98 results on '"Lackey L"'
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2. A Program for Improving the Interpersonal Competence of High School Students. Final Report.
- Author
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Human Resources Research Organization, Alexandria, VA. and Lackey, L. L.
- Abstract
This report describes a project dealing with the development and implementation of a model for training the interpersonal aspect of competence. The project had four purposes for the student participants: (a) increase the interpersonal competence of students who previously exhibited deficiencies in interpersonal relations; (b) lessen the communication problems between students and teachers and between students of different ethnic groups; (c) reduce student perceptions of rejection by their peers; and (d) develop more positive attitudes toward school, teachers, and students of the other ethnic group. In Phase I, specially selected students were trained both in the implementation of an interpersonal relations training model and in the conduct of small discussion groups of peers. In Phase II, these selected students served as interpersonal relations training group leaders in conducting the training program for volunteers from the high schools in the Taylor County, Georgia school system. The effectiveness of the training program in accomplishing the specified purposes was evaluated by means of several questionnaires developed for this project. The results showed that the training program had a significant behavioral impact upon the student participants. (Author)
- Published
- 1974
3. Instructor's Manual for a Program for Improving the Interpersonal Competence of High School Students.
- Author
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Human Resources Research Organization, Alexandria, VA. and Lackey, L. L.
- Abstract
This document describes the procedures which were followed in conducting a training program in the Taylor County, Georgia Public School System. The program which was conducted focused on training high school students in performing appropriately assertive behavior in various social situations. In this program, a number of high school students were selected on the basis of their leadership potential and emotional maturity. These students were given assertive training, as well as training and practice in the conduct of discussion groups. This activity constituted Phase I of the project. Phase II consisted of assigning other students volunteering to participate in the training program to discussion groups, each of which had 10-13 members. Each group was led by two of the students who had been trained in Phase I. While the foregoing describes the approach used in the Taylor County project, the material presented in subsequent sections can be modified to fit other requirements. One modification which occurred in the course of this project was an expansion of the initial focus on appropriately assertive behavior to one which included all aspects of interpersonal relations. (Author)
- Published
- 1974
4. The Effects of Command Position upon Evaluations of Leader Behavior.
- Author
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Human Resources Research Organization, Alexandria, VA. and Lackey, L. L.
- Abstract
The study was designed to determine the effects of command position--battalion commander and company commander--upon evaluations of the desirability of certain leader actions. Twenty-two U.S. Army officers who had served as battalion commanders (Group I) and 22 who had served as company commanders (Group II) rated 36 leader actions on their desirability for battalion and for company commanders. Battalion commanders do not differentiate between the two command levels on the desirability of leader actions. Company commanders differentiate about actions concerned with the centralization of authority and responsibility and consider these to be more desirable for both command levels. Both groups rated positive motivation and emotional support as desirable and punitive or negatively motivating actions as slightly undesirable. The implications of the differences in expectations about leader behavior on effective organizational functioning, leadership doctrine, and training are discussed. (Author)
- Published
- 1972
5. A Study of the Success and Work Expectancies of Public Service Career Employees. Final Report.
- Author
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Human Resources Research Organization, Alexandria, VA., Lackey, L. L., and Jacobs, T. O.
- Abstract
The study attempted to measure world-of-work values and perceptions at entry and after a period of employment of enrollees in Plan D of the Public Service Careers (PSC) Program, a Federal program designed to bring disadvantaged individuals into Federal employment. A PSC Enrollee Questionnaire, developed from a logical taxonomy of world-of-work values based on an extensive review of related literature, was administered twice, along with supervisor evaluations, for initial testing and at six months after employment. The first session involved 328 enrollees in the entry-level component, 106 individuals in the upgrade component, and 95 Federal employees holding equivalent positions to those of PSC entry-level workers. The second session involved 211 PSC entry-level enrollees and 137 of their supervisors. Project background, methodology, data analysis, summary of findings and recommendations are presented, with 27 tables. Appended material, encompassing half the document, presents the data collecting instruments and responses. Conclusions state that PSC enrollee perceptions of world-of-work values were congruent with the "middle-class value system", these values were maintained through job experience, and the PSC employee is generally underemployed in the entry job and might continue to be after one promotion. (LH)
- Published
- 1972
6. The effects of rare SERPINA1 variants on lung function and emphysema in SPIROMICS
- Author
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Peters, S.P., Cooper, C., Han, M.K., Paine, R., Laederach, A., Pirozzi, C., Barjaktarevic, I., Hawkins, G.A., O'Neal, W.K., Ortega, V.E., Woodruff, P.G., Grayeski, P.J., Kleerup, E.C., Ampleford, E., Hoffman, E.A., Martinez, F.J., Couper, D., Barr, R.G., Kanner, R.E., Rennard, S.I., Meyers, D.A., Lackey, L., Li, X., and Bleecker, E.R.
- Subjects
respiratory tract diseases - Abstract
Rationale: The role of PI (protease inhibitor) type Z heterozygotes and additional rare variant genotypes in the gene encoding alpha-1 antitrypsin, SERPINA1 (serpin peptidase inhibitor, clade A,member 1), in determining chronic obstructive pulmonary disease risk and severity is controversial. Objectives: To comprehensively evaluate the effects of rare SERPINA1 variants on lung function and emphysema phenotypes in subjects with significant tobacco smoke exposure using deep gene resequencing and alpha-1 antitrypsin concentrations. Methods: DNA samples from 1,693 non-Hispanic white individuals, 385 African Americans, and 90 Hispanics with >20 pack-years smoking were resequenced for the identification of rare variants (allele frequency,0.05) in 16.9 kB of SERPINA1. Measurements and Main Results: White PI Z heterozygotes confirmed by sequencing (MZ; n = 74) had lower postbronchodilator FEV1 (P = 0.007), FEV1/FVC (P = 0.003), and greater computed tomography-based emphysema (P = 0.02) compared with 1,411 white individuals without PI Z, S, or additional rare variants denoted as VR. PI Z-containing compound heterozygotes (ZS/ZVR; n = 7) had lower FEV1/FVC (P = 0.02) and forced expiratory flow, midexpiratory phase (P = 0.009). Nineteen white heterozygotes for five non-S/Z coding variants associated with lower alpha-1 antitrypsin had greater computed tomography-based emphysema compared with those without rare variants. In African Americans, a 59 untranslated region insertion (rs568223361) was associated with lower alpha-1 antitrypsin and functional small airway disease (P = 0.007). Conclusions: In this integrative deep sequencing study of SERPINA1 with alpha-1 antitrypsin concentrations in a heavy smoker and chronic obstructive pulmonary disease cohort, we confirmed the effects of PI Z heterozygote and compound heterozygote genotypes. We demonstrate the cumulative effects of multiple SERPINA1 variants on alpha-1 antitrypsin deficiency, lung function, and emphysema, thus significantly increasing the frequency of SERPINA1 variation associated with respiratory disease in at-risk smokers.
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- 2020
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7. Pseudomonas putida B2: a tod-lux bioluminescent reporter for toluene and trichloroethylene co-metabolism
- Author
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Applegate, B, Kelly, C, Lackey, L, McPherson, J, Kehrmeyer, S, Menn, F-M, Bienkowski, P, and Sayler, G
- Published
- 1997
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8. Biodegradation of chlorinated aliphatic hydrocarbon mixtures in a single-pass packed-bed reactor
- Author
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Lackey, L. W., Phelps, T. J., Bienkowski, P. R., and White, D. C.
