170 results on '"Johnston RA"'
Search Results
2. Selective inhibition of human solute carrier transporters by multikinase inhibitors
- Author
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Johnston, RA, Rawling, T, Chan, T, Zhou, F, Murray, M, Johnston, RA, Rawling, T, Chan, T, Zhou, F, and Murray, M
- Abstract
© 2014 by The American Society for Pharmacology and Experimental Therapeutics. Solute carrier (SLC) transporters regulate the cellular influx and disposition of endogenous and xenobiotic compounds, including anticancer agents such as the multikinase inhibitors (MKIs). Recent evidence suggests that MKIs may also inhibit SLC-dependent transport of coadministered drugs, although present information on the relative susceptibilities of multiple SLC transporters is limited. This study evaluated 18 MKI drugs and metabolites as inhibitors of prototypic substrate uptake by 13 SLC transporters that were overexpressed in human embryonic kidney cells. Organic anion transporting polypeptides (OATPs) 1A2, 1B3, and 2B1, organic anion transporter 3 (OAT3), and organic cation transporter 1 (OCT1) were inhibited by most MKIs, whereas substrate uptake by OATP1B1, OAT1, 2, and 4, OCT2 and 3, and organic zwitterion/cation transporter 1 (OCTN1) was less susceptible to inhibition; OCTN2 was also inhibited by cediranib. In further studies, IC50 values were determined for the most effective MKIs, and erlotinib and cediranib were found to be potent competitive inhibitors of OATP2B1 (Ki= 41 nM) and OATP1A2 (Ki= 33 nM), respectively. From predictive approaches, several MKI-SLC interactions were found to be of potential in vivo significance. Copyright
- Published
- 2014
3. Thoracic radiculopathy caused by a myodil cyst
- Author
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M. O. Fitzpatrick, Goyal K, and Johnston Ra
- Subjects
Radicular Syndrome ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Cysts ,Contrast Media ,General Medicine ,Middle Aged ,medicine.disease ,Thoracic Vertebrae ,Thoracic radiculopathy ,Surgery ,medicine ,Humans ,Cyst ,Female ,Spinal Diseases ,Neurology (clinical) ,Complication ,business ,Iophendylate ,Radiculopathy ,Myelography - Abstract
We report the case of a myodil cyst causing a thoracic radiculopathy in a patient who had undergone a myelogram 30 years previously. Although myodil is no longer used, sequelae can continue to be seen for many years.
- Published
- 2000
4. Transoral evacuation of a clivus extradural haematoma with good recovery: a case report
- Author
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Johnston Ra, Marks Sm, and Paramaraswaren Rn
- Subjects
Hematoma, Epidural, Cranial ,medicine.medical_specialty ,Joint Dislocations ,Quadriplegia ,Extradural haematoma ,Respiratory paralysis ,Hematoma ,Clivus ,medicine ,Humans ,Good outcome ,Child ,Tetraplegia ,Surgical approach ,business.industry ,Accidents, Traffic ,General Medicine ,medicine.disease ,nervous system diseases ,Surgery ,body regions ,medicine.anatomical_structure ,Atlanto-Axial Joint ,Cranial Fossa, Posterior ,Female ,Neurology (clinical) ,Transoral surgery ,business ,Tomography, X-Ray Computed - Abstract
We report a case of traumatic atlanto-axial dislocation with a clivus and upper cervical extradural haematoma causing tetraplegia and respiratory paralysis. Surgical evacuation via the transoral route with posterior atlanto-axial fixation resulted in survival with a good outcome.
- Published
- 1997
5. Impact of Plasminogen Activator Inhibitor-1 (PAI-1) Deficiency on Pulmonary Responses to Ozone (O3).
- Author
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Johnston, RA, primary, Hernandez, CB, additional, and Hallberg, LM, additional
- Published
- 2009
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6. Interlaminar Clamp for Posterior Fusions
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Seex K and Johnston Ra
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Clamp ,business.industry ,Medicine ,Anatomy ,business - Published
- 1991
7. Age of acquisition effects on an object-name verification task.
- Author
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Catling JC and Johnston RA
- Abstract
Naming latencies for words, objects and faces have been shown to be affected by the age at which an item is acquired (AoA). Originally, this effect was explained in terms of differential access to name representations. However, a number of recent studies have found AoA effects in tasks which do not require access to names (e.g. Brysbaert, Van Wijnendaele, & De Deynes, 2000; Lewis, 1999; Moore, Smith Spark, & Valentine, 2004; Moore & Valentine, 1999). Ellis and Lambon Ralph (2000) propose an alternative account of AoA, predicting that the effect should arise in any task where previously stored information is retrieved. The current study explored the effect of AoA on an object-name verification task. Experiments 1 and 2 demonstrated that early acquired objects were verified significantly faster than later acquired objects. A third experiment collected naming latencies for the same picture stimuli in order to allow a comparison of the magnitude of the AoA effect for object verification and naming. The implications of these findings for accounts of AoA and its locus of effect are discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2006
- Full Text
- View/download PDF
8. Age of acquisition effects in the semantic processing of pictures.
- Author
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Johnston RA and Barry C
- Abstract
In two experiments, we investigated the role of age of acquisition (AoA) in the categorizing of objects in semantic tasks that do not require access to the object names. In both a found inside or outside the house (Experiment 1A) and a smaller or larger than a loaf of bread (Experiment 2A) classification task, objects with earlier-acquired names were categorized more quickly than those with later-acquired names. Experiments 1B and 2B also showed AoA effects on object-naming times for the same pictures. We conclude that AoA operates within the identification process in a fashion not simply restricted to name retrieval. These effects may be better explained in terms of the connectionist model proposed by Ellis and Lambon Ralph (2000) or by accounts that locate AoA within the semantic system (e.g., Brysbaert, Van Wijnendaele, & De Deyne, 2000; van Loon-Vervoorn, 1989). [ABSTRACT FROM AUTHOR]
- Published
- 2005
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9. Delayed hydrocephalus as an unusual complication of a stab injury to the spine.
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Joseph, G, Johnston, RA, Fraser, MH, and McLean, AN
- Subjects
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SPINAL cord injuries , *STAB wounds , *DISEASE complications , *HYDROCEPHALUS , *CERVICAL vertebrae , *TEACHING hospitals - Abstract
STUDY DESIGN::Case report. OBJECTIVE::To report a rare complication following a stab injury to the upper cervical spine and cord. SETTING::National spinal injury unit in a Scottish university teaching hospital. CASE REPORT::A 19-year-old male sustained a stab injury to his upper cervical spine, with a partial cord transection. After 5 months of rehabilitation, his condition deteriorated. CT scans showed hydrocephalus, which was treated by shunting. After shunting, the patient's condition improved but he remained tetraplegic requiring ventilatory support at night. CONCLUSION::Hydrocephalus as a late complication of a cervical spine injury is rare but should be considered if the condition of the patient with an upper cervical spine injury deteriorates. The likely mechanism of the hydrocephalus development is also discussed.Spinal Cord (2005) 43, 56-58. doi:10.1038/sj.sc.3101655; Published online 10 August 2004 [ABSTRACT FROM AUTHOR]
- Published
- 2005
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10. Congenital Disorders and Infections and Cancer. Handbook of the Spinal Cord Vols 4 & 5
- Author
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Johnston, RA
- Subjects
Book Reviews - Published
- 1987
11. Advanced Intraoperative Technologies in Neurosurgery
- Author
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Johnston, RA
- Subjects
Book Reviews - Published
- 1986
12. An analysis of 641 repeat cesarean sections
- Author
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Morgan and Johnston Ra
- Subjects
medicine.medical_specialty ,Biometry ,business.industry ,Obstetrics ,Cesarean Section ,Pregnancy ,Medicine ,Humans ,Female ,General Medicine ,Cesarean Section, Repeat ,business - Published
- 1957
13. SPC-P1: a pathogenicity-associated prophage of Salmonella paratyphi C
- Author
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Li Yong-Guo, Feng Ye, Zhu Hong-Yun, Li Qing-Hai, Zou Qing-Hua, Johnston Randal N, Liu Gui-Rong, and Liu Shu-Lin
- Subjects
Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background Salmonella paratyphi C is one of the few human-adapted pathogens along with S. typhi, S. paratyphi A and S. paratyphi B that cause typhoid, but it is not clear whether these bacteria cause the disease by the same or different pathogenic mechanisms. Notably, these typhoid agents have distinct sets of large genomic insertions, which may encode different pathogenicity factors. Previously we identified a novel prophage, SPC-P1, in S. paratyphi C RKS4594 and wondered whether it might be involved in pathogenicity of the bacteria. Results We analyzed the sequence of SPC-P1 and found that it is an inducible phage with an overall G+C content of 47.24%, similar to that of most Salmonella phages such as P22 and ST64T but significantly lower than the 52.16% average of the RKS4594 chromosome. Electron microscopy showed short-tailed phage particles very similar to the lambdoid phage CUS-3. To evaluate its roles in pathogenicity, we lysogenized S. paratyphi C strain CN13/87, which did not have this prophage, and infected mice with the lysogenized CN13/87. Compared to the phage-free wild type CN13/87, the lysogenized CN13/87 exhibited significantly increased virulence and caused multi-organ damages in mice at considerably lower infection doses. Conclusions SPC-P1 contributes pathogenicity to S. paratyphi C in animal infection models, so it is possible that this prophage is involved in typhoid pathogenesis in humans. Genetic and functional analyses of SPC-P1 may facilitate the study of pathogenic evolution of the extant typhoid agents, providing particular help in elucidating the pathogenic determinants of the typhoid agents.
