgomery, Carolyne J., Kennedy, Ross A., Merrick, Pamela M., Yamashita, M., Wada, K., LeMay, Sylvie, Hardy, Jean-François, Morgan, Pamela, Halpern, Steven, Evers, Jana, Ronaldson, P., Rose, D. K., Dexter, F., Cohen, M. M., Wigglesworth, D., Writer, Desmond, Muir, Holly, Shukla, Romesh, Nunn, Rob, Scovil, John, Pridham, Jeremy, Rosaeg, Ola, Sandier, Allan, Morley-Foster, Patricia, Lucy, Simon, Crone, Lesley-Ann, Zimmer, Karen, Wilson, Deborah J., Heid, Robert, Douglas, M. Joanne, Rurak, Dan W., Fabrizi, Anna, Crochetière, Chantal T., Roy, Louise, Villeneuve, Edith, Lortie, Louise, Katsiris, Sandra, Leighton, Barbara, Halpern, Stephen, Wilson, Donna, Kronberg, Jean, Swica, Leszek, Midgley, Janet, Nunn, Robert, Muir, Holly, Shukla, Romesh, Smith, Bruce, Rooney, Michael E., Campbell, David C., Riben, Celina M., Crone, Lesley-Ann, Yip, Ray W., Halpern, Stephen, Halpern, Stephen, MacDonell, Jo, Levine, Tracey, and Wilson, Donna

Published
1998
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26. Validation of molecular simulation: an overview of issues

Author

van Gunsteren, WF, Daura, X, Hansen, N, Mark, AE, Oostenbrink, C, Riniker, S, and Smith, LJ

Abstract

Computer simulation of molecular systems enables structure―energy―function relationships of molecular processes to be described at the sub-atomic, atomic, supraatomic or supra-molecular level and plays an increasingly important role in chemistry, biology and physics. To interpret results of such simulations appropriately, the quality of the calculated properties must be evaluated. This depends on (1) the degrees of freedom simulated, (2) the accuracy of the molecular model, interaction function or force field, (3) the equations of motion, integration scheme or other method used to sample degrees of freedom as well as the degree of sampling, (4) the boundary conditions, (5) the simulation software, and (6) how the software is used. When validating simulations against values of experimental observable quantities Qexp, one must also consider (1) the accuracy of Qexp, (2) the accuracy of the function Q(r N) used to calculate Q based on a molecular configuration r N of N particles,(3) the sensitivity of the function Q(r N)to the configuration r N, (4) the relative time scales of the simulation and experiment, (5) the degree to which the calculated and experimental properties are equivalent, and (6) the degree to which the system simulated matches the experimental conditions. Validation by comparison between experiment and simulation is seldom straightforward. Experimental data is limited in scope and generally corresponds to averages over both time and space. A critical analysis of the various factors that influence the apparent degree of (dis)agreement between simulations and experiment is presented and illustrated using examples from the literature. What can be done to enhance the validation of molecular simulation is also discussed.

Published
2017

27. Legacy ExtraGalactic UV Survey with The $\textit{Hubble Space Telescope}$: Stellar Cluster Catalogs and First Insights Into Cluster Formation and Evolution in NGC 628

Author

Adamo, A, Ryon, JE, Messa, M, Kim, H, Grasha, K, Cook, DO, Calzetti, D, Lee, JC, Whitmore, BC, Elmegreen, BG, Ubeda, L, Smith, LJ, Bright, SN, Runnholm, A, Andrews, JE, Fumagalli, M, Gouliermis, DA, Kahre, L, Nair, P, Thilker, D, Walterbos, R, Wofford, A, Aloisi, A, Ashworth, G, Brown, TM, Chandar, R, Christian, C, Cignoni, M, Clayton, GC, Dale, DA, Mink, SED, Dobbs, C, Elmegreen, DM, Evans, AS, III, JSG, Grebel, EK, Herrero, A, Hunter, DA, Johnson, KE, Kennicutt, RC, Krumholz, MR, Lennon, D, Levay, K, Martin, C, Nota, A, Ostlin, G, Pellerin, A, Prieto, J, Regan, MW, Sabbi, E, Sacchi, E, Schaerer, D, Shabani, DSF, Tosi, M, Dyk, SDV, Zackrisson, E, Kennicutt, Robert [0000-0001-5448-1821], and Apollo - University of Cambridge Repository

Subjects
stars: formation, galaxies: individual (NGC 628, M74), Astrophysics::High Energy Astrophysical Phenomena, galaxies: star formation, galaxies: star clusters: general, Astrophysics::Solar and Stellar Astrophysics, Astrophysics::Cosmology and Extragalactic Astrophysics, Astrophysics::Galaxy Astrophysics
Abstract

