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3. Abnormal movements and diaphragmatic flutter in a case of suspected induced illness

Author

Thomas Clayton, Rahul S Joshi, Rebecca Arvier, and Monique Dade

Subjects
0301 basic medicine, Bradycardia, Tachycardia, Case Report, 030105 genetics & heredity, 03 medical and health sciences, 0302 clinical medicine, Breathing pattern, medicine, Humans, Glasgow Coma Scale, Diaphragmatic flutter, Child, Dyskinesias, business.industry, Infant, General Medicine, Abnormal movements, Clonidine, Lisdexamfetamine, Anesthesia, Female, medicine.symptom, business, 030217 neurology & neurosurgery, medicine.drug
Abstract

A 6-month-old girl presented to hospital via ambulance with a decreased conscious level (initial Glasgow Coma Scale of 3) and an abnormal breathing pattern described as diaphragmatic flutter. She then developed abnormal movements and continued to have episodes of fluctuating conscious levels so was transferred to a tertiary hospital paediatric intensive care unit for further investigation. During her 16-day stay in hospital, she continued to experience discrete episodes of drowsiness, bradycardia, unusual breathing patterns and abnormal movements which were associated with agitation, tachycardia, hypertension and insomnia. The patient underwent extensive investigation for her symptoms and, after some delay in waiting for initial results before considering a urine drug screen, she was ultimately found to have lisdexamfetamine and clonidine in her urine drug screen. Her symptoms subsequently resolved after her mother’s visits were restricted.

Published
2023

4. Supplementary Table S1 from Avadomide Induces Degradation of ZMYM2 Fusion Oncoproteins in Hematologic Malignancies

Author

Benjamin L. Ebert, Steven A. Carr, Philip P. Chamberlain, Mark Rolfe, Jean-Michel Cayuela, Jean-Jacques Kiladjian, Stéphane De Botton, Véronique Saada, Christophe Marzac, Sophie Cotteret, Rob S. Sellar, Andrew A. Guirguis, Alexander Tepper, Kaushik Viswanathan, Marie McConkey, Thomas Clayton, Mary E. Matyskiela, Namrata D. Udeshi, Pierre M. Jean Beltran, Daniel E. Grinshpun, Jessica A. Gasser, and Aline Renneville

Abstract

Supplementary Table 1. Proteomic data

Published
2023
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5. Supplementary Data from Avadomide Induces Degradation of ZMYM2 Fusion Oncoproteins in Hematologic Malignancies

Author

Benjamin L. Ebert, Steven A. Carr, Philip P. Chamberlain, Mark Rolfe, Jean-Michel Cayuela, Jean-Jacques Kiladjian, Stéphane De Botton, Véronique Saada, Christophe Marzac, Sophie Cotteret, Rob S. Sellar, Andrew A. Guirguis, Alexander Tepper, Kaushik Viswanathan, Marie McConkey, Thomas Clayton, Mary E. Matyskiela, Namrata D. Udeshi, Pierre M. Jean Beltran, Daniel E. Grinshpun, Jessica A. Gasser, and Aline Renneville

Abstract

Supplementary Methods, Figures, and Tables

Published
2023
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6. Data from Avadomide Induces Degradation of ZMYM2 Fusion Oncoproteins in Hematologic Malignancies

Author

Benjamin L. Ebert, Steven A. Carr, Philip P. Chamberlain, Mark Rolfe, Jean-Michel Cayuela, Jean-Jacques Kiladjian, Stéphane De Botton, Véronique Saada, Christophe Marzac, Sophie Cotteret, Rob S. Sellar, Andrew A. Guirguis, Alexander Tepper, Kaushik Viswanathan, Marie McConkey, Thomas Clayton, Mary E. Matyskiela, Namrata D. Udeshi, Pierre M. Jean Beltran, Daniel E. Grinshpun, Jessica A. Gasser, and Aline Renneville

Abstract

Thalidomide analogues exert their therapeutic effects by binding to the CRL4CRBN E3 ubiquitin ligase, promoting ubiquitination and subsequent proteasomal degradation of specific protein substrates. Drug-induced degradation of IKZF1 and IKZF3 in B-cell malignancies demonstrates the clinical utility of targeting disease-relevant transcription factors for degradation. Here, we found that avadomide (CC-122) induces CRBN-dependent ubiquitination and proteasomal degradation of ZMYM2 (ZNF198), a transcription factor involved in balanced chromosomal rearrangements with FGFR1 and FLT3 in aggressive forms of hematologic malignancies. The minimal drug-responsive element of ZMYM2 is a zinc-chelating MYM domain and is contained in the N-terminal portion of ZMYM2 that is universally included in the derived fusion proteins. We demonstrate that avadomide has the ability to induce proteasomal degradation of ZMYM2–FGFR1 and ZMYM2–FLT3 chimeric oncoproteins, both in vitro and in vivo. Our findings suggest that patients with hematologic malignancies harboring these ZMYM2 fusion proteins may benefit from avadomide treatment.Significance:We extend the potential clinical scope of thalidomide analogues by the identification of a novel avadomide-dependent CRL4CRBN substrate, ZMYM2. Avadomide induces ubiquitination and degradation of ZMYM2–FGFR1 and ZMYM2–FLT3, two chimeric oncoproteins involved in hematologic malignancies, providing a proof of concept for drug-induced degradation of transcription factor fusion proteins by thalidomide analogues.

Published
2023
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7. CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells

Author

Joshua Hansen, John E. Dick, Philip P Chamberlain, Emily Rychak, Gang Lu, In Sock Jang, Jean C.Y. Wang, Thomas Clayton, Celia Fontanillo, Derek Mendy, Michael Pourdehnad, Jinhong Fan, Stanley W.K. Ng, Eileen Tran, Mark Rolfe, Nathan Mbong, Kai Wang, Chin-Chun Lu, James Carmichael, Christine Surka, Mary E Matyskiela, Daniel W. Pierce, Mark D. Minden, Liqing Jin, Antonia Lopez-Girona, Brian E. Cathers, Elizabeth Anne Tindall, Adrian Contreras, and Christy Hsu

Subjects
Models, Molecular, 0301 basic medicine, Myeloid, Protein Conformation, Mice, SCID, Isoindoles, 01 natural sciences, Biochemistry, Mice, Mice, Inbred NOD, Acetamides, Molecular Targeted Therapy, biology, Chemistry, TOR Serine-Threonine Kinases, Myeloid leukemia, U937 Cells, Hematology, Neoplasm Proteins, Ubiquitin ligase, Leukemia, Myeloid, Acute, Leukemia, medicine.anatomical_structure, Neoplastic Stem Cells, Nuclear Factor 45 Protein, Stem cell, Peptide Termination Factors, Proteasome Endopeptidase Complex, Ubiquitin-Protein Ligases, Immunology, Small Molecule Libraries, 03 medical and health sciences, Stress, Physiological, Cell Line, Tumor, medicine, Animals, Humans, Integrated stress response, Nuclear Factor 90 Proteins, Piperidones, PI3K/AKT/mTOR pathway, Adaptor Proteins, Signal Transducing, 010405 organic chemistry, Cereblon, Ubiquitination, Cell Biology, medicine.disease, Xenograft Model Antitumor Assays, 0104 chemical sciences, 030104 developmental biology, Proteolysis, biology.protein, Cancer research, CRISPR-Cas Systems, Protein Processing, Post-Translational
Abstract

A number of clinically validated drugs have been developed by repurposing the CUL4-DDB1-CRBN-RBX1 (CRL4CRBN) E3 ubiquitin ligase complex with molecular glue degraders to eliminate disease-driving proteins. Here, we present the identification of a first-in-class GSPT1-selective cereblon E3 ligase modulator, CC-90009. Biochemical, structural, and molecular characterization demonstrates that CC-90009 coopts the CRL4CRBN to selectively target GSPT1 for ubiquitination and proteasomal degradation. Depletion of GSPT1 by CC-90009 rapidly induces acute myeloid leukemia (AML) apoptosis, reducing leukemia engraftment and leukemia stem cells (LSCs) in large-scale primary patient xenografting of 35 independent AML samples, including those with adverse risk features. Using a genome-wide CRISPR-Cas9 screen for effectors of CC-90009 response, we uncovered the ILF2 and ILF3 heterodimeric complex as a novel regulator of cereblon expression. Knockout of ILF2/ILF3 decreases the production of full-length cereblon protein via modulating CRBN messenger RNA alternative splicing, leading to diminished response to CC-90009. The screen also revealed that the mTOR signaling and the integrated stress response specifically regulate the response to CC-90009 in contrast to other cereblon modulators. Hyperactivation of the mTOR pathway by inactivation of TSC1 and TSC2 protected against the growth inhibitory effect of CC-90009 by reducing CC-90009-induced binding of GSPT1 to cereblon and subsequent GSPT1 degradation. On the other hand, GSPT1 degradation promoted the activation of the GCN1/GCN2/ATF4 pathway and subsequent apoptosis in AML cells. Collectively, CC-90009 activity is mediated by multiple layers of signaling networks and pathways within AML blasts and LSCs, whose elucidation gives insight into further assessment of CC-90009s clinical utility. These trials were registered at www.clinicaltrials.gov as #NCT02848001 and #NCT04336982).

Published
2021
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8. Crystal structure of the SALL4–pomalidomide–cereblon–DDB1 complex

Author

Mary E Matyskiela, Thomas Clayton, Philip P Chamberlain, Aaron Carpenter, Mark Rolfe, Barbra Pagarigan, Joseph J. McDonald, Gang Lu, Eileen Tran, Christopher Mayne, Lawrence G Hamann, and Xinde Zheng

Subjects
Zinc finger, 0303 health sciences, biology, Chemistry, Cereblon, Rational design, Pomalidomide, eye diseases, Cell biology, Ubiquitin ligase, Thalidomide, 03 medical and health sciences, DDB1, 0302 clinical medicine, Structural Biology, medicine, biology.protein, Molecular Biology, Transcription factor, 030217 neurology & neurosurgery, 030304 developmental biology, medicine.drug
Abstract

Thalidomide-dependent degradation of the embryonic transcription factor SALL4 by the CRL4CRBN E3 ubiquitin ligase is a plausible major driver of thalidomide teratogenicity. The structure of the second zinc finger of SALL4 in complex with pomalidomide, cereblon and DDB1 reveals the molecular details of recruitment. Sequence differences and a shifted binding position relative to Ikaros offer a path to the rational design of cereblon-binding drugs with reduced teratogenic risk.

Published
2020
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9. Strategyproofness-Exposing Mechanism Descriptions

Author

Gonczarowski, Yannai A., Heffetz, Ori, and Thomas, Clayton

Subjects
FOS: Economics and business, FOS: Computer and information sciences, Computer Science - Computational Complexity, Computer Science - Computer Science and Game Theory, Economics - Theoretical Economics, Theoretical Economics (econ.TH), Computational Complexity (cs.CC), Computer Science and Game Theory (cs.GT)
Abstract

A menu description presents a mechanism to player $i$ in two steps. Step (1) uses the reports of other players to describe $i$'s menu: the set of $i$'s potential outcomes. Step (2) uses $i$'s report to select $i$'s favorite outcome from her menu. Can menu descriptions better expose strategyproofness, without sacrificing simplicity? We propose a new, simple menu description of Deferred Acceptance. We prove that -- in contrast with other common matching mechanisms -- this menu description must differ substantially from the corresponding traditional description. We demonstrate, with a lab experiment on two elementary mechanisms, the promise and challenges of menu descriptions.

Published
2022
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10. Structural Complexities of Matching Mechanisms

Author

Gonczarowski, Yannai A. and Thomas, Clayton

Subjects
FOS: Computer and information sciences, FOS: Economics and business, Computer Science - Computational Complexity, Computer Science - Computer Science and Game Theory, Economics - Theoretical Economics, Theoretical Economics (econ.TH), Computational Complexity (cs.CC), Computer Science and Game Theory (cs.GT)
Abstract

We study various novel complexity measures for two-sided matching mechanisms, applied to the two canonical strategyproof matching mechanisms, Deferred Acceptance (DA) and Top Trading Cycles (TTC). Our metrics are designed to capture the complexity of various structural (rather than computational) concerns, in particular ones of recent interest from economics. We consider a canonical, flexible approach to formalizing our questions: define a protocol or data structure performing some task, and bound the number of bits that it requires. Our results apply this approach to four questions of general interest; for matching applicants to institutions, we ask: (1) How can one applicant affect the outcome matching? (2) How can one applicant affect another applicant's set of options? (3) How can the outcome matching be represented / communicated? (4) How can the outcome matching be verified? We prove that DA and TTC are comparable in complexity under questions (1) and (4), giving new tight lower-bound constructions and new verification protocols. Under questions (2) and (3), we prove that TTC is more complex than DA. For question (2), we prove this by giving a new characterization of which institutions are removed from each applicant's set of options when a new applicant is added in DA; this characterization may be of independent interest. For question (3), our result gives lower bounds proving the tightness of existing constructions for TTC. This shows that the relationship between the matching and the priorities is more complex in TTC than in DA, formalizing previous intuitions from the economics literature. Together, our results complement recent work that models the complexity of observing strategyproofness and shows that DA is more complex than TTC. This emphasizes that diverse considerations must factor into gauging the complexity of matching mechanisms.

Published
2022
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11. Factors influencing outcome following severe musculo-skeletal traumatic injury

Author

Thomas, Clayton Holwell.

Subjects
ComputingMilieux_COMPUTERSANDEDUCATION, ComputerApplications_COMPUTERSINOTHERSYSTEMS, Uncategorized
Abstract

This thesis was scanned from the print manuscript for digital preservation and is copyright the author. Researchers can access this thesis by asking their local university, institution or public library to make a request on their behalf. Monash staff and postgraduate students can use the link in the References field.

Published
2022
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13. Profiling CELMoD-Mediated Degradation of Cereblon Neosubstrates

Author

Joel W, Thompson, Thomas, Clayton, Gody, Khambatta, Leslie A, Bateman, Christopher W, Carroll, Philip P, Chamberlain, and Mary E, Matyskiela

Subjects
Proteasome Endopeptidase Complex, Ubiquitin-Protein Ligases, Proteolysis, Ubiquitination, Adaptor Proteins, Signal Transducing, Nanostructures
Abstract

Targeted protein degradation is garnering increased attention as a therapeutic modality due in part to its promise of modulating targets previously considered undruggable. Cereblon E3 Ligase Modulating Drugs (CELMoDs) are one of the most well-characterized therapeutics employing this modality. CELMoDs hijack Cereblon E3 ligase activity causing neosubstrates to be ubiquitinated and degraded in the proteasome. Here, we describe a suite of assays-cellular substrate degradation, confirmation of CELMoD mechanism of action, in vitro ubiquitination, and Cereblon binding-that can be used to characterize CELMoD-mediated degradation of Cereblon neosubstrates. While the assays presented herein can be run independently, when combined they provide a strong platform to support the discovery and optimization of CELMoDs and fuel validation of targets degraded by this drug modality.

Published
2021

14. Avadomide induces degradation of ZMYM2 fusion oncoproteins in hematologic malignancies

Author

Andrew A Guirguis, Benjamin L. Ebert, Sophie Cotteret, Marie McConkey, Rob S. Sellar, Mary E Matyskiela, Jessica A. Gasser, Christophe Marzac, Aline Renneville, Steven A. Carr, Alexander Tepper, Mark Rolfe, Namrata D. Udeshi, Kaushik Viswanathan, Stéphane de Botton, Thomas Clayton, Jean-Michel Cayuela, Philip P Chamberlain, Véronique Saada, Jean-Jacques Kiladjian, Pierre M. Jean Beltran, and Daniel E Grinshpun

Subjects
Zinc finger, Oncogene Proteins, biology, Chemistry, General Medicine, Fusion protein, IKZF3, In vitro, Article, Ubiquitin ligase, Thalidomide, DNA-Binding Proteins, Ubiquitin, In vivo, Hematologic Neoplasms, biology.protein, Cancer research, Humans, Transcription factor, Lenalidomide, Transcription Factors
Abstract

Thalidomide analogues exert their therapeutic effects by binding to the CRL4CRBN E3 ubiquitin ligase, promoting ubiquitination and subsequent proteasomal degradation of specific protein substrates. Drug-induced degradation of IKZF1 and IKZF3 in B-cell malignancies demonstrates the clinical utility of targeting disease-relevant transcription factors for degradation. Here, we found that avadomide (CC-122) induces CRBN-dependent ubiquitination and proteasomal degradation of ZMYM2 (ZNF198), a transcription factor involved in balanced chromosomal rearrangements with FGFR1 and FLT3 in aggressive forms of hematologic malignancies. The minimal drug-responsive element of ZMYM2 is a zinc-chelating MYM domain and is contained in the N-terminal portion of ZMYM2 that is universally included in the derived fusion proteins. We demonstrate that avadomide has the ability to induce proteasomal degradation of ZMYM2–FGFR1 and ZMYM2–FLT3 chimeric oncoproteins, both in vitro and in vivo. Our findings suggest that patients with hematologic malignancies harboring these ZMYM2 fusion proteins may benefit from avadomide treatment. Significance: We extend the potential clinical scope of thalidomide analogues by the identification of a novel avadomide-dependent CRL4CRBN substrate, ZMYM2. Avadomide induces ubiquitination and degradation of ZMYM2–FGFR1 and ZMYM2–FLT3, two chimeric oncoproteins involved in hematologic malignancies, providing a proof of concept for drug-induced degradation of transcription factor fusion proteins by thalidomide analogues.

Published
2021

15. Profiling CELMoD-Mediated Degradation of Cereblon Neosubstrates

Author

Philip P Chamberlain, Gody Khambatta, Leslie A. Bateman, Christopher W Carroll, Joel W Thompson, Mary E Matyskiela, and Thomas Clayton

Subjects
biology, Chemistry, Cereblon, Protein degradation, Substrate degradation, Ubiquitin ligase, Cell biology, Proteasome, Mechanism of action, Ubiquitin, biology.protein, medicine, Degradation (geology), medicine.symptom
Abstract

Targeted protein degradation is garnering increased attention as a therapeutic modality due in part to its promise of modulating targets previously considered undruggable. Cereblon E3 Ligase Modulating Drugs (CELMoDs) are one of the most well-characterized therapeutics employing this modality. CELMoDs hijack Cereblon E3 ligase activity causing neosubstrates to be ubiquitinated and degraded in the proteasome. Here, we describe a suite of assays-cellular substrate degradation, confirmation of CELMoD mechanism of action, in vitro ubiquitination, and Cereblon binding-that can be used to characterize CELMoD-mediated degradation of Cereblon neosubstrates. While the assays presented herein can be run independently, when combined they provide a strong platform to support the discovery and optimization of CELMoDs and fuel validation of targets degraded by this drug modality.

Published
2021
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16. Cereblon Modulators Target ZBTB16 and Its Oncogenic Fusion Partners for Degradation via Distinct Structural Degrons

Author

Laurie LeBrun, Kristina Danga, Michelle Slade, Jinyi Zhu, Joel W Thompson, Gang Lu, Xinde Zheng, Mary E Matyskiela, Philip P Chamberlain, Hon Kit Wong, Mark Labow, Thomas Clayton, and Joshua M. Baughman

Subjects
0301 basic medicine, Acute promyelocytic leukemia, Oncogene Proteins, Fusion, Ubiquitin-Protein Ligases, Druggability, Protein degradation, 01 natural sciences, Biochemistry, Substrate Specificity, 03 medical and health sciences, Leukemia, Promyelocytic, Acute, medicine, Humans, Promyelocytic Leukemia Zinc Finger Protein, Transcription factor, Adaptor Proteins, Signal Transducing, Zinc finger, biology, 010405 organic chemistry, Chemistry, Cereblon, Retinoic Acid Receptor alpha, General Medicine, medicine.disease, Fusion protein, 0104 chemical sciences, Ubiquitin ligase, Cell biology, 030104 developmental biology, Proteolysis, biology.protein, Molecular Medicine
Abstract

There is a growing interest in using targeted protein degradation as a therapeutic modality in view of its potential to expand the druggable proteome. One avenue to using this modality is via molecular glue based Cereblon E3 Ligase Modulating Drug compounds. Here, we report the identification of the transcription factor ZBTB16 as a Cereblon neosubstrate. We also report two new Cereblon modulators, CC-3060 and CC-647, that promote ZBTB16 degradation. Unexpectedly, CC-3060 and CC-647 target ZBTB16 for degradation by primarily engaging distinct structural degrons on different zinc finger domains. The reciprocal fusion proteins, ZBTB16-RARα and RARα-ZBTB16, which cause a rare acute promyelocytic leukemia, contain these same structural degrons and can be targeted for proteasomal degradation with Cereblon modulator treatment. Thus, a targeted protein degradation approach via Cereblon modulators may represent a novel therapeutic strategy in acute promyelocytic leukemia where ZBTB16/RARA rearrangements are critical disease drivers.

