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2. Antibody agonists trigger immune receptor signaling through local exclusion of receptor-type protein tyrosine phosphatases

Author

Lippert, Anna H., Paluch, Christopher, Gaglioni, Meike, Vuong, Mai T., McColl, James, Jenkins, Edward, Fellermeyer, Martin, Clarke, Joseph, Sharma, Sumana, Moreira da Silva, Sara, Akkaya, Billur, Anzilotti, Consuelo, Morgan, Sara H., Jessup, Claire F., Körbel, Markus, Gileadi, Uzi, Leitner, Judith, Knox, Rachel, Chirifu, Mami, Huo, Jiandong, Yu, Susan, Ashman, Nicole, Lui, Yuan, Wilkinson, Ian, Attfield, Kathrine E., Fugger, Lars, Robertson, Nathan J., Lynch, Christopher J., Murray, Lynne, Steinberger, Peter, Santos, Ana Mafalda, Lee, Steven F., Cornall, Richard J., Klenerman, David, and Davis, Simon J.

Published
2024
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3. Analyzing MCMC Output

Author

Vats, Dootika, Robertson, Nathan, Flegal, James M, and Jones, Galin L

Subjects
Statistics - Computation, Statistics - Methodology
Abstract

Markov chain Monte Carlo (MCMC) is a sampling-based method for estimating features of probability distributions. MCMC methods produce a serially correlated, yet representative, sample from the desired distribution. As such it can be difficult to know when the MCMC method is producing reliable results. We introduce some fundamental methods for ensuring a trustworthy simulation experiment. In particular, we present a workflow for output analysis in MCMC providing estimators, approximate sampling distributions, stopping rules, and visualization tools.

Published
2019

4. Assessing and Visualizing Simultaneous Simulation Error

Author

Robertson, Nathan, Flegal, James M., Vats, Dootika, and Jones, Galin L.

Subjects
Statistics - Computation, Statistics - Methodology, 65C05, 62F15
Abstract

Monte Carlo experiments produce samples in order to estimate features of a given distribution. However, simultaneous estimation of means and quantiles has received little attention, despite being common practice. In this setting we establish a multivariate central limit theorem for any finite combination of sample means and quantiles under the assumption of a strongly mixing process, which includes the standard Monte Carlo and Markov chain Monte Carlo settings. We build on this to provide a fast algorithm for constructing hyperrectangular confidence regions having the desired simultaneous coverage probability and a convenient marginal interpretation. The methods are incorporated into standard ways of visualizing the results of Monte Carlo experiments enabling the practitioner to more easily assess the reliability of the results. We demonstrate the utility of this approach in various Monte Carlo settings including simulation studies based on independent and identically distributed samples and Bayesian analyses using Markov chain Monte Carlo sampling., Comment: 23 pages, 7 figures

Published
2019

6. From structure to clinic: Design of a muscarinic M1 receptor agonist with the potential to treat Alzheimer’s disease

Author

Brown, Alastair J.H., Bradley, Sophie J., Marshall, Fiona H., Brown, Giles A., Bennett, Kirstie A., Brown, Jason, Cansfield, Julie E., Cross, David M., de Graaf, Chris, Hudson, Brian D., Dwomoh, Louis, Dias, João M., Errey, James C., Hurrell, Edward, Liptrot, Jan, Mattedi, Giulio, Molloy, Colin, Nathan, Pradeep J., Okrasa, Krzysztof, Osborne, Greg, Patel, Jayesh C., Pickworth, Mark, Robertson, Nathan, Shahabi, Shahram, Bundgaard, Christoffer, Phillips, Keith, Broad, Lisa M., Goonawardena, Anushka V., Morairty, Stephen R., Browning, Michael, Perini, Francesca, Dawson, Gerard R., Deakin, John F.W., Smith, Robert T., Sexton, Patrick M., Warneck, Julie, Vinson, Mary, Tasker, Tim, Tehan, Benjamin G., Teobald, Barry, Christopoulos, Arthur, Langmead, Christopher J., Jazayeri, Ali, Cooke, Robert M., Rucktooa, Prakash, Congreve, Miles S., Weir, Malcolm, and Tobin, Andrew B.