- Published
- 2010
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14. Multiple genetic switches spontaneously modulating bacterial mutability
- Author
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Johnston Randal N, Eisenstark Abraham, Liu Wei-Qiao, Chen Fang, Liu Gui-Rong, and Liu Shu-Lin
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Evolution ,QH359-425 - Abstract
Abstract Background All life forms need both high genetic stability to survive as species and a degree of mutability to evolve for adaptation, but little is known about how the organisms balance the two seemingly conflicting aspects of life: genetic stability and mutability. The DNA mismatch repair (MMR) system is essential for maintaining genetic stability and defects in MMR lead to high mutability. Evolution is driven by genetic novelty, such as point mutation and lateral gene transfer, both of which require genetic mutability. However, normally a functional MMR system would strongly inhibit such genomic changes. Our previous work indicated that MMR gene allele conversion between functional and non-functional states through copy number changes of small tandem repeats could occur spontaneously via slipped-strand mis-pairing during DNA replication and therefore may play a role of genetic switches to modulate the bacterial mutability at the population level. The open question was: when the conversion from functional to defective MMR is prohibited, will bacteria still be able to evolve by accepting laterally transferred DNA or accumulating mutations? Results To prohibit allele conversion, we "locked" the MMR genes through nucleotide replacements. We then scored changes in bacterial mutability and found that Salmonella strains with MMR locked at the functional state had significantly decreased mutability. To determine the generalizability of this kind of mutability 'switching' among a wider range of bacteria, we examined the distribution of tandem repeats within MMR genes in over 100 bacterial species and found that multiple genetic switches might exist in these bacteria and may spontaneously modulate bacterial mutability during evolution. Conclusions MMR allele conversion through repeats-mediated slipped-strand mis-pairing may function as a spontaneous mechanism to switch between high genetic stability and mutability during bacterial evolution.
- Published
- 2010
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15. Diverse genome structures of Salmonella paratyphi C
- Author
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Qi Danni, Xu Guo-Min, Li Jun-Qian, Liu Gui-Rong, Liu Wei-Qiao, He Xiao-Yan, Deng Juan, Zhang Feng-Min, Johnston Randal N, and Liu Shu-Lin
- Subjects
Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Background Salmonella paratyphi C, like S. typhi, is adapted to humans and causes typhoid fever. Previously we reported different genome structures between two strains of S. paratyphi C, which suggests that S. paratyphi C might have a plastic genome (large DNA segments being organized in different orders or orientations on the genome). As many but not all host-adapted Salmonella pathogens have large genomic insertions as well as the supposedly resultant genomic rearrangements, bacterial genome plasticity presents an extraordinary evolutionary phenomenon. Events contributing to genomic plasticity, especially large insertions, may be associated with the formation of particular Salmonella pathogens. Results We constructed a high resolution genome map in S. paratyphi C strain RKS4594 and located four insertions totaling 176 kb (including the 90 kb SPI7) and seven deletions totaling 165 kb relative to S. typhimurium LT2. Two rearrangements were revealed, including an inversion of 1602 kb covering the ter region and the translocation of the 43 kb I-CeuI F fragment. The 23 wild type strains analyzed in this study exhibited diverse genome structures, mostly as a result of recombination between rrn genes. In at least two cases, the rearrangements involved recombination between genomic sites other than the rrn genes, possibly homologous genes in prophages. Two strains had a 20 kb deletion between rrlA and rrlB, which is a highly conservative region and no deletion has been reported in this region in any other Salmonella lineages. Conclusion S. paratyphi C has diverse genome structures among different isolates, possibly as a result of large genomic insertions, e.g., SPI7. Although the Salmonella typhoid agents may not be more closely related among them than each of them to other Salmonella lineages, they may have evolved in similar ways, i.e., acquiring typhoid-associated genes followed by genome structure rearrangements. Comparison of multiple Salmonella typhoid agents at both single sequenced genome and population levels will facilitate the studies on the evolutionary process of typhoid pathogenesis, especially the identification of typhoid-associated genes.
- Published
- 2007
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16. Macrophage inflammatory protein-2 levels are associated with changes in serum leptin concentrations following ozone-induced airway inflammation.
- Author
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Johnston RA, Schwartzman IN, and Shore SA
- Published
- 2003
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17. Age of acquisition, word frequency, and the locus of repetition priming of picture naming.
- Author
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Barry C, Hirsh KW, Johnston RA, and Williams CL
- Abstract
We examined the roles of age of acquisition (AoA) and word frequency in picture naming latencies and studied repetition priming to illuminate the locus and mechanism by which the effective variable has its effect. Experiment 1 found that AoA affected naming latencies when frequency was controlled, and Experiment 2 found that frequency had no effect when AoA was controlled. Experiment 3 found no effects of either AoA or frequency in delayed picture naming. Picture naming was facilitated by the prior naming of identical pictures and, to a lesser extent, by the prior reading aloud of the names. Repetition priming interacted with AoA but did not interact with frequency. We conclude that both AoA and long-lasting repetition priming operate at the level of lexical-phonological retrieval and that repetition interacts with AoA because it facilitates the retrieval of lexical-phonological elements required for naming, which benefits late-acquired words differentially. Copyright 2001 Academic Press. [ABSTRACT FROM AUTHOR]
- Published
- 2001
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18. Clinical Neurosurgery. (Congress of Neurological Surgeons Vol 32.).
- Author
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Johnston, Ra
- Published
- 1986
19. Cerebrospinal Fluid Pulse Pressure and Craniospinal Dynamics. A Theoretical, Clinical and Experimental Study.
- Author
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Johnston, Ra
- Published
- 1984
20. The path less traveled: Using structural equation modeling to investigate factors influencing bone functional morphology.
- Author
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Johnston RA and Cowgill LW
- Subjects
- Humans, Female, Male, Adult, Middle Aged, Exercise physiology, Nutrition Surveys, Bone Density physiology, Aged, Young Adult, Body Composition physiology, Body Mass Index, Latent Class Analysis, Bone and Bones physiology
- Abstract
Objectives: The relationship between an organism's mechanical environment and its bone strength has been long established by experimental research. Multiple intrinsic and extrinsic factors, including body mass, muscle strength, genetic background, and nutritional and/or hormonal status, are likely to influence bone deposition and resorption throughout the lifespan, complicating this relationship. Structural equation modeling (SEM) is uniquely positioned to parse this complex set of influences., Materials and Methods: Data from the Third National Health and Nutrition Examination Survey, including sex, total body mass, lean body mass, exercise frequency, peak body mass, and age, were analyzed using SEM to determine how they affect bone strength both individually and combined., Results: Body mass is typically the driver of cross-sectional area, but body mass and lean mass have similar effects on the polar moment of area (J). Peak body mass had a strong direct effect on J, despite decreasing strongly with increases in lean mass. Exercise also did not confer a large direct effect on cross-sectional area or J but did modify body mass and lean mass. In females, intentional weight loss was associated with decreased exercise levels., Discussion: SEM is a useful tool for parsing complex systems in bone functional morphology and has the potential to uncover causal links in the study of skeletal remodeling, including factors like weight loss or exercise that may have secondary effects., (© 2024 Wiley Periodicals LLC.)
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- 2024
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21. Weighted Breaths: Exploring Biologic and Non-Biologic Therapies for Co-Existing Asthma and Obesity.