- Published
- 1993
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9. A functional riboSNitch in the 3' untranslated region of FKBP5 alters MicroRNA-320a binding efficiency and mediates vulnerability to chronic post-traumatic pain
- Author
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Tsai, Y.-H., Domeier, R., Linnstaedt, S.D., Pearson, C., Kaushik, S., Lewandowski, C., O'neil, B., Laederach, A., Lackey, L., McLean, S.A., McCarthy, K.R., Kutchko, K.M., Parker, J.S., Hendry, P.L., Rueckeis, C.A., Riker, K.D., Kurz, M.C., and Datner, E.
- Abstract
Previous studies have shown that common variants of the gene coding for FK506-binding protein 51 (FKBP5), a critical regulator of glucocorticoid sensitivity, affect vulnerability to stress-related disorders. In a previous report, FKBP5 rs1360780 was identified as a functional variant because of its effect on gene methylation. Here we report evidence for a novel functional FKBP5 allele, rs3800373. This study assessed the association between rs3800373 and post-traumatic chronic pain in 1607 women and men from two ethnically diverse human cohorts. The molecular mechanism through which rs3800373 affects adverse outcomes was established via in silico, in vivo, and in vitro analyses. The rs3800373 minor allele predicted worse adverse outcomes after trauma exposure, such that individuals with the minor (risk) allele developed more severe post-traumatic chronic musculoskeletal pain. Among these individuals, peritraumatic circulating FKBP5 expression levels increased as cortisol and glucocorticoid receptor (NR3C1) mRNA levels increased, consistent with increased glucocorticoid resistance. Bioinformatic, in vitro, and mutational analyses indicate that the rs3800373 minor allele reduces the binding of a stress-and pain-associated microRNA, miR-320a, to FKBP5 via altering the FKBP5 mRNA 3'UTR secondary structure (i.e., is a riboSNitch). This results in relatively greater FKBP5 translation, unchecked by miR-320a. Overall, these results identify an important gene–miRNA interaction influencing chronic pain risk in vulnerable individuals and suggest that exogenous methods to achieve targeted reduction in poststress FKBP5 mRNA expression may constitute useful therapeutic strategies.
- Published
- 2018
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10. P3.11-05 Use of Electronic Medical Record (EMR)-Embedded Clinical Decision Support Tools Improves Lung Cancer Screening Rates
- Author
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Doty, J., primary, Lackey, L., additional, Ersek, J., additional, Howard, D., additional, and Clary, A., additional
- Published
- 2018
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11. Does sexual selection shape sex differences in longevity and senescence patterns across vertebrates? A review and new insights from captive ruminants
- Author
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Tidiere, M., Gaillard, J. M., Muller, D. W., Lackey, L. B., Gimenez, O., Clauss, M., Lemaitre, J. F., Biodémographie évolutive, Département écologie évolutive [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), and Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
[SDV]Life Sciences [q-bio] ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience
- Published
- 2015
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12. Life expectancy in zoo mammals: what a zoo veterinarian should know
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Hatt, Jean-Michel, Müller, Dennis W H, Bingaman Lackey, L, Clauss, Marcus, and University of Zurich
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10253 Department of Small Animals ,630 Agriculture ,570 Life sciences ,biology - Published
- 2011
13. Mating system, feeding type and ex situ conservation effort determine life expectancy in captive ruminants
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Müller, Dennis W H, Bingaman Lackey, L, Streich, W J, Fickel, J, Hatt, Jean-Michel, Clauss, Marcus, and University of Zurich
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2300 General Environmental Science ,10253 Department of Small Animals ,630 Agriculture ,1300 General Biochemistry, Genetics and Molecular Biology ,2400 General Immunology and Microbiology ,570 Life sciences ,biology ,1100 General Agricultural and Biological Sciences - Published
- 2011
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14. How to measure husbandry success? The life expectancy of zoo ruminants
- Author
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Müller, Dennis W H, Bingaman Lackey, L, Streich, W J, Fickel, J, Hatt, Jean-Michel, Clauss, Marcus, and University of Zurich
- Subjects
10253 Department of Small Animals ,630 Agriculture ,570 Life sciences ,biology - Published
- 2011
15. Less can be more: considering seasonal differences of newborn mortality in breeding regimes
- Author
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Müller, Dennis W H, Müller, S I, Bingaman Lackey, L, Hammer, C, Hammer, S, Leus, K, Maier, M, Hatt, Jean-Michel, Clauss, Marcus, and University of Zurich
- Subjects
10253 Department of Small Animals ,630 Agriculture ,570 Life sciences ,biology - Published
- 2010
16. Life expectancy in zoo mammals: what a zoo veterinarian should know
- Author
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Hatt, Jean-Michel; https://orcid.org/0000-0002-7043-7430, Müller, Dennis W H, Bingaman Lackey, L, Clauss, Marcus; https://orcid.org/0000-0003-3841-6207, Hatt, Jean-Michel; https://orcid.org/0000-0002-7043-7430, Müller, Dennis W H, Bingaman Lackey, L, and Clauss, Marcus; https://orcid.org/0000-0003-3841-6207
- Published
- 2011
17. Leukoencephalomyelopathy of Mature Captive Cheetahs and Other Large Felids
- Author
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Brower, A. I., primary, Munson, L., additional, Radcliffe, R. W., additional, Citino, S. B., additional, Lackey, L. B., additional, Van Winkle, T. J., additional, Stalis, I., additional, Terio, K. A., additional, Summers, B. A., additional, and de Lahunta, A., additional
- Published
- 2013
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18. Design, Operation, and Analysis of a Biological Sand Filter Using Copper as a Disinfectant
- Author
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Lackey, L. W., primary, Smith, C., additional, Poole, T., additional, Fair, A., additional, Hyde, E., additional, McCreanor, P. T., additional, and Mines, Jr., R. O., additional
- Published
- 2013
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19. Survival on the ark: life-history trends in captive parrots
- Author
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Young, A. M., primary, Hobson, E. A., additional, Lackey, L. Bingaman, additional, and Wright, T. F., additional
- Published
- 2011
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20. Will the EU ban on bird imports mean the demise of bird populations in EAZA collections?
- Author
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WALTER, O., primary, ELLIS, J. A., additional, and BINGAMAN LACKEY, L., additional
- Published
- 2009
- Full Text
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21. Risks of Exposure to Antimicrobial Resistant E. Coli Among Workers in Industrial Food Animal Production
- Author
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Silbergeld, E, primary, Price, L, additional, Lackey, L, additional, and Evans, S, additional
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- 2007
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22. Parallel Bench-Scale Digestion Studies
- Author
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Mines, Jr., R. O., primary, Lackey, L. W., additional, Murchison, M. B., additional, and Norfhernor, C. B., additional
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- 2007
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23. Ozonation of acid yellow 17 dye in a semi-batch bubble column
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LACKEY, L, primary, MINESJR, R, additional, and MCCREANOR, P, additional
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- 2006
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24. Bench-Scale Digestion Studies
- Author
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Mines, Jr., R. O., primary, Lackey, L. W., additional, and Butler, A. J., additional
- Published
- 2006
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25. BOD Performance Correlation at Georgia WWTPs
- Author
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Sheppard, J. C., primary, Mines, Jr., R. O., additional, Lackey, L. W., additional, and Behrend, G. R., additional
- Published
- 2005
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26. Ozone Treatment of Acid Yellow 17 Dye
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Lackey, L. W., primary and Mines, R. O., additional
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- 2004
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27. Leukoencephalomyelopathy of Mature Captive Cheetahs and Other Large Felids: A Novel Neurodegenerative Disease That Came and Went?
- Author
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Brower, A. I., Munson, L., Radcliffe, R. W., Citino, S. B., Lackey, L. B., Van Winkle, T. J., Stalis, I., Terio, K. A., Summers, B. A., and de Lahunta, A.
