40 results on '"Alexander J. Stewart"'
Search Results
2. Radical and Ionic Mechanisms in Rearrangements of o-Tolyl Aryl Ethers and Amines Initiated by the Grubbs–Stoltz Reagent, Et3SiH/KOtBu
- Author
-
Krystian Kolodziejczak, Alexander J. Stewart, Tell Tuttle, and John A. Murphy
- Subjects
Truce–Smiles rearrangement ,Grubbs–Stoltz reagent ,radical ,electron transfer ,aryl substitution ,diarylmethanes ,Organic chemistry ,QD241-441 - Abstract
Rearrangements of o-tolyl aryl ethers, amines, and sulfides with the Grubbs–Stoltz reagent (Et3SiH + KOtBu) were recently announced, in which the ethers were converted to o-hydroxydiarylmethanes, while the (o-tol)(Ar)NH amines were transformed into dihydroacridines. Radical mechanisms were proposed, based on prior evidence for triethylsilyl radicals in this reagent system. A detailed computational investigation of the rearrangements of the aryl tolyl ethers now instead supports an anionic Truce–Smiles rearrangement, where the initial benzyl anion can be formed by either of two pathways: (i) direct deprotonation of the tolyl methyl group under basic conditions or (ii) electron transfer to an initially formed benzyl radical. By contrast, the rearrangements of o-tolyl aryl amines depend on the nature of the amine. Secondary amines undergo deprotonation of the N-H followed by a radical rearrangement, to form dihydroacridines, while tertiary amines form both dihydroacridines and diarylmethanes through radical and/or anionic pathways. Overall, this study highlights the competition between the reactive intermediates formed by the Et3SiH/KOtBu system.
- Published
- 2021
- Full Text
- View/download PDF
3. The Evolvability of Cooperation under Local and Non-Local Mutations
- Author
-
Alexander J. Stewart and Joshua B. Plotkin
- Subjects
cooperation ,evolvability ,adaptive dynamics ,iterated games ,memory-1 strategies ,payoff evolution ,evolution of investment ,Technology ,Social Sciences - Abstract
We study evolutionary dynamics in a population of individuals engaged in pairwise social interactions, encoded as iterated games. We consider evolution within the space of memory-1strategies, and we characterize all evolutionary robust outcomes, as well as their tendency to evolve under the evolutionary dynamics of the system. When mutations are restricted to be local, as opposed to non-local, then a wider range of evolutionary robust outcomes tend to emerge, but mutual cooperation is more difficult to evolve. When we further allow heritable mutations to the player’s investment level in each cooperative interaction, then co-evolution leads to changes in the payoff structure of the game itself and to specific pairings of robust games and strategies in the population. We discuss the implications of these results in the context of the genetic architectures that encode how an individual expresses its strategy or investment.
- Published
- 2015
- Full Text
- View/download PDF
4. Incorporating Computational Challenges into a Multidisciplinary Course on Stochastic Processes.
- Author
-
Mark Jayson Cortez, Alan Eric Akil, Kresimir Josic, and Alexander J. Stewart
- Published
- 2023
- Full Text
- View/download PDF
5. Information gerrymandering and undemocratic decisions.
- Author
-
Alexander J. Stewart, Mohsen Mosleh, Marina Diakonova, Antonio A. Arechar, David G. Rand, and Joshua B. Plotkin
- Published
- 2019
- Full Text
- View/download PDF
6. Evolution of empathetic moral evaluation
- Author
-
Arunas L Radzvilavicius, Alexander J Stewart, and Joshua B Plotkin
- Subjects
game theory ,cooperation ,social psychology ,theory of mind ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Social norms can promote cooperation by assigning reputations to individuals based on their past actions. A good reputation indicates that an individual is likely to reciprocate. A large body of research has established norms of moral assessment that promote cooperation, assuming reputations are objective. But without a centralized institution to provide objective evaluation, opinions about an individual’s reputation may differ across a population. In this setting we study the role of empathy–the capacity to form moral evaluations from another person’s perspective. We show that empathy tends to foster cooperation by reducing the rate of unjustified defection. The norms of moral evaluation previously considered most socially beneficial depend on high levels of empathy, whereas different norms maximize social welfare in populations incapable of empathy. Finally, we show that empathy itself can evolve through social contagion. We conclude that a capacity for empathy is a key component for sustaining cooperation in societies.