Published
2020

17. New Activities of CELMoDs, Cereblon E3 Ligase-modulating Drugs

Author

Leslie A. Bateman, Laurie LeBrun, Philip P Chamberlain, Mary E. Matyskiela, Thomas Clayton, Joel W Thompson, and Christopher W Carroll

Subjects
Specific protein, biology, Chemistry, Mechanism (biology), Cereblon, Small molecule, Cell biology, Ubiquitin ligase, Cellular degradation, Ubiquitin, Mechanism of action, biology.protein, medicine, medicine.symptom
Abstract

CELMoDs (cereblon E3 ligase-modulating drugs) are low-molecular-weight small molecules that induce the recruitment of specific protein targets to the cereblon-CRL4 ubiquitin ligase for ubiquitination and subsequent cellular degradation. CELMoDs act to scaffold direct protein–protein interactions between cereblon and substrate, working through a so-called “molecular glue” mechanism. We discuss recent discoveries in CELMoD mechanism of action, including approaches taken to expand the scope of cereblon neosubstrates, and discuss the future and breadth of this emerging class of molecules.

Published
2020
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18. Tiered Random Matching Markets: Rank is Proportional to Popularity

Author

Ashlagi, Itai, Braverman, Mark, Saberi, Amin, Thomas, Clayton, and Zhao, Geng

Subjects
FOS: Computer and information sciences, FOS: Economics and business, Computer Science - Computer Science and Game Theory, Stable matching, Economics - Theoretical Economics, Theoretical Economics (econ.TH), tiered random markets, stable marriage problem, deferred acceptance, Theory of computation → Algorithmic game theory and mechanism design, Computer Science and Game Theory (cs.GT)
Abstract

We study the stable marriage problem in two-sided markets with randomly generated preferences. Agents on each side of the market are divided into a constant number of "soft" tiers, which capture agents' qualities. Specifically, every agent within a tier has the same public score, and agents on each side have preferences independently generated proportionally to the public scores of the other side. We compute the expected average rank which agents in each tier have for their partners in the man-optimal stable matching, and prove concentration results for the average rank in asymptotically large markets. Furthermore, despite having a significant effect on ranks, public scores do not strongly influence the probability of an agent matching to a given tier of the other side. This generalizes the results by Pittel [Pittel, 1989], which analyzed markets with uniform preferences. The results quantitatively demonstrate the effect of competition due to the heterogeneous attractiveness of agents in the market., LIPIcs, Vol. 185, 12th Innovations in Theoretical Computer Science Conference (ITCS 2021), pages 46:1-46:16

Published
2020

19. SALL4 mediates teratogenicity as a thalidomide-dependent cereblon substrate

Author

Mariko Riley, Katie Stamp, Xinde Zheng, Yan Ren, Kate Blease, Chin-Chun Lu, Julia Hui, Lawrence G Hamann, Philip P Chamberlain, Gang Lu, Polat Abdubek, Mary E Matyskiela, Gondi Kumar, Maria Wang, Wei Fang, Aaron Carpenter, Thomas Clayton, Clifton Drew, Suzana Couto, Chung-Wein Lee, Mark Rolfe, Rupert Vessey, and James Hartke

Subjects
Male, 0301 basic medicine, Ubiquitin-Protein Ligases, Transgene, Induced Pluripotent Stem Cells, Mice, Transgenic, Nerve Tissue Proteins, Phocomelia, Protein degradation, Ligands, medicine.disease_cause, 01 natural sciences, Mice, 03 medical and health sciences, SALL4, Testis, Animals, Humans, Medicine, Molecular Biology, Adaptor Proteins, Signal Transducing, Zinc finger, Mutation, 010405 organic chemistry, business.industry, Cereblon, Homozygote, Zinc Fingers, Cell Biology, medicine.disease, Immunohistochemistry, eye diseases, Thalidomide, 0104 chemical sciences, DNA-Binding Proteins, Teratogens, 030104 developmental biology, Gene Expression Regulation, Proteolysis, Cancer research, Rabbits, business, Peptide Hydrolases, Transcription Factors, medicine.drug
Abstract

Targeted protein degradation via small-molecule modulation of cereblon offers vast potential for the development of new therapeutics. Cereblon-binding therapeutics carry the safety risks of thalidomide, which caused an epidemic of severe birth defects characterized by forelimb shortening or phocomelia. Here we show that thalidomide is not teratogenic in transgenic mice expressing human cereblon, indicating that binding to cereblon is not sufficient to cause birth defects. Instead, we identify SALL4 as a thalidomide-dependent cereblon neosubstrate. Human mutations in SALL4 cause Duane-radial ray, IVIC, and acro-renal-ocular syndromes with overlapping clinical presentations to thalidomide embryopathy, including phocomelia. SALL4 is degraded in rabbits but not in resistant organisms such as mice because of SALL4 sequence variations. This work expands the scope of cereblon neosubstrate activity within the formerly 'undruggable' C2H2 zinc finger family and offers a path toward safer therapeutics through an improved understanding of the molecular basis of thalidomide-induced teratogenicity.

Published
2018
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20. Classification of Priorities Such That Deferred Acceptance is Obviously Strategyproof

Author

Thomas, Clayton

Subjects
FOS: Economics and business, FOS: Computer and information sciences, Computer Science - Computer Science and Game Theory, Economics - Theoretical Economics, Theoretical Economics (econ.TH), Computer Science and Game Theory (cs.GT)
Abstract

We study the strategic simplicity of stable matching mechanisms where one side has fixed preferences, termed priorities. Specifically, we ask which priorities are such that the strategyproofness of deferred acceptance (DA) can be recognized by agents unable to perform contingency reasoning, that is, \emph{when is DA obviously strategyproof} (Li, 2017)? We answer this question by completely characterizing those priorities which make DA obviously strategyproof (OSP). This solves an open problem of Ashlagi and Gonczarowski, 2018. We find that when DA is OSP, priorities are either acyclic (Ergin, 2002), a restrictive condition which allows priorities to only differ on only two agents at a time, or contain an extremely limited cyclic pattern where all priority lists are identical except for exactly two. We conclude that, for stable matching mechanisms, the tension between understandability (in the sense of OSP) and expressiveness of priorities is very high.

Published
2020
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21. The Short-Side Advantage in Random Matching Markets

Author

Cai, Linda and Thomas, Clayton

Subjects
FOS: Computer and information sciences, Computer Science - Computer Science and Game Theory, Computer Science and Game Theory (cs.GT)
Abstract

A breakthrough of Ashlagi, Kanoria, and Leshno [AKL17] found that imbalance in the number of agents on either side of a random matching market has a profound effect on the market's expected characteristics. Specifically, across all stable matchings, the "long side" (i.e. the side with a greater number of agents) receives significantly worse matches in expectation than the short side. Intuitively, this occurs because an agent on the long side is essentially unneeded to create a stable matching -- a matching could form almost as easily without them. Thus, an agent on the long side has very little market power, and must settle for a match which is not much better than a random assignment. We provide a new and simpler proof for a result of [AKL17] which formalizes this intuition.

Published
2019

22. Crystal structure of the SALL4-pomalidomide-cereblon-DDB1 complex

Author

Mary E, Matyskiela, Thomas, Clayton, Xinde, Zheng, Christopher, Mayne, Eileen, Tran, Aaron, Carpenter, Barbra, Pagarigan, Joseph, McDonald, Mark, Rolfe, Lawrence G, Hamann, Gang, Lu, and Philip P, Chamberlain

Subjects
DNA-Binding Proteins, Protein Conformation, Multiprotein Complexes, Ubiquitin-Protein Ligases, Proteolysis, Ubiquitination, Humans, Crystallography, X-Ray, Adaptor Proteins, Signal Transducing, Protein Binding, Substrate Specificity, Thalidomide, Transcription Factors
Abstract

Thalidomide-dependent degradation of the embryonic transcription factor SALL4 by the CRL4

Published
2019

23. Representing All Stable Matchings by Walking a Maximal Chain

Author

Cai, Linda and Thomas, Clayton

Subjects
FOS: Computer and information sciences, FOS: Economics and business, Computer Science - Computer Science and Game Theory, Economics - Theoretical Economics, Theoretical Economics (econ.TH), Computer Science and Game Theory (cs.GT)
Abstract

The seminal book of Gusfield and Irving [GI89] provides a compact and algorithmically useful way to represent the collection of stable matches corresponding to a given set of preferences. In this paper, we reinterpret the main results of [GI89], giving a new proof of the characterization which is able to bypass a lot of the "theory building" of the original works. We also provide a streamlined and efficient way to compute this representation. Our proofs and algorithms emphasize the connection to well-known properties of the deferred acceptance algorithm.

Published
2019
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24. Cancelled operations: a 7-day cohort study of planned adult inpatient surgery in 245 UK National Health Service hospitals