- Author
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Pilkington AW 4th, Buragamadagu B, and Johnston RA
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- Humans, Probiotics therapeutic use, Asthma drug therapy, Asthma complications, Obesity complications, Obesity drug therapy, Anti-Asthmatic Agents therapeutic use, Biological Products therapeutic use
- Abstract
Purpose of Review: To discuss the effectiveness of biologics, some of which comprise the newest class of asthma controller medications, and non-biologics in the treatment of asthma co-existing with obesity., Recent Findings: Our review of recent preliminary and published data from clinical trials revealed that obese asthmatics respond favorably to dupilumab, mepolizumab, omalizumab, and tezepelumab, which are biologics currently indicated as add-on maintenance therapy for severe asthma. Furthermore, clinical trials are ongoing to assess the efficacy of non-biologics in the treatment of obese asthma, including a glucagon-like peptide-1 receptor agonist, a Janus kinase inhibitor, and probiotics. Although many biologics presently indicated as add-on maintenance therapy for severe asthma exhibit efficacy in obese asthmatics, other phenotypes of asthma co-existing with obesity may be refractory to these medications. Thus, to improve quality of life and asthma control, it is imperative to identify therapeutic options for all existing phenotypes of obese asthma., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)
- Published
- 2024
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22. Inconsequential role for chemerin-like receptor 1 in the manifestation of ozone-induced lung pathophysiology in male mice.
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Johnston RA, Pilkington AW 4th, Atkins CL, Boots TE, Brown PL, Jackson WT, Spencer CY, Siddiqui SR, and Haque IU
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- Animals, Mice, Male, Adiponectin pharmacology, Lung, Bronchoalveolar Lavage Fluid, Receptors, G-Protein-Coupled, Chemokines pharmacology, Intercellular Signaling Peptides and Proteins pharmacology, Ozone adverse effects, Pneumonia chemically induced, Asthma genetics
- Abstract
We executed this study to determine if chemerin-like receptor 1 (CMKLR1), a G
i/o protein-coupled receptor expressed by leukocytes and non-leukocytes, contributes to the development of phenotypic features of non-atopic asthma, including airway hyperresponsiveness (AHR) to acetyl-β-methylcholine chloride, lung hyperpermeability, airway epithelial cell desquamation, and lung inflammation. Accordingly, we quantified sequelae of non-atopic asthma in wild-type mice and mice incapable of expressing CMKLR1 (CMKLR1-deficient mice) following cessation of acute inhalation exposure to either filtered room air (air) or ozone (O3 ), a criteria pollutant and non-atopic asthma stimulus. Following exposure to air, lung elastic recoil and airway responsiveness were greater while the quantity of adiponectin, a multi-functional adipocytokine, in bronchoalveolar lavage (BAL) fluid was lower in CMKLR1-deficient as compared to wild-type mice. Regardless of genotype, exposure to O3 caused AHR, lung hyperpermeability, airway epithelial cell desquamation, and lung inflammation. Nevertheless, except for minimal genotype-related effects on lung hyperpermeability and BAL adiponectin, we observed no other genotype-related differences following O3 exposure. In summary, we demonstrate that CMKLR1 limits the severity of innate airway responsiveness and lung elastic recoil but has a nominal effect on lung pathophysiology induced by acute exposure to O3 ., (© 2024 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)- Published
- 2024
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23. DNA methylation signatures of early-life adversity are exposure-dependent in wild baboons.
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Anderson JA, Lin D, Lea AJ, Johnston RA, Voyles T, Akinyi MY, Archie EA, Alberts SC, and Tung J
- Subjects
- Animals, Nucleotide Motifs, Biological Assay, Papio genetics, DNA Methylation, Adverse Childhood Experiences
- Abstract
The early-life environment can profoundly shape the trajectory of an animal's life, even years or decades later. One mechanism proposed to contribute to these early-life effects is DNA methylation. However, the frequency and functional importance of DNA methylation in shaping early-life effects on adult outcomes is poorly understood, especially in natural populations. Here, we integrate prospectively collected data on fitness-associated variation in the early environment with DNA methylation estimates at 477,270 CpG sites in 256 wild baboons. We find highly heterogeneous relationships between the early-life environment and DNA methylation in adulthood: aspects of the environment linked to resource limitation (e.g., low-quality habitat, early-life drought) are associated with many more CpG sites than other types of environmental stressors (e.g., low maternal social status). Sites associated with early resource limitation are enriched in gene bodies and putative enhancers, suggesting they are functionally relevant. Indeed, by deploying a baboon-specific, massively parallel reporter assay, we show that a subset of windows containing these sites are capable of regulatory activity, and that, for 88% of early drought-associated sites in these regulatory windows, enhancer activity is DNA methylation-dependent. Together, our results support the idea that DNA methylation patterns contain a persistent signature of the early-life environment. However, they also indicate that not all environmental exposures leave an equivalent mark and suggest that socioenvironmental variation at the time of sampling is more likely to be functionally important. Thus, multiple mechanisms must converge to explain early-life effects on fitness-related traits., Competing Interests: Competing interests statement:The authors declare no competing interest.
- Published
- 2024
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24. DNA methylation-environment interactions in the human genome.
- Author
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Johnston RA, Aracena KA, Barreiro LB, Lea AJ, and Tung J
- Subjects
- Humans, Genome, Human, Biological Assay, Environmental Exposure, Interferon-alpha, DNA Methylation, Gene-Environment Interaction
- Abstract
Previously, we showed that a massively parallel reporter assay, mSTARR-seq, could be used to simultaneously test for both enhancer-like activity and DNA methylation-dependent enhancer activity for millions of loci in a single experiment (Lea et al., 2018). Here, we apply mSTARR-seq to query nearly the entire human genome, including almost all CpG sites profiled either on the commonly used Illumina Infinium MethylationEPIC array or via reduced representation bisulfite sequencing. We show that fragments containing these sites are enriched for regulatory capacity, and that methylation-dependent regulatory activity is in turn sensitive to the cellular environment. In particular, regulatory responses to interferon alpha (IFNA) stimulation are strongly attenuated by methyl marks, indicating widespread DNA methylation-environment interactions. In agreement, methylation-dependent responses to IFNA identified via mSTARR-seq predict methylation-dependent transcriptional responses to challenge with influenza virus in human macrophages. Our observations support the idea that pre-existing DNA methylation patterns can influence the response to subsequent environmental exposures-one of the tenets of biological embedding. However, we also find that, on average, sites previously associated with early life adversity are not more likely to functionally influence gene regulation than expected by chance., Competing Interests: RJ, KA, LB, AL No competing interests declared, JT Reviewing editor, eLife, (© 2023, Johnston et al.)
- Published
- 2024
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25. DNA methylation-environment interactions in the human genome.
- Author
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Johnston RA, Aracena KA, Barreiro LB, Lea AJ, and Tung J
- Abstract
Previously we showed that a massively parallel reporter assay, mSTARR-seq, could be used to simultaneously test for both enhancer-like activity and DNA methylation-dependent enhancer activity for millions of loci in a single experiment (Lea et al ., 2018). Here we apply mSTARR-seq to query nearly the entire human genome, including almost all CpG sites profiled either on the commonly used Illumina Infinium MethylationEPIC array or via reduced representation bisulfite sequencing. We show that fragments containing these sites are enriched for regulatory capacity, and that methylation-dependent regulatory activity is in turn sensitive to the cellular environment. In particular, regulatory responses to interferon alpha (IFNA) stimulation are strongly attenuated by methyl marks, indicating widespread DNA methylation-environment interactions. In agreement, methylation-dependent responses to IFNA identified via mSTARR-seq predict methylation-dependent transcriptional responses to challenge with influenza virus in human macrophages. Our observations support the idea that pre-existing DNA methylation patterns can influence the response to subsequent environmental exposures-one of the tenets of biological embedding. However, we also find that, on average, sites previously associated with early life adversity are not more likely to functionally influence gene regulation than expected by chance.
- Published
- 2023
- Full Text
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26. Building Career Paths for Ph.D., Basic and Translational Scientists in Clinical Departments in the United States: An Official American Thoracic Society Workshop Report.