Published
2021
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10. Structure of the complement C5a receptor bound to the extra-helical antagonist NDT9513727

Author

Robertson, Nathan, Rappas, Mathieu, Dor, Andrew S., Brown, Jason, Bottegoni, Giovanni, Koglin, Markus, Cansfield, Julie, Jazayeri, Ali, Cooke, Robert M., and Marshall, Fiona H.

Subjects
Complement (Immunology) -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Nathan Robertson [1]; Mathieu Rappas [1]; Andrew S. Dor [1]; Jason Brown [1]; Giovanni Bottegoni [1]; Markus Koglin [1]; Julie Cansfield [1]; Ali Jazayeri [1]; Robert M. Cooke [1]; [...]

Published
2018
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11. Visualizing Monte Carlo Error and Terminating Markov Chain Monte Carlo Simulation

Author

Robertson, Nathan Lane

Subjects
Statistics, Markov chain Monte Carlo, Monte Carlo, Sequential Stopping Rule, Visualization
Abstract

Markov chain Monte Carlo (MCMC) is a sampling technique that allows for estimating features of intractable probability distributions. Output analysis of MCMC samples aims to assess the quality of the sampler and the resulting estimates. We provide an example based overview of current best practices using visualizations and the estimation of features of interest using Markov chain central limit theorems. Most features of interest are functionals of expectations or quantiles. The estimation of quantiles has thus-far been limited to univariate theory and marginal limiting distributions, while the estimation of expectations enjoys multivariate approaches through a joint limiting distribution. In this work, we provide an extension to jointly estimate combinations of functionals of expectations and quantiles through a joint limiting distribution for the Monte Carlo error. We use this limiting distribution to establish a procedure for finding sets of simultaneous intervals forming confidence regions of approximately correct coverage probabilities. These simultaneous intervals motivate a class of visualizations for Monte Carlo errors for a broad class of estimation procedures for which a multivariate normal limiting distribution holds. Finally, we consider MCMC sample size through sequential stopping rules which terminate simulation once the Monte Carlo errors become suitably small. We develop a general sequential stopping rule for combinations of expectations and quantiles from Markov chain output and provide a simulation study to illustrate the validity.

Published
2019

12. Carbon starvation following a decade of experimental drought consumes old reserves in Pinus edulis.

Author

Peltier, Drew M. P., Carbone, Mariah S., McIntire, Cameron D., Robertson, Nathan, Thompson, R. Alex, Malone, Shealyn, LeMoine, Jim, Richardson, Andrew D., McDowell, Nate G., Adams, Henry D., Pockman, William T., and Trowbridge, Amy M.

Subjects
DROUGHT management, DROUGHTS, PINE, STARVATION, TREE growth, PHOTOSYNTHETIC rates, SAPWOOD
Abstract

Summary: Shifts in the age or turnover time of non‐structural carbohydrates (NSC) may underlie changes in tree growth under long‐term increases in drought stress associated with climate change. But NSC responses to drought are challenging to quantify, due in part to large NSC stores in trees and subsequently long response times of NSC to climate variation.We measured NSC age (Δ14C) along with a suite of ecophysiological metrics in Pinus edulis trees experiencing either extreme short‐term drought (−90% ambient precipitation plot, 2020–2021) or a decade of severe drought (−45% plot, 2010–2021). We tested the hypothesis that carbon starvation – consumption exceeding synthesis and storage – increases the age of sapwood NSC.One year of extreme drought had no impact on NSC pool size or age, despite significant reductions in predawn water potential, photosynthetic rates/capacity, and twig and needle growth. By contrast, long‐term drought halved the age of the sapwood NSC pool, coupled with reductions in sapwood starch concentrations (−75%), basal area increment (−39%), and bole respiration rates (−28%).Our results suggest carbon starvation takes time, as tree carbon reserves appear resilient to extreme disturbance in the short term. However, after a decade of drought, trees apparently consumed old stored NSC to support metabolism. [ABSTRACT FROM AUTHOR]

Published
2023
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14. Extra-helical binding site of a glucagon receptor antagonist

Author

Jazayeri, Ali, Doré, Andrew S., Lamb, Daniel, Krishnamurthy, Harini, Southall, Stacey M., Baig, Asma H., Bortolato, Andrea, Koglin, Markus, Robertson, Nathan J., Errey, James C., Andrews, Stephen P., Teobald, Iryna, Brown, Alastair J. H., Cooke, Robert M., Weir, Malcolm, and Marshall, Fiona H.