Author

Jennifer Morrish, Emily J Robson, Georgina Ashfield, Karuna Kotur, Jashmin Maria, Charlotte Downes, Shweta Patro, Mark Scrutton, George Gladstone, Andy Burton, Paula Mulligan, Wei Lin Allen, Michael McCusker, Dee Leonard, James Edwards, Sarah Dolling, Katherine Pass, Hywel Garrard, Francis Young, Paul Edgar, Elaine Matthews, Douglas Findlay, Helen Whittle, Aillison MacLean, Chris Levett, Claire-Marie Agius, Kim Porter, Nurse Charlotte White, Bridget Campbell, Gemma Scotland, Patrick Haywood, Liz Shenton, Tom Hatton, Laura McAffrey, Jane Hunt, Jaime Carungcong, Sara Owen, Fiona Christie, Lesley Milne, Liza Tharakan, Ruth Smith, Henry Nash, Timothy Gould, Jodie Fitzgerald, Wael Zghaibe, Mark Gaskell, Dushyanthi Jayasekera, Elana Owen, Kinga Dwornik, Amr Ali, Donna Cotterill, Martyn Cain, Peter Wicks, Daniel West, Catriona Walker, Rebecca Lee, Amanda Isaac, Naresh Rajasekar, Sally Collins, Laura Hammon, Tim Hendra, Yemi Adelaja, Mike Pollard, Ellen L. Brown, Matt Clayton, Rachel Bown, Sally Moore, Keyury Desai, Tony Kinsey, Charlotte Dunn, Li Lian Loh, Emelia Passaro, Timothy Faccini, Stephen Linter, Sumant Shanbhag, David Lee, David Restall, Angela Cook, Simon Ripoll, Rachael Bird, Vicky Murray, Alex Wollaston, Daniel Yarwood, Sonia Bhangu, Sahar Biuk, Jenny Ferry, Alexander Michael Stewart, Ceri Lynch, Lucy Sheppard, Denise Webster, Jamie Allen, Merle Cohen, James Hanison, Shilpa Rawat, Prabhakaran Premraj, Gamunu Ratnayake, Clare Bird, Lorna Filby, Clare Allcock, Babak Sedghi, Celly Weegenaar, Dawn Collier, Sreekanth Rayalu Uppugonduri, Amanda Whileman, Su Ying Ong, Jack Carmichael, Victoria O'Loughlin, Barbara Linklater-Jones, Maria Lackmann, Vitul Manhas, Albert Brennan, Alasdair Waite, Andrew Smallwood, Salvatore Bruni, Catriona Barr, Thomas Murphy, Gemma Hudson, Khalid Hasan, Alison J. Campbell, Radu Chiravasuta, Charlotte Maden, Roddy Chapman, Jon Clark, Nauman Iftikhar, Sarah Hagyard, Denis O'Leary, Steven Forde, Joanne Webb, Ryan W Haines, Andrea Galloway, Richard Siviter, Heidi Lightfoot, Hew D.T. Torrance, Christopher Smith, Hollie Robinson-Perrie, Josh Wall, Carina Cruz, Andrew Song, Stephen T. Webb, Nurse Sara-Beth Sutherland, Carol-Ann Woolley, Susan Martin, S.L.M. Walker, George Koshy, Renee Ford, Mona Mubarak, Robert Stuart, Keshava Reddy Burijinti Chenna, Rizana Ghafoor, Katie Hanlon, Fiona Faulds, Hiba Khaled, Richard Jones, Karin Duckett, Cathryn Matthews, Charles Chan, Sanjeewa Ranaweera, Nurse Rebecca Hinch, Richard Shawyer, Jo Cudlip, Marion Ashe, Steve Harris, Ravi K. Alagar, Jonathan Hetherington, Sara Churchill, Yolanda Baird, Maria Tritean, Gabriela Wong, Dermot Moloney, Lee Tbaily, Jonathan Finnity, Norbert Bokor, Peter Indoe, Lucy Stelfox, Simon Marcus, Bryony Burrill, Ellie Roderick, Carina Lilley, Alex Yusaf, Lucy Corbett, Esther Neilly, Christine Ryan, Amon Wijunamai, Katie Atterbury, Abigail Clarke, Josh Patch, Otto Mohr, Ronan Mukherjee, Asokan Krishnaier, Chen Yun-Han, Prasan Panagoda, Polly Rice, Katherine Jones, James Hudson, Sophie Uren, Peter Sutton, Evangelia Poimenidi, Tracy Marsden, Veronica Barnes, Alice Drysdale, Tara Lawrence, Lisa Sharpe, John G. Francis, N. M. Wharton, Claire Kurasz, Marina Iaverdino, Caradog Thomas, Emma Gold, Raj McNab, Tom E.F. Abbott, Claire Dowse, Jane Hamilton, Tony Sutherland, Robert P. Jones, Peter Alston, Daniel Haslam, Philippa Marshall, Bernadette Tilley, Cathleen Chabo, Adam Carpenter, Steve Cole, Nicholas Hooper, Kate Arrow, Alka Shah, Rosie Furness, Susie Chapman, Sachini Dhamaratne, Constandinos Papageorgiou, Michael Girgis, Sandra Pearson, Andrew W. Wood, Jaya Nariani, Sonia White, Christopher Godden, Mary Bellamy, Indra Chadbourn, Laura Parker, Peter Knowlden, Cat Griffiths, Jeanette Smith, David Brooks, Jonathan Smith-Williams, Elizabeth Barnes, Sunil Jamadarkhana, Andrew Feneley, Maria Croft, Tom Disney, Paramesh Kumara, Anna Warrington, Seetal Aggarwal, Zackriah Badsha, Suman Biswas, Suzanne Shuttleworth, Ben Jones, Jose Lourtie, Mark Stubbington, Asya Mussad, Patrick Johnson, Sister Amanda Cowton, James Spargo, Kelly Hard, Annette Fraine, William Weston, Farrukh Ameer, Andrew Prenter, Lisa Bacon, Sunil kumar Chaurasia, Claire Nicholas, Amy Kitching, Sneha Prasad, Catriona Ferguson, Martin P. Huntley, Claire Cameron, Hugh Cutler, Anne Harrison, Kunal Joshi, Anna Cormack, Rebecca Jones, Martin Paul, Jean Bage, Stephen Cole, Usman Razaque, Robert Lewis, David O'Callaghan, Samantha Strong, Victoria Frost, Peter Ip, Victoria Male, Mat Molyneux, Christopher Worth, Michael Brett, Megan Smith, Shayan Arshed, Timothy McMillan, Lorri James, Frances Lay, Jennifer Bennett-Britton, Patrick Colhoun, Alison Shaw, Michael Stewart, Maie Templeton, Karin Gupwell, Mujeeb Khan, Elena Stanton, Chandini Chuni, Janette Brown, Mariam Latif, Rebecca L. Wilson, Felix Fombon, Jo Novaga, Cindy Persad, Matthew Thomas, Maryna Garmash, Metod Oblak, Sarah Maher, Rahul Muddanyake, Morgan Foster, Kris Parker, Tim Sutton, Ndi Ekwere, Samuel Armanious, Mohammad Bhatti, Steve Phillips, Maria Rivero-Bosch, Nick Spittle, David Harding, Henry Hammerbeck, Rose Buckley, Jonathan Hatton, Ahmed Gilani, Ali Watts, Neeraj Bhardwaj, Lesley McShane, Simon Ridler, Martin Murphy, Vandana Goel, S Ramani Moonesinghe, Sophie Scutt, Sanniah Hussain, Hannah Donaldson, Tom Bennett, Helen Boys, David Steven Davies, Bev Hammond, Bryan Yates, Victoria Hawley, Chris Gibb, Ulrika Winstone, Keith Couper, Benedict Williams, Louise Duncan, Georgina Wilson, Anil Hormis, Emily Dana, Jens Full, Amina Chohan, Amanda Ebejer, Sian McKillop, Tomas Bakonyi, Georgina Bird, George Davies, Christina Penny, Helen Thornley, Karen Jewers, Kingsin Ang, Mishell Cunningham, Conny Blunt, Ronald Carrera, Kay Finney, Alvin Soosay, Nagaraj Rao, Jason Mann, Carol Edwards, Richard Lowe, Paul Stevens, Hilary Ashton, Rachel Codling, Rhys Davies, Muthuraj Kanakaraj, Zoe Apple, Kirsty Meats, Tammy Smith, Charmaine Beirnes, John Gardner, Peter Featherstone, Claire Williams, Rohit Mittal, Emma Shinn, Alex Moore, Michael Whitear, Hannah Rose, Paul Kelly, Megan Thomas, Matthew Gibbins, Jack Reid, Caroline Clarke, Victoria Irvine, Bhavesh Pratap, Ella Buchanan, Nurse Francesca Wright, Vatsharlan Santhirapala, Richard Gould, Dionne Dervin, Behzad Sohail, Lauren Duraman, Thecla Scully, Adnaan Qureshi, Muditha Peiris, Thomas Ratcliffe-Law, Samuel J. Clark, Ben Vowles, Sam Keable, Hoda Abou Ghoneim, Becky Morris, Aidan Hulbert, Rachael Craven, Ashish Kundu, Emma M. Casely, Maya Kommer, Tom Poulton, Greg Nussbaum, Ahmad Huda, Caroline Davis, Suzanne Gleeson, Paul Clements, Matt Willis, Isobel Amey, David J. Perry, Rachel Harford, Bianca Hulance, Kirsty Baron, Charlotte Grove, Sergio Dominguez, Susanna Richie-Mclean, John Stones, Ioana Simionescu, Khaled Razouk, Cristina Niciu, Ben Hyams, Mark Doran, Carolyn Colvin, Jonathan Rivers, Raluca Ene, Rebecca Jackson, Jonathan Edgar, Ben Robinson, Lisa Wilkinson-Guy, Aji Mathew, Christopher Patrick, Gauhar Sharih, Ismail Tariq, Andrea Kay, Joshua O'Donnell, Dafydd Watterson, Lail Zaheer, Fiona Reed, Tom Johnson, Christopher Oscier, Mirain Phillips, Edmund Gerrans, Joanna Hackney, Sally M. Dunlop, Elizabeth Willetts, Jiang Yuchen, Lizzie Ashton, Theresa Cooper, Paul W. Davies, Carly Brown, James Small, Julie Lowe, Amarjeet Patil, Filipe Helder, Joshua Cuddihy, Faisal Sheikh, Hayley Tarft, Enid Leung, Adrian Percuin, Paolo Mazzone, Rochelle Rhodes, Jane Pilsbury, Kerry Cullis, Peter Brook, Helen McNamara, Carin Swanevelder, Claire Frith, Adrian Clarke, Stuart Watson, Glenn Vetuz, Zoe Riddell, Drew Welch, Geoff Warnock, Lalani Induruwage, Paul Mallett, Elizabeth Cervi, Santinder Dalay, Supriya Antrolikar, Sinead O'Kane, Toby Hoskins, Stephen Duberley, Sophie Parcell, Jayne Sutherland, Lynn Fairless, Dave Parkinson, Matron Beryl Davis, Abigail Patrick, Jithu Jayan, Nicola Harvey, Catherine Pitman, Donata Banni, Samuel Passey, Omar Alex Pemberton, Becky Sands, Hon Sum Liu, Alexandra Mudd, Sheldon Zhang, Ange Lise John-Baptiste, Thomas Clayton, Charlotte Marriot, Tom Reevell, Nicola Mackenzie, Temitope Aiyedun, Andy Cruickshanks, Jacqueline Gunn, Alison Moss, Martyn Clark, Swetha Rambhatla, Claire Matata, Ben Cracknell, Pauline Mercer, Matthew Morgans, Catrin Williams, Shareef Madhi, Jane Montgomery, George Kohler, Yasir Hameed, Muneeba Ahmed, Glenn Saunders, Anand Kulkarni, Craig Pinner, Lauren Pearce, Vishnu Bhardwa, Judi Ramsey, Meghna Sharma, Rob Hull, Srinivasan Perumal, Julia Critchley, Stephen Hill, Bethany Fitzmaurice, Robert Crichton, Cormac O'Connor, M. Dickinson, Alison Pearce-Smith, Julie Toms, Kathleen Horan, Ammy Dodd, Rachel Crone, Graeme Finnie, Suman Shrestha, Saul Sundayi, Shamini Sivakumaran, Robert Collin, Janine Musselwhite, Yuvaraj Kummur, Mariana Bernardo, Amrinda Sayan, Gabrielle De Selincourt, Laura Bridge, Melissa Rosbergen, Philip Barclay, Garry Davenport, Daniel Murrell, Andrew Drummond, Eireann Allen, Emma Fadden, Subha Arunachalam, David Robinson, Stephanie Dukes, Catherine Jardine, Sunny Bhat, Hemantha Shiva, Amy Kerr, Henry Elms, Anam Asif, Sandra Evans, Girish Rangaswamy, Laura Thomson, Asad Javed, Jenny Shuttleworth Davies, Maren Kleine-Brueggeney, Sian Edwards, Jean-Paul Zahra, Jo simpson, Priya Verma, Bhamini Tharmalingam, Matthew Edmunds, Stephen Adshead, Hannah Luckhurst, Lara Allen, Colin Merrill, Fiona Lyle, Falguni Choksey, Mohyman El Habishi, Holly Notman, Lisa Murthen, Christiana Georgiou, Georgina Singleton, Tim Cook, Melba Knighton, Shirley Pyke, Amit Gadre, Maria Rehnstrom, Helen Hothersall, Anja Kuttler, Anita Boltres, Sarah Williams, Sarah Welch, Yamuna Madhu, Pramod Nalwaya, Alistair Coleman, Jeanie Worthington, Jasmine Samuel, Rajashekar Gowni, Karen Burt, Shamim Haque, Reynard Knoetze, Hakeem Yusuff, Tom Taylor, Val Parkinson, Sheik Pahary, Jonathan Fortune, Natalie Long, David Gilhooly, Karthick Duraisamy, Duncan Baines, Shondipon Laha, Marie Appleby, Jyothi Hosahalli, Christine Catley, Jasmine Jose, Damien Mantle, Dinkar Gowda, Permendra Singh, Ramesh Khoju, Carol Bradbury, Sarah Hazeldine, Karan Kanal, Sonal Lodhi, James Craig, Rachel Wong, Teresa Ferreira, Charis Banks, Ben Chandler, Asia Sarwar, Sivaprakash Vaitheeswaran, Sam Bews, Katie Hunter, Sohan Bisonoothan, Lauren Hunt, Melony Hayes, Nilesh Chauhan, Janet Pickett, Sharon Dealing, Jamie Plumb, Thomas Hollins, Claire Hill, Claire Hindmoor, Nicolas Hooker, Hannah Davis, Laura Mee, Elizabeth Thomas, James Self, Jenny May-Ling Cheung, Jane Varin, Manish Kakkar, Anuj Wali, Omar Siddique, Sophie Earl, Elizabeth Longdon, Alison Meadows, Shafi Ahmed, David MacPherson, Shaima Elnour, Suzi Hale, Ramez Ibrahim, Fei Long, Orlanda Allen, Alice Groves, Mohammed Wahid, Angela Stevens, Carl Ilyas, Richard Robley, Nichola Bleasby, Peter Havalda, Ursula McHugh, Judith Brade, Georgia Monantera, Stuart Younie, Brian Johnston, Jamie Brookes, Linda Park, Graeme Wilson, Mark Greasley, Lohita Nanda, Vineetha Jayakumar, Ian M. Lyons, Ayman Abdu, Paul Athanasopoulos, Justin Woods, Kariem El-Boghdadly, Diane Simpson, Georgina Williamson, Jonathan McCarter, Anil Golhar, Alicia Waite, Claire Halligan, Sarah Anne Leir, Joanne Turner, Matthew O'Meara, Claire Atkinson, Adam Yarnold, Mark Fernie, Rhiann Marie O'Shaughnessy, Jamie Elwood, Laura Harvey, Ali Atrah, Helen Terrett, Sam Scholes, Rebecca E. Saunders, Vin Vyapury, Amir Rafi, Peter Bradley, Srikant Ganesh, Zehrin Nassa, Ulf Buhmann, Laura Carrick, Natalie Rogers, Said Seifalan, Ian Ryder, Jennifer Partridge, Tim Lovell, Martin Priestley, Caroline Wrey Brown, Joanna Moore, Vidhya Nagaratnam, Saba Iqbal, Francesca Mazzola, Samantha Weller, Laura Gould, Helen Johnston, Jenny Spimpolo, Carmen Scott, Stephen J. Brett, Paul Cripps, Amit Kurani, Alexander Knight, Nirav Shah, Pushkar Patankar, Fraser Waterson, Sarah Martindale, Johannes Mellinghoff, Joanne Wootton, Sarah McCormick, Sameer Somanath, Bilal Yasin, Christopher Skeoch, Toby Jacobs, Katrina Eaton, Lynne Connell, Harry Soar, Yvonne Bramma, Tom Gately, Renjith Joseph, Anish Gupta, Lucie Hobson, Charindri Wariyapola, Maryam Zaky, Nimu Varsani, Gerhardus Van Rensberg, Jackie Evans, Rosahn Saleh, William Sutcliffe, Louise Potter, Harvey Dymond, Catherine (Katie) Patton, Andrew Selman, Stephen Traynor, Kate Tizzard, Rumyana Nyathi, Caroline Reavley, Saima Hashmi, Kerry Hughes, Isabelle Sykes, Kate Slade, Anne Troy, David Castillo, Jennifer Quinton, Anne Adams, Joanne Gresty, Stella Wright, Victoria Christenssen, Iain Mooney, Fiqry Fadhlillah, Seema Pai, Gabor Debreceni, Aleinmar Winthein, Denise Griffin, Hannah Beadle, Elisa Kam, Marie Williams, Helen Howes, Tariq Tabiner, Saxon Prentice, James Bedford, Emma Craig, Peter Standen, Stephen Petley, Janaki Pearson, Cheryl Marriott, Harry Barclay, Alexandra Matson, Michael P.W. Grocott, Alison Thorne, Joanne Humphreys, Vishal Patil, Nick Greenwood, Richard Wassall, S.K. Harris, Valpuri Luoma, Dancho Ignatov, Rebecca Fry, Anamika Sehgal, Antonio Paredes-Guerra, Manjula Yadagiri, Yuvraj Doriaswami, Benjamin O'Donovan, Adam Mounce, Stephanie Wright, Linda Webber, Tracy Hazelton, Ethan Bateson, Theresa Garrett, Chris Honstvet, John Scriven, Rahul Dimber, Phillip Lo, Jenny Stead, Catherine Plowright, Rachel Morris, Pallavbhai Desai, Nicola Johnson, Neil Muchatuta, Vijayakumar Gopal, Sherma Turner, Karina Fitzgibbon, John B. Davis, Sarah Patch, Erica Jolly, Rob Gregory, Christopher Lochrin, Geoffrey Ryder, Sam Michlig, Liana Zucco, Susan Nimmo, Jessica Whiston, Sarah Goellner, Rohan Babla, Deborah Skelton, Lucy Mcmanoman, Darcy Pearson, Diane Forrest, Sanjeev Garg, Joanne Bradley-Potts, Joel Perfitt, Danny J.N. Wong, Mike Weisz, Caroline Lowrie, Timothy Alce, Alice Michell, Charlotte Soulsby, Dominic Hayes, Arnab Mandal, Stephanie Ridgway, Angela Willberry, Alka Grover, Simran Minhas, Kerwei Tan, Sharon Jones, Sam Marcangelo, Ben Millette, Hilary Thatcher, Greg Foster, Krishna Balachandar, Megan McAtear, Richard Shellard, Chris Littler, Thunga Setty, Kavita Sasi-Kumar, Theodore Floyd, Duncan Adshead, Stephen Hickey, South Yorkshire Hospitals Audit, Amy Barker, Ewen Cameron, Dawn Trodd, Wendy Nichols, Beth Farr, Mike Salmon, Naomi Fleming, Umairali Ikram, Ben Straughan, Peter J O'Brien, Laura Purandare, Janine Thomas, Elizabeth Wood, Kate Bosworth, Stewart Mckie, Samantha Evans, Tamilselvan Rajamanickam, Srinivasan Dhileepan, Paul Hindmarch, Colin Bergin, Sange Mansoor, Lisa Armstrong, Nagendra Natarajan, Irmeet Banga, Fiona Osborne, Lynne Williams, Pieter Bothma, Jade Woolley, Joanne Finn, Bernd Oliver Rose, Shaman Jhanji, Bennur Katyayani, Gillian Robertson, Laura Bird, Pauline Fitzell, Sally Anne Smith, Serena Yen, Stuart Clelland, Thomas Urwin, Luff Delme, Rocio Ochoa Ferraro, Nurse Cheryl Padilla Harris, Asad Naqvi, Andy Cumpstey, Natalie C. Wood, Samar Al-Rawi, Pulak Padhi, Claire Botfield, Bhavesh Raithatha, Michael Briskoe, Jolyon Cohen, Ben Gibbison, John John, Stephen Washington, Jayne Foot, Karen Chadwick, Naomi Cochrane, Sophie Spencer, Alexandra Gatehouse, Susan Smolen, Aaron D'Sa, John Sturrock, Christopher P Bourdeaux, Kumud Bhandari, Neil Kellie, Elizabeth Denman, Samson Tou, Laura Kettley, Alex Eros, Stuart McLellan, Nicola Ball, Emily Kirk, Sue Smyth, Kim Gibson, Oliver Barker, Mohammad Masood, Dabeeruddeen Ahmed, Geoff Thorning, Jennifer Van Ross, Esme Elloway, Kat Rhead, Sei Nishimura, Maximiliane Kellner, Benjamin Jacobs, Sanjoy Shah, Matthew Stubbs, Faye Moore, Greg Cox, Nishita Patel, Ashok Nair, Elizabeth Hawes, A Espinosa, Kavita Wankhade, Vladimir Bashliyski, Carina Bautista, Susan Lyjko, Michelle Rowe, Nikita Whotton, Julie Temple, Inthu Kangesan, Gemma McIntosh, Samir Nazir, R. N. Kumar, Jen Warren, Alex Coombs, Marilyn Boampomaa, Kaya Jeyarajah, Heather Savill, Claudette Jones, Vinayak Vanjari, Caroline Tierney, Santhana Kannan, Jennifer Aston, Helen Melsom, Valantine Woodham, Nichola White, Niraj Barot, Paolo Perella, Mayumi Vianzon, Padmanabhan Vatsala, Claire Boynton, Alexandra Edwards, Elisa Masoni, Jayne Edwards, Julie Edwards, Thomas Garth, Amanda Skinner, Kate Blethyn, Jonathan Chambers, Katie Ramm, Rosada Jackson, Thomas Coleman, Tracey White, Emma McKenna, Kanchan Umbarje, Thomas Sheppard, Deepa Jumani, Emma Murphy, Peter Lawley, David Howe, Daisy Alston, Ania Dean, Prasun Mukerjee, Julian Hood, Mahmoud Alkholany, Sarah Goff, Gillian Rennie, Bridget Fuller, Ciara Walker, Jonathan Pipe, Alex Eeles, Wai Soon, Catherine McMillan, Martha Wrigley, Neil Brown, Peter Sandbach, Claire McCahill, Anna Wilson Charlotte Yates, Paul Sampson, Natasha Muzengi, Colum Slorach, Moyra Hynd, Arjun Ardeshna, Trish Boateng, James C. Geoghegan, Rhys Williams, Karoline Middleton, Brian Campbell, Srikanth Chukkambotla, Daniel Leslie, Sherrie Samuels, Michael Allan, Ruth Clarke, Christopher Nutt, Kirsten Reid, Hannah Smith, Surabhi Jain, Stephanie Reed, Hywel Evans, Irene Gardner, Ben Griffiths, Guy Shinner, Marek Frenkiel, Jacek Zeber, Gary Minto, Simon Parrington, Louise Harrison, Carlos Kidel, Hawa Desai, Lois Steuart, Claire Hirst, Johann Harten, Marc Slorach, Angela Christofides, Claire Macey, Helen Moore, Chantal Busby, Andrew Robertson, Leanne Milner, Catherine Chapman, Rebecca Reeves, Lawrence Wilson, Alice Aarvold, Lizzie Irvine, Narayanan Suresh, Kirsteen Brown, James Dalton, Sam Miller, Yasir Rashid, Andrew Swain, Liliana Czukowska, Natasha Permall, Carys Durie, Peter Carroll, Lauren Cooper, Prerna Mehrotra, Sarah Clayton, Martina McMonagle, Sarah Buckley, Enoch Onya, Elizabeth Perritt, Domonique Georgiou, Manjeet Save, Lauren Friedman, David W. Hewson, Katherine McAndrew, Simon Morton, James Morgan, Susan Underwood, Helen Bowyer, Avninder Chana, Lucy Sootheran, Kieron Rooney, Pooja Patel, Jessica Summers, Laura Farmer, Kiran Keshvara, Victoria Richardson, Hannah Crowther, Geejo Rappai, Adam E. Green, Sarah Willcock, Smitangshu Mukherjee, Samuel Tyrrell, Geraldine Landers, Claire McAteer, Jennifer Awolesi, Sarah Higgin, Orla O'Neill, Chrissie Chevis, Paul Winwright, Vikram Malhotra, Jonathan Ogor, Maria Muelmenstaedt, Richard Stead, Lindsay Roughley, Sara Balliston, Nevena Kalcheva, Marc Wittenberg, Adrian Taylor, Lydia Shatanda, Anjali Soodan, Angela Moon, Sarah Elgarf, Matthew Roche, Sanchita Bhatia, Clare Howcroft, Emma Butterfield, Emily Gannon, Matthew Needham, Jacqueline McCormick, Daniel Bendel, Victoria Martinson, David Hall, Richard A. Armstrong, Lara Herbert, Beverly Kilner, Kathy Dent, Victoria Thwaites, Issy Thomas, Maggie Peat, Lisa Macbeth, Alex James, Rachel Flight, Nick Black, Elizabeth Boyd, Catherine Gedling, Suzanne Body, Nadine Farrell, Samantha Clayton, Paula Hiltout, Richard Haddon, Bethany Philpott, Victoria A Burgess, John Jackson, Anita Patil, Chris Platt, Lindsey Iles, Chrissy Braybrook, Katherine Morris, Emma Karsten, Minna Meritahti, Anastasia Lynn-Smith, Dorothy Hutchinson, Rebecca Darbyshire, Joanne Riches, Astri Luoma, Andy Gibson, Dushanthi Thurairasa, Roisin Baker, Xantha Holmwood, Alda Remegoso, Trusha Mistry, Sarah Hennell, Suganthi Joachim, Stephen Harris, Sam Eggleston, Melanie Morrison, Boon Ang, Natalie Jackson, Nicola Jones, Zena Haslam, Beata Iwanicka, Laura Graham, King Dhar, Melanie Kent, Daniel Wirth, Umakanth Kempanna, Laura Troth, Robert Orme, D. Campbell, Raquel Duarte, Muzaffar Sheik, Robert Maher, Jon Bramall, Rebecca Coates, Tracey Cosier, Sarah Vest, Kajan Kamalanathan, Graeme Foggo, Amanda Mohabir, Ritoo Kapoor, Precious Basvi, Jamie McCanny, Christian Frey, Bruce Emerson, Anantharaman Venkataraman, Karen Burns, Gail Pottinger, Mohamed Elwkhiee, Farkhunda Waqas, Alison Loftus, Amanda Kirrage, Ilma Songaile, Craig Smith, Jo Mullender, Hannah McPhee, Miriam Namih, Linda Gregson, Rachel K. Walker, Iain K. Moppett, Christine Adamson, Katie Flower, Tina Stoycheva, Beena Parker, Caroline Thompson, Kootharajan Kamraj, Vignesh Ashok, Ranjit Gidda, Istvan Koczka, Sadie Perkin, Vandita Ralhan, Arun Sengottaiyans, Ruth Hodgson, Peter Valentine, David Nunn, John Hickman, Molly Waldron, Lauren Elliott, Irene Echaveznaguicni, Lisa Dunlop, Julian Sonksen, Robert Fallon, Huw Griffiths, Thoy Ruth, Olivia Clancy, Lucy Dudgeon, Alicia Rodgers, Pamela Oracki, Phoebe Syme, Maria Newton, Stuart P. D. Gill, Julie Foxton, Jane Perez, Liam Gleeson, Richard Green, Sally Beer, Rohit Juneja, Loretta Barnett, Alex Bonner, Eunice Emeakaroha, Andrew V. Bradley, Ravishankar Jakkala Saibaba, Dipali Verma, J. Joseph Kinsella, Swee Ang Tung, Anju Raina, Verity Calder, Andrea Ortu, Chris Walmsley, Suneal Sharma, Michelle Reichman, Tom Stocks, Annika Smith, Ross Cruikshank, Sharon Storton, Matyas Andorka, Abhishek Kakkar, Allison Daniels, Priya Datar, Nichola Wakeford, Sheila Black, Usman Choudhry, Stephen Hackett, Huw Wilkins, Kirtida Mukherjee, Tim Green, Rebecca Hill, Ishan Dharmarathna, Jennifer Crooks, Serah Mungai, Luisa Howlett, Niveen El-Wahab, Linda Prasad, Amy Sadler, David Sharpley, Daphne Varveris, Victoria Ashton, Rajeev Jeevananthan, Safia Begum, Helen Anderson, Katherine Nahajski, Vanessa Linnett, Laura Morland, Stephen Mowat, Nenette Abano, Kathryn James, Ian Butler, Madelaine Ocampo, D. Williams, Gabriella Frunza, Wendy Deamer, Dominic Espitalier-Noel, Sian Liddle, Jane McConniffe, Anthony E. Pickering, Lisha Aju, Catherine Morgan, Hao Ern Tan, Jemma Tate, Emma Dooks, Anna Moore, Alison Hardwick, Liam Scott, Zak Rob, Rajeev Jha, Sujesh Bansal, Lynda Connor, Seliat Sanusi, Sophie Mason, Nipun Agarwal, James Woodier, Julian Giles, Lauren Collis, Jill Brown, Natalie Constable, Nichola Cahill, Anne Cowley, Mai Wakatsuki, Kelly Mintrim, Glenn Arnold, Donna Doyle, Ryhs Millington, Richard Dobson, Monica Serrano, Saqib Naji, Walid Hammad, Jacob Osbourne-Wylde, David Rollins, Claudia Paoloni, Nathan Anderson, Rachel Ingham, Alison Whitcher, Vicky Hills, Nina Toms, Jon Witby, Amy Nash, Marcus Fletcher, Jane Gibson, Martin Warin, Katherine McDowall, William Malein, Madhurima Das, Wael Abdelrhamen, Tom Neal, Sister Jenny Ritzema, James Collins, Chandana Rao, Joyce Yeung, Nadeem Shakir, Andrea Weigert, Atideb Mitra, Hari Arunachalam, Amy Morgan, Richard J. Jackson, Julie Chadwick, Debbie Callaghan, Frank Swinton, Lorraine Lock, Rahul Wakhle, Krish Kapoor, Ryan Humphries, Sarah Beavis, John-Paul Cutts, Julie Wilson, Keith Kelly, James Gill, Angela Loughlin, Rhys Rhidian, Christopher McGovern, Tom Hickish, Rachel Campbell, James Pennington, James Tozer, Philip Coakley, Lynn Fenner, Sally Tomkins, Lester Ribeiro, Shabir Qadri, Hristina Petkova, Christina Timmons, Katy Smith, Jonathan Perry, Stephen