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Moore BB, Ballinger MN, Bauer NN, Blackwell TS, Borok Z, Budinger GRS, Camoretti-Mercado B, Erzurum SC, Himes BE, Keshamouni VG, Kulkarni HS, Mallampalli RK, Mariani TJ, Martinez FJ, McCombs JE, Newcomb DC, Johnston RA, O'Reilly MA, Prakash YS, Ridge KM, Sime PJ, Sperling AI, Violette S, Wilkes DS, and Königshoff M
- Subjects
- Adult, United States, Humans, Child, Personnel Selection, Leadership, Faculty, Medical, Academic Medical Centers, Physicians
- Abstract
Rationale: To identify barriers and opportunities for Ph.D., basic and translational scientists to be fully integrated into clinical units. Objectives: In 2022, an ad hoc committee of the American Thoracic Society developed a project proposal and workshop to identify opportunities and barriers for scientists who do not practice medicine to develop successful careers and achieve tenure-track faculty positions in clinical departments and divisions within academic medical centers (AMCs) in the United States. Methods: This document focuses on results from a survey of adult and pediatric pulmonary, critical care, and sleep medicine division chiefs as well as a survey of workshop participants, including faculty in departmental and school leadership roles in both basic science and clinical units within U.S. AMCs. Results: We conclude that full integration of non-clinically practicing basic and translational scientists into the clinical units, in addition to their traditional placements in basic science units, best serves the tripartite mission of AMCs to provide care, perform research, and educate the next generation. Evidence suggests clinical units do employ Ph.D. scientists in large numbers, but these faculty are often hired into non-tenure track positions, which do not provide the salary support, start-up funds, research independence, or space often associated with hiring in basic science units within the same institution. These barriers to success of Ph.D. faculty in clinical units are largely financial. Conclusions: Our recommendation is for AMCs to consider and explore some of our proposed strategies to accomplish the goal of integrating basic and translational scientists into clinical units in a meaningful way.
- Published
- 2023
- Full Text
- View/download PDF
27. DNA methylation signatures of early life adversity are exposure-dependent in wild baboons.
- Author
-
Anderson JA, Lin D, Lea AJ, Johnston RA, Voyles T, Akinyi MY, Archie EA, Alberts SC, and Tung J
- Abstract
The early life environment can profoundly shape the trajectory of an animal's life, even years or decades later. One mechanism proposed to contribute to these early life effects is DNA methylation. However, the frequency and functional importance of DNA methylation in shaping early life effects on adult outcomes is poorly understood, especially in natural populations. Here, we integrate prospectively collected data on fitness-associated variation in the early environment with DNA methylation estimates at 477,270 CpG sites in 256 wild baboons. We find highly heterogeneous relationships between the early life environment and DNA methylation in adulthood: aspects of the environment linked to resource limitation (e.g., low-quality habitat, early life drought) are associated with many more CpG sites than other types of environmental stressors (e.g., low maternal social status). Sites associated with early resource limitation are enriched in gene bodies and putative enhancers, suggesting they are functionally relevant. Indeed, by deploying a baboon-specific, massively parallel reporter assay, we show that a subset of windows containing these sites are capable of regulatory activity, and that, for 88% of early drought-associated sites in these regulatory windows, enhancer activity is DNA methylation-dependent. Together, our results support the idea that DNA methylation patterns contain a persistent signature of the early life environment. However, they also indicate that not all environmental exposures leave an equivalent mark and suggest that socioenvironmental variation at the time of sampling is more likely to be functionally important. Thus, multiple mechanisms must converge to explain early life effects on fitness-related traits.
- Published
- 2023
- Full Text
- View/download PDF
28. Monoclonal Antibodies Specific for SARS-CoV-2 Spike Protein Suitable for Multiple Applications for Current Variants of Concern.
- Author
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Morgan MS, Yan K, Le TT, Johnston RA, Amarilla AA, Muller DA, McMillan CLD, Modhiran N, Watterson D, Potter JR, Sng JDJ, Lor M, Paramitha D, Isaacs A, Khromykh AA, Hall RA, Suhrbier A, Rawle DJ, and Hobson-Peters J
- Subjects
- Animals, Humans, Mice, Spike Glycoprotein, Coronavirus genetics, SARS-CoV-2 genetics, Mice, Transgenic, Antibodies, Viral, Antibodies, Neutralizing, Antibodies, Monoclonal, COVID-19
- Abstract
The global coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spawned an ongoing demand for new research reagents and interventions. Herein we describe a panel of monoclonal antibodies raised against SARS-CoV-2. One antibody showed excellent utility for immunohistochemistry, clearly staining infected cells in formalin-fixed and paraffin embedded lungs and brains of mice infected with the original and the omicron variants of SARS-CoV-2. We demonstrate the reactivity to multiple variants of concern using ELISAs and describe the use of the antibodies in indirect immunofluorescence assays, Western blots, and rapid antigen tests. Finally, we illustrate the ability of two antibodies to reduce significantly viral tissue titers in K18-hACE2 transgenic mice infected with the original and an omicron isolate of SARS-CoV-2.
- Published
- 2022
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- View/download PDF
29. Interleukin-11 receptor subunit α-1 is required for maximal airway responsiveness to methacholine after acute exposure to ozone.
- Author
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Johnston RA, Atkins CL, Siddiqui SR, Jackson WT, Mitchell NC, Spencer CY, Pilkington AW 4th, Kashon ML, and Haque IU
- Subjects
- Humans, Mice, Animals, Methacholine Chloride adverse effects, Interleukin-11 adverse effects, Receptors, Interleukin-11, Bronchoalveolar Lavage Fluid, Ozone toxicity, Asthma genetics, Pneumonia chemically induced, Pneumonia genetics, Pneumonia complications
- Abstract
Interleukin (IL)-11, a multifunctional cytokine, contributes to numerous biological processes, including adipogenesis, hematopoiesis, and inflammation. Asthma, a respiratory disease, is notably characterized by reversible airway obstruction, persistent lung inflammation, and airway hyperresponsiveness (AHR). Nasal insufflation of IL-11 causes AHR in wild-type mice while lung inflammation induced by antigen sensitization and challenge, which mimics features of atopic asthma in humans, is attenuated in mice genetically deficient in IL-11 receptor subunit α-1 (IL-11Rα1-deficient mice), a transmembrane receptor that is required conjointly with glycoprotein 130 to transduce IL-11 signaling. Nevertheless, the contribution of IL-11Rα1 to characteristics of nonatopic asthma is unknown. Thus, based on the aforementioned observations, we hypothesized that genetic deficiency of IL-11Rα1 attenuates lung inflammation and increases airway responsiveness after acute inhalation exposure to ozone (O
3 ), a criteria pollutant and nonatopic asthma stimulus. Accordingly, 4 and/or 24 h after cessation of exposure to filtered room air or O3 , we assessed lung inflammation and airway responsiveness in wild-type and IL-11Rα1-deficient mice. With the exception of bronchoalveolar lavage macrophages and adiponectin, which were significantly increased and decreased, respectively, in O3 -exposed IL-11Rα1-deficient as compared with O3 -exposed wild-type mice, no other genotype-related differences in lung inflammation indices that we quantified were observed in O3 -exposed mice. However, airway responsiveness to acetyl-β-methylcholine chloride (methacholine) was significantly diminished in IL-11Rα1-deficient as compared with wild-type mice after O3 exposure. In conclusion, these results demonstrate that IL-11Rα1 minimally contributes to lung inflammation but is required for maximal airway responsiveness to methacholine in a mouse model of nonatopic asthma.- Published
- 2022
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30. High-fat Western diet consumption exacerbates silica-induced pulmonary inflammation and fibrosis.
- Author
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Thompson JA, Johnston RA, Price RE, Hubbs AF, Kashon ML, McKinney W, and Fedan JS
- Abstract
Consumption of a high-fat Western diet (HFWD) contributes to obesity, disrupted adipose endocrine function, and development of metabolic dysfunction (MetDys). Impaired lung function, pulmonary hypertension, and asthma are all associated with MetDys. Over 35% of adults in the U.S. have MetDys, yet interactions between MetDys and hazardous occupational inhalation exposures are largely unknown. Occupational silica-inhalation leads to chronic lung inflammation, progressive fibrosis, and significant respiratory morbidity and mortality. In this study, we aim to determine the potential of HFWD-consumption to alter silica-induced inflammatory responses in the lung. Six-wk old male F344 rats fed a high fat Western diet (HFWD; 45 kcal % fat, sucrose 22.2% by weight) to induce MetDys, or standard rat chow (STD, controls) for 16 wk were subsequently exposed to silica (6 h/d, 5 d/wk, 39 d; Min-U-Sil 5®, 15 mg/m
3 ) or filtered air; animals remained on their assigned diet for the study duration. Indices of lung inflammation and histopathologic assessment of lung tissue were quantified at 0, 4, and 8 wk after cessation of exposure. Combined HFWD+silica exposure increased bronchoalveolar lavage (BAL) total cells, leukocytes, and BAL lactate dehydrogenase compared to STD+silica exposure controls at all timepoints. HFWD+silica exposure increased BAL proinflammatory cytokines at 4 and 8 wk compared to STD+silica exposure. At 8 wk, histopathological analysis confirmed that alveolitis, epithelial cell hypertrophy and hyperplasia, lipoproteinosis, fibrosis, bronchoalveolar lymphoid hyperplasia and granulomas were exacerbated in the HFWD+silica-exposed group compared to STD+silica-exposed controls. Our results suggest an increased susceptibility to silica-induced lung disease caused by HFWD consumption., Competing Interests: The authors declare that they have no conflicts of interest in relation to this publication.- Published
- 2022
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31. High-fat western diet-consumption alters crystalline silica-induced serum adipokines, inflammatory cytokines and arterial blood flow in the F344 rat.