- Subjects
CHEETAH ,NEURODEGENERATION ,VISION disorders ,BLINDNESS ,NEUROLOGY - Abstract
A novel leukoencephalomyelopathy was identified in 73 mature male and female large captive felids between 1994 and 2005. While the majority of identified cases occurred in cheetahs (Acinonyx jubatus), the disease was also found in members of 2 other subfamilies of Felidae: 1 generic tiger (Panthera tigris) and 2 Florida panthers (Puma concolor coryi). The median age at time of death was 12 years, and all but 1 cheetah were housed in the United States. Characteristic clinical history included progressive loss of vision leading to blindness, disorientation, and/or difficulty eating. Neurologic deficits progressed at a variable rate over days to years. Mild to severe bilateral degenerative lesions were present in the cerebral white matter and variably and to a lesser degree in the white matter of the brain stem and spinal cord. Astrocytosis and swelling of myelin sheaths progressed to total white matter degeneration and cavitation. Large, bizarre reactive astrocytes are a consistent histopathologic feature of this condition. The cause of the severe white matter degeneration in these captive felids remains unknown; the lesions were not typical of any known neurotoxicoses, direct effects of or reactions to infectious diseases, or nutritional deficiencies. Leukoencephalomyelopathy was identified in 70 cheetahs, 1 tiger, and 2 panthers over an 11-year period, and to our knowledge, cases have ceased without planned intervention. Given what is known about the epidemiology of the disease and morphology of the lesions, an environmental or husbandry-associated source of neurotoxicity is suspected. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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28. Components of Organizational Competence: Test of a Conceptual Framework
- Author
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Olmstead, Joseph A., primary, Christensen, Harold E., primary, and Lackey, L. L., primary
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- 1973
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29. Survival on the ark: life-history trends in captive parrots.
- Author
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Young, A. M., Hobson, E. A., Lackey, L. Bingaman, and Wright, T. F.
- Subjects
PARROTS ,ENDANGERED species ,BIRD conservation ,COCKATOOS ,CACATUA ,CAPTIVE parrots - Abstract
Members of the order Psittaciformes (parrots and cockatoos) are among the most long-lived and endangered avian species. Comprehensive data on lifespan and breeding are critical to setting conservation priorities, parameterizing population viability models, and managing captive and wild populations. To meet these needs, we analyzed 83 212 life-history records of captive birds from the International Species Information System (ISIS) and calculated lifespan and breeding parameters for 260 species of parrots (71% of extant species). Species varied widely in lifespan, with larger species generally living longer than smaller ones. The highest maximum lifespan recorded was 92 years in Cacatua moluccensis, but only 11 other species had a maximum lifespan over 50 years. Our data indicate that while some captive individuals are capable of reaching extraordinary ages, median lifespans are generally shorter than widely assumed, albeit with some increase seen in birds presently held in zoos. Species that lived longer and bred later in life tended to be more threatened according to IUCN classifications. We documented several individuals of multiple species that were able to breed for more than two decades, but the majority of clades examined had much shorter active reproduction periods. Post-breeding periods were surprisingly long and in many cases surpassed the duration of active breeding. Our results demonstrate the value of the ISIS database to estimate life-history data for an at-risk taxon that is difficult to study in the wild, and provide life-history data that is crucial for predictive modeling of future species endangerment and proactively management of captive populations of parrots. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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30. Through the leaves, 1924
- Author
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Smith, George A., author; Jones, C. A., author; Harms, George, author; Wilson, Wallis D., author; Ward, E., Jr., author; Lackey, L. B., author; Austin, H. A., author; Brummet, W. S., author; Sheridan, Maude, author; Lowry, E. Monroe, author; Stewart, George, author; McCreery, N. R., author; Snyder, F. A., author; Hiller, W. F., author; Kidder, Waldo, author; Giese, H. C., author; Maddux, C. V., author; Bennett, C. C., author; Rosenow, A. C., author; Newell, Willard, author; Riddell, Harvey, author; Chamberlain, A. E., author; Henderson, W. S., author; Beattie, J. M., author; Snell, George, author; Scilley, H., author; Dopkins, Clyde D., author; Alden, Lee H., author; Barr, R. M., author; Deich, Frank, author; Lemley, Norman, author; Cady, G. H., Mrs., author; Mead, J. P., author; Stephen, A. B., author; Mondt, Lowell R., author; Conklin, George, author; Lackey, L. B., author; Mattoon, Max, author; Dale, Phil, author; Whiting, Frank, author; Billings, M. A., author; Forbes, Jesse, author; Maxson, Asa C., author; Henderson, J. Y., author; Jurgens, Herman, author; Evans, Charles E., author; Turner, C. H., author; Jarrell, J. F., author; Hinman, C. H., author; Johnson, Arthur C., author; Looper, H. S., author; Crownover, T. G., author; Heldt, A. H., author; Palmer, Truman G., author; McCarty, W. C., author; Varner, H. S., author; Myers, A. H., author; Johnson, D. C., author; Williams, J. L., author; Harms, H. M., author; Landis, I. H., author; Landis, N. B., author; Hover, Charles L., author; Strauss, C. W., author; English, J. G., author; Andrews, L. H., author; Lutton, George W., Mrs., author; Collopy, Mary G., author; Comer, John, author; King, Julia, author; Ogilvy, Lord, author; Sherier, J. M., author; Wieland, C. P., author; Simmons, Edmund, author; Bates, C. G., author; Stephens, T. D., author; Taylor, I. R., author; Maynard, E. J., author; Bennett, H. A., author; Dakin, Edwin, author; Hammond, L. M., author; Burdick, R. T., author; Morrison, James E., author; He and Smith, George A., author; Jones, C. A., author; Harms, George, author; Wilson, Wallis D., author; Ward, E., Jr., author; Lackey, L. B., author; Austin, H. A., author; Brummet, W. S., author; Sheridan, Maude, author; Lowry, E. Monroe, author; Stewart, George, author; McCreery, N. R., author; Snyder, F. A., author; Hiller, W. F., author; Kidder, Waldo, author; Giese, H. C., author; Maddux, C. V., author; Bennett, C. C., author; Rosenow, A. C., author; Newell, Willard, author; Riddell, Harvey, author; Chamberlain, A. E., author; Henderson, W. S., author; Beattie, J. M., author; Snell, George, author; Scilley, H., author; Dopkins, Clyde D., author; Alden, Lee H., author; Barr, R. M., author; Deich, Frank, author; Lemley, Norman, author; Cady, G. H., Mrs., author; Mead, J. P., author; Stephen, A. B., author; Mondt, Lowell R., author; Conklin, George, author; Lackey, L. B., author; Mattoon, Max, author; Dale, Phil, author; Whiting, Frank, author; Billings, M. A., author; Forbes, Jesse, author; Maxson, Asa C., author; Henderson, J. Y., author; Jurgens, Herman, author; Evans, Charles E., author; Turner, C. H., author; Jarrell, J. F., author; Hinman, C. H., author; Johnson, Arthur C., author; Looper, H. S., author; Crownover, T. G., author; Heldt, A. H., author; Palmer, Truman G., author; McCarty, W. C., author; Varner, H. S., author; Myers, A. H., author; Johnson, D. C., author; Williams, J. L., author; Harms, H. M., author; Landis, I. H., author; Landis, N. B., author; Hover, Charles L., author; Strauss, C. W., author; English, J. G., author; Andrews, L. H., author; Lutton, George W., Mrs., author; Collopy, Mary G., author; Comer, John, author; King, Julia, author; Ogilvy, Lord, author; Sherier, J. M., author; Wieland, C. P., author; Simmons, Edmund, author; Bates, C. G., author; Stephens, T. D., author; Taylor, I. R., author; Maynard, E. J., author; Bennett, H. A., author; Dakin, Edwin, author; Hammond, L. M., author; Burdick, R. T., author; Morrison, James E., author; He
- Abstract
Includes subject index (pages 614-619)., Issues of Through the Leaves for the year 1924 (volume 12). Includes articles, photographs, and illustrations related to beet farming in Colorado.