Crotty, Tanmay Patil, Mayavan Abayalingam, Ahmed Foly, Anna Wahed, Lewys Winfield-Young, Naomi Goodwin, Mark Verlander, Clare Donovan, Milena Vannahme, David Helm, Murali Vallabhaneni, Clare Ingram, Neil Moreland, Lorraine Stephenson, Jenny Jackson, Lindsay McOwat, Sathya Visvendra, Rhiannon Jones, Sarah Bird, M. H. Nathanson, Beryl Jones, Claire Davies, Beena David, Ian Sheldrake, Jeremy Guilford, Sister Bryony Storey, Rajeev Mishra, Irina Halfacree, Kiran Rait, Sameer Ahmed, Victoria Poyntz, Pamela Birks, Tom Kennedy, Angiy Michael, Michael McEvoy, Ian Davies, James Chan, Sajjad Ahmed, Laura Sweeney, Anne Whaley, Andrew Moores, Stella Gillies, Gearoid Crosbie, Antoinette Wilson, Iain Walker, Fiona Brailsford, Virginia Solanki, Elizabeth Turnbull, Lyndon Harkett, Sarah Ramsay, Thomas Syratt, Pushpaj Gajendragadkar, Cathal Small, Joanna Poole, Annabelle Whapples, Raghavendran Krishnaiyan, Elizabeth Smee, Richard Pierson, Taslima Rabbi, Alexandra Murphy, Angela Rooney, Sarah Crawford, Peter Bamford, Stephen Worthy, Sarah Munsie, Lucy Venyo, Henry Wang, Aditya Kuravi, Dennis Barnes, Ruth Han, Benjamin Gupta, Nurse Lynn Wren, Robert Hartley, Emma Edmunds, Laura Blood, Valerie J. Page, Thomas Judd, Puvan Suppiah, Emma Jenkins, Kate Gallagher, Fionnuala Lenehen, Rashidat Adeniba, Julius Cranshaw, Julie Wollaston, Kathryn Allison, Richard Kirkdale, Samantha Griffith-Norris, Jenna Kelly, Snehasish Guha, Stefan Schraag, Joy Dearden, Elizabeth Bell, Stephen Smith, Sarah Longhurst, Elizabeth Wilby, Annaliza Sevillano, Raksha Mistry, Aalisha Mariam Karimi, Kaung Pyae, Sarang Puranik, Maggie Collingborn, Karen Cranmer, Chandrashekhar Vaidyanath, M. Chincholkar, Narendra Siddaiah, Gillian Bell, Edward Rintoul, Nicki Devooght-Johnson, Tom Lovejoy, Eleanor Roscoe, Zoe Neilson, Joanne Hill, Kamal Sharif, Sharon Meehan, Bassey Nkanang, Thomas Georgiou, Martin Goodman, Prashant Kakodkar, Rebecca Martin, Philip Roddam, Evanna McEvoy, Peter Tsim, Janakan Anandarajah, Shub Gupta, Oliver Pratt, Yang Ng, Francesca Th'ng, Linda Kent, Graham Soulsby, Danielle Kirk, Ramana Govindaraju, Rebecca McClean, Samantha Harkett, Obaid Tarin, Shalini Chinna, Susan Gallagher, Laura Gardiner, Marc Turnbull, James Briscoe, Anna McSkeane, Melanie Claridge, Gillian Fleming, Thomas Huttley, Elaine Spruce, Lianne Hufton, Susan Hendy, Adrian Barry, Jeremy Drake, Cody Allen, James Hillier, Manju Patel, C. Gray, Nasreen Iqbal, Karen Markwell, Linzi Heaton, Michelle Nicholas, Gary Lau, Laura Catchpole, Nurse Sonia Walia, Kerry Elliott, Jake Hartford-Beynon, Amee Samani, Kathryn King, José William Martínez, Skylar Paulich, Ifan Patchell, Killian McCourt, Rebekah Rodgers, Christine Wood, Richard Wan, Karan Verma, H. W. Cain, Eleonore Quinn, Lisa Richardson, Muhammad Usman Latif, Nicholas Hingley, Rajesh Gilla, Roopa McCrossan, Mayeth Recto, Russell Hedley, Lucy McClelland, Suzie Marriott, Deepak Seharawat, Gururaj Mudimadagu, Claire Jones, Michelle Yare, Sophia Henderson, Rupinder Kaur, Emily Spence, David Wright, Bhaskar Dutta, Tom Pettigrew, Vikki Atkinson, Lorna Sissons, Segun Oladele, Sue Thomas, Hani Ali, Rebecca Robson, David Buckley, Kevin Hamilton, Amanda Hall, Anaesthetic Audit, Anna Watkin, Donna Kelly, Graham White, Sarah Sanders, Henry Boyle, Joao Galente, Thomas Williams, Justin Ang, Sarah Horton, Abdelrahman Soliman, Vijay Jeganath, Kavita Upadhyaya, Plamen Stoyanov, Murray Geddes, Alan Pope, Khaled Ellisy, Thomas Walker, Emma Finlay, Penny Parsons, McDonald Mupudzi, Adam Duffen, James Goodwin, Rob Penson, Laura O'Sullivan, Vinesh Mistry, Ravindra Mallavalli, Krzysztos Guz, Deepti Bhuwanee, Eleanor Andrews, Justine Burns, Sarah Kirk, Faith Kibutu, Sam Stafford, Julia Blackburn, Joellene Mitchell, Robert Spencer, Helen Williams, Karen Riley, Gabbie Young, Tom Williams, James Wu, Emma Wheatley, Alistair Johnstone, Rachel Stoeter, Timothy Cominos, Guy Coady, Ruth Mawhinney, Sam Spinney, ruthy Arumugam, Myura Nagendram, Jason Lie, Sian Hughes, Linda Bairkdar, Peter Evans, Daniel Pygall, Graeme Brown, Susan Livingstone, Norbert Skarbit, Amit Pruthi, Zakaulla Belagodu, Ben Linton-Willoughby, Richard A Cowan, Helena Prady, Mike Raffles, Sonia Rasoli, Katherine Cullen, Jessica Lees, Peter Lax, Ashok Puttapa, Fran Millinchamp, Aneta Oborska, Benita Adams, Kathryn Newton, Mrutyunjaya Rao Rambhatla, Sunny Nayee, Madlena Ivanova Vrazhalska, Jonathan Clarke, Aariana Sohal, Siobhan King, James Bain, Jessica Wilson, Anthony Carver, Jack Davies, Lucy Connolly, Samuel Morrish, Robyn Lee, Lucia Stancombe, Satyanarayan Jakkampudi, Kath Rosedale, Philip Hopkins, Clovis Rau, Katherine Hunter, Amy Farrow, Kathleen Holding, Elizabeth Vassell, Oliver Boney, Julia Icke, Ewa Prusack, Osi Egole, Fiona Linton, Suresh Eapen, Wendy Goddard, Ayda Borjian Boroojeny, Simon J. Davies, Jackie Terry, Fiona Graham, Thomas Pratt, Hanzla Naeem, Viv Colclough, Yeng Yap, Tejuswi Patel, Susan Midgley, Mark MacGregor, Ben Marshall, Talitha Devries, Cheng Ong, Katie Molloy, Kat Walker, Katy Irwin, Abbas Majeed, Mark Pinkerton, Nicki Russell, Sibtain Anwar, Ian A Jenkins, Lucy Allen, Elaine Coulborn, Ganesh Nair, Stewart Brown, Melissa Addy, Matt Milner, Amr Hassan, Victoria Millar, Sarah Turner, Gary Baigel, Amanda Lyle, Simon Young, Kathy Malinovszky, Heather Short, Mary Newmarch, Colin McAdam, Andrew Robert Bailey, Kevin Draper, Michael Agyemang, Kieran Oglesby, Clare Mewies, Ruth Ugochukwu, Shibu Jacob, Susan O'Connell, Charlotte Topham, Xiao Zhao, Shay Willoughby, Ossian Aukland Child, Manish Torne, Ben Wetherell, Divya Veluvolu, Dominic Wu, Elizabeth Evans, Daniel Eden, Suzannah Peggler, Lucy Emmett, Romit Samanta, Ravi Parekh, Jane Hermanowski, Will Shankey-Smith, Sam Papadopoullos, Julie Camsooksai, Sara Mistry, James Wigley, Anna Todd, Bally Purewal, Natalie Baldry, Kate Wilkinson, Aalia Sange, Kirsty Baillie, Joanne Topliffe, Denise McSorland, Saheli Das, Nikki Staines, Catherine Harris, Anna-Marie Boniface, Gemma Milne, Tessa Rowlands, Leanne Quinn, Svetlana Kulikouskaya, Christopher Bull, Angus Sutherland, Mihir Desai, Hannah Goodhand, Meenal Rana, John Bugo, Maria Chazapis, Sarah Kent, Sarah Siew, Marcin Pachucki, Tim Forsyth-Jones, John McKenna, Sarah Driscoll, Laura Hunter, Penny Bedoes, Natasha Santana-Vaz, Sandra Latham, Robert Coe, Sharon Christie, Lawrence R Kidd, Katy Redington, Alastair Sawyer, Abdalla Ali, Rekha Jayapal, Manfred Staber, Emma Pearson, Stuart Reilley, Tom Bird, Kristofor Inkpin, Annette Haines, Manish Verma, Naomi Wee, Ozerah Choudhry, Daniel Tucker, Euan Campbell, Aaron Stokes, Ashley Allan, Emma Reeves, Helen Fenner, Melanie Cockroft, Tom Nicholls, Sinan Bahlool, Sharon Drake, Nalini Sethia, Lesley Jordan, Martin Northey, Paul Glyn Jones, Lara Jeanes, Emma Simpson, Julia Brown, Samantha Coetzee, James Nicholas, Adam Samways, Ritesh Ganesh, Martin Ward Platt, Mizan Khondoker, Helen Wibberley, Lauren Simmonds, Sunita Agarwal, Linda Titinchi, Fran O'Higgins, David Pritchard, Laura Beard, Yvonne Lester, Charlotte Hirst, Louise Wills, Kevin Windsor, Haren Jyothiraj, Carmela Martella, Stephanie Bell, Christopher Nwaefulu, Hemamangala Venkatesh, Camilla Stagg, Soumi Ghosh, Thomas Dawes, Jennifer Lockhart, Stavros Papadopoulos, Nanci Doyle, Gillian Whalley, Rachael Britton, James Goddin, Maggie Dawson, Carole Holder, Elaine Morsman, Rachel Lovatt, Venu Mehta, John J.B. Allen, Anna Perham, Stephanie Wallis, Dmitry Zabauski, Peter Hart, Tracy Sharp, Martin Pope, Jo Knight, Jane Wright, Nageena Hussain, Josie Snell, Thomas Knight, Philippa Hill, Nic Martins, Robin Williams, Beverley Stidolph, Beth Peers, Brian Lafferty, Alicja A'Court, Joanna Collins, Charlie Kennedy, Andy Bates, Graham Walkden, Mia Marsden, Lauren Shillito, Poonam Bopanna, Raheel Ahmed, Ada Ezihe-Ejiofor, Kate Driver, Mevan Gooneratne, Carolyn Smith, Caroline Abernethy, Kathy Shammas, Chanice Alcock, Yin Yong Choo, Mark Vertue, Ratna Makker, Victoria C. Smith, Sachin Mehta, Clare Denford, Wint Mon, Jose Miguel Sabugueiro, Liz Varghese, Mohamed Ahmed, Rebekah Chan, Alexandra Williams, Stephanie Pauling, Maria Faulkner, Ryan Wilkins, Sara Stevenson, Kathryn Simpson, Moiz Alibhai, Patricia Williams, Pascal Defeyter, Siva Sangaralingham, Lucy Evans, Shirley Cocks, Simon Dyer, William Rea, Caroline Renton, Karl Braid, Ranjit Bains, Holly Owen, Sue Brixey, Calum Taylor, Laura Coleman, Andrew Peeling, Daniel Solomon, Christopher Perman, Roisin McCallum, Helen Church, Martin Watson, Amy Bamford, Elizabeth Bradshaw, Elizabeth Turner, Owen Vale, Suneetha Ramani Moonesinghe, Preeti Mahidik, Lynsey Cubitt, Catherine Hunter, Eleanor Warwick, Sam McAleer, Suresh Singaravelu, James Hilton, Rebecca Aspinall, Icel Souleimanova, Muna Elsheikh Idris, Wei Teo, Sarah El-Sheika, Adrienne Stewart, Sadia Habib, Emily Wade, Liesl Despy, Sharmin Shohelly, Colin Williams, Louise Shaw, Shree Voralia, Dafydd Lloyd, Barbara A. Crooks, Laura D Howe, Una Gunter, Edward Hare, Louise Nimako, Ruth Young, Helen Doherty, Sock Huang Koh, Stephen Merron, Martina Coulding, Agilan Kaliappan, Clare Bolton-Hill, Jill Wain, Maria O'Callaghan, Catherine Cartmell, Nicola Pemberton, Hannah Bennett, Lynda Garcia, Riquella Abbott, Sally Jeffrey, Thomas McLoughlin, Andrew Gratrix, Christopher Harrison, Matt Mackenzie, Jayshree Gracey, Chris Moore, Benjamin Parsons, Nehal Patel, Stephanie Brooks, Catherine Riley, Jemma Gilmore, Ilya Kantsedikas, Simon Whiteley, Emily Pallister, Angie Organ, Yohinee Rajendran, Gopinath Selvraj, Priya Thorat, Ilona Schmidt, Pauline Austin, Nitin Madhukar Sadavarte, James Haddock, Alastair Duncan, Richard Bateman, Elaine Chinery, Martin Gray, Felicity Corcoran, Shanelle Tharuka Wijesuria, Bryany Bond, Charlene Otieno, Sion Lewis, Cieron Roe, Dan Freshwater-Turner, Annette Bolger, Sarah Steynberg, Louie Saclot, Charlotte Busby, Jack Roberts, Richard Dagnan, Jasna Comara, Krishnakar Melachuri, Sian Gibson, Joanne Taylor, Manju Agarwal, Mark Sheils, Matthew Bell, Rosemary Anna Lewis, Kiran Patel, Mansoor Siddiqui, Christopher J. Groves, Mini Thankachen, Sharon Turney, Viral Dalal, Pele Banugo, Andrew Baird, Euan Kerr, Simon Tomlins, Laura Osbourne, Nicola Pattison, Stuart Joy, Susan Merotra, Lorna Ryan, Lisa-Jayne Cottam, Chye Siaw, Keelan Jerram, Nurse Diane Scarletta, Carole Paley, Jennie Smith, Will Gatfield, Stephen Alderson, Claire Swarbrick, Amelia van Manen, Stephan Clements, Sophia Strong-Sheldrake, Jake Drinkwater, John McLenachan, Lucinda Williams, Dianne Heaton, Sandor Orosz, Chloe O'Hara, Nina Barratt, Justine Elliot, Michael Gardner, Nicola Crowther, Bharati Rajdev, Linda Hall, Youssef Girgis, Michael Kinsella, Alison Potter, Matthew Martin, Rosie Reece-Anthony, Richard Pugh, Tracey Taylor, Esme Marshall, Wendy Stoker, Helen Worrell, Kay Housley, Rebecca Leslie, Helen Jewitt, Sandeep Sharma, Maire Gallagher, Jon Fenn, Jade Harrison, Hannah Watson, Natalie Morris, Lewis Schofield, Nisha Pattni, Charlotte Thomas, Eleanor Walshe, Richard Snooks, Ruth Murphy, Emily Pickford, Gnanshree Krishnamurthy, Donna McIntosh, Rachel Dolan, Emma Stoddard, Kelly Goffin, Shady Elhallous, Adrian Butler, Ildiko Nemeth, Hannah Wilson, James Sylvester, Melanie Sahni, James Wardlow, Ann Lachana, Emma Barr, Kayleigh Gilbert, Yazzim Hammoud, Peter Csabi, Maqsood Bajwa, James D Turner, Alex Hunt, Samantha Moore, Stephanie Hii, Philip Atkinson, Michelle Walter, Elizabeth Bailey, Frances Tait, Annie Newby, Jane Martin, Greg Forshaw, Bert Quartermain, Sally Humphreys, Aoife Hegarty, Caroline Bennett, Satyajeet Ghatge, Charles Prior, Kribashnie Nundlall, Priaykam Chowdhury, Jill Fitchett, Daiva Bernotaitis, Sandeep Varma, Alex Dunn, Rebecca Dooley, Mahamed Mostafa, Shelly Wood, James Humphreys, Anna Celnik, John Bailes, Mark Snazelle, Christina McCarroll, Matthew Govier, Emert White, Matthew Taylor, Alastair Rose, Brigid Hairsine, Natalie Whybro, Allen George, Robin Wilson, Filipe Vieira, Leon Cohen, Jonathan Womack, Thomas Woodward, Nimali Lochanie, Ben Howes, Joshua Nelson, Preea Gill, Gayle Clifford, Lushani Suntharanathan, Duncan Wagstaff, Steve Pryn, Lalindra Bandara, Sneh Shah, Nowfal Rahman, Iolo Roberts, Mirriam Sangombe, Shaik Subhani, Hannah Phelan, William Udall, Katy Allan, Nicola Zondo, Tim J Peters, James Roe, Catherine Addleton, Angus McKnight, James McCaul, Flora Kormendy, Anil Rao, Luke Vamplew, Andrew Rees, Jeanette Gilbert, Mandy Austin, Thomas Hunt, Sian Birch, Catherine Lloyd, Stewart D'Sylva, Jill Smith, Wendy Lum Hee, Michael Munro, Jean Denton, Julia Hindle, Alice Brown, Ursula Kirwan, Dinithi Yogya, Maria Mclaughlin, Nurse Louise Moran, Larysa Duniec, Sophie Benoliel, Gail Evans, Linda Bailey, Colin Hall, Katie Rowland, Krupali Patel, Ashwini Keshkamat, Zorba Begum, Resti Varquez, Victoria Apps, Giles Bond-Smith, Shirin Dastur, Andy Chapman, Amy Smith, Sarada Gurung, Ruth Delascasas, Nicole Issit, Pauline Sibley, Jaina Parmar, George Madden, Eveliina Nurmi, Katja van de Snepscheut-Jones, Louise Peacock, Vanja Srbljak, Kellie Allen, Andy Chamberlain, Suhail Zaidi, Andrew Boyle, Daniel Stolady, Rita Saha, Mark Clayton, Mitul Patel, Emily King, Hannah Oliver, Ewa Werpachowska, Holly Coles, John Dereix, Agnieszka Kubisz-Pudelko, Clare Watkinson, David Rogerson, Laurence Inman, Jaspreet Rayet, Jenny Finch, Emma Stewart, K. E. Wilson, Emma Tyson, Asif Gani, Reni Jacob, Neil Smith, Johnny Holland, Max Richardson, Mark Chen, Richard George, Helen Laycock, Anoushka Winton, Emily Hignell, Li Fang, Emma Welfare, Rochelle Velho, Fayaz Baba, Finbar O'Sullivan, Lisa Zeidan, N. Beauchamp, Neil Rasburn, Guy Rousseau, Victoria Roberts, Hollie Bancroft, Holly Maguire, Mechele Couch-Upite, Rahul Kumar, Chandra Bhimarasetty, Matt Lovell, Sujata Anipindi, Charlotte Small, Matthew Faulds, Alex Mattin, Alice O'Donnell, James Jack, Richard Boulding, Tarek Mostafa, Rhian Bull, Corinne Pawley, Ruth Killen, Jessica Lowe, Frances Taylor, Ethel Black, Michael F. M. James, Jenny Child, Lisa Emery, Kim Hoyland, David Hay, Janet Cotta, Josephine Stewart, Sue Spearritt, Laura MacNally, Fatma Lahloub, Katie Welham, Sanjoy Bhattacharyya, Shanteela McCooty, Heena Bidd, Hugo Buckley, Ervin Shpuza, Zaid Ahmed, Emily Craven, Amanda Cook, Caroline Dixon, Tara Pauley, Tariq Azad, Helena Barcraft-Barnes, Sindy Lee, Kate Penhaligon, Bernice Dudkowsky, Karen Ellis, Laura Montague, Ching Pang, Elsie Bickmore, Veronica Marsh, Toby Winterbottom, Marta Campbell, Rhys Hughes, Issie Gardner, Elizabeth Steel, Ramai Santhirapala, Katie Sweet, Michelle Scott, John Ekpa, Bhavia Janardhana, Catriona Frankling, Julia Ottaway, Alexander Middleditch, Elna Cifre, Annabel Pearson, Amanda Cotterill, Sarah Raut, Hannah Blanshard, Sara Eddy, Garry Henry, Elizabeth Hood, Maria Loy, Matthew Campbell, Marc Gimenez, Jessica Thrush, Jeremy Henning, Vlad Kushakavsky, Nikolaos Makris, Deborah Fradkin, Karen Fan, Fiona Hammonds, Kathryn Jackson, John Hadfield, Pyda Venkatesh, David Read, Daniel Zeinali, Ryan Hynd, James Carvell, Richard McCormick, Emily Dodds, Sana Rizvi, Amelia Daniel, Dan Sellers, Thomas E. Miller, Daniel Haigh, Nicky Moss, Patrick Dill-Russell, Priya Shekar, Teresa Melody, Randeep Dhaliwal, Nigel Hollister, Andrew Burtenshaw, Adrian Wagstaff, Ben Scoones, Eduardo Osorio, Joanna Allison, Lucy Willsher, Carol McArthur, Stephan Dalchow, Elaine Winkley, Eleanor Reeves, Ben Eden Green, Andrea Ingham, Mohammad Auldin, Freda Amoakwa-Adu, Jonathan Adams, Fiona Oglesby, Charlotte Steeds, Nurse Sara Greig, Obla Suganthi, Puja Chhaniyara, Clare De'Ath, Chandrakant Gosavi, Bart Ordys, Adele Flowerdew, Doug Tunney, Rachel Alexander, Oliver Griffith, Thomas Saunders, Matthew Maton-Howarth, Gabi Metiu, Akmal Shakoor, Elizabeth Willard, Katherine Russell, Matthew Robinson, Emma O'Kane, Meera Raja, Phillippa Falkner, Kerry Colling, Natasha Joshi, Laura Pearse, Tim J. Smith, Anitha James, Mona Mohamed, Richard Kennedy, Samson Ma, Tasmeen Ghafoor, Matthew N. Davies, Henry Lewith, Samuel Mindel, Sarah-Jane Dunn, Hemangini Barot, Sadie Diamond-Fox, Jenny Macallan, Arun Menon, Helen Farrah, Emma Plunkett, Brendon Spooner, Sorana White, Katie Samuel, David Crabtree, Katherine Cheshire, Gareth Harrop, Dionne Wortley, Tim Warrener, Joanne Mullen, Peter Taysum, John Whitaker, Kathy Wilkinson, Jean Dent, Nicola Farmer, Thelma Darian, Guru Hosdurga, Phillipa Wakefield, Christopher W Horner, Julie Steen, Elena Teh, Helen Gerrish, Betty Travasso, Mhairi Jhugursing, Michelle Gardener, Alexandra Crook, Edward W. Miles, Patricia Doble, Ashok Raj, Hanna Wong, Kay Protheroe, Chiraag Talati, Banher Sandhu, Cara Marshall, Matt Holl, Julie Sheriff, Frances Forrest, Adam Mitchell, Hindusha Keerthikumar, Mohamad Mahmoud, Simon Ben-Nathan, Janice Hartley, Danielle Ormandy, Hayleigh Morris, Steven Tran, Imogen Hayes, Trudy Smith, Kirsty Duell, Jennifer Cunningham, Richard Appleton, Lucy Pippard, Debroah Beeby, Hayley Bridger, Manuel Pinto, Susan Beames, Huiqi Wang, Cain Hunter, Flora Darch, Debbie Weller, Jonathan Hulme, Jacqueline Howes, Michael Kriger, Badrinath Manikundalam, D.J.N. Wong, Tim Arnold, Belinda Wroath, Rachel McKendry, Harry Knight, Caroline Bushell, Victoria Siddons, Louise Humphries, Joanne Vere, Vinanti Cherian, Janine Birch, Kate Blyth, Tatyana Bolonenkova, Meredith Harris, Alice Sisson, Sarah Clark, Sandeep Saxena, Samira Green, Amit Ranjan, Gillian Bennett, Chris Smales, Laura Ferguson, Ash Bharti, Francisca Mautadin, Katherine Brown, Lydia Jones, Christopher Adeney, Nikkita Carden, Sanjay Behl, Sonia Sathe, Elizabeth Neale, Helen French, Charlotte Mundy, Anna Batchelor, David Morris, Nithin Roy, Evelyn Philip, P.A.-A. Marc Hastie, Andrea Cole, Edmund Quak, Claire Totten, Karen McIntosh, Fiona Davis, Søren Kudsk-Iversen, Vanessa Unsworth, Andrew McIndoe, Jeremy Bewley, Sarbpreet Sarao, Laura Wood, Elaine Walker, Egidio Da Silva, Danielle Gilmour, Richard Yardley, Zara Eagle, Vijay Ragothaman, Sean Rayappu, Moira Tait, Alex Hamilton, Chris Gillett, Adeel Majeed, John Elton, Arlo Whitehouse, Fiona Robertson, Tim Martindale, Kin So, Kathryn Dixon, Toby Shipway, Fiona Mcneela, Simon Cousins, Brian Conway, Merate Place, Phil Duggleby, Rhian Morgan, Racquel Carpio, Carina Casey, Edward Mew, Jo Han Gan, Caroline Clark, Natasha Sharma, Kay Anne Mak, Gahan Bose, Chris Ford, Ruoling Yan, Anand Sathiapillai, Panagiotis Sgardelis, Sue Redhead, Arjun Alva, Cathy Jones, Vincent Hamlyn, Gemma Squires, Karen Smallshaw, John Whitwell, Sarah Shaw, Paul Watson, Michelle Cheeseman, Kimberley Netherton, Juneenath Karattuparambil, Niyesa Ranasinghe, Jeet Patel, Rob Lyons, Gemma Bown, Helen Bromhead, Zhana Ignatova, Kudakwashe Nyangoni, Linden Baxter, Thomas Moody, Sachin Valap, Esme Sleap, Mario Fernandes, Kinga Bodo, Jane Silk, Charlie Pope, Donna Ferraioli, Chloe Billingham, Rachel Butterworth, Andrew Kelly, Lesley Hawkins, Issac Gill, Hannah Greenlee, Sue Kirby, Jessica Giles, Anna Pierson, Roxana Sandhar, Claire Smyth, Rhona Younger, Ciara Coary, Arif Qureshi, Tahir Abbas, Corinne Rimmer, James Evans, Ida Ponce, Fenner Christoper, Buzz Shephard, Sophie Tang, Lauren Milian, Joanne Hiden, Dhania Haron, Jamie Calderwood, David Freeman, Virginia McTaggart, Carla Lewis, Chai Obeysekera, Alan H. Cohen, Melvin Leong, Jenni Law, Noor Elahi, Kim Holland, Victor Maduekwe, James Garwood, Lizzie Dawson, Virginia Iqbal, Thomas J Craig, Daniel Shuttleworth, Anand Perumal, Mahmood Saad, Seema Charters, Bethany Tookey, P Gunning, Suresh Panchakshariah, I.J. Wrench, Mayur Murali, Susan McInerney, Paul Foley, Charlotte Perkins, Marie-Louise Svensson, Karen Birnie, Samantha Hagan, Emily Hetherington, Anna-Marie Love, Annette Woods, Karen Green, Steve Hillier, Hannah Conway, Rebecca Reilly, Laura Bubb, Amy Ashford, Andrew Savva, Melody MacGregor, Stephen Lord, Ahmed Hassanin, Ramdas Howard, Laura Ashton, Arihant Jain, Simon Williams, Michael Shaw, Jill Deane, Abbie Singleton, Catriona Routley, Christopher Hall, Robin Webber, Tressy Pitt-Kerby, Stuart M. White, Shannon Gawley, Nick Heseltine, Christina Lalani, Claudia Dulea, Arindam Biswas, Rebecca Harris, Aislinn Brown, Nicholas Francis, Ben Holst, Ryan Perry, Cathie Melvin, Mark Darbyshire, Stephen Mulvany, Amy Ashton, Petrus Fourie, Emma Temlett, Jason Cupitt, Vanisha Patel, Alice Trimble, Andrew Brammar, Sarah Grayland, Eleanor Pett, Tom Standley, Carly Webb, Manamohan Rangaiah, Laura Peltola, Leanne Darwin, Yvonne Grimes, Elizabeth Brodier, Scott Berwick, Adam Janeczko, Madeleine McKee, Katherine Davidson, Jan Woodward, Saurabh Mehotra, Tara Keogh, Kofi Mensah, Joyce Guy, James King, Matt Aldridge, Nicolas Price, Alaine Done, Teresa Jones, Julia Sampson, Smita Bapat, Lauren Perkins, Tamas Szelei, Ryan Kingan, Suleman Mulla, Celia Montgomery, Alex Belcher, Salma Kadiri, Bryan Singizi, Peter Chater-Lea, Jennifer Claire Taylor, Lauren Oswald, Stephanie L. Lee, Rhys Griffiths, Samuel Pestell, John Livesy, Sarah Ciechanowicz, Alexander Stephen Harrison, Richard Partridge, Alex Daniels, Beth Penhaligan, Lyndsay Bibb, Jonathan Little, Margaret Cullen, Anya Eijk, Charlotte Earnshaw, Elena Lynes, Nicholas Jenkins, Inthekab Mohammed Ali, Madhu Balasubramaniam, Vusumuzi Shabangu, Paul-Simon Whitney, Rebecca Denyer, Kathryn Potts, Andrew Ray, Jonny Guy, Mike (Stephen) Kinsella, Pearl Baker, Olga Fernandez, Julian Berry, Callum Forbes, Southcoast Peri-operative Audit, Rebecca Rice, Lisa Horner, Sally Pitts, Kirat Panesar, Joe Stevens, Timothy Molitor, Oon Chiu, Piers Murphy, Sudeshkumar Muniyappa, David George, Jonathan Veitch, Shifa Yaruk, Lynn O'Donohoe, Theresa Murray, Laura Tasker, Johanna Wales, Diane Mellers, Robert Sparrow, Olivia Ward, Emma Shacklock, Janet Middle, Sarah MacLennan, Martin Knight, Lindsay Dawson, Teodora Orasanu, Jo Fletcher, Sarah Martin, Pnt Laloë, Gregor Imrie, Harriet Pudge, Tamsin Gregory, Andrea Wood, Colin Christie, James Penketh, Mia Andrews, Nicky Ford, Ellie Fisher, Sophie Robin, Richard Stewart, Steve Williams, Harriet Gardiner, Alison Evans, Guanmei Luo, Urmila Ratnasabapathy, Ruth Joslyn, R. Sneyd, John Westwood, Naomi Cassells, Olivia Kay, Jordi Margalef, S Butler, Hari Nageswaran, Chloe Searles, Geoffrey Wright, Thomas Potter, Drew Norwood-Green, Jonathan Ramsden, Sarah Bean, Emma Sadler, Anaesthetic Trainees, Stephanie Lewis, Kevin E. Thorpe, Sarah MacLean, Paul Ogle, Mary O'Sullivan, Diane Whitehouse, Mandy Oakley, Rachel Coathup, Harisg Venkatesh, Lisa Burgess, Daniela Smith, Kimberley Plummer, Hilary Robb, Jeanette Grocott, Rebecca Mairs, Helen Gilfillan, Moira Morrison, Sharon Garner, and Tammy Towers