Published
2016
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20. Corrigendum: Crystal structure of the GLP-1 receptor bound to a peptide agonist

Author

Jazayeri, Ali, Rappas, Mathieu, Brown, Alastair J. H., Kean, James, Errey, James C., Robertson, Nathan J., Fiez-Vandal, Cdric, Andrews, Stephen P., Congreve, Miles, Bortolato, Andrea, Mason, Jonathan S., Baig, Asma H., Teobald, Iryna, Dor, Andrew S., Weir, Malcolm, Cooke, Robert M., and Marshall, Fiona H.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Ali Jazayeri; Mathieu Rappas; Alastair J. H. Brown; James Kean; James C. Errey; Nathan J. Robertson; Cdric Fiez-Vandal; Stephen P. Andrews; Miles Congreve; Andrea Bortolato; Jonathan S. Mason; Asma [...]

Published
2017
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21. Crystal structure of the GLP-1 receptor bound to a peptide agonist

Author

Jazayeri, Ali, Rappas, Mathieu, Brown, Alastair J. H., Kean, James, Errey, James C., Robertson, Nathan J., Fiez-Vandal, Cdric, Andrews, Stephen P., Congreve, Miles, Bortolato, Andrea, Mason, Jonathan S., Baig, Asma H., Teobald, Iryna, Dor, Andrew S., Weir, Malcolm, Cooke, Robert M., and Marshall, Fiona H.

Subjects
Crystal structure -- Analysis, Type 2 diabetes -- Care and treatment, Peptides, Diabetes therapy, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Glucagon-like peptide 1 (GLP-1) regulates glucose homeostasis through the control of insulin release from the pancreas. GLP-1 peptide agonists are efficacious drugs for the treatment of diabetes. To gain insight into the molecular mechanism of action of GLP-1 peptides, here we report the crystal structure of the full-length GLP-1 receptor bound to a truncated peptide agonist. The peptide agonist retains an -helical conformation as it sits deep within the receptor-binding pocket. The arrangement of the transmembrane helices reveals hallmarks of an active conformation similar to that observed in class A receptors. Guided by this structural information, we design peptide agonists with potent in vivo activity in a mouse model of diabetes., Author(s): Ali Jazayeri [1]; Mathieu Rappas [1]; Alastair J. H. Brown [1]; James Kean [1]; James C. Errey [1]; Nathan J. Robertson [1]; Cdric Fiez-Vandal [1]; Stephen P. Andrews [1]; [...]

Published
2017
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24. Development of a novel mammalian display system for selection of antibodies against membrane proteins

Author

Robertson, Nathan, primary, Lopez-Anton, Nancy, additional, Gurjar, Shalom A., additional, Khalique, Hena, additional, Khalaf, Zainab, additional, Clerkin, Siobhan, additional, Leydon, Vaughan R., additional, Parker-Manuel, Richard, additional, Raeside, Alexander, additional, Payne, Tom, additional, Jones, Tim D., additional, Seymour, Len, additional, and Cawood, Ryan, additional

Published
2020
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25. HERMES: the Hopkins Electronic Resource Management System

Author

Cyzyk, Mark and Robertson, Nathan D.M.

