444 results on '"Johnson DG"'
Search Results
2. Thermal Sensors
- Author
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Johnson, DG., primary
- Published
- 2018
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3. Extended clique initialisation in examination timetabling
- Author
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Carter, MW and Johnson, DG
- Subjects
Operations research -- Analysis - Abstract
Many examination timetabling procedures employ a phased approach in which the first phase is often the allocation of a large set of mutually conflicting examinations which form a clique in the associated problem graph. The usual practice is to identify a single maximum clique, often quite arbitrarily, in this first phase. We show that in typical examination timetabling problems, unlike random graphs, there are often many alternative maximum cliques, and even larger dense subsets of nodes that are almost cliques. A number of methods are proposed for extending the scope of the clique initialisation to include a larger subset of examinations by considering sub-maximum cliques and/or quasi-cliques. Keywords: timetabling; graph; clique
- Published
- 2001
4. MuSIP multi-sensor image processing system
- Author
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Sawyer, G, primary, Mason, DC, additional, Hindley, N, additional, Johnson, DG, additional, Jones-Parry, IH, additional, Oddy, CJ, additional, Pike, TK, additional, Plassard, T, additional, Rye, AJ, additional, de Salabert, A, additional, Serpico, B, additional, and Wielogorski, AL, additional
- Published
- 1992
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5. Aminophylline Suppository Decomposition: GC Mass Spectrometry and GC-Mass Spectrometry of the Decomposition Products
- Author
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Pryce-Jones, RH, primary, Johnson, DG, additional, Watson, DG, additional, and Eccleston, GM, additional
- Published
- 1990
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6. Expression of transcription factor E2F1 and telomerase in glioblastomas: mechanistic linkage and prognostic significance.
- Author
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Alonso MM, Fueyo J, Shay JW, Aldape KD, Jiang H, Lee O, Johnson DG, Xu J, Kondo Y, Kanzawa T, Kyo S, Bekele BN, Zhou X, Nigro J, McDonald JM, Yung WKA, and Gomez-Manzano C
- Published
- 2005
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7. GENETIC VARIATION AT THE THIRD LOCUS OF PHOSPHOGLUCOMUTASE IN PLACENTAS FROM AUSTRALIA AND PAPUA NEW GUINEA.
- Author
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Wierst, Bronya, Blake, NM, Kirk, RL, Jacobs, DS, and Johnson, DG
- Published
- 1973
- Full Text
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8. Forensic pathology: separating fact from fiction.
- Author
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Johnson DG
- Abstract
The world of the imaginary forensic pathologist made famous by popular television series and movies is far removed from that of the real-world doctors and criminalists. Follow in the footsteps of a Colorado doctor who documents a day in the morgue as she unravels the intricate details of a tragic death - and dispels some common celluloid myths. [ABSTRACT FROM AUTHOR]
- Published
- 2003
9. Study of U.S. medical school applicants, 1971-72
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Nelson Bc, Johnson Dg, and W. F. Dube
- Subjects
Adult ,Male ,Asia ,Students, Medical ,Adolescent ,Higher education ,Statistics as Topic ,International Educational Exchange ,Education ,Humans ,Education, Graduate ,Minority Groups ,Schools, Medical ,Medical education ,Geography ,business.industry ,Age Factors ,Australia ,Medical school ,General Medicine ,Middle Aged ,South America ,Achievement ,United States ,Europe ,Africa ,North America ,Female ,Educational Measurement ,business ,Psychology - Published
- 1973
10. Conference on preparation for medical education in the traditionally Negro college
- Author
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Johnson Dg
- Subjects
Medical education ,medicine.medical_specialty ,business.industry ,Family medicine ,Medicine ,General Medicine ,business ,Education - Published
- 1968
11. Genetic variation at the third locus of phosphoglucomutase in placentas from Australia and Papua New Guinea
- Author
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Robert Kirk, Jacobs Ds, Johnson Dg, N. M. Blake, and Van Wierst B
- Subjects
Native Hawaiian or Other Pacific Islander ,Placenta ,Clinical Biochemistry ,Immunology ,Electrophoresis, Starch Gel ,Black People ,Locus (genetics) ,Biology ,White People ,Gene Frequency ,Pregnancy ,parasitic diseases ,Genetic variation ,Humans ,Alleles ,Mercaptoethanol ,Genetics ,New Guinea ,Australia ,New guinea ,Genetic Variation ,Cell Biology ,General Medicine ,Phenotype ,Phosphoglucomutase ,Female - Abstract
GENETIC VARIATION AT THE THIRD LOCUS OF PHOSPHOGLUCOMUTASE IN PLACENTAS FROM AUSTRALIA AND PAPUA NEW GUINEA
- Published
- 1973
12. Maintenance of Adult-rat Liver Slices in Dynamic Organ-culture
- Author
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UCL, Smith, PF., Krack, G., Mckee, RL., Johnson, DG., Gandolfi, AJ., Hruby, VJ., Krumdieck, CL., Brendel, K., UCL, Smith, PF., Krack, G., Mckee, RL., Johnson, DG., Gandolfi, AJ., Hruby, VJ., Krumdieck, CL., and Brendel, K.
- Published
- 1986
13. GENETIC VARIATION AT THE THIRD LOCUS OF PHOSPHOGLUCOMUTASE IN PLACENTAS FROM AUSTRALIA AND PAPUA NEW GUINEA
- Author
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Wierst, Bronya, primary, Blake, NM, additional, Kirk, RL, additional, Jacobs, DS, additional, and Johnson, DG, additional
- Published
- 1973
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14. Combinatorial analysis for route first-cluster second vehicle routing
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Mole, RH, primary, Johnson, DG, additional, and Wells, K, additional
- Published
- 1983
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15. Embryologic collateral venous channel on radionuclide liver/spleen study
- Author
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Wilkinson, RH, primary and Johnson, DG, additional
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- 1983
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16. Blood flow and oxygen consumption with adrenergic blockade in hemorrhagic shock
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Baue, AE, primary, Johnson, DG, additional, and Parkins, WM, additional
- Published
- 1966
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17. Conference on increasing representation in medical schools of Afro-Americans, Mexican-Americans, and American Indians
- Author
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Johnson Dg
- Subjects
Students, Medical ,Education, Medical ,Anthropology ,General Medicine ,Mexican americans ,United States ,Education ,Representation (politics) ,Black or African American ,Ethnicity ,Indians, North American ,Workforce ,Sociology ,Cultural competence ,Minority Groups - Published
- 1969
18. OEO-AAMC grant
- Author
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Johnson Dg
- Subjects
Engineering ,Students, Medical ,business.industry ,Library science ,General Medicine ,Training Support ,United States ,Education ,Socioeconomic Factors ,Health Occupations ,United States Office of Economic Opportunity ,business ,Minority Groups ,Schools, Medical ,Societies, Medical - Published
- 1969
19. Supporting Emergency Medical Services Clinicians Through Acute and Sustained Crises With Informal Peer Support and Intentional Acts of Kindness: The Emergency Medical Services Code Lavender Program.
