13 results on '"Purser N"'
Search Results
2. Gas gangrene
- Author
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Pitt, M. and Purser, N. J.
- Published
- 1996
3. Beam Blanking Studies in Environmental Scanning Electron Microscopy
- Author
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Dobberstein, H, primary, Purser, N J, additional, Fairhead, T W, additional, Stokes, D J, additional, and Knowles, R W, additional
- Published
- 2005
- Full Text
- View/download PDF
4. Nipple core biopsy for the deformed or scaling nipple
- Author
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Aryal, K.R., primary, Lengyel, A.J., additional, Purser, N., additional, Harrison, N., additional, Aluwihare, N., additional, and Isgar, B., additional
- Published
- 2004
- Full Text
- View/download PDF
5. The stresst'er ergometer
- Author
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Laws, P., primary, Purser, N., additional, and Williams, D., additional
- Published
- 1998
- Full Text
- View/download PDF
6. Development of quinolone resistance in Salmonella: Failure to prevent splenic abscess
- Author
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BOSWELL, T, primary, COLEMAN, D, additional, PURSER, N, additional, and COBB, R, additional
- Published
- 1997
- Full Text
- View/download PDF
7. Cullin-RING ligases employ geometrically optimized catalytic partners for substrate targeting.
- Author
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Li J, Purser N, Liwocha J, Scott DC, Byers HA, Steigenberger B, Hill S, Tripathi-Giesgen I, Hinkle T, Hansen FM, Prabu JR, Radhakrishnan SK, Kirkpatrick DS, Reichermeier KM, Schulman BA, and Kleiger G
- Subjects
- Humans, Ubiquitination, Ubiquitin metabolism, Polyubiquitin metabolism, Carrier Proteins metabolism, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases metabolism, Cullin Proteins genetics, Cullin Proteins metabolism
- Abstract
Cullin-RING ligases (CRLs) ubiquitylate specific substrates selected from other cellular proteins. Substrate discrimination and ubiquitin transferase activity were thought to be strictly separated. Substrates are recognized by substrate receptors, such as Fbox or BCbox proteins. Meanwhile, CRLs employ assorted ubiquitin-carrying enzymes (UCEs, which are a collection of E2 and ARIH-family E3s) specialized for either initial substrate ubiquitylation (priming) or forging poly-ubiquitin chains. We discovered specific human CRL-UCE pairings governing substrate priming. The results reveal pairing of CUL2-based CRLs and UBE2R-family UCEs in cells, essential for efficient PROTAC-induced neo-substrate degradation. Despite UBE2R2's intrinsic programming to catalyze poly-ubiquitylation, CUL2 employs this UCE for geometrically precise PROTAC-dependent ubiquitylation of a neo-substrate and for rapid priming of substrates recruited to diverse receptors. Cryo-EM structures illuminate how CUL2-based CRLs engage UBE2R2 to activate substrate ubiquitylation. Thus, pairing with a specific UCE overcomes E2 catalytic limitations to drive substrate ubiquitylation and targeted protein degradation., Competing Interests: Declaration of interests B.A.S. is a member of the scientific advisory boards of Interline Therapeutics and BioTheryX and co-inventor of intellectual property licensed to Cinsano. D.S.K. and K.M.R. were employees of Genentech/Roche at the time the work was completed. T.H. is currently an employee of Genentech/Roche. D.S.K. is an employee and shareholder of Orion Medicines. S.H. is currently an employee and shareholder of Amgen., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