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- 1924
31. The Effects of Command Position upon Evaluations of Leader Behavior.
- Author
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HUMAN RESOURCES RESEARCH ORGANIZATION ALEXANDRIA VA, Lackey,L. L., Olmstead,Joseph A., Christensen,Harold E., HUMAN RESOURCES RESEARCH ORGANIZATION ALEXANDRIA VA, Lackey,L. L., Olmstead,Joseph A., and Christensen,Harold E.
- Abstract
FICERS WHO HAD SERVED AS BATTALION COMMANDERS (Group I) and 22 who had served as company commanders (Group II) rated 36 leader actions on their desirability for battalion and for company commanders. Battalion commanders do not differentiate between the two command levels on the desirability of the leader actions. Company commanders differentiate about actions concerned with the centralization of authority and responsibility, and consider these to be more desirable for both command levels. Both groups rated positive motivation and emotional support as desirable and punitive or negatively motivating actions as slightly undesirable. The implications of the differences in expectations about leader behavior on effective organizational functioning, leadership doctrine, and training are discussed. (Author)
- Published
- 1972
32. Through the leaves, 1925
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Maxson, Asa C., author; Robbins, W. W., author; Kezer, Alvin, author; Barbour, Neal A., author; Rodewald, R. G., author; Kobliansky, Nicholas, author; Rodewald, C. J., author; Holden, James A., author; Barr, Robert M., author; Conklin, George, author; Williams, Alfred R., author; Moorhouse, L. A., author; Looper, H. S., author; Natwick, O. O., author; Nelson, E. B., author; McCann, Roud, author; Harmon, L. W., author; Anderson, Elmer, author; Wing, DeWitt C., author; Buck, Roy, author; Griffin, H. H., author; Reed, G. O., author; Frisbie, Otto E., author; Smith, George A., author; Montgomery, N. J., author; Wilson, M. B., author; Wieland, C. P., author; Nelson, W. A., author; Lackey, L. B., author; Stelk, O. F., author; Beattie, J. M., author; Skuderna, A. W., author; Brown, Sara A., author; Sargent, Robie O., author; Jurgens, Herman, author; Morrison, J. E., author; Doherty, C. W., author; Jarrell, J. F., author; English, J. Gordon, author; Summers, Thomas H., author; Forbes, Jesse, author; McMaster, P. H., author; Mattoon, Maxwell, author; Stephens, T. D., author; Whiting, Frank, author; Titus, E. G., author; Brummett, W. S., author; Gross, D. L., author; Clement, M. S., author; Dale, Phil, author; Heldt, A. H., author; Allen, Ida Bailey, author; Lemon, Melvin, author; Maynard, E. J., author; Pack, Dean A., author; Comer, John, author; Simmons, Edmund, author; Riddell, Harvey, author; Mendelson, H., author; Partridge, Ralph L., author; Scilley, H., author; Maddux, C. V., author; Sackett, Walter G., author; Farrell, F. D., author; Jean, F. C., author; Wilson, Scotty, author; Ogilvy, Lord, author; Bluebaugh, James V., author; Droge, W. F., author; Lascelles, H. R., author; Sarle, C. F., author; Even, C. E., author; Nida, Tom, author; Parshall, R. L., author; Mann, Charles, author; Bentley, V. W., author; Edmundson, W. C., author; Andrews, L. H., author; Ward, E., author; Evvard, John M., author; Wooley, George A., author; Varner, H. S., author; Robertson, D. W., aut and Maxson, Asa C., author; Robbins, W. W., author; Kezer, Alvin, author; Barbour, Neal A., author; Rodewald, R. G., author; Kobliansky, Nicholas, author; Rodewald, C. J., author; Holden, James A., author; Barr, Robert M., author; Conklin, George, author; Williams, Alfred R., author; Moorhouse, L. A., author; Looper, H. S., author; Natwick, O. O., author; Nelson, E. B., author; McCann, Roud, author; Harmon, L. W., author; Anderson, Elmer, author; Wing, DeWitt C., author; Buck, Roy, author; Griffin, H. H., author; Reed, G. O., author; Frisbie, Otto E., author; Smith, George A., author; Montgomery, N. J., author; Wilson, M. B., author; Wieland, C. P., author; Nelson, W. A., author; Lackey, L. B., author; Stelk, O. F., author; Beattie, J. M., author; Skuderna, A. W., author; Brown, Sara A., author; Sargent, Robie O., author; Jurgens, Herman, author; Morrison, J. E., author; Doherty, C. W., author; Jarrell, J. F., author; English, J. Gordon, author; Summers, Thomas H., author; Forbes, Jesse, author; McMaster, P. H., author; Mattoon, Maxwell, author; Stephens, T. D., author; Whiting, Frank, author; Titus, E. G., author; Brummett, W. S., author; Gross, D. L., author; Clement, M. S., author; Dale, Phil, author; Heldt, A. H., author; Allen, Ida Bailey, author; Lemon, Melvin, author; Maynard, E. J., author; Pack, Dean A., author; Comer, John, author; Simmons, Edmund, author; Riddell, Harvey, author; Mendelson, H., author; Partridge, Ralph L., author; Scilley, H., author; Maddux, C. V., author; Sackett, Walter G., author; Farrell, F. D., author; Jean, F. C., author; Wilson, Scotty, author; Ogilvy, Lord, author; Bluebaugh, James V., author; Droge, W. F., author; Lascelles, H. R., author; Sarle, C. F., author; Even, C. E., author; Nida, Tom, author; Parshall, R. L., author; Mann, Charles, author; Bentley, V. W., author; Edmundson, W. C., author; Andrews, L. H., author; Ward, E., author; Evvard, John M., author; Wooley, George A., author; Varner, H. S., author; Robertson, D. W., aut
- Abstract
Includes subject index (pages 514-519)., Issues of Through the Leaves for the year 1925 (volume 13). Includes articles, photographs, and illustrations related to beet farming in Colorado.
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- 1925
33. The effects of command position upon evaluations of leader behavior.
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Lackey, L. L., primary, Olmstead, Joseph A., additional, and Christensen, Harold E., additional
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- 1972
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34. A glimpse of how senior engineering students understand engineering as a profession
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Codone, S., primary, Lackey, L., additional, and Grady, H., additional
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35. Industrial Food Animal Production: Food Safety, Socioeconomic, and Environmental Health Concerns.
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Silbergeld, E K, Graham, J, Price, L, Liebler, J, Evans, S, Vailles, R, Lackey, L, Peterson, A, Davis, M, Arriola, C S, and Resnick, C
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- 2008
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36. Precursor RNA structural patterns at SF3B1 mutation sensitive cryptic 3' splice sites.