- Author
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Maloney LM, Hoffman J, Peralta E, Princi R, Thode HC Jr, Tomlin M, DiDonato C, LaBarbera A, Lambert E, King J, Johnson DG, Edouard S, and Williams S
- Subjects
- Humans, Male, Female, Adult, Crisis Intervention, Peer Group, Surveys and Questionnaires, Middle Aged, Emergency Medical Technicians psychology, Social Support, Emergency Medical Services
- Abstract
Objective: Given the recommendations against the use of critical incident stress debriefing, the emergency medical services (EMS) Code Lavender program was created as a mechanism to consistently recognize and reach out to EMS clinicians after acute crisis events, offer nonintrusive informal peer support and acts of kindness, and provide stepwise support via mental health professionals as needed. The study aimed to assess program utilization and evaluate the program's impact on EMS clinicians' perceptions of support and resources available to them after an acute crisis event., Methods: Anonymous surveys were distributed before program implementation and 18 months later. Program utilization was tracked using REDCap (Vanderbilt University, Nashville, TN). Fisher exact tests and logistic regression were used to analyze the survey results., Results: Within 30 months, 87 referrals were made. Seventy-seven preprogram (59% response rate) and 104 intraprogram (88% response rate) surveys were collected. There were no differences between respondents by sex or role. There were significant improvements in knowing where to go for help (from 40% to 85%, P < .001) and willingness to seek help if needed (from 40% to 59%, P = .02)., Conclusion: The implementation of an EMS Code Lavender program led to significant increases in EMS clinician self-reported knowledge of where to go and willingness to seek help after acute crisis events., Competing Interests: Declaration of Competing Interest L.M.M. and J.H. received an honorarium and travel support to present the EMS Code Lavender Program during the 2023 Critical Care Transport Medicine Conference. Otherwise, the authors report no other conflicts of interest., (Copyright © 2024 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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20. Loss of the methylarginine reader function of SND1 confers resistance to hepatocellular carcinoma.
- Author
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Wright T, Wang Y, Stratton SA, Sebastian M, Liu B, Johnson DG, and Bedford MT
- Subjects
- Animals, Mice, Nuclear Proteins metabolism, Transcription Factors, Genetic Predisposition to Disease, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular pathology, Endonucleases genetics, Liver Neoplasms genetics, Liver Neoplasms pathology
- Abstract
Staphylococcal nuclease Tudor domain containing 1 (SND1) protein is an oncogene that 'reads' methylarginine marks through its Tudor domain. Specifically, it recognizes methylation marks deposited by protein arginine methyltransferase 5 (PRMT5), which is also known to promote tumorigenesis. Although SND1 can drive hepatocellular carcinoma (HCC), it is unclear whether the SND1 Tudor domain is needed to promote HCC. We sought to identify the biological role of the SND1 Tudor domain in normal and tumorigenic settings by developing two genetically engineered SND1 mouse models, an Snd1 knockout (Snd1 KO) and an Snd1 Tudor domain-mutated (Snd1 KI) mouse, whose mutant SND1 can no longer recognize PRMT5-catalyzed methylarginine marks. Quantitative PCR analysis of normal, KO, and KI liver samples revealed a role for the SND1 Tudor domain in regulating the expression of genes encoding major acute phase proteins, which could provide mechanistic insight into SND1 function in a tumor setting. Prior studies indicated that ectopic overexpression of SND1 in the mouse liver dramatically accelerates the development of diethylnitrosamine (DEN)-induced HCC. Thus, we tested the combined effects of DEN and SND1 loss or mutation on the development of HCC. We found that both Snd1 KO and Snd1 KI mice were partially protected against malignant tumor development following exposure to DEN. These results support the development of small molecule inhibitors that target the SND1 Tudor domain or the use of upstream PRMT5 inhibitors, as novel treatments for HCC., (© 2023 The Author(s).)
- Published
- 2023
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21. Exocrine Proteins Including Trypsin(ogen) as a Key Biomarker in Type 1 Diabetes.
- Author
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Bakinowska L, Vartak T, Phuthego T, Taylor M, Chandler K, Jerram ST, Williams S, Feldmann M, Johnson DG, Patel KA, Williams AJK, Long AE, Leslie RD, and Gillespie KM
- Subjects
- Adult, Humans, Trypsin, Proteomics, Biomarkers, Diabetes Mellitus, Type 1 genetics
- Abstract
Objective: Proteomic profiling can identify useful biomarkers. Monozygotic (MZ) twins discordant for a condition represent an ideal test population. We aimed to investigate and validate proteomic profiling in twins with type 1 diabetes and in other well-characterized cohorts., Research Design and Methods: A broad, multiplex analysis of 4,068 proteins in serum samples from MZ twins concordant (n = 43) and discordant (n = 27) for type 1 diabetes identified major differences that were subsequently validated by a trypsin(ogen) assay in MZ pairs concordant (n = 39) and discordant (n = 42) for type 1 diabetes, individuals at risk for (n = 195) and with (n = 990) type 1 diabetes, as well as individuals with non-insulin-requiring adult-onset diabetes diagnosed as either autoimmune (n = 96) or type 2 (n = 291)., Results: Proteomic analysis identified major differences between exocrine enzyme levels in discordant MZ twin pairs despite a strong correlation between twins, whether concordant or discordant for type 1 diabetes (P < 0.01 for both). In validation experiments, trypsin(ogen) levels were lower in twins with diabetes than in the co-twin without diabetes (P < 0.0001) and healthy control participants (P < 0.0001). In recently diagnosed participants, trypsin(ogen) levels were lower than in control participants across a broad age range. In at-risk relatives, levels <15 ng/mL were associated with an increased risk of progression (uncorrected P = 0.009). Multiple linear regression in recently diagnosed participants showed that trypsin(ogen) levels were associated with insulin dose and diabetic ketoacidosis, while age and BMI were confounders., Conclusions: Type 1 diabetes is associated with altered exocrine function, even before onset. Twin data suggest roles for genetic and nongenetically determined factors. Exocrine/endocrine interactions are important underinvestigated factors in type 1 diabetes., (© 2023 by the American Diabetes Association.)
- Published
- 2023
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22. Prescription quantity and duration predict progression from acute to chronic opioid use in opioid-naïve Medicaid patients.
- Author
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Johnson DG, Ho VT, Hah JM, Humphreys K, Carroll I, Curtin C, Asch SM, and Hernandez-Boussard T
- Abstract
Opiates used for acute pain are an established risk factor for chronic opioid use (COU). Patient characteristics contribute to progression from acute opioid use to COU, but most are not clinically modifiable. To develop and validate machine-learning algorithms that use claims data to predict progression from acute to COU in the Medicaid population, Adult opioid naïve Medicaid patients from 6 anonymized states who received an opioid prescription between 2015 and 2019 were included. Five machine learning (ML) Models were developed, and model performance assessed by area under the receiver operating characteristic curve (auROC), precision and recall. In the study, 29.9% (53820/180000) of patients transitioned from acute opioid use to COU. Initial opioid prescriptions in COU patients had increased morphine milligram equivalents (MME) (33.2 vs. 23.2), tablets per prescription (45.6 vs. 36.54), longer prescriptions (26.63 vs 24.69 days), and higher proportions of tramadol (16.06% vs. 13.44%) and long acting oxycodone (0.24% vs 0.04%) compared to non- COU patients. The top performing model was XGBoost that achieved average precision of 0.87 and auROC of 0.63 in testing and 0.55 and 0.69 in validation, respectively. Top-ranking prescription-related features in the model included quantity of tablets per prescription, prescription length, and emergency department claims. In this study, the Medicaid population, opioid prescriptions with increased tablet quantity and days supply predict increased risk of progression from acute to COU in opioid-naïve patients. Future research should evaluate the effects of modifying these risk factors on COU incidence., Competing Interests: Competing interests: The authors have declared that no competing interests exist.