- Published
- 2019
- Full Text
- View/download PDF
7. Parasitic nematodes of the genus Syphacia Seurat, 1916 infecting Cricetidae in the British Isles: the enigmatic status of Syphacia nigeriana
- Author
-
Gemma Cooper, Anna Bajer, Ann Lowe, Jerzy M. Behnke, John M. Kinsella, Lesley R. Smales, Alexander J. Stewart, Jonathan Fenn, Stefano Catalano, Christophe Diagne, Joanne P. Webster, Jeremy S. Herman, and Dorota Dwużnik-Szarek
- Subjects
biology ,Phylogenetic tree ,Rodent ,Range (biology) ,Zoology ,biology.organism_classification ,Infectious Diseases ,Genus ,Mastomys ,biology.animal ,parasitic diseases ,Parasite hosting ,Animal Science and Zoology ,Parasitology ,Microtus ,Cricetidae - Abstract
Oxyurid nematodes (Syphacia spp.) from bank (Myodes glareolus) and field/common (Microtus spp.) voles, from disparate geographical sites in the British Isles, were examined morphologically and genetically. The genetic signatures of 118 new isolates are provided, based primarily on the rDNA internal transcribed spacers (ITS1-5.8S-ITS2) region and for representative isolates also on the small subunit 18S rDNA region and cytochrome c oxidase subunit 1 (cox-1) gene locus. Genetic data on worms recovered from Microtus spp. from the European mainland and from other rodent genera from the Palaearctic, North America and West Africa are also included. We test historical hypotheses indicating that S. nigeriana is a generalist species, infecting a range of different rodent genera. Our results establish that S. nigeriana is a parasite of both bank and field voles in the British Isles. An identical genotype was also recorded from Hubert's multimammate mouse (Mastomys huberti) from Senegal, but Mastomys spp. from West Africa were additionally parasitized by a related, although genetically distinct Syphacia species. We found no evidence for S. petrusewiczi in voles from the British Isles but isolates from Russia and North America were genetically distinct and formed their own separate deep branch in maximum likelihood molecular phylogenetic trees.
- Published
- 2022
8. Inequality, identity, and partisanship: How redistribution can stem the tide of mass polarization
- Author
-
Alexander J. Stewart, Joshua B. Plotkin, Nolan McCarty, and University of St Andrews. Applied Mathematics
- Subjects
General Economics (econ.GN) ,Multidisciplinary ,T-NDAS ,05 social sciences ,Cultural evolution ,Risk aversion ,Social Sciences ,SDG 10 - Reduced Inequalities ,HN ,JK Political institutions (United States) ,JK ,0506 political science ,FOS: Economics and business ,Inequality ,Polarization ,HN Social history and conditions. Social problems. Social reform ,0502 economics and business ,050602 political science & public administration ,QA Mathematics ,050207 economics ,QA ,10. No inequality ,Economics - General Economics - Abstract
The form of political polarization where citizens develop strongly negative attitudes toward out-party members and policies has become increasingly prominent across many democracies. Economic hardship and social inequality, as well as intergroup and racial conflict, have been identified as important contributing factors to this phenomenon known as “affective polarization.” Research shows that partisan animosities are exacerbated when these interests and identities become aligned with existing party cleavages. In this paper, we use a model of cultural evolution to study how these forces combine to generate and maintain affective political polarization. We show that economic events can drive both affective polarization and the sorting of group identities along party lines, which, in turn, can magnify the effects of underlying inequality between those groups. But, on a more optimistic note, we show that sufficiently high levels of wealth redistribution through the provision of public goods can counteract this feedback and limit the rise of polarization. We test some of our key theoretical predictions using survey data on intergroup polarization, sorting of racial groups, and affective polarization in the United States over the past 50 y. Postprint
- Published
- 2021
9. Untargeted saliva metabolomics reveals COVID-19 severity
- Author
-
Danni Greener, Matt Spick, Katherine A. Hollywood, Katie Longman, Catia Costa, George Evetts, Holly M. Lewis, Andrew R. Pitt, Perdita E. Barran, Deborah K. Dunn-Walters, Debra J. Skene, Melanie J. Bailey, Drupad Trivedi, Cecile Frampas, and Alexander J. Stewart
- Subjects