- Full Text
- View/download PDF
8. Mechanism of millisecond Lys48-linked poly-ubiquitin chain formation by cullin-RING ligases.
- Author
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Liwocha J, Li J, Purser N, Rattanasopa C, Maiwald S, Krist DT, Scott DC, Steigenberger B, Prabu JR, Schulman BA, and Kleiger G
- Subjects
- Ubiquitin-Protein Ligases metabolism, Ubiquitination, Ubiquitin metabolism, Polyubiquitin metabolism, Cullin Proteins metabolism, Ubiquitin-Conjugating Enzymes metabolism
- Abstract
E3 ubiquitin ligases, in collaboration with E2 ubiquitin-conjugating enzymes, modify proteins with poly-ubiquitin chains. Cullin-RING ligase (CRL) E3s use Cdc34/UBE2R-family E2s to build Lys48-linked poly-ubiquitin chains to control an enormous swath of eukaryotic biology. Yet the molecular mechanisms underlying this exceptional linkage specificity and millisecond kinetics of poly-ubiquitylation remain unclear. Here we obtain cryogenic-electron microscopy (cryo-EM) structures that provide pertinent insight into how such poly-ubiquitin chains are forged. The CRL RING domain not only activates the E2-bound ubiquitin but also shapes the conformation of a distinctive UBE2R2 loop, positioning both the ubiquitin to be transferred and the substrate-linked acceptor ubiquitin within the active site. The structures also reveal how the ubiquitin-like protein NEDD8 uniquely activates CRLs during chain formation. NEDD8 releases the RING domain from the CRL, but unlike previous CRL-E2 structures, does not contact UBE2R2. These findings suggest how poly-ubiquitylation may be accomplished by many E2s and E3s., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
9. Catalysis of non-canonical protein ubiquitylation by the ARIH1 ubiquitin ligase.
- Author
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Purser N, Tripathi-Giesgen I, Li J, Scott DC, Horn-Ghetko D, Baek K, Schulman BA, Alpi AF, and Kleiger G
- Subjects
- Ubiquitination, Proteins metabolism, Catalysis, Ubiquitin genetics, Ubiquitin metabolism, Ubiquitin-Protein Ligases metabolism
- Abstract
Protein ubiquitylation typically involves isopeptide bond formation between the C-terminus of ubiquitin to the side-chain amino group on Lys residues. However, several ubiquitin ligases (E3s) have recently been identified that ubiquitylate proteins on non-Lys residues. For instance, HOIL-1 belongs to the RING-in-between RING (RBR) class of E3s and has an established role in Ser ubiquitylation. Given the homology between HOIL-1 and ARIH1, an RBR E3 that functions with the large superfamily of cullin-RING E3 ligases (CRLs), a biochemical investigation was undertaken, showing ARIH1 catalyzes Ser ubiquitylation to CRL-bound substrates. However, the efficiency of ubiquitylation was exquisitely dependent on the location and chemical environment of the Ser residue within the primary structure of the substrate. Comprehensive mutagenesis of the ARIH1 Rcat domain identified residues whose mutation severely impacted both oxyester and isopeptide bond formation at the preferred site for Ser ubiquitylation while only modestly affecting Lys ubiquitylation at the physiological site. The results reveal dual isopeptide and oxyester protein ubiquitylation activities of ARIH1 and set the stage for physiological investigations into this function of emerging importance., (© 2023 The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