- Published
- 2022
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23. Aquatic Activity-Related Craniofacial Injuries Presenting to United States Emergency Departments, 2010 to 2019.
- Author
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Yang SC, Johnson DG, Keefe SH, and Bast BT
- Subjects
- Adult, Emergency Service, Hospital, Female, Humans, Male, Retrospective Studies, United States epidemiology, Athletic Injuries epidemiology, Athletic Injuries etiology, Fractures, Bone, Lacerations
- Abstract
Purpose: Aquatic activities are some of the most widely enjoyed sports and recreational activities in the United States. This study aimed to analyze the risks and types of craniofacial injuries associated with various aquatic activities., Methods: We retrospectively analyzed aquatic activity-related craniofacial injuries between 2010 and 2019 using the National Electronic Injury Surveillance System database. Aquatic activities included swimming, diving, surfing, water skiing, and water tubing. Risks and types of craniofacial injuries were analyzed according to the types of aquatic activities, age, and sex., Results: Among 48,112 patients with aquatic activity-related injuries, 9,529 (19.8%) had craniofacial injuries. In decreasing order of frequency, the causes of craniofacial injuries were swimming (79.6%), diving (7.5%), surfing (5.9%), water skiing (3.6%), and water tubing (3.5%). The proportion of craniofacial injuries among all injuries was higher in males than in females (22.8 vs 16.3%, P < .001), and decreased with age: 27.7% in 0 to 5 years, 21.5% in 6 to 11 years, 20.5% in 12 to 17 years, and 15.2% in ≥18 years (P < .001). Additionally, the proportion of craniofacial injuries was highest in diving (38.7%), and lowest in swimming (18.1%, P < .001). The male-to-female ratio in the proportion of patients with craniofacial injuries was highest in swimming at 1.42, and close to unity (0.97-1.13) in other activities. The most common type of craniofacial injury was laceration (43.5%), followed by concussion/internal organ injury (38.9%), contusion/abrasion (11.3%), and fracture (3%). Among all craniofacial injuries, the proportion of craniofacial fractures was highest in water tubing (8.5%) and lowest in swimming (2.2%, P < .001)., Conclusions: Craniofacial injuries are a frequent cause of morbidity related to aquatic activities. Substantial variability exists in the risk and pattern of craniofacial injuries depending on the type of activity, age, and sex. These findings may aid in instituting educational programs and preventive measures against aquatic activity-related craniofacial injuries., (Copyright © 2021 The American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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24. Social-Cognitive and Affective Antecedents of Code Switching and the Consequences of Linguistic Racism for Black People and People of Color.
- Author
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Johnson DG, Mattan BD, Flores N, Lauharatanahirun N, and Falk EB
- Abstract
Linguistic racism shapes the psychological antecedents of code switching and its consequences for Black people and other people of color. We highlight mentalizing as an antecedent of code switching. We posit that stereotype threat arises in contexts where racism is salient, prompting scrutiny of others' mental states (i.e., mentalizing) when making choices about linguistic self-presentation. Additionally, we posit that sustained appraisals of stereotype threat add cognitive load and reinforce self-protective code switching. We highlight potential consequences of linguistic racism for Black people and other people of color, including reduced opportunities for authentic self-presentation, increased emotional effort, and stress. Finally, we outline paths forward for research and practice: (1) recognizing the heterogeneity of language and thereby reducing linguistic racism, (2) implementing changes that promote racially affirming environments that reduce demands for self-protective code switching, and (3) adapting and creating scalable psychometric tools to measure linguistic choices and linguistic racism., Competing Interests: Conflict of InterestOn behalf of all authors, the corresponding author states that there is no conflict of interest., (© The Society for Affective Science 2021.)
- Published
- 2021
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25. Direct Regulation of DNA Repair by E2F and RB in Mammals and Plants: Core Function or Convergent Evolution?
- Author
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Manickavinayaham S, Dennehey BK, and Johnson DG
- Abstract
Members of the E2F transcription factor family regulate the expression of genes important for DNA replication and mitotic cell division in most eukaryotes. Homologs of the retinoblastoma (RB) tumor suppressor inhibit the activity of E2F factors, thus controlling cell cycle progression. Organisms such as budding and fission yeast have lost genes encoding E2F and RB, but have gained genes encoding other proteins that take on E2F and RB cell cycle-related functions. In addition to regulating cell proliferation, E2F and RB homologs have non-canonical functions outside the mitotic cell cycle in a variety of eukaryotes. For example, in both mammals and plants, E2F and RB homologs localize to DNA double-strand breaks (DSBs) and directly promote repair by homologous recombination (HR). Here, we discuss the parallels between mammalian E2F1 and RB and their Arabidopsis homologs, E2FA and RB-related (RBR), with respect to their recruitment to sites of DNA damage and how they help recruit repair factors important for DNA end resection. We also explore the question of whether this role in DNA repair is a conserved ancient function of the E2F and RB homologs in the last eukaryotic common ancestor or whether this function evolved independently in mammals and plants.
- Published
- 2021
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26. The E2F1 transcription factor and RB tumor suppressor moonlight as DNA repair factors.
- Author
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Manickavinayaham S, Velez-Cruz R, Biswas AK, Chen J, Guo R, and Johnson DG
- Subjects
- Acetylation, Animals, Chromatin Assembly and Disassembly, E2F1 Transcription Factor genetics, Histones metabolism, Humans, Retinoblastoma Protein genetics, p300-CBP Transcription Factors metabolism, DNA Damage, DNA Repair, E2F1 Transcription Factor metabolism, Retinoblastoma Protein metabolism
- Abstract
The E2F1 transcription factor and RB tumor suppressor are best known for their roles in regulating the expression of genes important for cell cycle progression but, they also have transcription-independent functions that facilitate DNA repair at sites of damage. Depending on the type of DNA damage, E2F1 can recruit either the GCN5 or p300/CBP histone acetyltransferases to deposit different histone acetylation marks in flanking chromatin. At DNA double-strand breaks, E2F1 also recruits RB and the BRG1 ATPase to remodel chromatin and promote loading of the MRE11-RAD50-NBS1 complex. Knock-in mouse models demonstrate important roles for E2F1 post-translational modifications in regulating DNA repair and physiological responses to DNA damage. This review highlights how E2F1 moonlights in DNA repair, thus revealing E2F1 as a versatile protein that recruits many of the same chromatin-modifying enzymes to sites of DNA damage to promote repair that it recruits to gene promoters to regulate transcription.
- Published
- 2020
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27. Free Standing, Large-Area Silicon Nitride Membranes for High Toxin Clearance in Blood Surrogate for Small-Format Hemodialysis.