Saliva ,medicine.medical_specialty ,Metabolomics ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Internal medicine ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Medicine ,Sampling (medicine) ,Disease ,business ,Triage ,Cohort study - Abstract
BackgroundThe COVID-19 pandemic is likely to represent an ongoing global health issue given the potential for vaccine escape and the low likelihood of eliminating all reservoirs of the disease. Whilst diagnostic testing has progressed at pace, there is an unmet clinical need to develop tests that are prognostic, to triage the high volumes of patients arriving in hospital settings. Recent research has shown that serum metabolomics has potential for prognosis of disease progression. 1 In a hospital setting, collection of saliva samples is more convenient for both staff and patients, and therefore offers an alternative sampling matrix to serum. We demonstrate here for the first time that saliva metabolomics can reveal COVID-19 severity.Methods88 saliva samples were collected from hospitalised patients with clinical suspicion of COVID-19, alongside clinical metadata. COVID-19 diagnosis was confirmed using RT-PCR testing. COVID severity was classified using clinical descriptors first proposed by SR Knight et al. Metabolites were extracted from saliva samples and analysed using liquid chromatography mass spectrometry.ResultsIn this work, positive percent agreement of 1.00 between a PLS-DA metabolomics model and the clinical diagnosis of COVID severity was achieved. The negative percent agreement with the clinical severity diagnosis was also 1.00, for overall percent agreement of 1.00.ConclusionsThis research demonstrates that liquid chromatography-mass spectrometry can identify salivary biomarkers capable of separating high severity COVID-19 patients from low severity COVID-19 patients in a small cohort study.
- Published
- 2021
10. The natural selection of good science
- Author
-
Alexander J. Stewart, Joshua B. Plotkin, and University of St Andrews. Applied Mathematics
- Subjects
Q Science ,Physics - Physics and Society ,Social Psychology ,Computer science ,Science ,FOS: Physical sciences ,Experimental and Cognitive Psychology ,Physics and Society (physics.soc-ph) ,03 medical and health sciences ,Behavioral Neuroscience ,0302 clinical medicine ,Empirical research ,Cultural Evolution ,Replication (statistics) ,False positive paradox ,Selection (linguistics) ,Humans ,QA Mathematics ,Quantitative Biology - Populations and Evolution ,Set (psychology) ,Sociocultural evolution ,QA ,Publication ,030304 developmental biology ,0303 health sciences ,business.industry ,Publications ,Populations and Evolution (q-bio.PE) ,Reproducibility of Results ,DAS ,Models, Theoretical ,Data science ,Incentive ,FOS: Biological sciences ,business ,030217 neurology & neurosurgery - Abstract
Scientists in some fields are concerned that many, or even most, published results are false. A high rate of false positives might arise accidentally, from shoddy research practices. Or it might be the inevitable result of institutional incentives that reward publication irrespective of veracity. Recent models and discussion of scientific culture predict selection for false-positive publications, as research labs that publish more positive findings out-compete more diligent labs. There is widespread debate about how scientific practices should be modified to avoid this degeneration. Some analyses suggest that "bad science" will persist even when labs are incentivized to undertake replication studies, and penalized for publications that later fail to replicate. Here we develop a framework for modelling the cultural evolution of research practices that allows labs to expend effort on theory - enabling them, at a cost, to focus on hypotheses that are more likely to be true on theoretical grounds. Theory restores the evolution of high effort in laboratory practice, and it suppresses false-positive publications to a technical minimum, even in the absence of replication. In fact, the mere ability choose between two sets of hypotheses - one with greater chance of being correct than the other - promotes better science than can be achieved by having effortless access to the better set of hypotheses. Combining theory and replication can have a synergistic effect in promoting good scientific methodology and reducing the rate of false-positive publications. Based on our analysis we propose four simple rules to promote good science in the face of pressure to publish.