Subjects
Adult, medicine.medical_specialty, Adolescent, State Medicine, Cohort Studies, 03 medical and health sciences, Young Adult, 0302 clinical medicine, 030202 anesthesiology, Pregnancy, Risk Factors, Neoplasms, medicine, Humans, 030212 general & internal medicine, Prospective Studies, Young adult, Prospective cohort study, health care economics and organizations, Aged, Aged, 80 and over, Health Facility Size, Postoperative Care, Models, Statistical, business.industry, Incidence (epidemiology), Incidence, Health services research, Operating room management, Odds ratio, Middle Aged, Confidence interval, United Kingdom, Surgery, Obstetrics, Anesthesiology and Pain Medicine, Hospital Bed Capacity, General Surgery, Female, business, Emergency Service, Hospital, human activities, Cohort study
Abstract

Background: cancellation of planned surgery impacts substantially on patients and health systems. This study describes the incidence and reasons for cancellation of inpatient surgery in the UK NHS. Methods: we conducted a prospective observational cohort study over 7 consecutive days in March 2017 in 245 NHS hospitals. Occurrences and reasons for previous surgical cancellations were recorded. Using multilevel logistic regression, we identified patient- and hospital-level factors associated with cancellation due to inadequate bed capacity. Results: we analysed data from 14 936 patients undergoing planned surgery. A total of 1499 patients (10.0%) reported previous cancellation for the same procedure; contemporaneous hospital census data indicated that 13.9% patients attending inpatient operations were cancelled on the day of surgery. Non-clinical reasons, predominantly inadequate bed capacity, accounted for a large proportion of previous cancellations. Independent risk factors for cancellation due to inadequate bed capacity included requirement for postoperative critical care [odds ratio (OR)=2.92; 95% confidence interval (CI), 2.12–4.02; PConclusions: a significant proportion of patients presenting for surgery have experienced a previous cancellation for the same procedure. Cancer surgery is relatively protected, but bed capacity, including postoperative critical care requirements, are significant risk factors for previous cancellations.

Published
2018

25. Aflibercept Action in a Rabbit Model of Chronic Retinal Neovascularization: Reversible Inhibition of Pathologic Leakage With Dose-Dependent Duration

Author

Thomas Clayton MacPherson, Stanley J. Wiegand, George D. Yancopoulos, Jingtai Cao, Carmelo Romano, Yang Liu, Bibiana V. Iglesias, and Natasha Tirko

Subjects
Male, Vascular Endothelial Growth Factor A, medicine.medical_specialty, Time Factors, Angiogenesis, Recombinant Fusion Proteins, Angiogenesis Inhibitors, Retinal Neovascularization, Capillary Permeability, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Ophthalmology, Blood-Retinal Barrier, medicine, Animals, Fluorescein Angiography, Aflibercept, Retina, medicine.diagnostic_test, Dose-Response Relationship, Drug, business.industry, Fundus photography, Retinal Vessels, Retinal, Fluorescein angiography, Immunohistochemistry, Vitreous Body, Dose–response relationship, Disease Models, Animal, medicine.anatomical_structure, Receptors, Vascular Endothelial Growth Factor, chemistry, Chronic Disease, Intravitreal Injections, 030221 ophthalmology & optometry, Rabbits, business, 030217 neurology & neurosurgery, Tomography, Optical Coherence, medicine.drug
Abstract

Purpose We establish and characterize the chronic retinal neovascularization (RNV) induced by intravitreal (IVT) injection of DL-α-aminoadipic acid (AAA) in a rabbit model and investigate the extent and duration of inhibitory actions induced by IVT aflibercept on the RNV. Methods Rabbits received a single IVT injection of AAA, with weekly follow-up fundus photography, fluorescein angiography (FA), and optical coherence tomography (OCT). After 10 weeks, they received a single IVT aflibercept or control injection. RNV leakage was quantified from FA by image analysis with Photoshop. Some eyes were collected for histologic analysis. Results IVT AAA produced neuronal degeneration over a large fraction of the retina. RNV formed in the damaged area and by 10 weeks exhibited stable morphology and leakage, which persisted for at least 65 weeks. Control IVT injections did not affect RNV leakage, but IVT aflibercept completely blocked RNV leakage. The inhibition was reversible (i.e., the leakage returned as the drug cleared), and the duration of antileak effects with 500 μg aflibercept was approximately 8 weeks. Partial regression of the pathologic vasculature also occurred with aflibercept, with reestablishment as the drug cleared. Conclusions This model mimics a chronic human disease in its stability and persistence, and the antileak action of aflibercept is fully reversible with a dose-dependent duration. Therefore, this large eye model is uniquely suitable for investigations into the efficacy and duration of action of novel formulations and pharmacotherapies for retinal vascular diseases, and for studying the underlying pathobiology of retinal angiogenesis.

Published
2018

27. Applications of Connected Vehicle Infrastructure Technologies to Enhance Transit Service Efficiency and Safety, Part 2

Author

Lee, Young-Jae, Thomas, Clayton, and Dadvar, Seyedehsan

Subjects
connected vehicles, transit apps, transit passenger safety, dynamic transit routing, user preferences
Abstract

Many transit agencies provide real-time operational information and trip-planning tools through phone, Web, and smartphone applications. These services utilize a one-way information flow from transit agencies to transit users. Current smartphone technology and connected vehicle infrastructure (CVI), however, can allow a two-directional information flow from users to transit agencies and back. This report provides a literature review on the state of current transit apps; proposes a system architecture for a smartphone app that allows for dynamic flexible routing and increased transit user safety; and presents the results of a survey conducted on the perception and acceptability of the model app. Survey results were analyzed in terms of safety, efficiency, and privacy for different demographic, travel behavior, and geographic characteristics. Results showed that users did not significantly consider the privacy issues (7.1 on a scale from 1 [least acceptable] to 10 [most acceptable]) but believed that it could improve nighttime safety (7.3/10.0). Users believed that the app could improve nighttime pedestrian safety if it were connected to the police department (7.8/10.0). This app was also expected to improve transit efficiency and increase ridership, and is eventually recommendable (7.3/10.0). The least expected improvement was daytime safety (6.4/10.0), which is reasonable and expectable.

Published
2016

28. Efficient architecture and scheduling technique for pairwise sequence alignment

Author

Thomas Clayton, Khaled Benkrid, and Mohd Nazrin Md Isa

Subjects
Hardware architecture, Dynamic programming, Numerical linear algebra, Computer science, General Medicine, Parallel computing, Architecture, computer.software_genre, Field-programmable gate array, computer, Implementation, Reconfigurable computing, Scheduling (computing)
Abstract

A novel efficient hardware architecture to optimize the execution time of dynamic programming-based (DP) pairwise sequence alignment algorithms in hardware is proposed. It is realized by introducing an efficient overlapped scheduling of alignment matrix computation and substitution coefficients' pre-loading onto processing elements (PEs) in folded systolic arrays. A new metric is also proposed as an independent performance evaluator to compare different core implementations on different FPGA platforms fairly. Implementation results show that the new hardware architecture for sequence alignment achieves a minimum of 40 percent area normalized speed-up compared to the state-of-the-art hardware implementation, with the speed-up growing linearly with the number of folds e.g. 120 percent speed-up for 16-fold. Compared to equivalent software implementations, the novel hardware architecture achieves a minimum of 103x speed-up, with the speed-up growing linearly with the number of folds e.g. 140x speed-up for 20-fold.

Published
2012
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29. Digital Hardware Design Teaching

Author

Thomas Clayton and Khaled Benkrid

Subjects
General Computer Science, business.industry, Computer science, Teaching method, Constructive alignment, Reconfigurable computing, Education, Engineering education, ComputingMilieux_COMPUTERSANDEDUCATION, Curriculum development, Verilog, business, Field-programmable gate array, computer, Curriculum, Computer hardware, computer.programming_language
Abstract

This article presents the design and implementation of a complete review of undergraduate digital hardware design teaching in the School of Engineering at the University of Edinburgh. Four guiding principles have been used in this exercise: learning-outcome driven teaching, deep learning, affordability, and flexibility. This has identified discrete electronics as key components in the early stages of the curriculum and FPGAs as an economical platform for the teaching of various digital hardware design concepts and techniques in later stages of the curriculum. In particular, the article presents the detailed design and implementation of one digital hardware design laboratory, called Gateway, which introduces students to synchronous digital circuit development from high level functional specifications, uses Verilog for hardware description and FPGAs as an implementation platform. Biggs’ theory of constructive alignment was applied in the design of this lab’s learning outcomes, lab content, teaching and learning methods, and assessment methods. The lab makes extensive use of multimedia in both lab content delivery and demonstration applications developed by students. Student feedback following the deployment of this lab was overwhelmingly positive and an evaluation of the lab results compared to previous lab offerings’ shows the merit of the approach taken.

Published
2012
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30. The crystal structure of a bacterial Sufu-like protein defines a novel group of bacterial proteins that are similar to the N-terminal domain of human Sufu

Author

Gye Won Han, Dana Weekes, Lian Duan, Keith O. Hodgson, Polat Abdubek, Winnie W Lam, Joanna C Grant, Hsiu-Ju Chiu, Herbert L. Axelrod, Mitchell D. Miller, Dennis Carlton, Ashley M. Deacon, Anna Grzechnik, Ian A. Wilson, Christina Puckett, Sanjay Krishna, Kyle Ellrott, Mark W. Knuth, John Wooley, Abhinav Kumar, Ron Reyes, Connie Chen, Thomas Clayton, Qingping Xu, Kevin K. Jin, Henry van den Bedem, Debanu Das, Andrew P. Yeh, Tiffany Wooten, Edward Nigoghossian, Tamara Astakhova, Christine B Trame, Jiadong Zhou, Robert D. Finn, Lukasz Jaroszewski, Julie Feuerhelm, Linda Okach, Scott A. Lesley, Marc C. Deller, Andrew T. Morse, Marc André Elsliger, Constantina Bakolitsa, Xiaohui Cai, Piotr Kozbial, David Marciano, Henry J Tien, Adam Godzik, Heath E. Klock, Carol L. Farr, Amanda Nopakun, and Michelle Chiu

Subjects
0303 health sciences, Sequence analysis, Repressor, Sequence alignment, Plasma protein binding, Biology, Biochemistry, Hedgehog signaling pathway, Structural genomics, 03 medical and health sciences, 0302 clinical medicine, 030220 oncology & carcinogenesis, Molecular Biology, Peptide sequence, Function (biology), 030304 developmental biology
Abstract

Sufu (Suppressor of Fused), a two-domain protein, plays a critical role in regulating Hedgehog signaling and is conserved from flies to humans. A few bacterial Sufu-like proteins have previously been identified based on sequence similarity to the N-terminal domain of eukaryotic Sufu proteins, but none have been structurally or biochemically characterized and their function in bacteria is unknown. We have determined the crystal structure of a more distantly related Sufu-like homolog, NGO1391 from Neisseria gonorrhoeae, at 1.4 A resolution, which provides the first biophysical characterization of a bacterial Sufu-like protein. The structure revealed a striking similarity to the N-terminal domain of human Sufu (r.m.s.d. of 2.6 A over 93% of the NGO1391 protein), despite an extremely low sequence identity of ∼15%. Subsequent sequence analysis revealed that NGO1391 defines a new subset of smaller, Sufu-like proteins that are present in ∼200 bacterial species and has resulted in expansion of the SUFU (PF05076) family in Pfam.