- Author
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Miller JJ, Carter JA, Hill K, DesOrmeaux JS, Carter RN, Gaborski TR, Roussie JA, McGrath JL, and Johnson DG
- Abstract
Developing highly-efficient membranes for toxin clearance in small-format hemodialysis presents a fabrication challenge. The miniaturization of fluidics and controls has been the focus of current work on hemodialysis (HD) devices. This approach has not addressed the membrane efficiency needed for toxin clearance in small-format hemodialysis devices. Dr. Willem Kolff built the first dialyzer in 1943 and many changes have been made to HD technology since then. However, conventional HD still uses large instruments with bulky dialysis cartridges made of ~2 m
2 of 10 micron thick, tortuous-path membrane material. Portable, wearable, and implantable HD systems may improve clinical outcomes for patients with end-stage renal disease by increasing the frequency of dialysis. The ability of ultrathin silicon-based sheet membranes to clear toxins is tested along with an analytical model predicting long-term multi-pass experiments from single-pass clearance experiments. Advanced fabrication methods are introduced that produce a new type of nanoporous silicon nitride sheet membrane that features the pore sizes needed for middle-weight toxin removal. Benchtop clearance results with sheet membranes (~3 cm2 ) match a theoretical model and indicate that sheet membranes can reduce (by orders of magnitude) the amount of membrane material required for hemodialysis. This provides the performance needed for small-format hemodialysis.- Published
- 2020
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28. Second Generation Nanoporous Silicon Nitride Membranes for High Toxin Clearance and Small Format Hemodialysis.
- Author
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Hill K, Walker SN, Salminen A, Chung HL, Li X, Ezzat B, Miller JJ, DesOrmeaux JS, Zhang J, Hayden A, Burgin T, Piraino L, May MN, Gaborski TR, Roussie JA, Taylor J, DiVincenti L Jr, Shestopalov AA, McGrath JL, and Johnson DG
- Subjects
- Animals, Humans, Membranes, Artificial, Rats, Renal Dialysis, Silicon Compounds, Kidney Failure, Chronic, Nanopores
- Abstract
Conventional hemodialysis (HD) uses floor-standing instruments and bulky dialysis cartridges containing ≈2 m
2 of 10 micrometer thick, tortuous-path membranes. Portable and wearable HD systems can improve outcomes for patients with end-stage renal disease by facilitating more frequent, longer dialysis at home, providing more physiological toxin clearance. Developing devices with these benefits requires highly efficient membranes to clear clinically relevant toxins in small formats. Here, the ability of ultrathin (<100 nm) silicon-nitride-based membranes to reduce the membrane area required to clear toxins by orders of magnitude is shown. Advanced fabrication methods are introduced that produce nanoporous silicon nitride membranes (NPN-O) that are two times stronger than the original nanoporous nitride materials (NPN) and feature pore sizes appropriate for middle-weight serum toxin removal. Single-pass benchtop studies with NPN-O (1.4 mm2 ) demonstrate the extraordinary clearance potential of these membranes (105 mL min-1 m-2 ), and their intrinsic hemocompatibility. Results of benchtop studies with nanomembranes, and 4 h dialysis of uremic rats, indicate that NPN-O can reduce the membrane area required for hemodialysis by two orders of magnitude, suggesting the performance and robustness needed to enable small-format hemodialysis, a milestone in the development of small-format hemodialysis systems., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2020
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29. E2F1 acetylation directs p300/CBP-mediated histone acetylation at DNA double-strand breaks to facilitate repair.
- Author
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Manickavinayaham S, Vélez-Cruz R, Biswas AK, Bedford E, Klein BJ, Kutateladze TG, Liu B, Bedford MT, and Johnson DG
- Subjects
- Acetylation, Animals, Cell Cycle Proteins metabolism, DNA Helicases metabolism, DNA Repair genetics, DNA-Binding Proteins metabolism, E2F1 Transcription Factor genetics, Gene Knock-In Techniques, Histone Acetyltransferases, Lysine Acetyltransferase 5 metabolism, Mice, Nuclear Proteins metabolism, Protein Interaction Domains and Motifs, Radiation, Ionizing, Trans-Activators metabolism, Transcription Factors metabolism, p300-CBP Transcription Factors metabolism, CREB-Binding Protein metabolism, DNA Breaks, Double-Stranded, E1A-Associated p300 Protein metabolism, E2F1 Transcription Factor metabolism, Histones metabolism
- Abstract
E2F1 and retinoblastoma (RB) tumor-suppressor protein not only regulate the periodic expression of genes important for cell proliferation, but also localize to DNA double-strand breaks (DSBs) to promote repair. E2F1 is acetylated in response to DNA damage but the role this plays in DNA repair is unknown. Here we demonstrate that E2F1 acetylation creates a binding motif for the bromodomains of the p300/KAT3B and CBP/KAT3A acetyltransferases and that this interaction is required for the recruitment of p300 and CBP to DSBs and the induction of histone acetylation at sites of damage. A knock-in mutation that blocks E2F1 acetylation abolishes the recruitment of p300 and CBP to DSBs and also the accumulation of other chromatin modifying activities and repair factors, including Tip60, BRG1 and NBS1, and renders mice hypersensitive to ionizing radiation (IR). These findings reveal an important role for E2F1 acetylation in orchestrating the remodeling of chromatin structure at DSBs to facilitate repair.
- Published
- 2019
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30. Protein Separation and Hemocompatibility of Nitride Membranes in Microfluidic Filtration Systems.
- Author
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Salminen A, Hill K, Henry Chung L, James McGrath L, and Johnson DG
- Subjects
- Filtration, Humans, Kidney Failure, Chronic therapy, Membranes, Artificial, Microfluidics, Renal Dialysis
- Abstract
Improving the health outcomes for end-stage renal Disease (ESRD) patients on hemodialysis (HD) requires new technologies for wearable HD such as a highly efficient membrane that can achieve standard toxic clearance rates in small device footprints. Our group has developed nanoporous silicon nitride (NPN) membranes which are 100 to 1000 times thinner than conventional membranes and are orders-ofmagnitude more efficient for dialysis. Counter flow dialysis separation experiments were performed to measure urea clearance while microdialysis experiments were performed in a stirred beaker to measure the separation of cytochrome-c and albumin. Hemodialysis experiments testing for platelet activation as well as protein adhesion were performed. Devices for the counter flow experiments were constructed with polydimethylsiloxane (PDMS) and a NPN membrane chip. The counter flow devices reduced the urea by as much as 20%. The microdialysis experiments showed a diffusion of ~ 60% for the cytochrome-c while clearing ~ 20% of the Albumin. Initial hemocompatibility studies show that the NPN membrane surface is less prone to both protein adhesion and platelet activation when compared to positive control (glass).
- Published
- 2018
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31. Contrasting effects of an Mdm2 functional polymorphism on tumor phenotypes.