- Published
- 2021
11. The impact of COVID-19 on children with oesophageal atresia and/or tracheo-oesophageal fistula (OA/TOF)
- Author
-
Alexander J. Stewart, Claire Smith, Jo Wray, De Coppi P, and Simon Eaton
- Subjects
medicine.medical_specialty ,Isolation (health care) ,business.industry ,media_common.quotation_subject ,Telehealth ,Family medicine ,Pandemic ,Health care ,medicine ,Global health ,Anxiety ,Thematic analysis ,Worry ,medicine.symptom ,business ,media_common - Abstract
PurposeThe COVID-19 pandemic has resulted in a global health crisis of unparalleled magnitude. The direct risk to the health of children is low. However, disease containment measures have society-wide impacts. This study explored the pandemic experiences of parents of children with oesophageal atresia/tracheo-oesophageal fistula in the UK.DesignAn online forum was conducted using a private group on Facebook, in collaboration with a patient support group. Thematic analysis was used to identify key themes.ResultsThe online forum ran between 7th November-18th December 2020 with 109 participants. Themes related to healthcare and non-healthcare impacts. Parents experienced changes and limitations to healthcare access, anxiety regarding health risks, “collateral” damage to well-being because of isolation and an impact on finances and employment. Parents described a transition from worry about direct health risks to concern about the impact of isolation on socialisation and development. A process of risk-benefit analysis led some to transition to a more “normal life”, while others continued to isolate. Benefits to their child’s health from isolation, positive experiences with remote healthcare and a gradual easing of anxiety were also identified.Implications and relevanceThis study highlights the wide-ranging impact of the COVID-19 pandemic on children and their families. Although focussed on oesophageal atresia/tracheo-oesophageal fistula, the emerging themes will be relevant to many children with complex, chronic health conditions. There are implications for healthcare delivery, including telehealth, during and after the pandemic period. Accurate and consistent messaging is required. Third sector organisations are ideally positioned support this.