10. E3 ligase autoinhibition by C-degron mimicry maintains C-degron substrate fidelity.
- Author
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Scott DC, King MT, Baek K, Gee CT, Kalathur R, Li J, Purser N, Nourse A, Chai SC, Vaithiyalingam S, Chen T, Lee RE, Elledge SJ, Kleiger G, and Schulman BA
- Subjects
- Humans, Carrier Proteins, Proteins metabolism, Ubiquitin-Protein Ligases metabolism
- Abstract
E3 ligase recruitment of proteins containing terminal destabilizing motifs (degrons) is emerging as a major form of regulation. How those E3s discriminate bona fide substrates from other proteins with terminal degron-like sequences remains unclear. Here, we report that human KLHDC2, a CRL2 substrate receptor targeting C-terminal Gly-Gly degrons, is regulated through interconversion between two assemblies. In the self-inactivated homotetramer, KLHDC2's C-terminal Gly-Ser motif mimics a degron and engages the substrate-binding domain of another protomer. True substrates capture the monomeric CRL2
KLHDC2 , driving E3 activation by neddylation and subsequent substrate ubiquitylation. Non-substrates such as NEDD8 bind KLHDC2 with high affinity, but its slow on rate prevents productive association with CRL2KLHDC2 . Without substrate, neddylated CRL2KLHDC2 assemblies are deactivated via distinct mechanisms: the monomer by deneddylation and the tetramer by auto-ubiquitylation. Thus, substrate specificity is amplified by KLHDC2 self-assembly acting like a molecular timer, where only bona fide substrates may bind before E3 ligase inactivation., Competing Interests: Declaration of interests B.A.S. is a member of the scientific advisory boards of Interline Therapeutics and BioTheryX. B.A.S. and D.C.S. are co-inventors of intellectual property licensed to Cinsano., (Copyright © 2023 Elsevier Inc. All rights reserved.)- Published
- 2023
- Full Text
- View/download PDF
11. The effect of a first flush rainwater harvesting and subsurface irrigation system on E. coli and pathogen concentrations in irrigation water, soil, and produce.
- Author
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Morgado ME, Hudson CL, Chattopadhyay S, Ta K, East C, Purser N, Allard S, Ferrier MD, Sapkota AR, Sharma M, and Goldstein RR
- Subjects
- Agricultural Irrigation, Agriculture, Food Safety, Water Microbiology, Escherichia coli, Soil
- Abstract
Climate change is stressing irrigation water sources, necessitating the evaluation of alternative waters such as harvested rainwater to determine if they meet water quality and food safety standards. We collected water, soil, and produce samples between June and August 2019 from two vegetable rain garden (VRG) sites in Frederick, Maryland that harvest rainwater using a first flush system, and deliver this water to produce through subsurface irrigation. The raised VRG beds include layers of gravel, sand, and soil that act as filters. We recorded the average surface soil moisture in each bed as well as antecedent precipitation. All water (n = 29), soil (n = 55), and produce (n = 57) samples were tested for generic E. coli using standard membrane filtration, and water samples were also tested for Salmonella spp. and Listeria monocytogenes by selective enrichment. No Salmonella spp. or L. monocytogenes isolates were detected in any water samples throughout the study period. Average E. coli levels from all harvested rainwater samples at both sites (1.2 and 24.4 CFU/100 mL) were well below the Good Agricultural Practices food safety guidelines. Only 7 % (3/44) of produce samples from beds irrigated with harvested rainwater were positive for E. coli. E. coli levels in soil samples were positively associated with average surface soil moisture (r
2 = 0.13, p = 0.007). Additionally, E. coli presence in water samples was marginally associated with a shorter length of antecedent dry period (fewer days since preceding rainfall) (p = 0.058). Our results suggest that harvested rainwater collected through a first flush system and applied to produce through subsurface irrigation meets current food safety standards. Soil moisture monitoring could further reduce E. coli contamination risks from harvested rainwater-irrigated produce. First flush and subsurface irrigation systems could help mitigate climate change-related water challenges while protecting food safety and security., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)- Published