- Author
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Ortiz GJ, Li Y, Post SM, Pant V, Xiong S, Larsson CA, El-Naggar AK, Johnson DG, and Lozano G
- Subjects
- Alleles, Animals, Carcinogens toxicity, Carcinoma, Squamous Cell etiology, Carcinoma, Squamous Cell mortality, Carcinoma, Squamous Cell pathology, Disease-Free Survival, E2F6 Transcription Factor genetics, Female, Keratinocytes, Male, Mice, Mice, Inbred C57BL, Neoplasms, Experimental etiology, Neoplasms, Experimental genetics, Phenotype, Polymorphism, Single Nucleotide, Primary Cell Culture, Sex Factors, Skin cytology, Skin drug effects, Skin pathology, Skin radiation effects, Skin Neoplasms etiology, Skin Neoplasms mortality, Skin Neoplasms pathology, Ultraviolet Rays adverse effects, Carcinoma, Squamous Cell genetics, E2F6 Transcription Factor metabolism, Genetic Predisposition to Disease, Proto-Oncogene Proteins c-mdm2 genetics, Skin Neoplasms genetics
- Abstract
MDM2, an E3 ubiquitin ligase, is a potent inhibitor of the p53 tumor suppressor and is elevated in many human cancers that retain wild-type p53. MDM2 SNP309G is a functional polymorphism that results in elevated levels of MDM2 (due to enhanced SP1 binding to the MDM2 promoter) thus decreasing p53 activity. Mdm2
SNP309G/G mice are more prone to spontaneous tumor formation than Mdm2SNP309T/T mice, providing direct evidence for the impact of this SNP in tumor development. We asked whether environmental factors impact SNP309G function and show that SNP309G cooperates with ionizing radiation to exacerbate tumor development. Surprisingly, ultraviolet B light or Benzo(a)pyrene exposure of skin shows that SNP309G allele actually protects against squamous cell carcinoma susceptibility. These contrasting differences led us to interrogate the mechanism by which Mdm2 SNP309 regulates tumor susceptibility in a tissue-specific manner. Although basal Mdm2 levels were significantly higher in most tissues in Mdm2SNP309G/G mice compared with Mdm2SNP309T/T mice, they were significantly lower in Mdm2SNP309G/G keratinocytes, the cell-type susceptible to squamous cell carcinoma. The assessment of potential transcriptional regulators in ENCODE ChIP-seq database identified transcriptional repressor E2F6 as a possible negative regulator of MDM2 expression. Our data show that E2F6 suppresses Mdm2 expression in cells harboring the SNP309G allele but not the SNP309T allele. Thus, Mdm2 SNP309G exhibits tissue-specific regulation and differentially impacts cancer risk.- Published
- 2018
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32. The Retinoblastoma (RB) Tumor Suppressor: Pushing Back against Genome Instability on Multiple Fronts.
- Author
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Vélez-Cruz R and Johnson DG
- Subjects
- Animals, E2F Transcription Factors genetics, E2F Transcription Factors metabolism, Humans, Retinoblastoma Protein genetics, Retinoblastoma-Like Protein p107 genetics, Retinoblastoma-Like Protein p107 metabolism, Retinoblastoma-Like Protein p130 genetics, Retinoblastoma-Like Protein p130 metabolism, DNA Repair, Gene Silencing, Genomic Instability, Retinoblastoma Protein metabolism, Telomere Homeostasis
- Abstract
The retinoblastoma (RB) tumor suppressor is known as a master regulator of the cell cycle. RB is mutated or functionally inactivated in the majority of human cancers. This transcriptional regulator exerts its function in cell cycle control through its interaction with the E2F family of transcription factors and with chromatin remodelers and modifiers that contribute to the repression of genes important for cell cycle progression. Over the years, studies have shown that RB participates in multiple processes in addition to cell cycle control. Indeed, RB is known to interact with over 200 different proteins and likely exists in multiple complexes. RB, in some cases, acts through its interaction with E2F1, other members of the pocket protein family (p107 and p130), and/or chromatin remodelers and modifiers. RB is a tumor suppressor with important chromatin regulatory functions that affect genomic stability. These functions include the role of RB in DNA repair, telomere maintenance, chromosome condensation and cohesion, and silencing of repetitive regions. In this review we will discuss recent advances in RB biology related to RB, partner proteins, and their non-transcriptional functions fighting back against genomic instability., Competing Interests: The authors declare no conflict of interest.
- Published
- 2017
- Full Text
- View/download PDF
33. The p53 R72P polymorphism does not affect the physiological response to ionizing radiation in a mouse model.
- Author
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Domínguez ER, Orona J, Lin K, Pérez CJ, Benavides F, Kusewitt DF, and Johnson DG
- Subjects
- Amino Acid Substitution, Animals, Apoptosis, Bone Marrow pathology, Bone Marrow radiation effects, DNA Breaks, Double-Stranded, Female, Intestines pathology, Intestines radiation effects, Male, Mice, Transgenic, Polymorphism, Single Nucleotide, Radiation Injuries, Experimental pathology, Spleen pathology, Spleen radiation effects, Thymus Gland pathology, Thymus Gland radiation effects, Radiation Injuries, Experimental genetics, Tumor Suppressor Protein p53 genetics
- Abstract
Tissue culture and mouse model studies show that the presence of the arginine (R) or proline (P) coding single nucleotide polymorphism (SNP) of the tumor suppressor gene p53 at codon 72 (p53 R72P) differentially affects the responses to genotoxic insult. Compared to the P variant, the R variant shows increased apoptosis in most cell cultures and mouse model tissues in response to genotoxins, and epidemiological studies suggest that the R variant may enhance cancer survival and reduce the risks of adverse reactions to genotoxic cancer treatment. As ionizing radiation (IR) treatment is often used in cancer therapy, we sought to test the physiological effects of IR in mouse models of the p53 R72P polymorphism. By performing blood counts, immunohistochemical (IHC) staining and survival studies in mouse populations rigorously controlled for strain background, sex and age, we discovered that p53 R72P polymorphism did not differentially affect the physiological response to IR. Our findings suggest that genotyping for this polymorphism to personalize IR therapy may have little clinical utility.
- Published
- 2017
- Full Text
- View/download PDF
34. RB localizes to DNA double-strand breaks and promotes DNA end resection and homologous recombination through the recruitment of BRG1.