Published
2010
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31. Structure of BT_3984, a member of the SusD/RagB family of nutrient-binding molecules

Author

Mark W. Knuth, Linda Okach, Keith O. Hodgson, Winnie W Lam, Tamara Astakhova, Debanu Das, Lukasz Jaroszewski, Kevin K. Jin, Abhinav Kumar, Scott A. Lesley, Joanna C Grant, Daniel McMullan, Gye Won Han, Herbert L. Axelrod, Amanda Nopakun, Kyle Ellrott, John Wooley, Piotr Kozbial, Henry J Tien, Polat Abdubek, Christine B Trame, Ashley M. Deacon, Sanjay Krishna, Christopher L. Rife, Henry van den Bedem, Ron Reyes, Lian Duan, Dana Weekes, Adam Godzik, Heath E. Klock, Marc André Elsliger, Carol L. Farr, David Marciano, Ian A. Wilson, Julie Feuerhelm, Christina Puckett, Edward Nigoghossian, Marc C. Deller, Qingping Xu, Constantina Bakolitsa, Connie Chen, Dennis Carlton, Hsiu-Ju Chiu, Mitchell D. Miller, Anna Grzechnik, Thomas Clayton, and Andrew T. Morse

Subjects
Models, Molecular, Protein Structure, Glycan, Operon, 1.1 Normal biological development and functioning, Molecular Sequence Data, Biophysics, gut microbiome, Sequence (biology), Biology, Crystallography, X-Ray, Biochemistry, Structural genomics, Vaccine Related, 03 medical and health sciences, Bacterial Proteins, Models, Underpinning research, Structural Biology, Genetics, Bacteroides, Amino Acid Sequence, Peptide sequence, Structural Homology, 030304 developmental biology, metagenomics, 0303 health sciences, Crystallography, Human Gut Microbiome, Protein, 030302 biochemistry & molecular biology, Molecular, structural genomics, Biological Sciences, Condensed Matter Physics, biology.organism_classification, Protein Structure, Tertiary, Tetratricopeptide, starch-utilization system, Structural Homology, Protein, Chemical Sciences, X-Ray, biology.protein, Bacteroides thetaiotaomicron, Tertiary
Abstract

The crystal structure of BT_3984, a SusD-family protein, reveals a TPR N-terminal region providing support for a loop-rich C-terminal subdomain and suggests possible interfaces involved in sus complex formation., The crystal structure of the Bacteroides thetaiotaomicron protein BT_3984 was determined to a resolution of 1.7 Å and was the first structure to be determined from the extensive SusD family of polysaccharide-binding proteins. SusD is an essential component of the sus operon that defines the paradigm for glycan utilization in dominant members of the human gut microbiota. Structural analysis of BT_3984 revealed an N-terminal region containing several tetratricopeptide repeats (TPRs), while the signature C-terminal region is less structured and contains extensive loop regions. Sequence and structure analysis of BT_3984 suggests the presence of binding interfaces for other proteins from the polysaccharide-utilization complex.

Published
2010
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32. Structure ofBacteroides thetaiotaomicronBT2081 at 2.05 Å resolution: the first structural representative of a new protein family that may play a role in carbohydrate metabolism

Author

Andrew P. Yeh, John Wooley, Edward Nigoghossian, Qingping Xu, Christine B Trame, Gye Won Han, Kevin K. Jin, Dana Weekes, Kyle Ellrott, David Marciano, Lian Duan, Scott A. Lesley, Lukasz Jaroszewski, Debanu Das, Ashley M. Deacon, Linda Okach, Herbert L. Axelrod, Hsiu-Ju Chiu, Abhinav Kumar, Thomas Clayton, Connie Chen, Heath E. Klock, Marc André Elsliger, Carol L. Farr, Henry van den Bedem, Andrew T. Morse, Mitchell D. Miller, Anna Grzechnik, Daniel McMullan, Dennis Carlton, Keith O. Hodgson, Joanna C Grant, Winnie W Lam, Amanda Nopakun, Polat Abdubek, Tiffany Wooten, Julie Feuerhelm, Sanjay Krishna, Michelle Chiu, Adam Godzik, Marc C. Deller, Tamara Astakhova, Constantina Bakolitsa, Xiaohui Cai, Piotr Kozbial, Henry J Tien, Ron Reyes, Ian A. Wilson, Christina Puckett, and Mark W. Knuth

Subjects
Models, Molecular, gut microbiome, Crystallography, X-Ray, Biochemistry, fluids and secretions, Protein structure, Models, Structural Biology, polycyclic compounds, Bacteroides, Peptide sequence, 0303 health sciences, Crystallography, Human Gut Microbiome, 030302 biochemistry & molecular biology, Biological Sciences, Condensed Matter Physics, immunoglobulin-like fold, GenBank, Carbohydrate Metabolism, Bacteroides thetaiotaomicron, Protein Structure, Protein family, 1.1 Normal biological development and functioning, Molecular Sequence Data, Carbohydrates, Biophysics, Sequence alignment, Biology, digestive system, Structural genomics, 03 medical and health sciences, jelly-roll fold, Bacterial Proteins, Underpinning research, Genetics, Amino Acid Sequence, Binding site, Structural Homology, 030304 developmental biology, Binding Sites, Protein, Molecular, structural genomics, Protein Structure, Tertiary, carbohydrates (lipids), sugars, Structural Homology, Protein, Chemical Sciences, X-Ray, bacteria, Sequence Alignment, Tertiary
Abstract

The crystal structure of BT2081 from B. thetaiotaomicron reveals a two-domain protein with a putative carbohydrate-binding site in the C-­terminal domain., BT2081 from Bacteroides thetaiotaomicron (GenBank accession code NP_810994.1) is a member of a novel protein family consisting of over 160 members, most of which are found in the different classes of Bacteroidetes. Genome-context analysis lends support to the involvement of this family in carbohydrate metabolism, which plays a key role in B. thetaiotaomicron as a predominant bacterial symbiont in the human distal gut microbiome. The crystal structure of BT2081 at 2.05 Å resolution represents the first structure from this new protein family. BT2081 consists of an N-terminal domain, which adopts a β-sandwich immunoglobulin-like fold, and a larger C-terminal domain with a β-sandwich jelly-roll fold. Structural analyses reveal that both domains are similar to those found in various carbohydrate-active enzymes. The C-terminal β-jelly-roll domain contains a potential carbohydrate-binding site that is highly conserved among BT2081 homologs and is situated in the same location as the carbohydrate-binding sites that are found in structurally similar glycoside hydrolases (GHs). However, in BT2081 this site is partially occluded by surrounding loops, which results in a deep solvent-accessible pocket rather than a shallower solvent-exposed cleft.

Published
2010
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33. Structures of three members of Pfam PF02663 (FmdE) implicated in microbial methanogenesis reveal a conserved α+β core domain and an auxiliary C-terminal treble-clef zinc finger

Author

Lukasz Jaroszewski, Polat Abdubek, Sanjay Krishna, Adam Godzik, Henry van den Bedem, Dennis Carlton, Marc-André Elsliger, Natasha Sefcovic, Edward Nigoghossian, Piotr Kozbial, Henry J Tien, Thomas Clayton, Debanu Das, Qingping Xu, Joanna C Grant, Gye Won Han, Heath E. Klock, Carol L. Farr, Ron Reyes, Daniel McMullan, John Wooley, Hsiu-Ju Chiu, Marc C. Deller, Herbert L. Axelrod, Connie Chen, Amanda Nopakun, Tamara Astakhova, Ian A. Wilson, Kevin K. Jin, Christine B Trame, Christina Puckett, Constantina Bakolitsa, David Marciano, Keith O. Hodgson, Winnie W Lam, Ashley M. Deacon, Andrew T. Morse, Mitchell D. Miller, Anna Grzechnik, Julie Feuerhelm, Abhinav Kumar, Tiffany Wooten, Dana Weekes, Lian Duan, Linda Okach, Mark W. Knuth, Scott A. Lesley, and Kyle Ellrott

Subjects
Pfam family PF02663, Models, Molecular, Secondary, Ligands That Aid in Function Characterization, metalloproteins, Crystallography, X-Ray, Biochemistry, Protein Structure, Secondary, Structural Biology, Models, domain swapping, Zinc finger, chemistry.chemical_classification, 0303 health sciences, Crystallography, biology, 030302 biochemistry & molecular biology, Thermoplasma acidophilum, Zinc Fingers, methanogenesis, Biological Sciences, Condensed Matter Physics, Aldehyde Oxidoreductases, Methane, Protein Structure, Molecular Sequence Data, Biophysics, chemistry.chemical_element, Context (language use), Zinc, Desulfitobacterium, Formylmethanofuran dehydrogenase, Structural genomics, 03 medical and health sciences, Rare Diseases, Oxidoreductase, Genetics, Amino Acid Sequence, 030304 developmental biology, Structural Homology, Protein, Active site, Molecular, structural genomics, biology.organism_classification, Protein Structure, Tertiary, chemistry, Structural Homology, Protein, Chemical Sciences, biology.protein, X-Ray, Tertiary
Abstract

The first structures from the FmdE Pfam family (PF02663) reveal that some members of this family form tightly intertwined dimers consisting of two domains (N-terminal α+β core and C-terminal zinc-finger domains), whereas others contain only the core domain. The presence of the zinc-finger domain suggests that some members of this family may perform functions associated with transcriptional regulation, protein–protein interaction, RNA binding or metal-ion sensing., Examination of the genomic context for members of the FmdE Pfam family (PF02663), such as the protein encoded by the fmdE gene from the methanogenic archaeon Methanobacterium thermoautotrophicum, indicates that 13 of them are co-transcribed with genes encoding subunits of molybdenum formylmethanofuran dehydrogenase (EC 1.2.99.5), an enzyme that is involved in microbial methane production. Here, the first crystal structures from PF02663 are described, representing two bacterial and one archaeal species: B8FYU2_DESHY from the anaerobic dehalogenating bacterium Desulfito­bacterium hafniense DCB-2, Q2LQ23_SYNAS from the syntrophic bacterium Syntrophus aciditrophicus SB and Q9HJ63_THEAC from the thermoacidophilic archaeon Thermoplasma acidophilum. Two of these proteins, Q9HJ63_THEAC and Q2LQ23_SYNAS, contain two domains: an N-terminal thioredoxin-like α+β core domain (NTD) consisting of a five-stranded, mixed β-sheet flanked by several α-helices and a C-terminal zinc-finger domain (CTD). B8FYU2_DESHY, on the other hand, is composed solely of the NTD. The CTD of Q9HJ63_THEAC and Q2LQ23_SYNAS is best characterized as a treble-clef zinc finger. Two significant structural differences between Q9HJ63_THEAC and Q2LQ23_SYNAS involve their metal binding. First, zinc is bound to the putative active site on the NTD of Q9HJ63_THEAC, but is absent from the NTD of Q2LQ23_SYNAS. Second, whereas the structure of the CTD of Q2LQ23_SYNAS shows four Cys side chains within coordination distance of the Zn atom, the structure of Q9HJ63_THEAC is atypical for a treble-cleft zinc finger in that three Cys side chains and an Asp side chain are within coordination distance of the zinc.

Published
2010

34. The structure ofHaemophilus influenzaeprephenate dehydrogenase suggests unique features of bifunctional TyrA enzymes

Author

Andrew T. Morse, Mark W. Knuth, Debanu Das, Marc C. Deller, John Wooley, Daniel McMullan, Dennis Carlton, Lian Duan, Dana Weekes, Ron Reyes, Heath E. Klock, Joanna C Grant, Tamara Astakhova, Adam Godzik, Gye Won Han, Kevin K. Jin, Piotr Kozbial, Henry J Tien, Julie Feuerhelm, Polat Abdubek, Hsiu-Ju Chiu, Sanjay Krishna, Edward Nigoghossian, Herbert L. Axelrod, Keith O. Hodgson, Henry van den Bedem, Ian A. Wilson, Ashley M. Deacon, Marc André Elsliger, Scott A. Lesley, Christine B Trame, David Marciano, Abhinav Kumar, Lukasz Jaroszewski, Qingping Xu, Thomas Clayton, Mitchell D. Miller, Anna Grzechnik, and Linda Okach

Subjects
Ligands That Aid in Function Characterization, 1.1 Normal biological development and functioning, Biophysics, Isomerase, Crystallography, X-Ray, chorismate, Biochemistry, 03 medical and health sciences, Bacterial Proteins, Underpinning research, Multienzyme Complexes, Structural Biology, Oxidoreductase, Genetics, Tyrosine, 030304 developmental biology, Prephenate Dehydrogenase, Tyrosine binding, chemistry.chemical_classification, 0303 health sciences, Crystallography, biology, 030302 biochemistry & molecular biology, Active site, Prephenate dehydrogenase, structural genomics, Biological Sciences, Condensed Matter Physics, Haemophilus influenzae, tyrosine biosynthesis, 3. Good health, chemistry, Arogenate dehydrogenase, prephenate, Chemical Sciences, X-Ray, biology.protein, Chorismate mutase
Abstract

The crystal structure of the prephenate dehydrogenase component of the bifunctional H. influenzae TyrA reveals unique structural differences between bifunctional and monofunctional TyrA enzymes., Chorismate mutase/prephenate dehydrogenase from Haemophilus influenzae Rd KW20 is a bifunctional enzyme that catalyzes the rearrangement of chorismate to prephenate and the NAD(P)+-dependent oxidative decarboxyl­ation of prephenate to 4-hydroxyphenylpyruvate in tyrosine biosynthesis. The crystal structure of the prephenate dehydrogenase component (HinfPDH) of the TyrA protein from H. influenzae Rd KW20 in complex with the inhibitor tyrosine and cofactor NAD+ has been determined to 2.0 Å resolution. HinfPDH is a dimeric enzyme, with each monomer consisting of an N-terminal α/β dinucleotide-binding domain and a C-terminal α-helical dimerization domain. The structure reveals key active-site residues at the domain interface, including His200, Arg297 and Ser179 that are involved in catalysis and/or ligand binding and are highly conserved in TyrA proteins from all three kingdoms of life. Tyrosine is bound directly at the catalytic site, suggesting that it is a competitive inhibitor of HinfPDH. Comparisons with its structural homologues reveal important differences around the active site, including the absence of an α–β motif in HinfPDH that is present in other TyrA proteins, such as Synechocystis sp. arogenate dehydrogenase. Residues from this motif are involved in discrimination between NADP+ and NAD+. The loop between β5 and β6 in the N-terminal domain is much shorter in HinfPDH and an extra helix is present at the C-terminus. Furthermore, HinfPDH adopts a more closed conformation compared with TyrA proteins that do not have tyrosine bound. This conformational change brings the substrate, cofactor and active-site residues into close proximity for catalysis. An ionic network consisting of Arg297 (a key residue for tyrosine binding), a water molecule, Asp206 (from the loop between β5 and β6) and Arg365′ (from the additional C-terminal helix of the adjacent monomer) is observed that might be involved in gating the active site.

Published
2010
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35. Structure of a membrane-attack complex/perforin (MACPF) family protein from the human gut symbiontBacteroides thetaiotaomicron

Author

Keith O. Hodgson, Kyle Ellrott, Debanu Das, Qingping Xu, Tamara Astakhova, Winnie W Lam, Polat Abdubek, Sanjay Krishna, Mark W. Knuth, Hsiu-Ju Chiu, Andrew Yeh, Jiadong Zhou, Henry van den Bedem, Lukasz Jaroszewski, Thomas Clayton, Linda Okach, Mitchell D. Miller, Anna Grzechnik, Dennis Carlton, Gye Won Han, Heath E. Klock, Abhinav Kumar, Kevin K. Jin, Edward Nigoghossian, Adam Godzik, Christine B Trame, Carol L. Farr, Andrew T. Morse, Dana Weekes, Ron Reyes, Marc C. Deller, Joanna C Grant, Scott A. Lesley, Herbert L. Axelrod, Xiaohui Cai, Piotr Kozbial, Henry J Tien, David Marciano, John Wooley, Tiffany Wooten, Lian Duan, Constantina Bakolitsa, Marc André Elsliger, Connie Chen, Julie Feuerhelm, Ashley M. Deacon, Ian A. Wilson, Christina Puckett, and Amanda Nopakun

Subjects
Models, Molecular, Crystallography, X-Ray, Biochemistry, Protein structure, Models, Structural Biology, 2.2 Factors relating to the physical environment, Bacteroides, perforins, Aetiology, transmembrane pores, Peptide sequence, 0303 health sciences, MACPF, Crystallography, Human Gut Microbiome, biology, pathogenesis, 030302 biochemistry & molecular biology, Biological Sciences, Condensed Matter Physics, Transmembrane protein, Cell biology, Infection, Bacteroides thetaiotaomicron, Protein Structure, 1.1 Normal biological development and functioning, Molecular Sequence Data, Biophysics, Microbiology, 03 medical and health sciences, Bacterial Proteins, Underpinning research, Genetics, Amino Acid Sequence, Structural Homology, 030304 developmental biology, Perforin, Protein, Molecular, membrane-attack complexes, biology.organism_classification, Protein Structure, Tertiary, Structural Homology, Protein, Chemical Sciences, X-Ray, biology.protein, Complement membrane attack complex, Sequence Alignment, Tertiary
Abstract

The crystal structure of a novel MACPF protein, which may play a role in the adaptation of commensal bacteria to host environments in the human gut, was determined and analyzed., Membrane-attack complex/perforin (MACPF) proteins are transmembrane pore-forming proteins that are important in both human immunity and the virulence of pathogens. Bacterial MACPFs are found in diverse bacterial species, including most human gut-associated Bacteroides species. The crystal structure of a bacterial MACPF-domain-containing protein BT_3439 (Bth-MACPF) from B. thetaiotaomicron, a predominant member of the mammalian intestinal microbiota, has been determined. Bth-MACPF contains a membrane-attack complex/perforin (MACPF) domain and two novel C-terminal domains that resemble ribonuclease H and interleukin 8, respectively. The entire protein adopts a flat crescent shape, characteristic of other MACPF proteins, that may be important for oligomerization. This Bth-MACPF structure provides new features and insights not observed in two previous MACPF structures. Genomic context analysis infers that Bth-MACPF may be involved in a novel protein-transport or nutrient-uptake system, suggesting an important role for these MACPF proteins, which were likely to have been inherited from eukaryotes via horizontal gene transfer, in the adaptation of commensal bacteria to the host environment.

Published
2010
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36. A conserved fold for fimbrial components revealed by the crystal structure of a putative fimbrial assembly protein (BT1062) from Bacteroides thetaiotaomicron at 2.2 Å resolution

Author

Gye Won Han, Mark W. Knuth, Natasha Sefcovic, Marc André Elsliger, Tamara Astakhova, Marc C. Deller, Heath E. Klock, Carol L. Farr, Xiaohui Cai, Piotr Kozbial, Adam Godzik, Thomas Clayton, Edward Nigoghossian, Qingping Xu, Ian A. Wilson, Herbert L. Axelrod, Henry J Tien, Constantina Bakolitsa, Christine B Trame, Lian Duan, Dana Weekes, Debanu Das, Daniel McMullan, Amanda Nopakun, Christina Puckett, Keith O. Hodgson, Joanna C Grant, Ron Reyes, Kevin K. Jin, David Marciano, Connie Chen, Jiadong Zhou, Dennis Carlton, Abhinav Kumar, Kyle Ellrott, Lukasz Jaroszewski, Andrew Yeh, Tiffany Wooten, Andrew T. Morse, Polat Abdubek, Michelle Chiu, Henry van den Bedem, Linda Okach, Sanjay Krishna, John Wooley, Ashley M. Deacon, Hsiu-Ju Chiu, Mitchell D. Miller, Anna Grzechnik, Scott A. Lesley, and Julie Feuerhelm

Subjects
Models, Molecular, Protein Folding, Fimbria, Crystallography, X-Ray, Biochemistry, fimbriae, Pilus, Fimbriae Proteins, fluids and secretions, Structural Biology, Models, Bacteroides, Peptide sequence, 0303 health sciences, Crystallography, biology, Human Gut Microbiome, Bacterial, food and beverages, Biological Sciences, Condensed Matter Physics, pili, PG0179, Bacteroides thetaiotaomicron, Protein Structure, DUF1812, Mfa2, Molecular Sequence Data, Biophysics, Sequence alignment, digestive system, Fimbriae, 03 medical and health sciences, Genetics, Amino Acid Sequence, BT1062, Porphyromonas gingivalis, PGN0288, 030304 developmental biology, Structural Homology, 030306 microbiology, Protein, Molecular, biochemical phenomena, metabolism, and nutrition, biology.organism_classification, bacterial infections and mycoses, Protein Structure, Tertiary, carbohydrates (lipids), Structural Homology, Protein, Fimbriae, Bacterial, Chemical Sciences, X-Ray, bacteria, PF08842, Digestive Diseases, Sequence Alignment, Tertiary
Abstract

The crystal structure of BT1062 from Bacteroides thetaiotaomicron revealed a conserved fold that is widely adopted by fimbrial components., BT1062 from Bacteroides thetaiotaomicron is a homolog of Mfa2 (PGN0288 or PG0179), which is a component of the minor fimbriae in Porphyromonas gingivalis. The crystal structure of BT1062 revealed a conserved fold that is widely adopted by fimbrial components.