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Herbert A, Hatfield A, Randazza A, Miyamoto V, Palmer K, and Lackey L
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SF3B1 is a core component of the spliceosome involved in branch point recognition and 3' splice site selection. SF3B1 mutation is common in myelodysplastic syndrome and other blood disorders. The most common mutation in SF3B1 is K700E, a lysine to glutamic acid change within the pre-mRNA interacting heat repeat domain. A hallmark of SF3B1 mutation is an increased use of cryptic 3' splice sites; however, the properties distinguishing SF3B1-sensitive splice junctions from other alternatively spliced junctions are unknown. We identify a subset of 192 core splice junctions that are mis-spliced with SF3B1 K700E mutation. We use our core set to test whether SF3B1-sensitive splice sites are different from control cryptic 3' splice sites via RNA structural accessibility. As a comparison, we define a set of SF3B1-resistant splice junctions with cryptic splice site use that does not change with SF3B1 K700E mutation. We find sequence differences between SF3B1-sensitive and SF3B1-resistant junctions, particularly at the cryptic sites. SF3B1-sensitive cryptic 3' splice sites are within an extended polypyrimidine tract and have lower splice site strength scores. We develop experimental RNA structure data for 83 SF3B1-sensitive junctions and 39 SF3B1-resistant junctions. We find that the pattern of structural accessibility at the NAG splicing motif in cryptic and canonical 3' splice sites is similar. In addition, this pattern can be found in both SF3B1-resistant and SF3B1-sensitive junctions. However, SF3B1-sensitive junctions have cryptic splice sites that are less structurally distinct from the canonical splice sites. In addition, SF3B1-sensitive splice junctions are overall more flexible than SF3B1-resistant junctions. Our results suggest that the SF3B1-sensitive splice junctions have unique structure and sequence properties, containing poorly differentiated, weak splice sites that lead to altered 3' splice site recognition in the presence of SF3B1 mutation.
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- 2025
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37. Teratogenic Risk Impact and Mitigation (TRIM): Study Protocol for the Development of a Decision Support Tool to Prioritize Medications for Risk Mitigation.
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Winterstein AG, Ewig CLY, Wang Y, Smolinski NE, Toyserkani GA, LaCivita C, Lackey L, Eggers S, Zhou EH, Diaby V, Sarayani A, Thai T, Maro JC, and Rasmussen SA
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- Humans, Pregnancy, Female, Risk Assessment methods, United States, Teratogens, Decision Support Techniques, Risk Evaluation and Mitigation
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Introduction: Preventing prenatal exposure to teratogenic medications is an important goal of regulatory risk mitigation efforts. In the USA, as of March 2024, 11 teratogenic medications have a required Risk Evaluation and Mitigation Strategy (REMS) program. It is unclear whether these programs target those medications with the most significant impact on public health and adverse pregnancy outcomes., Objectives: This study aims to develop an innovative decision support tool that uses explicit, quantifiable criteria to facilitate prioritization of teratogenic medications for risk mitigation strategies., Methods: The Teratogenic Risk Impact and Mitigation (TRIM) decision support tool will be developed by a national panel via a modified Delphi approach to define measurable criteria, and a multi-criteria decision analysis to estimate criteria weights within a discrete choice experiment. The TRIM scores will then be calculated for 12 teratogenic drugs with active or eliminated REMS programs and for 12 teratogenic drugs without REMS. These drugs will be identified based on highest prenatal exposure prevalence in claims data of privately and publicly insured individuals. Data for the TRIM criteria levels for these 24 drugs will be identified from evidence searches and ad hoc analyses of the same claims data., Conclusions: Teratogenic Risk Impact and Mitigation is intended to inform regulatory decision making about the need for risk mitigation programs for teratogenic medications by providing explicit, quantifiable, evidence-based criteria. The TRIM scores of 24 teratogenic drugs may provide benchmarks for considering REMS for marketed and new teratogenic medications., Competing Interests: Declarations. Funding: This study was funded by contract HHS75F40121C00188 with the US Food and Drug Administration. Disclaimer: The views in this manuscript are those of the authors and not necessarily those of the US Food and Drug Administration. Conflict of Interest: AGW has received research funding from Merck, Sharp and Dohme and has served as consultant for Merck, Bayer KG, Genentech Inc., Ipsen, Novo Nordisk, and Arbor Pharmaceuticals. AGW is an editorial board member of Drug Safety. AGW was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. NES owns stock through inheritance in Baxter, CVS Health, Edwards LifeSciences, and Takeda unrelated to this work. SAR serves on scientific advisory committees for several pregnancy registries, including registries for Wakix (Harmony), Sunosi (Axsome), Nurtec (Biohaven, recently acquired by Pfizer), and the Myfembree (Myovant Sciences). VD is presently an employee at Otsuka Pharmaceutical Development Corporation Inc. He declares that there are no conflicts of interest that could be perceived as influencing the content of this manuscript. At the time of study protocol development, VD’s professional affiliation was with the University of Florida. AS contributed to this study protocol during his previous tenure at the University of Florida, and his current employer, Janssen Research and Development, did not provide funding nor had any role in the conception, design, or decision to publish this manuscript. The remaining authors have no conflict of interest relevant to the content of this study. Code Availability: Not applicable. Ethics Approval: Not applicable at the design stage. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Availability of Data and Materials: Not applicable. Author Contributions: All authors made substantial contributions to conception or design of the work; AGW, CE, NES, AS, TT and SAR acquired funding; AGW drafted the manuscript, and all other authors reviewed it critically for important intellectual content and gave final approval of the version to be published., (© 2024. The Author(s).)
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- 2025
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38. Key Opinion Leaders' Interviews to Inform the Future of Benefit-Risk Planning in the Medical Total Product Life Cycle of Global Pharmaceutical and Medical Device Organizations.
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Simonetti A, Colilla S, Edwards B, Kübler J, Lackey L, Rodriguez L, Talbot S, Yang H, Wang W, Williams D, and Higginson JM
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- Humans, Risk Assessment, Drug Industry, Interviews as Topic, Leadership, Equipment and Supplies
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Background and Objectives: Key opinion leader (KOL) interviews were conducted by the Benefit-Risk Assessment Planning (BRAP) Taskforce to seek expert opinion mainly from industry and regulatory bodies, about the current status and future direction of benefit-risk assessment (BRA) planning in the lifecycle of medical product development. The findings from these interviews are intended to help communication concerning planning for BRA between industry and regulators and shape future guidance., Methods: Key opinion leader interviews consisted of 5 questions related to BRA planning, which were administered to volunteers (mainly clinicians and statisticians) within a pool of experienced pharmaceutical and medical device professionals representing academia, industry, regulatory agencies and a patient group. The interviewees' responses to the 5 questions were summarized. To analyze the qualitative data, a Coding System was developed to label themes arising from the interviews. The key findings from the interviews were summarized into a Master Template. A quantitative analysis based on descriptive statistics was also conducted., Results: Of the 27 interviewees, there were 11 professionals from regulatory agencies, 11 from industry, 4 from academia and 1 from a patient advocacy group. Key findings based on the comments provided by 48% of the interviewees indicated the need of incorporating BRA into other (e.g., existing) processes with the importance of alignment between processes being stressed in the comments provided by 59% of the interviewees. Commencing BRA early in the product lifecycle was emphasized in comments provided by 44% of the interviewees. Among other needs identified were an appropriate contextualization of benefits and risks (based on comments provided by 41% of interviewees) through adoption of an integrated approach with structured support by regulatory agencies and a need for understanding the audience with better communication of benefit-risk (BR) among all stakeholders (based on comments provided by 44% of the interviewees). Almost all comments provided by interviewees (96%) highlighted the importance of utilizing patient experience/preference to guide new product development and BRA. Comments provided by 74% of the interviewees expressed the need to understand patient tolerance for risk and trade-offs, with a majority (78%) of interviewees highlighting how to gather information, and 59% stressing the need for the selection and development of appropriate methodologies as important considerations for enhancing the quality and relevance of the data collected from patients., Conclusions: Interviewees indicated that BRA should commence early in the medical product development and inform decision-making throughout the product lifecycle. Better planning and integration of BRA into existing processes within industry would be valuable. The importance of incorporating the patient voice into BRA and medical product development was emphasized. Other key findings from the KOL interviews included a need for improved communication of BR information, and establishment of methodologies for performing BRA and soliciting patient input., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
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- 2024
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39. Incorporating Prior Data in Quantitative Benefit-Risk Assessments: Case Study of a Bayesian Method.