Subjects
Web site management software, CD-ROM catalog, Database, Company licensing agreement, CD-ROM database, Johns Hopkins University, Databases -- Case studies -- Product information -- Licensing agreements, Electronic records -- Licensing agreements -- Product information -- Case studies, Library catalogs -- Case studies -- Product information, Web site management software -- Product information -- Licensing agreements -- Case studies, Information storage and retrieval systems -- Case studies -- Product information -- Licensing agreements, Catalogs -- Product information -- Case studies -- Licensing agreements
Abstract

This article describes a project undertaken by the Johns Hopkins University libraries to develop a systemwide, Web-based application to facilitate the selection, procurement, implementation, and management of electronic resources and […]

Published
2003

30. From Structure to Clinic: Discovery of A M1 Muscarinic Acetylcholine Receptor Agonist for the Treatment of Memory Loss in Alzheimer's Disease

Author

Brown, Alastair J. H., primary, Bradley, Sophie J., additional, Brown, Giles A., additional, Bennett, Kirstie A., additional, Brown, Jason, additional, Cansfield, Julie E., additional, Cross, David M., additional, Dias, João M., additional, Errey, James C., additional, Hurrell, Edward, additional, Liptrot, Jan, additional, Molloy, Colin, additional, Nathan, Pradeep J., additional, Okrasa, Krzysztof, additional, Osbourne, Greg, additional, Patel, Jayesh C., additional, Pickworth, Mark, additional, Robertson, Nathan, additional, Shahabi, Shahram, additional, Bundgaard, Christoffer, additional, Phillips, Keith, additional, Broad, Lisa M., additional, Goonawardena, Anushka V., additional, Morairty, Stephen R., additional, Browning, Michael, additional, Perini, Francesca, additional, Dawson, Gerard R., additional, Deakin, John F. W., additional, Smith, Robert T., additional, Sexton, Patrick M., additional, Warneck, Julie, additional, Vinson, Mary, additional, Tasker, Tim, additional, Tehan, Benjamin G., additional, Teobald, Barry, additional, Christopoulos, Arthur, additional, Langmead, Christopher J., additional, Jazayeri, Ali, additional, Cooke, Robert M., additional, Marshall, Fiona H., additional, Rucktooa, Prakash, additional, Congreve, Miles S., additional, Weir, Malcolm, additional, and Tobin, Andrew, additional

Published
2020
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34. Assessing and Visualizing Simultaneous Simulation Error.

Author

Robertson, Nathan, Flegal, James M., Vats, Dootika, and Jones, Galin L.

Subjects
*CONFIDENCE regions (Mathematics), *MONTE Carlo method, *MARKOV processes, *CENTRAL limit theorem, *BAYESIAN analysis, *CONFIDENCE intervals, *MARKOV chain Monte Carlo
Abstract

Monte Carlo experiments produce samples to estimate features such as means and quantiles of a given distribution. However, simultaneous estimation of means and quantiles has received little attention. In this setting, we establish a multivariate central limit theorem for any finite combination of sample means and quantiles under the assumption of a strongly mixing process, which includes the standard Monte Carlo and Markov chain Monte Carlo settings. We build on this to provide a fast algorithm for constructing hyperrectangular confidence regions having the desired simultaneous coverage probability and a convenient marginal interpretation. The methods are incorporated into standard ways of visualizing the results of Monte Carlo experiments enabling the practitioner to more easily assess the reliability of the results. We demonstrate the utility of this approach in various Monte Carlo settings including simulation studies based on independent and identically distributed samples and Bayesian analyses using Markov chain Monte Carlo sampling. for this article are available online. [ABSTRACT FROM AUTHOR]

Published
2021
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36. How do short chain non-ionic detergents destabilize GPCRs?

Author

Lee, Sangbae, Mao, Allen, Bhattacharya, Supriyo, Robertson, Nathan, Grisshammer, Reinhard, Tate, Christopher G., and Vaidehi, Nagarajan

Subjects
Receptor, Adenosine A2A, Protein Stability, Detergents, Mutation, Molecular Dynamics Simulation, Article
Abstract