- Author
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Thompson JA, Krajnak K, Johnston RA, Kashon ML, McKinney W, and Fedan JS
- Abstract
Adipose tissue (AT) plays a central role in the maintenance of whole-body energy homeostasis through release of adipokines. High-fat Western diet (HFWD)-consumption contributes to obesity, disruption of adipocyte metabolism, chronic systemic inflammation, and metabolic dysfunction (MetDys). MetDys is associated with impaired lung function, pulmonary hypertension, and asthma. Thirty-five percent of adults in the U.S. have MetDys, yet the impact of MetDys on susceptibility to occupational hazards is unknown. The aim of this study was to determine the potential of HFWD-consumption to alter inhaled crystalline silica dust-induced metabolic responses. Six-wk old male F344 rats were fed a HFWD (45 kcal % fat, sucrose 22.2 % by weight) or standard rat chow (STD, controls), and exposed to silica-inhalation (6 h/d, 5 d/wk, 39 d; Min-U-Sil 5®, 15 mg/m
3 ) or filtered air. Indices of MetDys and systemic inflammation were measured at 0, 4, and 8 wk following cessation of silica exposure. At 8 wk post-exposure, silica reduced serum leptin and adiponectin levels, and increased arterial pulse frequency. HFWD-consumption induced weight gain, altered adipokines, liver, kidney, and pancreatic function, and increased tail artery blood flow. At 8 wk in HFWD + SIL-treated animals, the levels of serum pro-inflammatory cytokines (IFN-γ, CXCL-1, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-10 and IL-13) were increased compared to STD + SIL but were less than HFWD + AIR-induced levels. In conclusion, consumption of a HFWD altered silica-induced metabolic responses and silica exposure disrupted AT endocrine function. These findings demonstrate previously unknown interactions between HFWD-consumption and occupational silica exposure., Competing Interests: The authors report no declarations of interest., (© 2021 The Authors.)- Published
- 2021
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32. K Locus Effects in Gray Wolves: Experimental Assessment of TLR3 Signaling and the Gene Expression Response to Canine Distemper Virus.
- Author
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Johnston RA, Rheinwald JG, vonHoldt BM, Stahler DR, Lowry W, Tung J, and Wayne RK
- Subjects
- Alleles, Animals, Dogs, Gene Expression, Toll-Like Receptor 3 genetics, Distemper Virus, Canine genetics, Wolves genetics
- Abstract
In North American gray wolves, black coat color is dominantly inherited via a 3 base pair coding deletion in the canine beta defensin 3 (CBD103) gene. This 3 base pair deletion, called the KB allele, was introduced through hybridization with dogs and subsequently underwent a selective sweep that increased its frequency in wild wolves. Despite apparent positive selection, KBB wolves have lower fitness than wolves with the KyB genotype, even though the 2 genotypes show no observable differences in black coat color. Thus, the KB allele is thought to have pleiotropic effects on as-yet unknown phenotypes. Given the role of skin-expressed CBD103 in innate immunity, we hypothesized that the KB allele influences the keratinocyte gene expression response to TLR3 pathway stimulation and/or infection by canine distemper virus (CDV). To test this hypothesis, we developed a panel of primary epidermal keratinocyte cell cultures from 24 wild North American gray wolves of both Kyy and KyB genotypes. In addition, we generated an immortalized Kyy line and used CRISPR/Cas9 editing to produce a KyB line on the same genetic background. We assessed the transcriptome-wide responses of wolf keratinocytes to the TLR3 agonist polyinosinic:polycytidylic acid (polyI:C), and to live CDV. K locus genotype did not predict the transcriptional response to either challenge, suggesting that variation in the gene expression response does not explain pleiotropic effects of the KB allele on fitness. This study supports the feasibility of using cell culture methods to investigate the phenotypic effects of naturally occurring genetic variation in wild mammals., (© The American Genetic Association. 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2021
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33. Age of acquisition effects in recognition without identification tasks.
- Author
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Catling JC, Pymont C, Johnston RA, Elsherif MM, Clark R, and Kendall E
- Subjects
- Humans, Recognition, Psychology, Semantics
- Abstract
The Age of Acquisition (AoA) effect results in early-acquired words being processed more quickly and accurately than later-acquired words. This effect is argued to result from a gradual development of semantic representations and a changing neural network throughout development (Chang, Y.-N., Monaghan, P., & Welbourne, S., 2019). Some forms of the Recognition Without Identification (RWI) effects have been observed at a perceptual level. The present study used the RWI paradigm to examine whether the AoA effect is located at the perceptual loci. A total of 174 participants were presented a list of pictures (Experiment 1) or words (Experiment 2) followed by a list of mixed early- and late-acquired picture or word fragments that participants had to identify; half of which corresponded to studied words and half of which to unstudied words. Irrespective of whether the item was identified, participants then rated the likelihood that the item appeared in the study phase. In both experiments, results showed that studied items were recognised more accurately than unstudied items, even when they could not be identified and late-acquired items were recognised more than early-acquired items, even when they were not identified. Finally, RWI interacted with the AoA effect only in pictorial stimuli, suggesting that the RWI and AoA effects are located at the perceptual level.
- Published
- 2021
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34. Morphological and genomic shifts in mole-rat 'queens' increase fecundity but reduce skeletal integrity.
- Author
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Johnston RA, Vullioud P, Thorley J, Kirveslahti H, Shen L, Mukherjee S, Karner CM, Clutton-Brock T, and Tung J
- Subjects
- Age Factors, Animals, Cooperative Behavior, Gene Expression Regulation, Mole Rats genetics, Mole Rats psychology, Sex Factors, Social Behavior, Biological Evolution, Bone Development genetics, Femur growth & development, Fertility genetics, Genome, Lumbar Vertebrae growth & development, Mole Rats growth & development, Sexual Behavior, Animal
- Abstract
In some mammals and many social insects, highly cooperative societies are characterized by reproductive division of labor, in which breeders and nonbreeders become behaviorally and morphologically distinct. While differences in behavior and growth between breeders and nonbreeders have been extensively described, little is known of their molecular underpinnings. Here, we investigate the consequences of breeding for skeletal morphology and gene regulation in highly cooperative Damaraland mole-rats. By experimentally assigning breeding 'queen' status versus nonbreeder status to age-matched littermates, we confirm that queens experience vertebral growth that likely confers advantages to fecundity. However, they also upregulate bone resorption pathways and show reductions in femoral mass, which predicts increased vulnerability to fracture. Together, our results show that, as in eusocial insects, reproductive division of labor in mole-rats leads to gene regulatory rewiring and extensive morphological plasticity. However, in mole-rats, concentrated reproduction is also accompanied by costs to bone strength., Competing Interests: RJ, PV, JT, HK, LS, SM, CK, TC No competing interests declared, JT Jenny Tung is a Reviewing Editor at eLife., (© 2021, Johnston et al.)
- Published
- 2021
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35. High social status males experience accelerated epigenetic aging in wild baboons.