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Dharmarajan S, Yuan Z, Chen YF, Lackey L, Mukhopadhyay S, Singh P, and Tiwari R
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- Humans, Risk Assessment, Decision Support Techniques, Randomized Controlled Trials as Topic, Peripheral Arterial Disease drug therapy, Factor Xa Inhibitors therapeutic use, Factor Xa Inhibitors adverse effects, Factor Xa Inhibitors administration & dosage, Bayes Theorem, Rivaroxaban therapeutic use, Rivaroxaban adverse effects
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Background: Multiple criteria decision analysis (MCDA) and stochastic multi-criteria acceptability analysis (SMAA) in their current implementation cannot incorporate prior or external information on benefits and risks. We demonstrate how to incorporate prior data using a Bayesian mixture model approach while conducting quantitative benefit-risk assessments (qBRA) for medical products., Methods: We implemented MCDA and SMAA in a Bayesian framework. To incorporate information from a prior study, we use mixture priors on each benefit and risk attribute that mixes information from a previous study with a vague prior distribution. The degree of borrowing is varied using a mixing proportion parameter., Results: A demonstration case study for qBRA using the supplementary New Drug Application (sNDA) filing for Rivaroxaban for the indication of reduction in the risk of major thrombotic vascular events in patients with peripheral artery disease (PAD) was used to illustrate the method. Net utility scores, obtained from the randomized controlled trial data to support the sNDA, from the MCDA for Rivaraxoban and comparator were 0.48 and 0.56, respectively, with Rivaroxaban being the preferred alternative only 33% of the time. We show that with only 30% borrowing from a previous RCT, the MCDA and SMAA results are favorable for Rivaroxaban, accounting for the seemingly aberrant results on all-cause death in the trial data used to support the sNDA., Conclusion: Our method to formally incorporate prior data in MCDA and SMAA is easy to use and interpret. Software in the form of an RShiny App is available here: https://sai-dharmarajan.shinyapps.io/BayesianMCDA_SMAA/ ., (© 2024. The Author(s), under exclusive licence to The Drug Information Association, Inc.)
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- 2024
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40. Correction: Incorporating Prior Data in Quantitative Benefit-Risk Assessments: Case Study of a Bayesian Method.
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Dharmarajan S, Yuan Z, Chen YF, Lackey L, Mukhopadhyay S, Singh P, and Tiwari R
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- 2024
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41. How does precursor RNA structure influence RNA processing and gene expression?
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Herbert A, Hatfield A, and Lackey L
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- Humans, RNA genetics, Polyadenylation, Gene Expression, RNA Precursors genetics, RNA Precursors metabolism, RNA Splicing
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RNA is a fundamental biomolecule that has many purposes within cells. Due to its single-stranded and flexible nature, RNA naturally folds into complex and dynamic structures. Recent technological and computational advances have produced an explosion of RNA structural data. Many RNA structures have regulatory and functional properties. Studying the structure of nascent RNAs is particularly challenging due to their low abundance and long length, but their structures are important because they can influence RNA processing. Precursor RNA processing is a nexus of pathways that determines mature isoform composition and that controls gene expression. In this review, we examine what is known about human nascent RNA structure and the influence of RNA structure on processing of precursor RNAs. These known structures provide examples of how other nascent RNAs may be structured and show how novel RNA structures may influence RNA processing including splicing and polyadenylation. RNA structures can be targeted therapeutically to treat disease., (© 2023 The Author(s).)
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- 2023
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42. The historical development of zoo elephant survivorship.
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Scherer L, Bingaman Lackey L, Clauss M, Gries K, Hagan D, Lawrenz A, Müller DWH, Roller M, Schiffmann C, and Oerke AK
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- Animals, Survivorship, Animal Welfare, Animals, Zoo, Animal Husbandry, Elephants
- Abstract
In the discussion about zoo elephant husbandry, the report of Clubb et al. (2008, Science 322: 1649) that zoo elephants had a "compromised survivorship" compared to certain non-zoo populations is a grave argument, and was possibly one of the triggers of a large variety of investigations into zoo elephant welfare, and changes in zoo elephant management. A side observation of that report was that whereas survivorship in African elephants (Loxodonta africana) improved since 1960, this was not the case in Asian elephants (Elephas maximus). We used historical data (based on the Species360 database) to revisit this aspect, including recent developments since 2008. Assessing the North American and European populations from 1910 until today, there were significant improvements of adult (≥10 years) survivorship in both species. For the period from 1960 until today, survivorship improvement was significant for African elephants and close to a significant improvement in Asian elephants; Asian elephants generally had a higher survivorship than Africans. Juvenile (<10 years) survivorship did not change significantly since 1960 and was higher in African elephants, most likely due to the effect of elephant herpes virus on Asian elephants. Current zoo elephant survivorship is higher than some, and lower than some other non-zoo populations. We discuss that in our view, the shape of the survivorship curve, and its change over time, are more relevant than comparisons with specific populations. Zoo elephant survivorship should be monitored continuously, and the expectation of a continuous trend towards improvement should be met., (© 2022 The Authors. Zoo Biology published by Wiley Periodicals LLC.)
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- 2023
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43. Global 5'-UTR RNA structure regulates translation of a SERPINA1 mRNA.
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Grayeski PJ, Weidmann CA, Kumar J, Lackey L, Mustoe AM, Busan S, Laederach A, and Weeks KM
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- 5' Untranslated Regions, Humans, Protease Inhibitors, RNA, Messenger metabolism, Protein Biosynthesis, Pulmonary Disease, Chronic Obstructive genetics, alpha 1-Antitrypsin genetics
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SERPINA1 mRNAs encode the protease inhibitor α-1-antitrypsin and are regulated through post-transcriptional mechanisms. α-1-antitrypsin deficiency leads to chronic obstructive pulmonary disease (COPD) and liver cirrhosis, and specific variants in the 5'-untranslated region (5'-UTR) are associated with COPD. The NM_000295.4 transcript is well expressed and translated in lung and blood and features an extended 5'-UTR that does not contain a competing upstream open reading frame (uORF). We show that the 5'-UTR of NM_000295.4 folds into a well-defined multi-helix structural domain. We systematically destabilized mRNA structure across the NM_000295.4 5'-UTR, and measured changes in (SHAPE quantified) RNA structure and cap-dependent translation relative to a native-sequence reporter. Surprisingly, despite destabilizing local RNA structure, most mutations either had no effect on or decreased translation. Most structure-destabilizing mutations retained native, global 5'-UTR structure. However, those mutations that disrupted the helix that anchors the 5'-UTR domain yielded three groups of non-native structures. Two of these non-native structure groups refolded to create a stable helix near the translation initiation site that decreases translation. Thus, in contrast to the conventional model that RNA structure in 5'-UTRs primarily inhibits translation, complex folding of the NM_000295.4 5'-UTR creates a translation-optimized message by promoting accessibility at the translation initiation site., (© The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.)
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- 2022
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44. Quantitative prediction of variant effects on alternative splicing in MAPT using endogenous pre-messenger RNA structure probing.