We report the large effort that is producing comprehensive high-level young star cluster (YSC) catalogs for a significant fraction of galaxies observed with the Legacy ExtraGalactic UV Survey (LEGUS) Hubble treasury program. We present the methodology developed to extract cluster positions, verify their genuine nature, produce multiband photometry (from NUV to NIR), and derive their physical properties via spectral energy distribution fitting analyses. We use the nearby spiral galaxy NGC 628 as a test case for demonstrating the impact that LEGUS will have on our understanding of the formation and evolution of YSCs and compact stellar associations within their host galaxy. Our analysis of the cluster luminosity function from the UV to the NIR finds a steepening at the bright end and at all wavelengths suggesting a dearth of luminous clusters. The cluster mass function of NGC 628 is consistent with a power-law distribution of slopes $\sim -2$ and a truncation of a few times 105 ${M}_{\odot }$. After their formation, YSCs and compact associations follow different evolutionary paths. YSCs survive for a longer time frame, confirming their being potentially bound systems. Associations disappear on timescales comparable to hierarchically organized star-forming regions, suggesting that they are expanding systems. We find mass-independent cluster disruption in the inner region of NGC 628, while in the outer part of the galaxy there is little or no disruption. We observe faster disruption rates for low mass (≤104 ${M}_{\odot }$) clusters, suggesting that a mass-dependent component is necessary to fully describe the YSC disruption process in NGC 628., A.A. acknowledges partial support from the Swedish Royal Academy. G.A. acknowledges support from the Science and Technology Facilities Council (ST/L00075X/1 and ST/M503472/1). C.D. acknowledges funding from the FP7 ERC starting grant LOCALSTAR (no. 280104). M.F. acknowledges support by the Science and Technology Facilities Council (grant number ST/L00075X/1). D.A.G. kindly acknowledges financial support by the German Research Foundation (DFG) through program GO 1659/3-2. A.H. thanks the Spanish MINECO for grant AYA2015-68012-c2-1. These observations are associated with program # 13364. Support for program # 13364 was provided by NASA through a grant from the Space Telescope Science Institute. Based on observations obtained with the NASA/ESA Hubble Space Telescope, at the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., under NASA contract NAS 5-26555.

Published
2017
Full Text
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28. Legacy ExtraGalactic UV Survey with The Hubble Space Telescope: Stellar Cluster Catalogs and First Insights Into Cluster Formation and Evolution in NGC 628

Author

Adamo, A, Adamo, A, Ryon, JE, Messa, M, Kim, H, Grasha, K, Cook, DO, Calzetti, D, Lee, JC, Whitmore, BC, Elmegreen, BG, Ubeda, L, Smith, LJ, Bright, SN, Runnholm, A, Andrews, JE, Fumagalli, M, Gouliermis, DA, Kahre, L, Nair, P, Thilker, D, Walterbos, R, Wofford, A, Aloisi, A, Ashworth, G, Brown, TM, Chandar, R, Christian, C, Cignoni, M, Clayton, GC, Dale, DA, de Mink, SE, Dobbs, C, Elmegreen, DM, Evans, AS, Gallagher, JSIII, Grebel, EK, Herrero, A, Hunter, DA, Johnson, KE, Kennicutt, RC, Krumholz, MR, Lennon, D, Levay, K, Martin, C, Nota, A, Ostlin, G, Pellerin, A, Prieto, J, Regan, MW, Sabbi, E, Sacchi, E, Schaerer, D, Schiminovich, D, Shabani, F, Tosi, M, Van Dyk, SD, Zackrisson, E, Adamo, A, Adamo, A, Ryon, JE, Messa, M, Kim, H, Grasha, K, Cook, DO, Calzetti, D, Lee, JC, Whitmore, BC, Elmegreen, BG, Ubeda, L, Smith, LJ, Bright, SN, Runnholm, A, Andrews, JE, Fumagalli, M, Gouliermis, DA, Kahre, L, Nair, P, Thilker, D, Walterbos, R, Wofford, A, Aloisi, A, Ashworth, G, Brown, TM, Chandar, R, Christian, C, Cignoni, M, Clayton, GC, Dale, DA, de Mink, SE, Dobbs, C, Elmegreen, DM, Evans, AS, Gallagher, JSIII, Grebel, EK, Herrero, A, Hunter, DA, Johnson, KE, Kennicutt, RC, Krumholz, MR, Lennon, D, Levay, K, Martin, C, Nota, A, Ostlin, G, Pellerin, A, Prieto, J, Regan, MW, Sabbi, E, Sacchi, E, Schaerer, D, Schiminovich, D, Shabani, F, Tosi, M, Van Dyk, SD, and Zackrisson, E

Published
2017

29. Characterisation of protein unfolding by NMR diffusion measurements

Author

Jones, JA, Wilkins, DK, Smith, LJ, and Dobson, CM

Subjects
Quantitative Biology::Biomolecules
Abstract

The characterisation of non-native states of proteins is a key problem in studies of protein folding. Complete characterisation of these states requires a description of both local and global properties, including molecular dimensions. Here we present results from pulsed field gradient experiments designed to compare the effective hydrodynamic radii of a protein in native and non-native states. Measurements performed on lysozyme indicate that the effective hydrodynamic radius increases by 38±1% on unfolding in urea, a result completely consistent with a recent study by small-angle X-ray scattering.