- Author
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Anderson JA, Johnston RA, Lea AJ, Campos FA, Voyles TN, Akinyi MY, Alberts SC, Archie EA, and Tung J
- Subjects
- Age Factors, Animals, Animals, Wild psychology, Ecosystem, Female, Health Status, Life Expectancy, Male, Papio cynocephalus psychology, Sex Factors, Aging genetics, Animals, Wild genetics, Behavior, Animal, DNA Methylation, Epigenesis, Genetic, Papio cynocephalus genetics, Psychological Distance, Social Behavior
- Abstract
Aging, for virtually all life, is inescapable. However, within populations, biological aging rates vary. Understanding sources of variation in this process is central to understanding the biodemography of natural populations. We constructed a DNA methylation-based age predictor for an intensively studied wild baboon population in Kenya. Consistent with findings in humans, the resulting 'epigenetic clock' closely tracks chronological age, but individuals are predicted to be somewhat older or younger than their known ages. Surprisingly, these deviations are not explained by the strongest predictors of lifespan in this population, early adversity and social integration. Instead, they are best predicted by male dominance rank: high-ranking males are predicted to be older than their true ages, and epigenetic age tracks changes in rank over time. Our results argue that achieving high rank for male baboons - the best predictor of reproductive success - imposes costs consistent with a 'live fast, die young' life-history strategy., Competing Interests: JA, RJ, AL, FC, TV, MA, SA, EA No competing interests declared, JT Reviewing editor, eLife, (© 2021, Anderson et al.)
- Published
- 2021
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36. Filling a hole in ozone research: The impacts of early life microbiome alterations on pulmonary responses to a non-atopic asthma trigger.
- Author
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Johnston RA and Belenky P
- Subjects
- Animals, Lung, Male, Mice, Asthma, Microbiota, Ozone
- Published
- 2020
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- View/download PDF
37. Genome-wide quantification of the effects of DNA methylation on human gene regulation.
- Author
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Lea AJ, Vockley CM, Johnston RA, Del Carpio CA, Barreiro LB, Reddy TE, and Tung J
- Subjects
- Chromatin chemistry, Computational Biology methods, CpG Islands, High-Throughput Nucleotide Sequencing, Humans, K562 Cells, Regulatory Sequences, Nucleic Acid, Sequence Analysis, DNA methods, Transcription Factors metabolism, Chromatin metabolism, DNA Methylation, Epigenesis, Genetic, Genome, Human, Sequence Analysis, DNA statistics & numerical data, Transcription Factors genetics
- Abstract
Changes in DNA methylation are involved in development, disease, and the response to environmental conditions. However, not all regulatory elements are functionally methylation-dependent (MD). Here, we report a method, mSTARR-seq, that assesses the causal effects of DNA methylation on regulatory activity at hundreds of thousands of fragments (millions of CpG sites) simultaneously. Using mSTARR-seq, we identify thousands of MD regulatory elements in the human genome. MD activity is partially predictable using sequence and chromatin state information, and distinct transcription factors are associated with higher activity in unmethylated versus methylated DNA. Further, pioneer TFs linked to higher activity in the methylated state appear to drive demethylation of experimentally methylated sites. MD regulatory elements also predict methylation-gene expression relationships across individuals, where they are 1.6x enriched among sites with strong negative correlations. mSTARR-seq thus provides a map of MD regulatory activity in the human genome and facilitates interpretation of differential methylation studies., Competing Interests: AL, CV, RJ, CD, LB, TR, JT No competing interests declared, (© 2018, Lea et al.)
- Published
- 2018
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38. Low-dose administration of bleomycin leads to early alterations in lung mechanics.
- Author
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Headley L, Bi W, Wilson C, Collum SD, Chavez M, Darwiche T, Mertens TCJ, Hernandez AM, Siddiqui SR, Rosenbaum S, Johnston RA, and Karmouty-Quintana H
- Subjects
- Animals, Bronchoalveolar Lavage Fluid cytology, Disease Models, Animal, Male, Mice, Mice, Inbred C57BL, Pulmonary Fibrosis drug therapy, Bleomycin administration & dosage, Lung drug effects, Respiratory Mechanics drug effects
- Abstract
New Findings: What is the central question of this study? When do alterations in pulmonary mechanics occur following chronic low-dose administration of bleomycin? What is the main finding and its importance? Remarkably, we report changes in lung mechanics as early as day 7 that corresponded to parameters determined from single-frequency forced oscillation manoeuvres and pressure-volume loops. These changes preceded substantial histological changes or changes in gene expression levels. These findings are significant to refine drug discovery in idiopathic pulmonary fibrosis, where preclinical studies using lung function parameters would enhance the translational potential of drug candidates where lung function readouts are routinely performed in the clinic., Abstract: Idiopathic pulmonary fibrosis (IPF) is the most widespread form of interstitial lung disease and, currently, there are only limited treatment options available. In preclinical animal models of lung fibrosis, the effectiveness of experimental therapeutics is often deemed successful via reductions in collagen deposition and expression of profibrotic genes in the lung. However, in clinical studies, improvements in lung function are primarily used to gauge the success of therapeutics directed towards IPF. Therefore, we examined whether changes in respiratory system mechanics in the early stages of an experimental model of lung fibrosis can be used to refine drug discovery approaches for IPF. C57BL/6J mice were administered bleomycin (BLM) or a vehicle control i.p. twice a week for 4 weeks. At 7, 14, 21, 28 and 33 days into the BLM treatment regimen, indices of respiratory system mechanics and pressure-volume relationships were measured. Concomitant with these measurements, histological and gene analyses relevant to lung fibrosis were performed. Alterations in respiratory system mechanics and pressure-volume relationships were observed as early as 7 days after the start of BLM administration. Changes in respiratory system mechanics preceded the appearance of histological and molecular indices of lung fibrosis. Administration of BLM leads to early changes in respiratory system mechanics that coincide with the appearance of representative histological and molecular indices of lung fibrosis. Consequently, these data suggest that dampening the early changes in respiratory system mechanics might be used to assess the effectiveness of experimental therapeutics in preclinical animal models of lung fibrosis., (© 2018 The Authors. Experimental Physiology © 2018 The Physiological Society.)
- Published
- 2018
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39. Biomechanical implications of the onset of walking.
- Author
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Cowgill LW and Johnston RA
- Subjects
- Adolescent, Animals, Biomechanical Phenomena, Child, Child, Preschool, Cross-Sectional Studies, Growth, Humans, Infant, Infant, Newborn, Femur physiology, Humerus physiology, Neanderthals physiology, Tibia physiology, Walking
- Abstract
Changes in long bone strength associated with the onset of bipedal walking in humans have been previously documented in a longitudinal growth sample. However, it is unclear if this transition can be detected using archaeological, cross-sectional data, which likely encompass more cultural and biological variation than a single dataset of living children. Focusing on variation in cross-sectional polar second moment of area, we evaluate the ratios of femoral, tibial, and humeral strength in seven temporally diverse samples of individuals from birth to the age of eighteen years (n = 501), with subsequent comparisons to immature Late Pleistocene fossils. Using these samples, we determine whether changes related to the developmental onset of bipedality can be detected in a large, multi-population sample, test for differences in long bone strength ratios among Holocene groups that may indicate developmental differences in the onset of walking, and determine whether immature Late Pleistocene samples follow the same patterns as modern humans. Despite great variation within the Holocene sample, clear changes in these ratios are apparent around the age of the onset of walking. Humeral-to-femoral strength increases briefly prior to the age of one, with a sharp decline in relative humeral strength thereafter until age four. A similar pattern is apparent in the ratio of humeral/tibial and femoral/tibial strength. While the general pattern is consistent across all human groups sampled, these ratios vary by skeletal population, which seems to be closely related to variation in tibial length among samples. Although the extremely small fossil sample makes differences difficult to interpret, Neandertals also differ from both Late Pleistocene and Holocene modern humans in their strength ratios. Further research in this area may provide additional information about the skeletal impact of the onset of walking in the past and in additional fossil taxa., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
40. Chemokine (C-C Motif) Receptor-Like 2 is not essential for lung injury, lung inflammation, or airway hyperresponsiveness induced by acute exposure to ozone.