- Author
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Vélez-Cruz R, Manickavinayaham S, Biswas AK, Clary RW, Premkumar T, Cole F, and Johnson DG
- Subjects
- Animals, Cell Line, Cell Line, Tumor, DNA Helicases genetics, DNA Repair genetics, E2F1 Transcription Factor genetics, E2F1 Transcription Factor metabolism, Gamma Rays, Gene Knock-In Techniques, Genomic Instability genetics, Humans, Male, Mice, Mutagens pharmacology, Mutation, Nuclear Proteins genetics, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Protein Transport genetics, Retinoblastoma Protein genetics, Transcription Factors genetics, Whole-Body Irradiation mortality, DNA Breaks, Double-Stranded drug effects, DNA Breaks, Double-Stranded radiation effects, DNA Helicases metabolism, Homologous Recombination genetics, Nuclear Proteins metabolism, Retinoblastoma Protein metabolism, Transcription Factors metabolism
- Abstract
The retinoblastoma (RB) tumor suppressor is recognized as a master regulator that controls entry into the S phase of the cell cycle. Its loss leads to uncontrolled cell proliferation and is a hallmark of cancer. RB works by binding to members of the E2F family of transcription factors and recruiting chromatin modifiers to the promoters of E2F target genes. Here we show that RB also localizes to DNA double-strand breaks (DSBs) dependent on E2F1 and ATM kinase activity and promotes DSB repair through homologous recombination (HR), and its loss results in genome instability. RB is necessary for the recruitment of the BRG1 ATPase to DSBs, which stimulates DNA end resection and HR. A knock-in mutation of the ATM phosphorylation site on E2F1 (S29A) prevents the interaction between E2F1 and TopBP1 and recruitment of RB, E2F1, and BRG1 to DSBs. This knock-in mutation also impairs DNA repair, increases genomic instability, and renders mice hypersensitive to IR. Importantly, depletion of RB in osteosarcoma and breast cancer cell lines results in sensitivity to DNA-damaging drugs, which is further exacerbated by poly-ADP ribose polymerase (PARP) inhibitors. We uncovered a novel, nontranscriptional function for RB in HR, which could contribute to genome instability associated with RB loss., (© 2016 Vélez-Cruz et al.; Published by Cold Spring Harbor Laboratory Press.)
- Published
- 2016
- Full Text
- View/download PDF
35. Nanoporous membrane robustness / stability in small form factor microfluidic filtration system.
- Author
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Johnson DG, Pan S, Hayden A, and McGrath JL
- Subjects
- Filtration, Humans, Kidney Failure, Chronic therapy, Microfluidics, Nanopores, Renal Dialysis instrumentation
- Abstract
The development of wearable hemodialysis (HD) devices that replace center-based HD holds the promise to improve both outcomes and quality-of-life for patients with end-stage-renal disease (ERD). A prerequisite for these devices is the development of highly efficient membranes that can achieve high toxin clearance in small footprints. The ultrathin nanoporous membrane material developed by our group is orders of magnitude more permeable than conventional HD membranes. We report on our progress making a prototype wearable dialysis unit. First, we present data from benchtop studies confirming that clinical levels of urea clearance can be obtained in a small animal model with low blood flow rates. Second, we report on efforts to improve the mechanical robustness of high membrane area dialysis devices.
- Published
- 2016
- Full Text
- View/download PDF
36. Towards an Implantable, Low Flow Micropump That Uses No Power in the Blocked-Flow State.
- Author
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Johnson DG and Borkholder DA
- Abstract
Low flow rate micropumps play an increasingly important role in drug therapy research. Infusions to small biological structures and lab-on-a-chip applications require ultra-low flow rates and will benefit from the ability to expend no power in the blocked-flow state. Here we present a planar micropump based on gallium phase-change actuation that leverages expansion during solidification to occlude the flow channel in the off-power state. The presented four chamber peristaltic micropump was fabricated with a combination of Micro Electro Mechanical System (MEMS) techniques and additive manufacturing direct write technologies. The device is 7 mm × 13 mm × 1 mm (<100 mm³) with the flow channel and exterior coated with biocompatible Parylene-C, critical for implantable applications. Controllable pump rates from 18 to 104 nL/min were demonstrated, with 11.1 ± 0.35 nL pumped per actuation at an efficiency of 11 mJ/nL. The normally-closed state of the gallium actuator prevents flow and diffusion between the pump and the biological system or lab-on-a-chip, without consuming power. This is especially important for implanted applications with periodic drug delivery regimens.
- Published
- 2016
- Full Text
- View/download PDF
37. TIE2-mediated tyrosine phosphorylation of H4 regulates DNA damage response by recruiting ABL1.
- Author
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Hossain MB, Shifat R, Johnson DG, Bedford MT, Gabrusiewicz KR, Cortes-Santiago N, Luo X, Lu Z, Ezhilarasan R, Sulman EP, Jiang H, Li SS, Lang FF, Tyler J, Hung MC, Fueyo J, and Gomez-Manzano C
- Subjects
- Angiotensin I metabolism, Cell Line, Tumor, DNA End-Joining Repair, Humans, Protein Binding, Protein Transport, Proto-Oncogene Mas, Radiation Tolerance genetics, Radiation, Ionizing, Receptor, TIE-2 genetics, DNA Damage, Histones metabolism, Proto-Oncogene Proteins c-abl metabolism, Receptor, TIE-2 metabolism, Tyrosine metabolism
- Abstract
DNA repair pathways enable cancer cells to survive DNA damage induced after genotoxic therapies. Tyrosine kinase receptors (TKRs) have been reported as regulators of the DNA repair machinery. TIE2 is a TKR overexpressed in human gliomas at levels that correlate with the degree of increasing malignancy. Following ionizing radiation, TIE2 translocates to the nucleus, conferring cells with an enhanced nonhomologous end-joining mechanism of DNA repair that results in a radioresistant phenotype. Nuclear TIE2 binds to key components of DNA repair and phosphorylates H4 at tyrosine 51, which, in turn, is recognized by the proto-oncogene ABL1, indicating a role for nuclear TIE2 as a sensor for genotoxic stress by action as a histone modifier. H4Y51 constitutes the first tyrosine phosphorylation of core histones recognized by ABL1, defining this histone modification as a direct signal to couple genotoxic stress with the DNA repair machinery.
- Published
- 2016
- Full Text
- View/download PDF
38. Structure of Amido Pyridinium Betaines: Persistent Intermolecular C-H⋅⋅⋅N Hydrogen Bonding in Solution.
- Author
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Thatcher RJ, Johnson DG, Slattery JM, and Douthwaite RE
- Abstract
A hydrogen bond of the type C-H⋅⋅⋅X (X=O or N) is known to influence the structure and function of chemical and biological systems in solution. C-H⋅⋅⋅O hydrogen bonding in solution has been extensively studied, both experimentally and computationally, whereas the equivalent thermodynamic parameters have not been enumerated experimentally for C-H⋅⋅⋅N hydrogen bonds. This is, in part, due to the lack of systems that exhibit persistent C-H⋅⋅⋅N hydrogen bonds in solution. Herein, a class of molecule based on a biologically active norharman motif that exhibits unsupported intermolecular C-H⋅⋅⋅N hydrogen bonds in solution has been described. A pairwise interaction leads to dimerisation to give bond strengths of about 7 kJ mol
-1 per hydrogen bond, which is similar to chemically and biologically relevant C-H⋅⋅⋅O hydrogen bonding. The experimental data is supported by computational work, which provides additional insight into the hydrogen bonding by consideration of electrostatic and orbital interactions and allowed a comparison between calculated and extrapolated NMR chemical shifts., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2016
- Full Text
- View/download PDF
39. Gold-Catalyzed Proto- and Deuterodeboronation.
- Author
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Barker G, Webster S, Johnson DG, Curley R, Andrews M, Young PC, Macgregor SA, and Lee AL
- Abstract
A mild gold-catalyzed protodeboronation reaction, which does not require acid or base additives and can be carried out in "green" solvents, is described. As a result, the reaction is very functional-group-tolerant, even to acid- and base-sensitive functional groups, and should allow for the boronic acid group to be used as an effective traceless directing or blocking group. The reaction has also been extended to deuterodeboronations for regiospecific ipso-deuterations of aryls and heteroaryls from the corresponding organoboronic acid. Based on density functional theory calculations, a mechanism is proposed that involves nucleophilic attack of water at boron followed by rate-limiting B-C bond cleavage and facile protonolysis of a Au-σ-phenyl intermediate.