- 2022
- Full Text
- View/download PDF
12. Linkage-specific ubiquitin chain formation depends on a lysine hydrocarbon ruler.
- Author
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Liwocha J, Krist DT, van der Heden van Noort GJ, Hansen FM, Truong VH, Karayel O, Purser N, Houston D, Burton N, Bostock MJ, Sattler M, Mann M, Harrison JS, Kleiger G, Ovaa H, and Schulman BA
- Subjects
- Binding Sites, Cloning, Molecular, Crystallography, X-Ray, Escherichia coli genetics, Escherichia coli metabolism, Gene Expression, Genetic Vectors chemistry, Genetic Vectors metabolism, Humans, Kinetics, Lysine metabolism, Models, Molecular, NEDD8 Protein genetics, NEDD8 Protein metabolism, Nuclear Proteins chemistry, Nuclear Proteins genetics, Nuclear Proteins metabolism, Polyubiquitin genetics, Polyubiquitin metabolism, Protein Binding, Protein Interaction Domains and Motifs, Protein Structure, Secondary, Recombinant Proteins chemistry, Recombinant Proteins genetics, Recombinant Proteins metabolism, Substrate Specificity, Transcription Factors chemistry, Transcription Factors genetics, Transcription Factors metabolism, Ubiquitin genetics, Ubiquitin metabolism, Ubiquitin-Conjugating Enzymes chemistry, Ubiquitin-Conjugating Enzymes genetics, Ubiquitin-Conjugating Enzymes metabolism, Ubiquitination, Lysine chemistry, NEDD8 Protein chemistry, Polyubiquitin chemistry, Protein Processing, Post-Translational, Ubiquitin chemistry
- Abstract
Virtually all aspects of cell biology are regulated by a ubiquitin code where distinct ubiquitin chain architectures guide the binding events and itineraries of modified substrates. Various combinations of E2 and E3 enzymes accomplish chain formation by forging isopeptide bonds between the C terminus of their transiently linked donor ubiquitin and a specific nucleophilic amino acid on the acceptor ubiquitin, yet it is unknown whether the fundamental feature of most acceptors-the lysine side chain-affects catalysis. Here, use of synthetic ubiquitins with non-natural acceptor site replacements reveals that the aliphatic side chain specifying reactive amine geometry is a determinant of the ubiquitin code, through unanticipated and complex reliance of many distinct ubiquitin-carrying enzymes on a canonical acceptor lysine.
- Published
- 2021
- Full Text
- View/download PDF
13. A phase 1 trial testing an enteral solution patterned after human amniotic fluid to treat feeding intolerance.
- Author
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Barney CK, Purser N, and Christensen RD
- Subjects
- Growth Substances therapeutic use, Humans, Infant, Infant, Newborn, Pilot Projects, Recombinant Proteins therapeutic use, Amniotic Fluid, Enteral Nutrition, Gastrointestinal Diseases therapy, Infant, Premature
- Abstract
Objective: Feeding intolerance is a common problem in neonates; in some cases it may be related to atrophic changes in the small bowel mucosa. In these infants, feeding tolerance might improve after oral administration of enterocyte growth factors in a sterile, isotonic, noncaloric solution patterned after human amniotic fluid., Study Design: Ten infants who met the study criteria for feeding intolerance were enrolled in this pilot trial. The test solution was administered, 2.5 mL/kg every 3 hours, until 80 mL/kg/day of milk feedings were tolerated, or for a maximum of 7 days. When milk feedings were prescribed, they were mixed with the test solution. Volumes of milk feedings were increased in amounts determined by the attending neonatologist and neonatal nurse practitioner. The outcome was the net average enteral kilocalories per kilogram of body weight per day (kcal/kg/day) for 3 periods: (1) the 3 days before the test treatment was begun, (2) the days the test treatment was administered, and (3) the 7 days following cessation of the test treatment., Results: At study entry the infants' chronological ages ranged from 3 to 65 days. All infants tolerated the test solution, which was given for a mean of 5 days (range 3 to 7 days). During that period, the infants received more enteral calories (mean 18 kcal/kg/day, range 1 to 32) than during the preceding 3 day period (mean 3 kcal/kg/day, range 0 to 7, P < 0.05). During the 7 days following the test treatment the infants received 87 enteral kcal/kg/day (range 11 to 109, P < 0.02 compared to the treatment period)., Conclusions: In this Phase 1 pilot trial, 10 heterogeneous infants in the neonatal intensive care unit with feeding intolerance had a significant increase in milk feedings after treatment with a sterile, isotonic, noncaloric solution patterned after human amniotic fluid.
- Published
- 2006
- Full Text
- View/download PDF
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