- Author
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Malik F, Cromar KR, Atkins CL, Price RE, Jackson WT, Siddiqui SR, Spencer CY, Mitchell NC, Haque IU, and Johnston RA
- Subjects
- Animals, Asthma etiology, Asthma genetics, Bronchoalveolar Lavage Fluid cytology, Chemokines genetics, Chemokines metabolism, Female, Genotype, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins metabolism, Lung Injury etiology, Lung Injury genetics, Male, Mice, Mice, Inbred C57BL, Receptors, CCR, Receptors, Chemokine metabolism, Respiratory Mucosa metabolism, Asthma metabolism, Lung Injury metabolism, Ozone adverse effects, Receptors, Chemokine genetics
- Abstract
Inhalation of ozone (O
3 ), a gaseous air pollutant, causes lung injury, lung inflammation, and airway hyperresponsiveness. Macrophages, mast cells, and neutrophils contribute to one or more of these sequelae induced by O3 Furthermore, each of these aforementioned cells express chemokine (C-C motif) receptor-like 2 (Ccrl2), an atypical chemokine receptor that facilitates leukocyte chemotaxis. Given that Ccrl2 is expressed by cells essential to the development of O3 -induced lung pathology and that chemerin, a Ccrl2 ligand, is increased in bronchoalveolar lavage fluid (BALF) by O3 , we hypothesized that Ccrl2 contributes to the development of lung injury, lung inflammation, and airway hyperresponsiveness induced by O3 To that end, we measured indices of lung injury (BALF protein, BALF epithelial cells, and bronchiolar epithelial injury), lung inflammation (BALF cytokines and BALF leukocytes), and airway responsiveness to acetyl- β -methylcholine chloride (respiratory system resistance) in wild-type and mice genetically deficient in Ccrl2 (Ccrl2-deficient mice) 4 and/or 24 hours following cessation of acute exposure to either filtered room air (air) or O3 In air-exposed mice, BALF chemerin was greater in Ccrl2-deficient as compared to wild-type mice. O3 increased BALF chemerin in mice of both genotypes, yet following O3 exposure, BALF chemerin was greater in Ccrl2-deficient as compared to wild-type mice. O3 increased indices of lung injury, lung inflammation, and airway responsiveness. Nevertheless, no indices were different between genotypes following O3 exposure. In conclusion, we demonstrate that Ccrl2 modulates chemerin levels in the epithelial lining fluid of the lungs but does not contribute to the development of O3 -induced lung pathology., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)- Published
- 2017
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41. Evidence for view-invariant face recognition units in unfamiliar face learning.
- Author
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Etchells DB, Brooks JL, and Johnston RA
- Subjects
- Adolescent, Adult, Drug Combinations, Ethinyl Estradiol, Female, Humans, Male, Norethindrone, Photic Stimulation, Reaction Time physiology, Young Adult, Face, Learning physiology, Pattern Recognition, Visual physiology, Recognition, Psychology physiology
- Abstract
Many models of face recognition incorporate the idea of a face recognition unit (FRU), an abstracted representation formed from each experience of a face which aids recognition under novel viewing conditions. Some previous studies have failed to find evidence of this FRU representation. Here, we report three experiments which investigated this theoretical construct by modifying the face learning procedure from that in previous work. During learning, one or two views of previously unfamiliar faces were shown to participants in a serial matching task. Later, participants attempted to recognize both seen and novel views of the learned faces (recognition phase). Experiment 1 tested participants' recognition of a novel view, a day after learning. Experiment 2 was identical, but tested participants on the same day as learning. Experiment 3 repeated Experiment 1, but tested participants on a novel view that was outside the rotation of those views learned. Results revealed a significant advantage, across all experiments, for recognizing a novel view when two views had been learned compared to single view learning. The observed view invariance supports the notion that an FRU representation is established during multi-view face learning under particular learning conditions.
- Published
- 2017
- Full Text
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42. Understanding how unfamiliar faces become familiar: Introduction to a special issue on face learning.
- Author
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Bindemann M and Johnston RA
- Subjects
- Humans, Discrimination Learning, Face, Pattern Recognition, Visual physiology, Recognition, Psychology physiology
- Published
- 2017
- Full Text
- View/download PDF
43. Perceptual and memorial contributions to developmental prosopagnosia.
- Author
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Ulrich PI, Wilkinson DT, Ferguson HJ, Smith LJ, Bindemann M, Johnston RA, and Schmalzl L
- Subjects
- Adult, Analysis of Variance, Association, Facial Expression, Famous Persons, Female, Humans, Judgment, Male, Middle Aged, Neuropsychological Tests, Signal Detection, Psychological, Face, Pattern Recognition, Visual physiology, Prosopagnosia physiopathology, Recognition, Psychology
- Abstract
Developmental prosopagnosia (DP) is commonly associated with the failure to properly perceive individuating facial properties, notably those conveying configural or holistic content. While this may indicate that the primary impairment is perceptual, it is conceivable that some cases of DP are instead caused by a memory impairment, with any perceptual complaint merely allied rather than causal. To investigate this possibility, we administered a battery of face perception tasks to 11 individuals who reported that their face recognition difficulties disrupt daily activity and who also performed poorly on two formal tests of face recognition. Group statistics identified, relative to age- and gender-matched controls, difficulties in apprehending global-local relations and the holistic properties of faces, and in matching across viewpoints, but these were mild in nature and were not consistently evident at the level of individual participants. Six of the 11 individuals failed to show any evidence of perceptual impairment. In the remaining five individuals, no single perceptual deficit, or combination of deficits, was necessary or sufficient for poor recognition performance. These data suggest that some cases of DP are better explained by a memorial rather than perceptual deficit, and highlight the relevance of the apperceptive/associative distinction more commonly applied to the allied syndrome of acquired prosopagnosia.
- Published
- 2017
- Full Text
- View/download PDF
44. Seasonal gene expression in a migratory songbird.
- Author
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Johnston RA, Paxton KL, Moore FR, Wayne RK, and Smith TB
- Subjects
- Animals, Photoperiod, Transcriptome, Animal Migration, Gene Expression, Seasons, Songbirds genetics
- Abstract
The annual migration of a bird can involve thousands of kilometres of nonstop flight, requiring accurately timed seasonal changes in physiology and behaviour. Understanding the molecular mechanisms controlling this endogenous programme can provide functional and evolutionary insights into the circannual biological clock and the potential of migratory species to adapt to changing environments. Under naturally timed photoperiod conditions, we maintained captive Swainson's thrushes (Catharus ustulatus) and performed RNA sequencing (RNA-Seq) of the ventral hypothalamus and optic chiasma to evaluate transcriptome-wide gene expression changes of individuals in migratory condition. We found that 188 genes were differentially expressed in relation to migratory state, 86% of which have not been previously linked to avian migration. Focal hub genes were identified that are candidate variables responsible for the occurrence of migration (e.g. CRABP1). Numerous genes involved in cell adhesion, proliferation and motility were differentially expressed (including RHOJ, PAK1 and TLN1), suggesting that migration-related changes are regulated by seasonal neural plasticity., (© 2016 John Wiley & Sons Ltd.)
- Published
- 2016
- Full Text
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45. Plasminogen activator inhibitor-1 does not contribute to the pulmonary pathology induced by acute exposure to ozone.
- Author
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Elkhidir HS, Richards JB, Cromar KR, Bell CS, Price RE, Atkins CL, Spencer CY, Malik F, Alexander AL, Cockerill KJ, Haque IU, and Johnston RA
- Abstract
Expression of plasminogen activator inhibitor (PAI)-1, the major physiological inhibitor of fibrinolysis, is increased in the lung following inhalation of ozone (O
3 ), a gaseous air pollutant. PAI-1 regulates expression of interleukin (IL)-6, keratinocyte chemoattractant (KC), and macrophage inflammatory protein (MIP)-2, which are cytokines that promote lung injury, pulmonary inflammation, and/or airway hyperresponsiveness following acute exposure to O3 Given these observations, we hypothesized that PAI-1 contributes to the severity of the aforementioned sequelae by regulating expression of IL-6, KC, and MIP-2 following acute exposure to O3 To test our hypothesis, wild-type mice and mice genetically deficient in PAI-1 (PAI-1-deficient mice) were acutely exposed to either filtered room air or O3 (2 ppm) for 3 h. Four and/or twenty-four hours following cessation of exposure, indices of lung injury [bronchoalveolar lavage fluid (BALF) protein and epithelial cells], pulmonary inflammation (BALF IL-6, KC, MIP-2, macrophages, and neutrophils), and airway responsiveness to aerosolized acetyl-β-methylcholine chloride (respiratory system resistance) were measured in wild-type and PAI-1-deficient mice. O3 significantly increased indices of lung injury, pulmonary inflammation, and airway responsiveness in wild-type and PAI-1-deficient mice. With the exception of MIP-2, which was significantly lower in PAI-1-deficient as compared to wild-type mice 24 h following cessation of exposure to O3 , no other genotype-related differences occurred subsequent to O3 exposure. Thus, following acute exposure to O3 , PAI-1 neither regulates pulmonary expression of IL-6 and KC nor functionally contributes to any of the pulmonary pathological sequelae that arise from the noxious effects of inhaled O3 ., (© 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)- Published
- 2016
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46. Pervasive Effects of Aging on Gene Expression in Wild Wolves.