- Published
- 2015
- Full Text
- View/download PDF
40. Chirality Transfer in Gold(I)-Catalysed Direct Allylic Etherifications of Unactivated Alcohols: Experimental and Computational Study.
- Author
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Barker G, Johnson DG, Young PC, Macgregor SA, and Lee AL
- Abstract
Gold(I)-catalysed direct allylic etherifications have been successfully carried out with chirality transfer to yield enantioenriched, γ-substituted secondary allylic ethers. Our investigations include a full substrate-scope screen to ascertain substituent effects on the regioselectivity, stereoselectivity and efficiency of chirality transfer, as well as control experiments to elucidate the mechanistic subtleties of the chirality-transfer process. Crucially, addition of molecular sieves was found to be necessary to ensure efficient and general chirality transfer. Computational studies suggest that the efficiency of chirality transfer is linked to the aggregation of the alcohol nucleophile around the reactive π-bound Au-allylic ether complex. With a single alcohol nucleophile, a high degree of chirality transfer is predicted. However, if three alcohols are present, alternative proton transfer chain mechanisms that erode the efficiency of chirality transfer become competitive., (© 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.)
- Published
- 2015
- Full Text
- View/download PDF
41. Palladium-catalyzed direct C-H functionalization of benzoquinone.
- Author
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Walker SE, Jordan-Hore JA, Johnson DG, Macgregor SA, and Lee AL
- Abstract
A direct Pd-catalyzed C-H functionalization of benzoquinone (BQ) can be controlled to give either mono- or disubstituted BQ, including the installation of two different groups in a one-pot procedure. BQ can now be directly functionalized with aryl, heteroaryl, cycloalkyl, and cycloalkene groups and, moreover, the reaction is conducted in environmentally benign water or acetone as solvents., (© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.)
- Published
- 2014
- Full Text
- View/download PDF
42. Gold(I)-catalysed direct thioetherifications using allylic alcohols: an experimental and computational study.
- Author
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Herkert L, Green SL, Barker G, Johnson DG, Young PC, Macgregor SA, and Lee AL
- Subjects
- Catalysis, Models, Molecular, Stereoisomerism, Allyl Compounds chemistry, Gold chemistry, Propanols chemistry, Sulfides chemistry
- Abstract
A gold(I)-catalysed direct thioetherification reaction between allylic alcohols and thiols is presented. The reaction is generally highly regioselective (S(N)2'). This dehydrative allylation procedure is very mild and atom economical, producing only water as the by-product and avoiding any unnecessary waste/steps associated with installing a leaving or activating group on the substrate. Computational studies are presented to gain insight into the mechanism of the reaction. Calculations indicate that the regioselectivity is under equilibrium control and is ultimately dictated by the thermodynamic stability of the products., (© 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.)
- Published
- 2014
- Full Text
- View/download PDF
43. Far-infrared spectroscopy of the troposphere: calibration with a cold background.
- Author
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Latvakoski H, Mlynczak MG, Cageao RP, Johnson DG, and Kratz DP
- Abstract
The far-infrared spectroscopy of the troposphere (FIRST) instrument is a Fourier-transform spectrometer developed to measure the Earth's thermal emission spectrum with a particular emphasis on the far-infrared. FIRST has observed the atmosphere from both the ground looking up and from a high-altitude balloon looking down. A recent absolute laboratory calibration of FIRST under ground-like operating conditions showed accuracy to better than 0.3 K at near-ambient temperatures (270-325 K) but reduced accuracy at lower temperatures. This paper presents calibration results for balloon-flight conditions using a cold blackbody to simulate the space view used for on-board calibration. An unusual detector nonlinearity was discovered and corrected, and stray light was measured and removed. Over most of the range of Earth scene temperatures (205-300 K), the accuracy of FIRST is 0.35-0.15 K (one sigma).
- Published
- 2014
- Full Text
- View/download PDF
44. Modeling gene-environment interactions in oral cavity and esophageal cancers demonstrates a role for the p53 R72P polymorphism in modulating susceptibility.
- Author
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Sarkar J, Dominguez E, Li G, Kusewitt DF, and Johnson DG
- Subjects
- Animals, Blotting, Western, Carcinogens toxicity, Cells, Cultured, DNA, Viral genetics, Esophageal Neoplasms metabolism, Esophageal Neoplasms pathology, Female, Humans, Immunoenzyme Techniques, Inflammation metabolism, Inflammation pathology, Keratinocytes cytology, Keratinocytes drug effects, Keratinocytes metabolism, Mice, Mice, Transgenic, Mouth Neoplasms metabolism, Mouth Neoplasms pathology, Oncogene Proteins, Viral physiology, Papillomaviridae genetics, Papillomavirus E7 Proteins physiology, Papillomavirus Infections metabolism, Papillomavirus Infections pathology, Phenotype, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Repressor Proteins physiology, Reverse Transcriptase Polymerase Chain Reaction, 4-Nitroquinoline-1-oxide toxicity, Esophageal Neoplasms etiology, Gene-Environment Interaction, Inflammation etiology, Mouth Neoplasms etiology, Papillomavirus Infections etiology, Polymorphism, Single Nucleotide genetics, Tumor Suppressor Protein p53 physiology
- Abstract
A large number of epidemiological studies have linked a common single-nucleotide polymorphism (SNP) in the human p53 gene to risk for developing a variety of cancers. This SNP encodes either an arginine or proline at position 72 (R72P) of the p53 protein, which can alter the apoptotic activity of p53 via transcriptional and non-transcriptional mechanisms. This SNP has also been reported to modulate the development of human papilloma virus (HPV)-driven cancers through differential targeting of the p53 variant proteins by the E6 viral oncoprotein. Mouse models for the p53 R72P polymorphism have recently been developed but a role for this SNP in modifying cancer risk in response to viral and chemical carcinogens has yet to be established experimentally. Here, we demonstrate that the p53 R72P polymorphism modulates the hyperprolferative, apoptotic and inflammatory phenotypes caused by expression of the HPV16 E6 and E7 oncoproteins. Moreover, the R72P SNP also modifies the carcinogenic response to the chemical carcinogen 4NQO, in the presence and absence of the HPV16 transgene. Our findings confirm several human epidemiological studies associating the codon 72 proline variant with increased risk for certain cancers but also suggest that there are tissue-specific differences in how the R72P polymorphism influences the response to environmental carcinogens., (© 2013 Wiley Periodicals, Inc.)