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Kumar J, Lackey L, Waldern JM, Dey A, Mustoe AM, Weeks KM, Mathews DH, and Laederach A
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- Exons, Introns, Mutation, RNA Splice Sites, RNA Splicing, RNA, Messenger genetics, Alternative Splicing, RNA Precursors genetics, RNA Precursors metabolism
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Splicing is highly regulated and is modulated by numerous factors. Quantitative predictions for how a mutation will affect precursor mRNA (pre-mRNA) structure and downstream function are particularly challenging. Here, we use a novel chemical probing strategy to visualize endogenous precursor and mature MAPT mRNA structures in cells. We used these data to estimate Boltzmann suboptimal structural ensembles, which were then analyzed to predict consequences of mutations on pre-mRNA structure. Further analysis of recent cryo-EM structures of the spliceosome at different stages of the splicing cycle revealed that the footprint of the B
act complex with pre-mRNA best predicted alternative splicing outcomes for exon 10 inclusion of the alternatively spliced MAPT gene, achieving 74% accuracy. We further developed a β-regression weighting framework that incorporates splice site strength, RNA structure, and exonic/intronic splicing regulatory elements capable of predicting, with 90% accuracy, the effects of 47 known and 6 newly discovered mutations on inclusion of exon 10 of MAPT . This combined experimental and computational framework represents a path forward for accurate prediction of splicing-related disease-causing variants., Competing Interests: JK, LL, JW, AD, AM, DM, AL No competing interests declared, KW is an advisor to and holds equity in Ribometrix, (© 2022, Kumar et al.)- Published
- 2022
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45. Alternative poly-adenylation modulates α1-antitrypsin expression in chronic obstructive pulmonary disease.
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Lackey L, Coria A, Ghosh AJ, Grayeski P, Hatfield A, Shankar V, Platig J, Xu Z, Ramos SBV, Silverman EK, Ortega VE, Cho MH, Hersh CP, Hobbs BD, Castaldi P, and Laederach A
- Subjects
- Cell Line, Codon, Terminator genetics, Gene Expression Regulation genetics, Hepatocytes metabolism, Humans, Liver metabolism, Lung pathology, Macrophages metabolism, Polyadenylation genetics, Proteinase Inhibitory Proteins, Secretory genetics, Proteinase Inhibitory Proteins, Secretory metabolism, Pulmonary Disease, Chronic Obstructive pathology, RNA-Seq, Single-Cell Analysis, T-Lymphocytes metabolism, Lung metabolism, Pulmonary Disease, Chronic Obstructive genetics, alpha 1-Antitrypsin genetics
- Abstract
α1-anti-trypsin (A1AT), encoded by SERPINA1, is a neutrophil elastase inhibitor that controls the inflammatory response in the lung. Severe A1AT deficiency increases risk for Chronic Obstructive Pulmonary Disease (COPD), however, the role of A1AT in COPD in non-deficient individuals is not well known. We identify a 2.1-fold increase (p = 2.5x10-6) in the use of a distal poly-adenylation site in primary lung tissue RNA-seq in 82 COPD cases when compared to 64 controls and replicate this in an independent study of 376 COPD and 267 controls. This alternative polyadenylation event involves two sites, a proximal and distal site, 61 and 1683 nucleotides downstream of the A1AT stop codon. To characterize this event, we measured the distal ratio in human primary tissue short read RNA-seq data and corroborated our results with long read RNA-seq data. Integrating these results with 3' end RNA-seq and nanoluciferase reporter assay experiments we show that use of the distal site yields mRNA transcripts with over 50-fold decreased translation efficiency and A1AT expression. We identified seven RNA binding proteins using enhanced CrossLinking and ImmunoPrecipitation precipitation (eCLIP) with one or more binding sites in the SERPINA1 3' UTR. We combined these data with measurements of the distal ratio in shRNA knockdown experiments, nuclear and cytoplasmic fractionation, and chemical RNA structure probing. We identify Quaking Homolog (QKI) as a modulator of SERPINA1 mRNA translation and confirm the role of QKI in SERPINA1 translation with luciferase reporter assays. Analysis of single-cell RNA-seq showed differences in the distribution of the SERPINA1 distal ratio among hepatocytes, macrophages, αβ-Tcells and plasma cells in the liver. Alveolar Type 1,2, dendritic cells and macrophages also vary in their distal ratio in the lung. Our work reveals a complex post-transcriptional mechanism that regulates alternative polyadenylation and A1AT expression in COPD., Competing Interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests: EKS received grant support from GlaxoSmithKline and Bayer. MHC has received grant support from GlaxoSmithKline and Bayer, consulting fees from Genentech and AstraZeneca, and speaking fees from Illumina. CPH reports grant support from Boehringer-Ingelheim, Novartis, Bayer, Vertex, and personal fees from Takeda outside of this study. PJC has received grant support from GlaxoSmithKline and Bayer and consulting fees from GlaxoSmithKline and Novartis. VEO received fees for participation in independent data and monitoring committees for Regeneron and Sanofi and consulting fees from Sanofi. AL has received consulting fees from Ribometrix. PJG holds equity in Ribometrix, to which correlated chemical probing technologies have been licensed. LL, AC, AJG, AH, VS, JP, ZX, SBVR, and BDH have no conflicts of interest to report.
- Published
- 2021
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46. The historical development of juvenile mortality and adult longevity in zoo-kept carnivores.
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Roller M, Müller DWH, Bertelsen MF, Bingaman Lackey L, Hatt JM, and Clauss M
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- Animals, Animals, Zoo, Longevity
- Abstract
Zoos need to evaluate their aim of high husbandry standards. One way of approaching this is to use the demographic data that has been collected by participating zoos for decades, assessing historical change over time to identify the presence or absence of progress. Using the example of carnivores, with data covering seven decades (1950-2019), 13 carnivore families, and 95 species, we show that juvenile mortality has decreased, and adult longevity increased, over this interval. While no reason for complacency, the results indicate that the commitment of zoos to continuously improve is having measurable consequences., (© 2021 The Authors. Zoo Biology Published by Wiley Periodicals LLC.)
- Published
- 2021
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47. FDA's Benefit-Risk Framework for Human Drugs and Biologics: Role in Benefit-Risk Assessment and Analysis of Use for Drug Approvals.
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Lackey L, Thompson G, and Eggers S
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- Drug Approval, Humans, Risk Assessment, United States, United States Food and Drug Administration, Biological Products, Pharmaceutical Preparations
- Abstract
Background: Structured, descriptive approaches are utilized by drug regulatory agencies to support and communicate approval decisions about human drugs and biologics. The US Food and Drug Administration (FDA) uses the Benefit-Risk Framework (BRF), which has been integrated into its drug review process. This paper reviews how FDA review teams have used the BRF to communicate approval decisions., Methods: This paper (1) uses content analysis to systematically review the decision factors communicated by FDA review teams in all BRFs associated with novel drugs approved by FDA in 2017-2018 and (2) presents a case study about how the BRF was used for three drugs approved for HIV-1 in 2018-2019., Results: The content analysis found most BRFs for novel drug approvals communicate what we call an "urgent" context and complicating decision factors around benefit and/or risk; the HIV-1 case study highlights the flexibility of the structured BRF tool., Conclusions: FDA's BRF provides a flexible mechanism for communicating important decision factors, allowing it to support the diversity of drug approval decisions made by FDA.
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- 2021
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48. The Effects of Rare SERPINA1 Variants on Lung Function and Emphysema in SPIROMICS.