- Author
-
Charruau P, Johnston RA, Stahler DR, Lea A, Snyder-Mackler N, Smith DW, vonHoldt BM, Cole SW, Tung J, and Wayne RK
- Subjects
- Age Factors, Animals, Animals, Wild, Biological Evolution, Dogs, Environment, Female, Gene Expression Profiling, High-Throughput Nucleotide Sequencing, Male, Phylogeny, Selection, Genetic, Sequence Analysis, RNA methods, Sex Factors, Aging genetics, Gene Expression Regulation, Wolves genetics
- Abstract
Gene expression levels change as an individual ages and responds to environmental conditions. With the exception of humans, such patterns have principally been studied under controlled conditions, overlooking the array of developmental and environmental influences that organisms encounter under conditions in which natural selection operates. We used high-throughput RNA sequencing (RNA-Seq) of whole blood to assess the relative impacts of social status, age, disease, and sex on gene expression levels in a natural population of gray wolves (Canis lupus). Our findings suggest that age is broadly associated with gene expression levels, whereas other examined factors have minimal effects on gene expression patterns. Further, our results reveal evolutionarily conserved signatures of senescence, such as immunosenescence and metabolic aging, between wolves and humans despite major differences in life history and environment. The effects of aging on gene expression levels in wolves exhibit conservation with humans, but the more rapid expression differences observed in aging wolves is evolutionarily appropriate given the species' high level of extrinsic mortality due to intraspecific aggression. Some expression changes that occur with age can facilitate physical age-related changes that may enhance fitness in older wolves. However, the expression of these ancestral patterns of aging in descendant modern dogs living in highly modified domestic environments may be maladaptive and cause disease. This work provides evolutionary insight into aging patterns observed in domestic dogs and demonstrates the applicability of studying natural populations to investigate the mechanisms of aging., (© The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2016
- Full Text
- View/download PDF
47. Genetic basis for body size variation between an anadromous and two derived lacustrine populations of threespine stickleback Gasterosteus aculeatus in southwest Alaska.
- Author
-
Bowles E, Johnston RA, Vanderzwan SL, and Rogers SM
- Abstract
Body size is a highly variable trait among geographically separated populations. Size-assortative reproductive isolation has been linked to recent adaptive radiations of threespine stickleback ( Gasterosteus aculeatus ) into freshwater, but the genetic basis of the commonly found size difference between anadromous and derived lacustrine sticklebacks has not been tested. We studied the genetic basis of size differences between recently diverging stickleback lineages in southwest Alaska using a common environment experiment. We crossed stickleback within one anadromous (Naknek River) and one lake (Pringle Lake) population and between the anadromous and two lake populations (Pringle and JoJo Lakes), and raised them in a salinity of 4-6 ppt. The F1 anadromous and freshwater forms differed significantly in size, whereas hybrids were intermediate or exhibited dominance toward the anadromous form. Additionally, the size of freshwater F1s differed from their wild counterparts, with within-population F1s from Pringle Lake growing larger than their wild counterparts, while there was no size difference between lab-raised and wild anadromous fish. Sexual dimorphism was always present in anadromous fish, but not in freshwater, and not always in the hybrid crosses. These results, along with parallel changes among anadromous and freshwater forms in other regions, suggest that this heritable trait is both plastic and may be under divergent and/or sexual selection.
- Published
- 2016
- Full Text
- View/download PDF
48. Resistin deficiency in mice has no effect on pulmonary responses induced by acute ozone exposure.
- Author
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Razvi SS, Richards JB, Malik F, Cromar KR, Price RE, Bell CS, Weng T, Atkins CL, Spencer CY, Cockerill KJ, Alexander AL, Blackburn MR, Alcorn JL, Haque IU, and Johnston RA
- Subjects
- Airway Resistance drug effects, Animals, Bronchoconstrictor Agents pharmacology, Female, Lung drug effects, Lung metabolism, Lung pathology, Male, Methacholine Chloride pharmacology, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Pneumonia chemically induced, Resistin blood, Air Pollutants toxicity, Ozone toxicity, Pneumonia metabolism, Resistin genetics
- Abstract
Acute exposure to ozone (O3), an air pollutant, causes pulmonary inflammation, airway epithelial desquamation, and airway hyperresponsiveness (AHR). Pro-inflammatory cytokines-including IL-6 and ligands of chemokine (C-X-C motif) receptor 2 [keratinocyte chemoattractant (KC) and macrophage inflammatory protein (MIP)-2], TNF receptor 1 and 2 (TNF), and type I IL-1 receptor (IL-1α and IL-1β)-promote these sequelae. Human resistin, a pleiotropic hormone and cytokine, induces expression of IL-1α, IL-1β, IL-6, IL-8 (the human ortholog of murine KC and MIP-2), and TNF. Functional differences exist between human and murine resistin; yet given the aforementioned observations, we hypothesized that murine resistin promotes O3-induced lung pathology by inducing expression of the same inflammatory cytokines as human resistin. Consequently, we examined indexes of O3-induced lung pathology in wild-type and resistin-deficient mice following acute exposure to either filtered room air or O3. In wild-type mice, O3 increased bronchoalveolar lavage fluid (BALF) resistin. Furthermore, O3 increased lung tissue or BALF IL-1α, IL-6, KC, TNF, macrophages, neutrophils, and epithelial cells in wild-type and resistin-deficient mice. With the exception of KC, which was significantly greater in resistin-deficient compared with wild-type mice, no genotype-related differences in the other indexes existed following O3 exposure. O3 caused AHR to acetyl-β-methylcholine chloride (methacholine) in wild-type and resistin-deficient mice. However, genotype-related differences in airway responsiveness to methacholine were nonexistent subsequent to O3 exposure. Taken together, these data demonstrate that murine resistin is increased in the lungs of wild-type mice following acute O3 exposure but does not promote O3-induced lung pathology., (Copyright © 2015 the American Physiological Society.)
- Published
- 2015
- Full Text
- View/download PDF
49. Face matching in a long task: enforced rest and desk-switching cannot maintain identification accuracy.
- Author
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Alenezi HM, Bindemann M, Fysh MC, and Johnston RA
- Abstract
In face matching, observers have to decide whether two photographs depict the same person or different people. This task is not only remarkably difficult but accuracy declines further during prolonged testing. The current study investigated whether this decline in long tasks can be eliminated with regular rest-breaks (Experiment 1) or room-switching (Experiment 2). Both experiments replicated the accuracy decline for long face-matching tasks and showed that this could not be eliminated with rest or room-switching. These findings suggest that person identification in applied settings, such as passport control, might be particularly error-prone due to the long and repetitive nature of the task. The experiments also show that it is difficult to counteract these problems.
- Published
- 2015
- Full Text
- View/download PDF
50. Dissemination of well water arsenic results to homeowners in Central Maine: influences on mitigation behavior and continued risks for exposure.
- Author
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Flanagan SV, Marvinney RG, Johnston RA, Yang Q, and Zheng Y
- Subjects
- Environmental Restoration and Remediation, Humans, Maine, Risk Assessment, Water Purification methods, Water Supply statistics & numerical data, Arsenic analysis, Environmental Exposure statistics & numerical data, Information Dissemination, Water Pollutants, Chemical analysis, Water Wells chemistry
- Abstract
Private wells in the United States are unregulated for drinking water standards and are the homeowner's responsibility to test and treat. Testing for water quality parameters such as arsenic (As) is a crucial first step for homeowners to take protective actions. This study seeks to identify key behavioral factors influencing homeowners' decisions to take action after receiving well As test results. A January 2013 survey of central Maine households (n=386, 73% response) who were notified 3-7 years earlier that their well water contained As above 10 μg/L found that 43% of households report installing As treatment systems. Another 30% report taking other mitigation actions such as drinking bottled water because of the As, but the remaining 27% of households did not act. Well water As level appears to be a motivation for mitigation: 31% of households with well water level between 10 and 50 μg/L did not act, compared to 11% of households with well water >50 μg/L. The belief that the untreated water is not safe to drink (risk) and that reducing drinking water As would increase home value (instrumental attitude) were identified as significant predictors of mitigating As. Mitigating As exposure is associated with less worry about the As level (affective attitude), possibly because those acting to reduce exposure feel less worried about As. Use of a treatment system specifically was significantly predicted by confidence that one can maintain a treatment system, even if there are additional costs (self-efficacy). An assessment of As treatment systems used by 68 of these households with well water As >10 μg/L followed up within August-November 2013 found that 15% of treatment units failed to produce water below As 10 μg/L, suggesting that there are continued risks for exposure even after the decision is made to treat., (Copyright © 2014 Elsevier B.V. All rights reserved.)
- Published
- 2015
- Full Text
- View/download PDF
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