Published
2016

31. Chemical shifts in denatured proteins: resonance assignments for denatured ubiquitin and comparisons with other denatured proteins

Author

Peti, W., Smith, Lj, Redfield, C., and Harald Schwalbe

Abstract

Chemical shift assignment is reported for the protein ubiquitin denatured in 8M urea at pH 2. The variations in 15N chemical shifts of three different proteins (ubiquitin, disulfide reduced, carboxymethylated lysozyme, all-Ala-alpha-lactalbumin), all without disulfides and denatured in 8M urea at pH 2 are compared to 'random coil shifts' of small model peptides (Braun et al., 1994) and to the averaged native chemical shifts taken from the BMRB database. Both parameterizations show a remarkable agreement with the averaged measured 15N chemical shifts in the three denatured proteins. Detailed analysis of these experimental 15N chemical shifts provides an estimate of the influence of nearest neighbors and conformational preferences on the chemical shift and provides a direct means to identify non-random structural preferences in denatured proteins.

Published
2016

37. Space Systems Cross-Compatibility

Author

Esper J, Smith LJ, Herrel L, Kobayashi C, Mendham P, Razzano E, Birrane E., D'ERRICO, Marco, Esper, J, Smith, Lj, D'Errico, Marco, Herrel, L, Kobayashi, C, Mendham, P, Razzano, E, and Birrane, E.

Published
2013

38. Comparison of the backbone dynamics of wild-type Hydrogenobacter thermophilus cytochrome c 552 and its b-type variant

Author

Tozawa, K, Ferguson, SJ, Redfield, C, and Smith, LJ

Abstract

© 2015 The Author(s). Cytochrome c 552 from the thermophilic bacterium Hydrogenobacter thermophilus is a typical c-type cytochrome which binds heme covalently via two thioether bonds between the two heme vinyl groups and two cysteine thiol groups in a CXXCH sequence motif. This protein was converted to a b-type cytochrome by substitution of the two cysteine residues by alanines (Tomlinson and Ferguson in Proc Natl Acad Sci USA 97:5156-5160, 2000a). To probe the significance of the covalent attachment of the heme in the c-type protein, 15N relaxation and hydrogen exchange studies have been performed for the wild-type and b-type proteins. The two variants share very similar backbone dynamic properties, both proteins showing high 15N order parameters in the four main helices, with reduced values in an exposed loop region (residues 18-21), and at the C-terminal residue Lys80. Some subtle changes in chemical shift and hydrogen exchange protection are seen between the wild-type and b-type variant proteins, not only for residues at and neighbouring the mutation sites, but also for some residues in the heme binding pocket. Overall, the results suggest that the main role of the covalent linkages between the heme group and the protein chain must be to increase the stability of the protein.

Published
2015

39. Structure of Alkaloid 275A, a Novel 1-Azabicyclo[5.3.0]decane from a Dendrobatid Frog, Dendrobates lehmanni: Synthesis of the Tetrahydrodiastereomers

Author

T. F. Spande, H. M. Garraffo, Smith Lj, Jain P, Zottig Ve, Daly Jw, and Tappey H. Jones

Subjects
Chromatography, Gas, Ketone, Stereochemistry, Pharmaceutical Science, Stereoisomerism, Chemical synthesis, Analytical Chemistry, Bridged Bicyclo Compounds, chemistry.chemical_compound, Alkaloids, Azepane, Salientia, Drug Discovery, Animals, Pharmacology, chemistry.chemical_classification, Aza Compounds, Molecular Structure, biology, Bicyclic molecule, Spectrum Analysis, Alkaloid, Organic Chemistry, Diastereomer, biology.organism_classification, Complementary and alternative medicine, chemistry, Molecular Medicine, Anura
Abstract

The principal alkaloid 275A in skins of the Colombian poison frog Dendrobates lehmanni has been identified as the pyrrolo[1,2-a]azepane (1), the first occurrence in nature of this "izidine" system. Tetrahydro-1 proved identical to one of the four synthetic diastereomers, 2a--2d, thereby establishing that 1 has the 5Z,10E relative stereochemistry. Alkaloid 1 is often accompanied by other congeners, in particular a 5Z,10Z diastereomer 15, a dihydro analogue 16, and a ketone 17. Such izidines in frogs may arise from dietary ants, as do other classes of izidines.