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Ortega VE, Li X, O'Neal WK, Lackey L, Ampleford E, Hawkins GA, Grayeski PJ, Laederach A, Barjaktarevic I, Barr RG, Cooper C, Couper D, Han MK, Kanner RE, Kleerup EC, Martinez FJ, Paine R 3rd, Peters SP, Pirozzi C, Rennard SI, Woodruff PG, Hoffman EA, Meyers DA, and Bleecker ER
- Subjects
- Adult, Black or African American, Aged, Aged, 80 and over, Female, Forced Expiratory Volume, Genotype, Heterozygote, Hispanic or Latino, Humans, Isoelectric Focusing, Male, Maximal Midexpiratory Flow Rate, Middle Aged, Phenotype, Polymorphism, Genetic, Pulmonary Disease, Chronic Obstructive epidemiology, Pulmonary Disease, Chronic Obstructive physiopathology, Pulmonary Emphysema epidemiology, Pulmonary Emphysema metabolism, Pulmonary Emphysema physiopathology, Tomography, X-Ray Computed, Vital Capacity, White People, alpha 1-Antitrypsin metabolism, Lung physiopathology, Pulmonary Disease, Chronic Obstructive genetics, Pulmonary Emphysema genetics, Smoking epidemiology, alpha 1-Antitrypsin genetics
- Abstract
Rationale: The role of PI (protease inhibitor) type Z heterozygotes and additional rare variant genotypes in the gene encoding alpha-1 antitrypsin, SERPINA1 (serpin peptidase inhibitor, clade A, member 1), in determining chronic obstructive pulmonary disease risk and severity is controversial. Objectives: To comprehensively evaluate the effects of rare SERPINA1 variants on lung function and emphysema phenotypes in subjects with significant tobacco smoke exposure using deep gene resequencing and alpha-1 antitrypsin concentrations. Methods: DNA samples from 1,693 non-Hispanic white individuals, 385 African Americans, and 90 Hispanics with ≥20 pack-years smoking were resequenced for the identification of rare variants (allele frequency < 0.05) in 16.9 kB of SERPINA1 . Measurements and Main Results: White PI Z heterozygotes confirmed by sequencing (MZ; n = 74) had lower post-bronchodilator FEV
1 ( P = 0.007), FEV1 /FVC ( P = 0.003), and greater computed tomography-based emphysema ( P = 0.02) compared with 1,411 white individuals without PI Z, S, or additional rare variants denoted as VR . PI Z-containing compound heterozygotes (ZS/ZVR ; n = 7) had lower FEV1 /FVC ( P = 0.02) and forced expiratory flow, midexpiratory phase ( P = 0.009). Nineteen white heterozygotes for five non-S/Z coding variants associated with lower alpha-1 antitrypsin had greater computed tomography-based emphysema compared with those without rare variants. In African Americans, a 5' untranslated region insertion (rs568223361) was associated with lower alpha-1 antitrypsin and functional small airway disease ( P = 0.007). Conclusions: In this integrative deep sequencing study of SERPINA1 with alpha-1 antitrypsin concentrations in a heavy smoker and chronic obstructive pulmonary disease cohort, we confirmed the effects of PI Z heterozygote and compound heterozygote genotypes. We demonstrate the cumulative effects of multiple SERPINA1 variants on alpha-1 antitrypsin deficiency, lung function, and emphysema, thus significantly increasing the frequency of SERPINA1 variation associated with respiratory disease in at-risk smokers.- Published
- 2020
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49. A Rabbit Monoclonal Antibody against the Antiviral and Cancer Genomic DNA Mutating Enzyme APOBEC3B.
- Author
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Brown WL, Law EK, Argyris PP, Carpenter MA, Levin-Klein R, Ranum AN, Molan AM, Forster CL, Anderson BD, Lackey L, and Harris RS
- Abstract
The DNA cytosine deaminase APOBEC3B (A3B) is normally an antiviral factor in the innate immune response. However, A3B has been implicated in cancer mutagenesis, particularly in solid tumors of the bladder, breast, cervix, head/neck, and lung. Here, we report data on the generation and characterization of a rabbit monoclonal antibody (mAb) for human A3B. One mAb, 5210-87-13, demonstrates utility in multiple applications, including ELISA, immunoblot, immunofluorescence microscopy, and immunohistochemistry. In head-to-head tests with commercial reagents, 5210-87-13 was the only rabbit monoclonal suitable for detecting native A3B and for immunohistochemical quantification of A3B in tumor tissues. This novel mAb has the potential to enable a wide range of fundamental and clinical studies on A3B in human biology and disease.
- Published
- 2019
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50. A Functional riboSNitch in the 3' Untranslated Region of FKBP5 Alters MicroRNA-320a Binding Efficiency and Mediates Vulnerability to Chronic Post-Traumatic Pain.
- Author
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Linnstaedt SD, Riker KD, Rueckeis CA, Kutchko KM, Lackey L, McCarthy KR, Tsai YH, Parker JS, Kurz MC, Hendry PL, Lewandowski C, Datner E, Pearson C, O'Neil B, Domeier R, Kaushik S, Laederach A, and McLean SA
- Subjects
- 3' Untranslated Regions, Adult, Black or African American genetics, Alleles, Chronic Pain metabolism, Female, Genotype, Humans, Male, MicroRNAs metabolism, Musculoskeletal Pain metabolism, Polymorphism, Single Nucleotide, Protein Binding, Protein Structure, Secondary, RNA, Messenger metabolism, Receptors, Glucocorticoid metabolism, Tacrolimus Binding Proteins metabolism, White People genetics, Young Adult, Chronic Pain genetics, MicroRNAs genetics, Musculoskeletal Pain genetics, Tacrolimus Binding Proteins genetics
- Abstract
Previous studies have shown that common variants of the gene coding for FK506-binding protein 51 ( FKBP5 ), a critical regulator of glucocorticoid sensitivity, affect vulnerability to stress-related disorders. In a previous report, FKBP5 rs1360780 was identified as a functional variant because of its effect on gene methylation. Here we report evidence for a novel functional FKBP5 allele, rs3800373. This study assessed the association between rs3800373 and post-traumatic chronic pain in 1607 women and men from two ethnically diverse human cohorts. The molecular mechanism through which rs3800373 affects adverse outcomes was established via in silico , in vivo , and in vitro analyses. The rs3800373 minor allele predicted worse adverse outcomes after trauma exposure, such that individuals with the minor (risk) allele developed more severe post-traumatic chronic musculoskeletal pain. Among these individuals, peritraumatic circulating FKBP5 expression levels increased as cortisol and glucocorticoid receptor ( NR3C1 ) mRNA levels increased, consistent with increased glucocorticoid resistance. Bioinformatic, in vitro , and mutational analyses indicate that the rs3800373 minor allele reduces the binding of a stress- and pain-associated microRNA, miR-320a, to FKBP5 via altering the FKBP5 mRNA 3'UTR secondary structure (i.e., is a riboSNitch). This results in relatively greater FKBP5 translation, unchecked by miR-320a. Overall, these results identify an important gene-miRNA interaction influencing chronic pain risk in vulnerable individuals and suggest that exogenous methods to achieve targeted reduction in poststress FKBP5 mRNA expression may constitute useful therapeutic strategies. SIGNIFICANCE STATEMENT FKBP5 is a critical regulator of the stress response. Previous studies have shown that dysregulation of the expression of this gene plays a role in the pathogenesis of chronic pain development as well as a number of comorbid neuropsychiatric disorders. In the current study, we identified a functional allele (rs3800373) in the 3'UTR of FKBP5 that influences vulnerability to chronic post-traumatic pain in two ethnic cohorts. Using multiple complementary experimental approaches, we show that the FKBP5 rs3800373 minor allele alters the secondary structure of FKBP5 mRNA, decreasing the binding of a stress- and pain-associated microRNA, miR-320a. This results in relatively greater FKBP5 translation, unchecked by miR-320a, increasing glucocorticoid resistance and increasing vulnerability to post-traumatic pain., (Copyright © 2018 the authors 0270-6474/18/388408-14$15.00/0.)
- Published
- 2018
- Full Text
- View/download PDF
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