Published
2010

37. Crystal Structure of the First Eubacterial Mre11 Nuclease Reveals Novel Features that May Discriminate Substrates During DNA Repair

Author

Mitchell D. Miller, Anna Grzechnik, Heath E. Klock, Keith O. Hodgson, Linda Okach, Prasad Burra, Polat Abdubek, John Wooley, Debanu Das, Qingping Xu, Sanjay Krishna, Thomas Clayton, Abhinav Kumar, Henry van den Bedem, Ian A. Wilson, Gye Won Han, Dana Weekes, Davide Moiani, Lian Duan, Christopher L. Rife, Jessica Paulsen, Julie Feuerhelm, Tamara Astakhova, Mark W. Knuth, Marc C. Deller, Ashley M. Deacon, Marc André Elsliger, Scott A. Lesley, Slawomir K. Grzechnik, John A. Tainer, Andrew T. Morse, Daniel McMullan, Lukasz Jaroszewski, Dennis Carlton, Edward Nigoghossian, Christine B Trame, David Marciano, Herbert L. Axelrod, Natasha Sefcovic, Hsiu-Ju Chiu, Joanna C Grant, Adam Godzik, Ron Reyes, Piotr Kozbial, Henry J Tien, Kevin K. Jin, and Dustin C. Ernst

Subjects
Exonuclease, DNA Repair, Protein Conformation, DNA repair, Molecular Sequence Data, DNA, Single-Stranded, Crystallography, X-Ray, Article, chemistry.chemical_compound, Bacterial Proteins, Structural Biology, Hydrolase, Thermotoga maritima, Amino Acid Sequence, Molecular Biology, Nuclease, Endodeoxyribonucleases, Sequence Homology, Amino Acid, biology, DNA, biology.organism_classification, enzymes and coenzymes (carbohydrates), DNA/RNA non-specific endonuclease, Exodeoxyribonucleases, Models, Chemical, chemistry, Biochemistry, biology.protein, Micrococcal nuclease
Abstract

Mre11 nuclease plays a central role in the repair of cytotoxic and mutagenic DNA double-strand breaks. As X-ray structural information has been available only for the Pyrococcus furiosus enzyme (PfMre11), the conserved and variable features of this nuclease across the domains of life have not been experimentally defined. Our crystal structure and biochemical studies demonstrate that TM1635 from Thermotoga maritima, originally annotated as a putative nuclease, is an Mre11 endo/exonuclease (TmMre11) and the first such structure from eubacteria. TmMre11 and PfMre11 display similar overall structures, despite sequence identity in the twilight zone of only approximately 20%. However, they differ substantially in their DNA-specificity domains and in their dimeric organization. Residues in the nuclease domain are highly conserved, but those in the DNA-specificity domain are not. The structural differences likely affect how Mre11 from different organisms recognize and interact with single-stranded DNA, double-stranded DNA and DNA hairpin structures during DNA repair. The TmMre11 nuclease active site has no bound metal ions, but is conserved in sequence and structure with the exception of a histidine that is important in PfMre11 nuclease activity. Nevertheless, biochemical characterization confirms that TmMre11 possesses both endonuclease and exonuclease activities on single-stranded and double-stranded DNA substrates, respectively.

Published
2010
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38. The structure of SSO2064, the first representative of Pfam family PF01796, reveals a novel two-domain zinc-ribbon OB-fold architecture with a potential acyl-CoA-binding role

Author

Polat Abdubek, Sanjay Krishna, Mark W. Knuth, Adam Godzik, Jonathan M. Caruthers, Linda Okach, Christopher L. Rife, Marc-André Elsliger, Edward Nigoghossian, David Marciano, Tamara Astakhova, L Aravind, Marc C. Deller, Andrew T. Morse, Kevin K. Jin, Lukasz Jaroszewski, Henry van den Bedem, Joanna C Grant, Daniel McMullan, Mitchell D. Miller, Ashley M. Deacon, Abhinav Kumar, Ron Reyes, Keith O. Hodgson, Ian A. Wilson, Constantina Bakolitsa, Scott A. Lesley, Lian Duan, Gye Won Han, Qingping Xu, John Wooley, Hsiu-Ju Chiu, Herbert L. Axelrod, Thomas Clayton, Heath E. Klock, Julie Feuerhelm, Dana Weekes, and Dennis Carlton

Subjects
Models, Molecular, Protein Folding, Domains of Unknown Function, acyl-coA, Plasma protein binding, Crystallography, X-Ray, Biochemistry, Protein structure, Models, Genome, Archaeal, Structural Biology, Acyl-CoA-binding protein, 2.1 Biological and endogenous factors, Aetiology, Peptide sequence, 0303 health sciences, Crystallography, Genome, 030302 biochemistry & molecular biology, Biological Sciences, Condensed Matter Physics, Zinc, Sulfolobus solfataricus, polyketide biosynthesis, Protein folding, Biotechnology, Protein Binding, Protein Structure, 1.1 Normal biological development and functioning, Archaeal Proteins, Molecular Sequence Data, Biophysics, Biology, acyl-carrier proteins, Structural genomics, 03 medical and health sciences, Polyketide, Underpinning research, Genetics, Amino Acid Sequence, 030304 developmental biology, Oligonucleotide, Molecular, structural genomics, Protein Structure, Tertiary, Archaeal, Chemical Sciences, X-Ray, Acyl Coenzyme A, Tertiary
Abstract

The crystal structure of SSO2064, the first structural representative of Pfam family PF01796 (DUF35), reveals a two-domain architecture comprising an N-terminal zinc-ribbon domain and a C-terminal OB-fold domain. Analysis of the domain architecture, operon organization and bacterial orthologs combined with the structural features of SSO2064 suggests a role involving acyl-CoA binding for this family of proteins., SSO2064 is the first structural representative of PF01796 (DUF35), a large prokaryotic family with a wide phylogenetic distribution. The structure reveals a novel two-domain architecture comprising an N-terminal, rubredoxin-like, zinc ribbon and a C-terminal, oligonucleotide/oligosaccharide-binding (OB) fold domain. Additional N-terminal helical segments may be involved in protein–protein interactions. Domain architectures, genomic context analysis and functional evidence from certain bacterial representatives of this family suggest that these proteins form a novel fatty-acid-binding component that is involved in the biosynthesis of lipids and polyketide antibiotics and that they possibly function as acyl-CoA-binding proteins. This structure has led to a re-evaluation of the DUF35 family, which has now been split into two entries in the latest Pfam release (v.24.0).

Published
2010
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39. Structures of the first representatives of Pfam family PF06938 (DUF1285) reveal a new fold with repeated structural motifs and possible involvement in signal transduction

Author

Hope A. Johnson, Joanna C Grant, Marc C. Deller, Polat Abdubek, Keith O. Hodgson, Sanjay Krishna, Debanu Das, Qingping Xu, Mark W. Knuth, John Wooley, Abhinav Kumar, Constantina Bakolitsa, Linda Okach, Tamara Astakhova, Christopher L. Rife, Christine B Trame, Mitchell D. Miller, Anna Grzechnik, Ashley M. Deacon, Ron Reyes, David Marciano, Lian Duan, Daniel McMullan, Henry van den Bedem, Julie Feuerhelm, Hsiu-Ju Chiu, Connie Chen, Natasha Sefcovic, Piotr Kozbial, Dana Weekes, Henry J Tien, Marc-André Elsliger, Ian A. Wilson, Heath E. Klock, Herbert L. Axelrod, Edward Nigoghossian, Thomas Clayton, Kevin K. Jin, Dustin C. Ernst, Dennis Carlton, Adam Godzik, Gye Won Han, Andrew T. Morse, Scott A. Lesley, Rafael Najmanovich, and Lukasz Jaroszewski

Subjects
Models, Molecular, Secondary, Protein Folding, Shewanella, domain duplication, Crystallography, X-Ray, Biochemistry, Protein Structure, Secondary, domain of unknown function, Protein structure, Models, Structural Biology, 2.1 Biological and endogenous factors, oxidative stress, Aetiology, Rhodobacteraceae, Structural motif, Genetics, 0303 health sciences, Crystallography, Genome, 030302 biochemistry & molecular biology, Bacterial, Biological Sciences, Condensed Matter Physics, Pleckstrin homology domain, Protein folding, Domain of unknown function, New Folds, signaling, Biotechnology, Protein Structure Initiative, Signal Transduction, Protein Structure, 1.1 Normal biological development and functioning, Molecular Sequence Data, Biophysics, Biology, Structural genomics, 03 medical and health sciences, Bacterial Proteins, Underpinning research, Amino Acid Sequence, Binding site, Structural Homology, 030304 developmental biology, Protein, Human Genome, Molecular, structural genomics, Protein Structure, Tertiary, Structural Homology, Protein, Chemical Sciences, X-Ray, Generic health relevance, Tertiary, Genome, Bacterial
Abstract

The crystal structures of SPO0140 and Sbal_2486 revealed a two-domain structure that adopts a novel fold. Analysis of the interdomain cleft suggests a nucleotide-based ligand with a genome context indicating signaling as a possible role for this family., The crystal structures of SPO0140 and Sbal_2486 were determined using the semiautomated high-throughput pipeline of the Joint Center for Structural Genomics (JCSG) as part of the NIGMS Protein Structure Initiative (PSI). The structures revealed a conserved core with domain duplication and a superficial similarity of the C-terminal domain to pleckstrin homology-like folds. The conservation of the domain interface indicates a potential binding site that is likely to involve a nucleotide-based ligand, with genome-context and gene-fusion analyses additionally supporting a role for this family in signal transduction, possibly during oxidative stress.

Published
2010

40. The structure of the first representative of Pfam family PF09836 reveals a two-domain organization and suggests involvement in transcriptional regulation

Author

Christopher L. Rife, Kyle Ellrott, Linda Okach, Dustin C. Ernst, Prasad Burra, Dana Weekes, Edward Nigoghossian, Polat Abdubek, Gye Won Han, Silvya Oommachen, Piotr Kozbial, John Wooley, Jessica Paulsen, Henry J Tien, Slawomir K. Grzechnik, Sanjay Krishna, Amanda Nopakun, Julie Feuerhelm, Abhinav Kumar, Henry van den Bedem, Lian Duan, Mark W. Knuth, Marc C. Deller, Tamara Astakhova, Michelle Chiu, Heath E. Klock, Carol L. Farr, Hsiu-Ju Chiu, Connie Chen, Joanna C Grant, Ron Reyes, Daniel McMullan, Tiffany Wooten, Ashley M. Deacon, Nick V. Grishin, Constantina Bakolitsa, Mitchell D. Miller, Anna Grzechnik, Ian A. Wilson, Christina Puckett, Thomas Clayton, Marc André Elsliger, Andrew T. Morse, Dennis Carlton, Adam Godzik, Herbert L. Axelrod, Keith O. Hodgson, Kevin K. Jin, Scott A. Lesley, Christine B Trame, David Marciano, Hope A. Johnson, Natasha Sefcovic, Qingping Xu, Lukasz Jaroszewski, and Debanu Das

Subjects
Models, Molecular, Transcription, Genetic, Domains of Unknown Function, Crystallography, X-Ray, medicine.disease_cause, Biochemistry, putative transcription regulators, Models, Structural Biology, Transcription (biology), Transcriptional regulation, Peptide sequence, Genetics, Regulation of gene expression, 0303 health sciences, Crystallography, Genome, PF09836, 030302 biochemistry & molecular biology, Bacterial, Biological Sciences, Condensed Matter Physics, Neisseria, Transcription, Protein Structure, 1.1 Normal biological development and functioning, Molecular Sequence Data, Biophysics, Biology, Structural genomics, Quaternary, DUF2063, 03 medical and health sciences, Genetic, Bacterial Proteins, Underpinning research, medicine, Amino Acid Sequence, putative DNA-binding proteins, Protein Structure, Quaternary, Structural Homology, 030304 developmental biology, Protein, NGO1945, Molecular, structural genomics, biology.organism_classification, Neisseria gonorrhoeae, Sequence identity, Protein Structure, Tertiary, Gene Expression Regulation, Structural Homology, Protein, Chemical Sciences, X-Ray, Tertiary, Genome, Bacterial
Abstract

The crystal structure of the NGO1945 gene product from N. gonorrhoeae (UniProt Q5F5IO) reveals that the N-terminal domain assigned as a domain of unknown function (DUF2063) is likely to bind DNA and that the protein may be involved in transcriptional regulation., Proteins with the DUF2063 domain constitute a new Pfam family, PF09836. The crystal structure of a member of this family, NGO1945 from Neisseria gonorrhoeae, has been determined and reveals that the N-terminal DUF2063 domain is likely to be a DNA-binding domain. In conjunction with the rest of the protein, NGO1945 is likely to be involved in transcriptional regulation, which is consistent with genomic neighborhood analysis. Of the 216 currently known proteins that contain a DUF2063 domain, the most significant sequence homologs of NGO1945 (∼40–99% sequence identity) are from various Neisseria and Haemophilus species. As these are important human pathogens, NGO1945 represents an interesting candidate for further exploration via biochemical studies and possible therapeutic intervention.

Published
2009
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41. Structure of LP2179, the first representative of Pfam family PF08866, suggests a new fold with a role in amino-acid metabolism

Author

Polat Abdubek, Keith O. Hodgson, Sanjay Krishna, Henry van den Bedem, Mitchell D. Miller, Herbert L. Axelrod, Dana Weekes, Marc C. Deller, Constantina Bakolitsa, Joanna C Grant, Mark W. Knuth, Heath E. Klock, Tamara Astakhova, Julie Feuerhelm, Abhinav Kumar, Marc-André Elsliger, Edward Nigoghossian, Daniel McMullan, Gye Won Han, Lian Duan, Silvya Oommachen, Thomas Clayton, Christina V. Trout, Qingping Xu, Christopher L. Rife, Kevin K. Jin, Lukasz Jaroszewski, Andrew T. Morse, Hsiu-Ju Chiu, Dennis Carlton, Jessica Paulsen, David Marciano, Ashley M. Deacon, Ian A. Wilson, Piotr Kozbial, Henry J Tien, Ron Reyes, Adam Godzik, Scott A. Lesley, Slawomir K. Grzechnik, John Wooley, and Linda Okach

Subjects
Models, Molecular, S-adenosylmethionine decarboxylase, Protein Folding, Crystallography, X-Ray, Biochemistry, Protein structure, Models, Structural Biology, Amino Acids, Peptide sequence, chemistry.chemical_classification, 0303 health sciences, Crystallography, 030302 biochemistry & molecular biology, Biological Sciences, Condensed Matter Physics, Amino acid, DUFs, Protein folding, New Folds, Biotechnology, Protein Structure, Protein family, Structural similarity, Molecular Sequence Data, Biophysics, Sequence alignment, Computational biology, Biology, Structural genomics, 03 medical and health sciences, Bacterial Proteins, Genetics, Amino Acid Sequence, Structural Homology, 030304 developmental biology, amino-acid metabolism, Protein, Human Genome, Molecular, structural genomics, Protein Structure, Tertiary, probiotics, chemistry, Structural Homology, Protein, Chemical Sciences, X-Ray, Sequence Alignment, Tertiary, Lactobacillus plantarum
Abstract

The first structural representative of the PF08866 (DUF1831) protein family reveals a potential new α+β fold and indicates a possible involvement in amino-acid metabolism., The structure of LP2179, a member of the PF08866 (DUF1831) family, suggests a novel α+β fold comprising two β-sheets packed against a single helix. A remote structural similarity to two other uncharacterized protein families specific to the Bacillus genus (PF08868 and PF08968), as well as to prokaryotic S-adenosylmethionine decarboxylases, is consistent with a role in amino-acid metabolism. Genomic neighborhood analysis of LP2179 supports this functional assignment, which might also then be extended to PF08868 and PF08968.

Published
2009
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42. The structure of KPN03535 (gi|152972051), a novel putative lipoprotein from Klebsiella pneumoniae, reveals an OB-fold

Author

Thomas Clayton, Debanu Das, John Wooley, Marc-André Elsliger, Heath E. Klock, Polat Abdubek, Edward Nigoghossian, Marc C. Deller, Carol L. Farr, Christopher L. Rife, Sanjay Krishna, Linda Okach, Abhinav Kumar, Mark W. Knuth, Constantina Bakolitsa, Tamara Astakhova, Joanna C Grant, Adam Godzik, Kyle Ellrott, Scott A. Lesley, Qingping Xu, Hsiu-Ju Chiu, Lian Duan, Ron Reyes, Daniel McMullan, Mitchell D. Miller, Dustin C. Ernst, Dana Weekes, Anna Grzechnik, Andrew T. Morse, Gye Won Han, Julie Feuerhelm, Silvya Oommachen, Piotr Kozbial, Henry van den Bedem, Henry J Tien, Jessica Paulsen, Tiffany Wooten, Kevin K. Jin, Ashley M. Deacon, Ian A. Wilson, Christina Puckett, Keith O. Hodgson, Michelle Chiu, Amanda Nopakun, Herbert L. Axelrod, Lukasz Jaroszewski, Natasha Sefcovic, Christine B Trame, Connie Chen, David Marciano, Hope A. Johnson, and Dennis Carlton

Subjects
Models, Molecular, Protein Folding, Klebsiella pneumoniae, Gut flora, Crystallography, X-Ray, Biochemistry, Protein structure, Models, Structural Biology, BOF, 2.1 Biological and endogenous factors, Aetiology, Lung, Peptide sequence, 0303 health sciences, Crystallography, biology, 030302 biochemistry & molecular biology, toxins, Hematology, Biological Sciences, Condensed Matter Physics, 3. Good health, Infectious Diseases, Pneumonia & Influenza, Protein folding, Infection, Protein Structure, 1.1 Normal biological development and functioning, Lipoproteins, Molecular Sequence Data, Biophysics, single-stranded DNA-binding proteins, DNA-binding protein, Structural genomics, Microbiology, 03 medical and health sciences, Bacterial Proteins, Underpinning research, Genetics, Amino Acid Sequence, 030304 developmental biology, Molecular, Pneumonia, structural genomics, biology.organism_classification, Protein Structure, Tertiary, NipE-like protein, Chemical Sciences, X-Ray, human gut pathogens, OB-fold, Novel Variants of Known Folds and Function, Tertiary, Lipoprotein
Abstract

KPN03535 is a protein unique to K. pneumoniae. The crystal structure reveals that KPN03535 represents a novel variant of the OB-fold and is likely to be a DNA-binding lipoprotein., KPN03535 (gi|152972051) is a putative lipoprotein of unknown function that is secreted by Klebsiella pneumoniae MGH 78578. The crystal structure reveals that despite a lack of any detectable sequence similarity to known structures, it is a novel variant of the OB-fold and structurally similar to the bacterial Cpx-pathway protein NlpE, single-stranded DNA-binding (SSB) proteins and toxins. K. pneumoniae MGH 78578 forms part of the normal human skin, mouth and gut flora and is an opportunistic pathogen that is linked to about 8% of all hospital-acquired infections in the USA. This structure provides the foundation for further investigations into this divergent member of the OB-fold family.