Published
2001

41. Intraventricular Alpha Interferon Therapy for Rasmussen’s Syndrome

Author

Bernard L. Maria, Smith Lj, Walter E. Drane, Ronald G. Quisling, J P Mickle, Reuman Pd, Robin L. Gilmore, and Deborah M. Ringdahl

Subjects
medicine.medical_specialty, business.industry, medicine.medical_treatment, Alpha interferon, General Medicine, Gastroenterology, Hemispherectomy, Neurology, Interferon, Internal medicine, medicine, Neurology (clinical), Rasmussen's syndrome, business, Adverse effect, Clinical progression, medicine.drug
Abstract

A 4-year-old boy developed Rasmussen’s syndrome and was treated with alpha interferon intraventricularly. An improvement in the epileptic and neurologic syndrome was noted for several weeks following interferon. No adverse side effects were encountered. Since hemispherectomy is the only established therapy in Rasmussen’s Syndrome, further studies are needed to establish if intraventricular alpha interferon may halt the clinical progression of the syndrome.

Published
1993

42. Large-Scale Genome-Wide Association Studies and Meta-Analyses of Longitudinal Change in Adult Lung Function

Author

Tang, WB, Kowgier, M, Loth, Daan, Artigas, MS, Joubert, BR, Hodge, E, Gharib, SA, Smith, AV, Ruczinski, I, Gudnason, V, Mathias, RA, Harris, TB, Hansel, NN, Launer, LJ (Lenore), Barnes, KC, Hansen, JG, Albrecht, E, Aldrich, MC, Allerhand, M, Barr, RG, Brusselle, Guy, Couper, DJ, Curjuric, I, Davies, G, Deary, IJ, Dupuis, J, Fall, T, Foy, M, Franceschini, N, Gao, W, Glaser, S, Gu, XJ, Hancock, DB, Heinrich, J (Joachim), Hofman, Bert, Imboden, M, Ingelsson, E, James, A, Karrasch, S, Koch, B, Kritchevsky, SB, Kumar, A, Lahousse, Lies, Li, G, Lind, L, Lindgren, C, Liu, YM, Lohman, K, Lumley, T, McArdle, WL, Meibohm, B, Morris, AP, Morrison, AC, Musk, B, North, KE, Palmer, LJ, Probst-Hensch, NM, Psaty, BM, Rivadeneira, Fernando, Rotter, JI, Schulz, H, Smith, LJ, Sood, A, Starr, JM, Strachan, DP, Teumer, A, Uitterlinden, André, Volzke, H, Voorman, A, Wain, LV, Wells, MT, Wilk, JB, Williams, OD, Heckbert, SR, Stricker, Bruno, London, SJ, Fornage, M, Tobin, MD, O'Connor, GT, Hall, IP, Cassano, PA, Tang, WB, Kowgier, M, Loth, Daan, Artigas, MS, Joubert, BR, Hodge, E, Gharib, SA, Smith, AV, Ruczinski, I, Gudnason, V, Mathias, RA, Harris, TB, Hansel, NN, Launer, LJ (Lenore), Barnes, KC, Hansen, JG, Albrecht, E, Aldrich, MC, Allerhand, M, Barr, RG, Brusselle, Guy, Couper, DJ, Curjuric, I, Davies, G, Deary, IJ, Dupuis, J, Fall, T, Foy, M, Franceschini, N, Gao, W, Glaser, S, Gu, XJ, Hancock, DB, Heinrich, J (Joachim), Hofman, Bert, Imboden, M, Ingelsson, E, James, A, Karrasch, S, Koch, B, Kritchevsky, SB, Kumar, A, Lahousse, Lies, Li, G, Lind, L, Lindgren, C, Liu, YM, Lohman, K, Lumley, T, McArdle, WL, Meibohm, B, Morris, AP, Morrison, AC, Musk, B, North, KE, Palmer, LJ, Probst-Hensch, NM, Psaty, BM, Rivadeneira, Fernando, Rotter, JI, Schulz, H, Smith, LJ, Sood, A, Starr, JM, Strachan, DP, Teumer, A, Uitterlinden, André, Volzke, H, Voorman, A, Wain, LV, Wells, MT, Wilk, JB, Williams, OD, Heckbert, SR, Stricker, Bruno, London, SJ, Fornage, M, Tobin, MD, O'Connor, GT, Hall, IP, and Cassano, PA

Abstract

Background: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. Methods: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. Results: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P = 5.71 x 10(-7)). In addition, meta-analysis using the five cohorts with >= 3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P = 2.18 x 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. Conclusions: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.

Published
2014

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