Stability of detergent-solubilized GPCRs is crucial for their purification in a biologically relevant state and it is well-known that short chain detergents such as octylglucoside are more denaturing than long chain detergents such as dodecylmaltoside. However, the molecular basis for this phenomenon is poorly understood. To gain insights into the mechanism of detergent destabilization of GPCRs, we used atomistic molecular dynamics simulations of thermostabilized adenosine receptor (A2AR) mutants embedded in either a lipid bilayer or detergent micelles of alkylmaltosides and alkyl-glucosides. A2AR mutants in dodecylmaltoside or phospholipid showed low flexibility and good interhelical packing. In contrast, A2AR mutants in either octylglucoside or nonylglucoside showed decreased α-helicity in transmembrane regions, decreased α-helical packing and the interpenetration of detergent molecules between transmembrane α-helices. This was not observed in octylglucoside containing phospholipid. Cholesteryl hemisuccinate in dodecylmaltoside increased the energetic stability of the receptor by wedging into crevices on the hydrophobic surface of A2AR, increasing packing interactions within the receptor and stiffening the detergent micelle. The data suggest a three-stage process for the initial events in the destabilization of GPCRs by octylglucoside: (i) highly mobile detergent molecules form small micelles around the receptor; (ii) loss of α-helicity and decreased interhelical packing interactions in transmembrane regions through increased receptor thermal motion; (iii) transient separation of transmembrane helices allowed penetration of detergent molecules into the core of the receptor. The relative hydration of the headgroup and alkyl chain correlates with detergent harshness and suggests new avenues to develop milder versions of octylglucoside for receptor crystallization.

Published
2016

39. Erratum: Corrigendum: Crystal structure of the GLP-1 receptor bound to a peptide agonist

Author

Jazayeri, Ali, primary, Rappas, Mathieu, additional, Brown, Alastair J. H., additional, Kean, James, additional, Errey, James C., additional, Robertson, Nathan J., additional, Fiez-Vandal, Cédric, additional, Andrews, Stephen P., additional, Congreve, Miles, additional, Bortolato, Andrea, additional, Mason, Jonathan S., additional, Baig, Asma H., additional, Teobald, Iryna, additional, Doré, Andrew S., additional, Weir, Malcolm, additional, Cooke, Robert M., additional, and Marshall, Fiona H., additional

Published
2017
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41. Structural elucidation of ligand binding sites in family B GPCRs and their application in drug discovery

Author

Jazayeri, Ali, primary, Doré, Andrew, additional, Lamb, Daniel, additional, Krishnamurthy, Harini, additional, Southall, Stacey, additional, Baig, Asma, additional, Bortolato, Andrea, additional, Koglin, Markus, additional, Robertson, Nathan, additional, Errey, James, additional, Andrews, Stephen, additional, Brown, Alastair, additional, Cooke, Robert, additional, Weir, Malcolm, additional, and Marshall, Fiona, additional

Published
2016
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45. Identification of Novel Adenosine A2A Receptor Antagonists by Virtual Screening

Author

Langmead, Christopher J., primary, Andrews, Stephen P., additional, Congreve, Miles, additional, Errey, James C., additional, Hurrell, Edward, additional, Marshall, Fiona H., additional, Mason, Jonathan S., additional, Richardson, Christine M., additional, Robertson, Nathan, additional, Zhukov, Andrei, additional, and Weir, Malcolm, additional

Published
2012
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46. Structure of the Adenosine A2A Receptor in Complex with ZM241385 and the Xanthines XAC and Caffeine

Author

Doré, Andrew S., primary, Robertson, Nathan, additional, Errey, James C., additional, Ng, Irene, additional, Hollenstein, Kaspar, additional, Tehan, Ben, additional, Hurrell, Edward, additional, Bennett, Kirstie, additional, Congreve, Miles, additional, Magnani, Francesca, additional, Tate, Christopher G., additional, Weir, Malcolm, additional, and Marshall, Fiona H., additional

Published
2011
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47. Biophysical Mapping of the Adenosine A2A Receptor

Author

Zhukov, Andrei, primary, Andrews, Stephen P., additional, Errey, James C., additional, Robertson, Nathan, additional, Tehan, Benjamin, additional, Mason, Jonathan S., additional, Marshall, Fiona H., additional, Weir, Malcolm, additional, and Congreve, Miles, additional

Published
2011
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