Published
2009

43. The structure of the first representative of Pfam family PF06475 reveals a new fold with possible involvement in glycolipid metabolism

Author

Edward Nigoghossian, Keith O. Hodgson, Mitchell D. Miller, Gye Won Han, Christopher L. Rife, Dennis Carlton, Aprilfawn White, Thomas Clayton, Abhinav Kumar, Silvya Oommachen, Scott A. Lesley, Daniel McMullan, Hsiu-Ju Chiu, Christina V. Trout, Henry van den Bedem, Jessica Paulsen, Linda Okach, Piotr Kozbial, Slawomir K. Grzechnik, Kevin K. Jin, Polat Abdubek, Dana Weekes, Adam Godzik, Ron Reyes, Marc André Elsliger, Ylva Elias, Sanjay Krishna, David Marciano, Andrew T. Morse, Joanna C Grant, Ashley M. Deacon, Ian A. Wilson, Mark W. Knuth, Tamara Astakhova, Rafael Najmanovich, Lian Duan, Julie Feuerhelm, Marc C. Deller, Constantina Bakolitsa, Qingping Xu, John Wooley, Heath E. Klock, and Lukasz Jaroszewski

Subjects
Models, Molecular, glycolipids, Protein Folding, Glycolipid metabolism, Crystallography, X-Ray, Biochemistry, Models, Structural Biology, 2.2 Factors relating to the physical environment, 2.1 Biological and endogenous factors, Aetiology, Peptide sequence, 0303 health sciences, Crystallography, Genome, 030302 biochemistry & molecular biology, Bacterial, food and beverages, Biological Sciences, Condensed Matter Physics, DUFs, Pseudomonas aeruginosa, Protein folding, lipids (amino acids, peptides, and proteins), New Folds, host–pathogen interactions, Protein Structure, Structural similarity, Molecular Sequence Data, Biophysics, Biology, Structural genomics, Quaternary, 03 medical and health sciences, Glycolipid, Bacterial Proteins, Genetics, Amino Acid Sequence, Protein Structure, Quaternary, 030304 developmental biology, A domain, Molecular, structural genomics, Protein Structure, Tertiary, Lipoprotein localization, Chemical Sciences, X-Ray, osmotic stress, Glycolipids, Tertiary, Genome, Bacterial
Abstract

PA1994, a Pfam PF06475 (DUF1089) family homolog from P. aeruginosa, reveals remote similarities to lipoprotein localization factors and a conserved putative glycolipid-binding site., The crystal structure of PA1994 from Pseudomonas aeruginosa, a member of the Pfam PF06475 family classified as a domain of unknown function (DUF1089), reveals a novel fold comprising a 15-stranded β-sheet wrapped around a single α-helix that assembles into a tight dimeric arrangement. The remote structural similarity to lipoprotein localization factors, in addition to the presence of an acidic pocket that is conserved in DUF1089 homologs, phospholipid-binding and sugar-binding proteins, indicate a role for PA1994 and the DUF1089 family in glycolipid metabolism. Genome-context analysis lends further support to the involvement of this family of proteins in glycolipid metabolism and indicates possible activation of DUF1089 homologs under conditions of bacterial cell-wall stress or host–pathogen interactions.

Published
2009

44. Crystal Structure of Histidine Phosphotransfer Protein ShpA, an Essential Regulator of Stalk Biogenesis in Caulobacter crescentus

Author

Marc C. Deller, Adam Godzik, Mark W. Knuth, Kevin K. Jin, Joanna C Grant, Ron Reyes, Ylva Elias, Henry van den Bedem, Andrew T. Morse, Linda Okach, Mitchell D. Miller, Anna Grzechnik, Keith O. Hodgson, Christopher L. Rife, Hsiu-Ju Chiu, Piotr Kozbial, Prasad Burra, Lian Duan, Heath E. Klock, Tamara Astakhova, Julie Feuerhelm, Jessica Paulsen, Abhinav Kumar, Thomas Clayton, Marc André Elsliger, Dana Weekes, Christina V. Trout, Gye Won Han, Edward Nigoghossian, Silvya Oommachen, Daniel McMullan, John Wooley, Polat Abdubek, Sanjay Krishna, Dennis Carlton, Natasha Sefcovic, Lukasz Jaroszewski, Qingping Xu, Christine B Trame, David Marciano, Ian A. Wilson, Scott A. Lesley, Ashley M. Deacon, and Slawomir K. Grzechnik

Subjects
Models, Molecular, Helix bundle, biology, Protein Conformation, Caulobacter crescentus, Molecular Sequence Data, Phosphotransferases, Histidine kinase, Crystallography, X-Ray, biology.organism_classification, Article, Response regulator, Protein structure, Bacterial Proteins, Biochemistry, Structural Biology, Phosphorylation, Histidine, Amino Acid Sequence, Molecular Biology, Biogenesis
Abstract

Cell cycle regulated stalk biogenesis in Caulobacter crescentus is controlled by a multi-step phosphorelay system consisting of the hybrid histidine kinase ShkA, the histidine-phosphotransfer protein ShpA and the response regulator TacA. ShpA shuttles phosphoryl groups between ShkA and TacA. When phosphorylated, TacA triggers a downstream transcription cascade for stalk synthesis in an RpoN-dependent manner. The crystal structure of ShpA was determined to 1.52 Å resolution. ShpA belongs to a family of monomeric histidine phosphotransfer (HPt) proteins, which feature a highly conserved four-helix bundle. The phosphorylatable histidine, His56, is located on the surface of the helix bundle and is fully solvent exposed. One end of the four-helix bundle in ShpA is shorter compared to other characterized histidine phosphotransfer proteins, whereas the face that potentially interacts with the response regulators is structurally conserved. Similarities of the interaction surface around the phosphorylation site suggest that ShpA is likely to share a common mechanism for molecular recognition and phosphotransfer with yeast phosphotransfer protein YPD1 despite low overall sequence similarity.

Published
2009
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45. Introducing Giovanni Gentile, the ‘Philosopher of Fascism’

Author

Thomas Clayton

Subjects
Scholarship, Politics, History and Philosophy of Science, Criticism, Sociology, Philosophy of education, Education, Epistemology
Abstract

This essay aims to introduce Giovanni Gentile to scholars of Gramsci studies broadly and Gramsci‐education studies more specifically. The largest part of the essay explores Gentile's academic life, his philosophical agenda, and his political career. Having established a basis for understanding the educational reform Gentile enacted as Mussolini's first Minister of Public Instruction, the essay then surveys the substantial contemporaneous and contemporary English‐language material about it. The essay engages this literature only lightly and briefly in conclusion, for the primary purpose of illustrating the danger of eschewing it.

Published
2009
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46. Crystal structure of a novel Sm-like protein of putative cyanophage origin at 2.60 Å resolution

Author

Lukasz Jaroszewski, Ashley M. Deacon, Julie Feuerhelm, Hsiu-Ju Chiu, Debanu Das, Dana Weekes, Jessica Paulsen, Qingping Xu, Marc C. Deller, Piotr Kozbial, Ian A. Wilson, Christina Puckett, Gye Won Han, Silvya Oommachen, Abhinav Kumar, Marc André Elsliger, Amanda Nopakun, Natasha Sefcovic, Linda Okach, Edward Nigoghossian, Herbert L. Axelrod, Keith O. Hodgson, Dennis Carlton, Scott A. Lesley, Mark W. Knuth, Heath E. Klock, Henry Tien, Carol L. Farr, Kevin D. Murphy, Hope A. Johnson, Slawomir K. Grzechnik, Kevin K. Jin, Henry van den Bedem, Ylva Elias, Adam Godzik, Dustin C. Ernst, Tamara Astakhova, Andrew T. Morse, Aprilfawn White, Thomas Clayton, John Wooley, Connie Chen, Christine B Trame, Daniel McMullan, Christina V. Trout, Joanna Hale, Ron Reyes, Claire Acosta, David Marciano, Polat Abdubek, Lian Duan, Sanjay Krishna, Christopher L. Rife, Prasad Burra, Sebastian Sudek, Mitchell D. Miller, and Anna Grzechnik

Subjects
Genetics, Viral protein, RNA, Cyanophage, RNA-binding protein, Biology, medicine.disease_cause, Biochemistry, Structural genomics, Protein structure, Structural Biology, Nucleic acid, medicine, Molecular Biology, Peptide sequence
Abstract

ECX21941 represents a very large family (over 600 members) of novel, ocean metagenome-specific proteins identified by clustering of the dataset from the Global Ocean Sampling expedition. The crystal structure of ECX21941 reveals unexpected similarity to Sm/LSm proteins, which are important RNA-binding proteins, despite no detectable sequence similarity. The ECX21941 protein assembles as a homopentamer in solution and in the crystal structure when expressed in Escherichia coli and represents the first pentameric structure for this Sm/LSm family of proteins, although the actual oligomeric form in vivo is currently not known. The genomic neighborhood analysis of ECX21941 and its homologs combined with sequence similarity searches suggest a cyanophage origin for this protein. The specific functions of members of this family are unknown, but our structure analysis of ECX21941 indicates nucleic acid-binding capabilities and suggests a role in RNA and/or DNA processing.

Published
2008
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47. Crystal structure of the Fic (Filamentation induced by cAMP) family protein SO4266 (gi|24375750) from Shewanella oneidensis MR-1 at 1.6 Å resolution

Author

Henry Tien, Keith O. Hodgson, Aprilfawn White, Linda Okach, Tamara Astakhova, Marc-André Elsliger, Qingping Xu, Edward Nigoghossian, Julie Feuerhelm, Kevin K. Jin, Dustin C. Ernst, Andrew T. Morse, Christine B Trame, Henry van den Bedem, Slawomir K. Grzechnik, Prasad Burra, Abhinav Kumar, Hsiu-Ju Chiu, Herbert L. Axelrod, Heath E. Klock, Thomas Clayton, David Marciano, Polat Abdubek, Gye Won Han, Marc C. Deller, Dennis Carlton, Christina V. Trout, Joanna Hale, Silvya Oommachen, Ashley M. Deacon, Natasha Sefcovic, Debanu Das, Scott A. Lesley, Sanjay Krishna, Lukasz Jaroszewski, Ylva Elias, Ian A. Wilson, Mitchell D. Miller, Anna Grzechnik, Christopher L. Rife, Daniel McMullan, John Wooley, Claire Acosta, Piotr Kozbial, Kevin D. Murphy, Mark W. Knuth, Adam Godzik, Dana Weekes, Lian Duan, Ron Reyes, and Jessica Paulsen

Subjects
Shewanella, Protein family, Protein Conformation, Protein subunit, Amino Acid Motifs, Molecular Sequence Data, Protein Data Bank (RCSB PDB), Biology, Crystallography, X-Ray, Biochemistry, DNA-binding protein, Article, Structural genomics, Protein structure, Bacterial Proteins, Structural Biology, Amino Acid Sequence, Molecular Biology, DNA, DNA-binding domain, computer.file_format, Protein Data Bank, Protein Structure, Tertiary, Dimerization, computer, Protein Binding
Abstract

The protein SO4266 (gi|24375750) from the bacterium Shewanella oneidensis MR-1 is annotated as a member of Pfam PF02661. This family consists of Fic (filamentation induced by cAMP) proteins and their relatives, and is characterized by the presence of a well-conserved HPFXXGNG motif 1. The biochemistry of Fic proteins has not been characterized extensively and their exact molecular functions remain unknown. From early studies in Escherichia coli, it is believed that Fic proteins and cAMP may be involved in a regulatory mechanism of cell division, including folate metabolism by the synthesis of p-aminobenzoic acid (PABA) or folate 1. Proteins containing the Fic domain are present in all kingdoms of life and range in size from ~200 to 500 amino acids. The Fic protein family contains 647 members, including two human proteins, according to Pfam (May 2008). Sequence-based clustering 2 of this protein family, at 30% sequence identity, groups these proteins into 18 clusters. Three crystal structures of Fic proteins from bacteria (unpublished) are available in the Protein Data Bank [accession codes 2g03 (194 residues, 2.2 A), 2f6s (201 residues, 2.5 A) and 3cuc (262 residues, 2.7 A)]. The first two of these proteins belong to a single cluster of 16 members and share ~60% sequence identity. The anti-apoptotic bacterial effector protein BepA, which is a type IV secretion (T4S) system substrate, also contains an N-terminal Fic domain 3. In humans, the Fic domain is present in the Huntingtin Interacting Protein E (HYPE; Uniprot entry Q9BVA6_HUMAN), a protein of unknown function that is thought to interact with Huntingtin, one of the major proteins in the Huntington's disease protein interaction network (listed as NAD- or FAD-binding) 4. Bioinformatics analysis of prokaryotic toxin-antitoxin networks 5 suggests that Fic proteins are putative death-on-curing (Doc) toxins that are part of the Phd-Doc system. These proteins likely function as metal-dependent nucleases or RNA-processing enzymes, 5 while more recent studies suggest that Doc toxicity is caused by inhibition of translation elongation 6. SO4266 (Uniprot entry Q8E9K5_SHEON), at 372 amino acids, is one of the largest Fic domain-containing proteins to have its structure determined. Interestingly, both HYPE and SO4266 belong to the largest sequence cluster in this family (n.b. our B. thetaiotaomicron {"type":"entrez-protein","attrs":{"text":"NP_811426.1","term_id":"29347923","term_text":"NP_811426.1"}}NP_811426.1 structure with PDB id 3cuc also belongs to this cluster), which comprises 466 out of 647 proteins, and share ~32% sequence identity in the Fic domain. Here, we report the crystal structure of the SO4266 protein at 1.6 A resolution. The structure reveals a dimeric protein with additional electron density in the vicinity of the highly conserved HPFXXGNG motif in the Fic domain of one subunit that corresponds to the N-terminus of a symmetry-related molecule. In addition, the study also reveals a C-terminal winged-helix DNA-binding domain that sets it apart from the other Fic protein structures. The structure presented here is a representative of the largest sequence cluster and together with the structures of the other Fic proteins paves the way for further structure-based functional characterization.

Published
2008
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48. Crystal structure of a novel archaeal AAA+ ATPase SSO1545 from Sulfolobus solfataricus

Author

John Wooley, Mark W. Knuth, Ashley M. Deacon, Lukasz Jaroszewski, Ian A. Wilson, Thomas Clayton, Hsiu-Ju Chiu, Lian Duan, Abhinav Kumar, Adam Godzik, Scott A. Lesley, Gye Won Han, Kevin K. Jin, Marc-André Elsliger, Joanna Hale, Silvya Oommachen, Edward Nigoghossian, Keith O. Hodgson, Heath E. Klock, Slawomir K. Grzechnik, Qingping Xu, Julie Feuerhelm, Mitchell D. Miller, Henry van den Bedem, Dennis Carlton, Christopher L. Rife, Ron Reyes, Andrew T. Morse, Jessica Paulsen, Linda Okach, Tamara Astakhova, Daniel McMullan, Polat Abdubek, and Sanjay Krishna

Subjects
ved/biology, Sulfolobus solfataricus, ved/biology.organism_classification_rank.species, Biology, Biochemistry, AAA proteins, Structural genomics, Protein structure, Structural Biology, NAIP, Sequence motif, Molecular Biology, Peptide sequence, Protein Structure Initiative
Abstract

Signal transduction ATPases with numerous domains (STAND), a large class of P-loop NTPases, belong to AAA+ ATPases. They include AP(apoptotic)-ATPases (e.g., animal apoptosis regulators CED4/Apaf-1, plant disease resistance proteins, and bacterial AfsR-like transcription regulators), NACHT NTPases (e.g. CARD4, NAIP, Het-E-1, TLP1), and several other less well-characterized families. STAND differ from other P-loop NTPases by their unique sequence motifs, which include an hhGRExE (h, hydrophobic; x, any residue) motif at the N-terminal region, a GxP/GxxP motif at the C-terminal region of the NTPase domain, in addition to a C-terminal helical domain and additional domains such as WD40, TPR, LRR or catalytic modules. Despite significant biological interests, structural coverage of STAND proteins is very limited and only two other structures are currently known: the cell death regulators Apaf-1 and CED-4. Here, we report the crystal structure of SSO1545 from Sulfolobus solfataricus, which was determined using the semi-automated, high-throughput pipeline of the Joint Center for Structural Genomics (JCSG; http://www.jcsg.org), as part of the National Institute of General Medical Sciences' Protein Structure Initiative (PSI). SSO1545 (NP-342973.1), a representative of the archaeal STANDs, is a member of Pfam PF01637 and encodes a protein of 356 residues with calculated molecular weight and isoelectric point of 41.7more » kD and 8.2, respectively.« less

Published
2008
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49. Crystal structures of MW1337R and lin2004: Representatives of a novel protein family that adopt a four-helical bundle fold

Author

Abhinav Kumar, Ron Reyes, Henry van den Bedem, Marc André Elsliger, Aprilfawn White, Scott A. Lesley, Ian A. Wilson, Keith O. Hodgson, Guenter Wolf, Linda Okach, David Marciano, Edward Nigoghossian, Piotr Kozbial, Christopher L. Rife, Chloe Zubieta, Ylva Elias, Eric Koesema, Ashley M. Deacon, Glen Spraggon, Kevin K. Jin, Kevin D. Murphy, Herbert L. Axelrod, Hsiu-Ju Chiu, Andrew T. Morse, Mitchell D. Miller, Dennis Carlton, Mark W. Knuth, Adam Godzik, Gye Won Han, Silvya Oommachen, John Wooley, Thomas Clayton, Christina V. Trout, Dana Weekes, Lian Duan, Daniel McMullan, Joanna Hale, Tamara Astakhova, Polat Abdubek, Sanjay Krishna, Claire Acosta, Slawomir K. Grzechnik, Lukasz Jaroszewski, Julie Feuerhelm, Marc C. Deller, Qingping Xu, and Heath E. Klock

Subjects
Genetics, Protein Folding, Accession number (library science), Operon, Molecular Sequence Data, Bacillus subtilis, Biology, Crystallography, X-Ray, biology.organism_classification, Biochemistry, Protein Structure, Secondary, Protein Structure, Tertiary, Structural genomics, chemistry.chemical_compound, Protein structure, Bacterial Proteins, chemistry, Structural Biology, Complementary DNA, Amino Acid Sequence, Molecular Biology, Gene, DNA
Abstract

To extend the structural coverage of proteins with unknown functions, we targeted a novel protein family (Pfam accession number PF08807, DUF1798) for which we proposed and determined the structures of two representative members. The MW1337R gene of Staphylococcus aureus subsp. aureus Rosenbach (Wood 46) encodes a protein with a molecular weight of 13.8 kDa (residues 1-116) and a calculated isoelectric point of 5.15. The lin2004 gene of the nonspore-forming bacterium Listeria innocua Clip11262 encodes a protein with a molecular weight of 14.6 kDa (residues 1-121) and a calculated isoelectric point of 5.45. MW1337R and lin2004, as well as their homologs, which, so far, have been found only in Bacillus, Staphylococcus, Listeria, and related genera (Geobacillus, Exiguobacterium, and Oceanobacillus), have unknown functions and are annotated as hypothetical proteins. The genomic contexts of MW1337R and lin2004 are similar and conserved in related species. In prokaryotic genomes, most often, functionally interacting proteins are coded by genes, which are colocated in conserved operons. Proteins from the same operon as MW1337R and lin2004 either have unknown functions (i.e., belong to DUF1273, Pfam accession number PF06908) or are similar to ypsB from Bacillus subtilis. The function of ypsB is unclear, although it has a strong similaritymore » to the N-terminal region of DivIVA, which was characterized as a bifunctional protein with distinct roles during vegetative growth and sporulation. In addition, members of the DUF1273 family display distant sequence similarity with the DprA/Smf protein, which acts downstream of the DNA uptake machinery, possibly in conjunction with RecA. The RecA activities in Bacillus subtilis are modulated by RecU Holliday-junction resolvase. In all analyzed cases, the gene coding for RecU is in the vicinity of MW1337R, lin2004, or their orthologs, but on a different operon located in the complementary DNA strand. Here, we report the crystal structures of MW1337R and lin2004, which were determined using the semiautomated, high-throughput pipeline of the Joint Center for Structural Genomics (JCSG), part of the National Institute of General Medical Sciences Protein Structure Initiative.« less

Published
2008
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50. Crystal structure of an ADP-ribosylated protein with a cytidine deaminase-like fold, but unknown function (TM1506), from Thermotoga maritima at 2.70 Å resolution

Author

Aprilfawn White, Jessica Paulsen, Polat Abdubek, Michael DiDonato, Sanjay Krishna, John Wooley, Daniel McMullan, Lian Duan, Andrew T. Morse, Henry van den Bedem, Christopher L. Rife, Slawomir K. Grzechnik, Mitchell D. Miller, Hsiu-Ju Chiu, Julie Feuerhelm, Keith O. Hodgson, Heath E. Klock, Marc-André Elsliger, Edward Nigoghossian, Thomas Clayton, Herbert L. Axelrod, Joanna Hale, Lukasz Jaroszewski, Qingping Xu, Scott A. Lesley, Piotr Kozbial, Ron Reyes, Scott M. Brittain, Ashley M. Deacon, Ian A. Wilson, Scott B. Ficarro, Adam Godzik, and Gye Won Han

Subjects
Biochemistry, Structural Biology, Thermophile, Thermotoga maritima, Posttranslational modification, Cytidine deaminase, Crystal structure, Biology, biology.organism_classification, Molecular Biology, Structural genomics
Published
2008
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