- Published
- 2014
- Full Text
- View/download PDF
45. E2F1 responds to ultraviolet radiation by directly stimulating DNA repair and suppressing carcinogenesis.
- Author
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Biswas AK, Mitchell DL, and Johnson DG
- Subjects
- Amino Acid Substitution, Animals, Cells, Cultured, DNA Damage, Gene Knock-In Techniques, Genes, Tumor Suppressor, Mice, Mice, Transgenic, Phosphorylation, Primary Cell Culture, Protein Processing, Post-Translational, Protein Stability, Protein Transport, Carcinogenesis genetics, DNA Repair, E2F1 Transcription Factor physiology, Skin Neoplasms genetics, Ultraviolet Rays
- Abstract
In response to DNA damage, the E2F1 transcription factor is phosphorylated at serine 31 (serine 29 in mouse) by the ATM or ATR kinases, which promotes E2F1 protein stabilization. Phosphorylation of E2F1 also leads to the recruitment of E2F1 to sites of DNA damage, where it functions to enhance DNA repair. To study the role of this E2F1 phosphorylation event in vivo, a knock-in mouse model was generated, in which serine 29 was mutated to alanine. The S29A mutation impairs E2F1 stabilization in response to ultraviolet (UV) radiation and doxorubicin treatment, but has little effect on the expression of E2F target genes. The apoptotic and proliferative responses to acute UV radiation exposure are also similar between wild-type and E2f1(S29A/) (S29A) mice. As expected, the S29A mutation prevents E2F1 association with damaged DNA and reduces DNA repair efficiency. Moreover, E2f1(S29A/) (S29A) mice display increased sensitivity to UV-induced skin carcinogenesis. This knock-in mouse model thus links the ability of E2F1 to directly promote DNA repair with the suppression of tumor development., (©2014 American Association for Cancer Research.)
- Published
- 2014
- Full Text
- View/download PDF
46. Slug expression in mouse skin and skin tumors is not regulated by p53.
- Author
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Perez CJ, Rundhaug JE, Johnson DG, Oberyszyn TM, Tober KL, and Kusewitt DF
- Subjects
- Animals, Mice, Mice, 129 Strain, Mice, Knockout, Skin metabolism, Skin Neoplasms metabolism, Skin Neoplasms pathology, Snail Family Transcription Factors, Transcription Factors metabolism, Keratinocytes physiology, Skin pathology, Skin Neoplasms genetics, Transcription Factors genetics, Tumor Suppressor Protein p53 genetics
- Published
- 2014
- Full Text
- View/download PDF
47. Identification of prohibitin and prohibiton as novel factors binding to the p53 induced gene 3 (PIG3) promoter (TGYCC)(15) motif.
- Author
-
Guan X, Liu Z, Wang L, Johnson DG, and Wei Q
- Subjects
- Apoptosis genetics, Apoptosis physiology, Base Sequence, Binding Sites genetics, Cell Line, Tumor, Gene Knockdown Techniques, Humans, Microsatellite Repeats, Prohibitins, Protein Binding, RNA, Messenger genetics, RNA, Messenger metabolism, RNA, Neoplasm genetics, RNA, Neoplasm metabolism, Repressor Proteins antagonists & inhibitors, Repressor Proteins genetics, Tumor Suppressor Protein p53 metabolism, Intracellular Signaling Peptides and Proteins genetics, Promoter Regions, Genetic, Proto-Oncogene Proteins genetics, Repressor Proteins metabolism
- Abstract
The promoter of p53 induced gene 3 (PIG3) contains a variable number of tandem repeats (VNTRs) of pentanucleotides (TGYCC)n that is known as a p53 binding site. In this study, we investigated whether other potential molecules could bind to this PIG3 promoter (TGYCC)n motif. Ligand-chromatography combined with liquid chromatography-tandem mass spectrometry analyses indicated direct interactions of prohibitin and/or prohibiton with the (TGYCC)15 motif, which was confirmed by electrophoretic mobility shift assay and super-gel shift analysis with anti-prohibitin and anti-prohibiton antibodies. Using the chromatin immunopercipipation assay, we further demonstrated that prohibitin and prohibiton associated with the (TGYCC)15 motif in vivo regardless of the p53 status and apoptotic stress. We also found that prohibitin and prohibiton up-regulated PIG3 transcription independent of p53, although p53 obviously enhanced this process, and that the knock-down of prohibitin and prohibiton inhibited camptothecin-induced apoptosis. Taken together, our findings suggest that prohibitin and prohibiton contribute to PIG3-mediated apoptosis by binding to the PIG3 promoter (TGYCC)15 motif., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
48. Ultrathin silicon membranes for wearable dialysis.
- Author
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Johnson DG, Khire TS, Lyubarskaya YL, Smith KJ, Desormeaux JP, Taylor JG, Gaborski TR, Shestopalov AA, Striemer CC, and McGrath JL
- Subjects
- Humans, Microfluidics methods, Nanopores, Renal Dialysis methods, Kidney Failure, Chronic therapy, Membranes, Artificial, Microfluidics instrumentation, Renal Dialysis instrumentation, Silicon therapeutic use
- Abstract
The development of wearable or implantable technologies that replace center-based hemodialysis (HD) hold promise to improve outcomes and quality of life for patients with ESRD. A prerequisite for these technologies is the development of highly efficient membranes that can achieve high toxin clearance in small-device formats. Here we examine the application of the porous nanocrystalline silicon (pnc-Si) to HD. pnc-Si is a molecularly thin nanoporous membrane material that is orders of magnitude more permeable than conventional HD membranes. Material developments have allowed us to dramatically increase the amount of active membrane available for dialysis on pnc-Si chips. By controlling pore sizes during manufacturing, pnc-Si membranes can be engineered to pass middle-molecular-weight protein toxins while retaining albumin, mimicking the healthy kidney. A microfluidic dialysis device developed with pnc-Si achieves urea clearance rates that confirm that the membrane offers no resistance to urea passage. Finally, surface modifications with thin hydrophilic coatings are shown to block cell and protein adhesion., (Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
49. Acute onset of lower limb weakness, sphincter dysfunction and sensory disturbance in an older woman.
- Author
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Lamprell L and Johnson DG
- Subjects
- Constipation etiology, Female, Humans, Imaging, Three-Dimensional, Low Back Pain etiology, Middle Aged, Muscle Weakness etiology, Sensation Disorders etiology, Tomography, X-Ray Computed, Urinary Retention etiology, Aorta, Abdominal diagnostic imaging, Aortic Aneurysm, Abdominal diagnostic imaging, Arterial Occlusive Diseases diagnosis, Thrombosis diagnostic imaging
- Published
- 2013
- Full Text
- View/download PDF
50. Chromatin: receiver and quarterback for cellular signals.
- Author
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Johnson DG and Dent SY
- Subjects
- Animals, Chromatin Assembly and Disassembly, Histones metabolism, Humans, Methylation, Ubiquitination, Chromatin metabolism, Signal Transduction
- Abstract
Signal transduction pathways converge upon sequence-specific DNA binding factors to reprogram gene expression. Transcription factors, in turn, team up with chromatin modifying activities. However, chromatin is not simply an endpoint for signaling pathways. Histone modifications relay signals to other proteins to trigger more immediate responses than can be achieved through altered gene transcription, which might be especially important to time-urgent processes such as the execution of cell-cycle check points, chromosome segregation, or exit from mitosis. In addition, histone-modifying enzymes often have multiple nonhistone substrates, and coordination of activity toward different targets might direct signals both to and from chromatin., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
- Full Text
- View/download PDF
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