- Published
- 2021
12. Under-Dominance Constrains the Evolution of Negative Autoregulation in Diploids.
- Author
-
Alexander J. Stewart, Robert M. Seymour, Andrew Pomiankowski, and Max Reuter
- Published
- 2013
- Full Text
- View/download PDF
13. CSF1R defines the mononuclear phagocyte system lineage in human blood in health and COVID-19
- Author
-
Theo W. Combes, A.S. Jeewaka R. Mendis, Siamon Gordon, Fernando O. Martinez, Federica Orsenigo, Alexander J. Stewart, Deborah K. Dunn-Walters, Combes, T, Orsenigo, F, Stewart, A, Mendis, A, Dunn-Walters, D, Gordon, S, and Martinez, F
- Subjects
0301 basic medicine ,Cell type ,Myeloid ,dendritic cell ,CD14 ,AcademicSubjects/MED00730 ,Biology ,CD16 ,Monocyte ,Dendritic cells ,03 medical and health sciences ,0302 clinical medicine ,medicine ,COVID-19 ,General Medicine ,Mononuclear phagocyte system ,CSF1R ,Blood ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Immunology ,Bone marrow ,Ex vivo ,Research Article ,Human - Abstract
Mononuclear Phagocytes defend tissues, present antigens and mediate recovery and healing. To date we lack a marker to unify mononuclear phagocytes in humans or that informs us about their origin. Here, we reassess Mononuclear Phagocyte ontogeny in human blood through the lineage receptor CSF1R, in the steady state and in COVID-19. We define CSF1R as the first sensitive and reproducible pan-phagocyte lineage marker, to identify and enumerate all conventional monocytes, and the myeloid dendritic cells. In the steady state CSF1R is sufficient for sorting and immuno-magnetic isolation. In pathology, changes in CSF1R are more sensitive than CD14 and CD16. In COVID-19, a significant drop in membrane CSF1R is useful for stratifying patients, beyond the power of cell categories published thus far, which fail to capture COVID-19 specific events. Importantly, CSF1R defines cells which are neither conventional monocytes nor DCs, which are missed in published analysis. CSF1R decrease can be linked ex vivo to high CSF1 levels. Blood assessment of CSF1R+ cells opens a developmental window to the Mononuclear Phagocyte System in transit from bone marrow to tissues, supports isolation and phenotypic characterisation, identifies novel cell types, and singles out CSF1R inhibition as therapeutic target in COVID-19 and other diseases., Graphical Abstract Graphical Abstract
- Published
- 2021
14. Changes to the sebum lipidome upon COVID-19 infection observed via non-invasive and rapid sampling from the skin
- Author
-
George Evetts, Andrew R. Pitt, Melanie J. Bailey, Drupad Trivedi, Holly M. Lewis, Catia Costa, Alexander J. Stewart, Cecile Frampas, Katherine Longman, Michael Wilde, Matt Spick, Deborah Dunn Walters, Perdita E. Barran, and Danni Greener
- Subjects
medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,Liquid chromatography–mass spectrometry ,business.industry ,Internal medicine ,Lipidomics ,medicine ,Sampling (medicine) ,Lipidome ,medicine.disease ,business ,Dyslipidemia - Abstract
The COVID-19 pandemic has led to an urgent and unprecedented demand for testing – both for diagnosis and prognosis. Here we explore the potential for using sebum, collected via swabbing of a patient’s skin, as a novel sampling matrix to fulfil these requirements. In this pilot study, sebum samples were collected from 67 hospitalised patients (30 PCR positive and 37 PCR negative). Lipidomics analysis was carried out using liquid chromatography mass spectrometry. Total fatty acid derivative levels were found to be depressed in COVID-19 positive participants, indicative of dyslipidemia. Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) modelling showed promising separation of COVID-19 positive and negative participants when comorbidities and medication were controlled for. Given that sebum sampling is rapid and non-invasive, this work may offer the potential for diagnostic and prognostic testing for COVID-19.
- Published
- 2020
15. Single-cell transcriptomic analyses define distinct peripheral B cell subsets and discrete development pathways
- Author
-
Franca Fraternali, Alexander J. Stewart, Deborah K. Dunn-Walters, Vasiliki Tsioligka, Gillian Wallis, and Joseph Chi Fung Ng
- Subjects
lcsh:Immunologic diseases. Allergy ,Adult ,Male ,B cell subsets ,Immunology ,Cell ,Population ,Computational biology ,Immunoglobulin E ,CD19 ,Transcriptome ,Immune system ,B cell development ,memory B cells ,medicine ,Humans ,Immunology and Allergy ,single-cellRNAseq ,education ,B cell ,Original Research ,B cells ,B-Lymphocytes ,education.field_of_study ,biology ,Gene Expression Profiling ,Phenotype ,medicine.anatomical_structure ,biology.protein ,Single-Cell Analysis ,lcsh:RC581-607 ,cell atlas ,Immunologic Memory ,Signal Transduction - Abstract
Separation of B cells into different subsets has been useful to understand their different functions in various immune scenarios. In some instances, the subsets defined by phenotypic FACS separation are relatively homogeneous and so establishing the functions associated with them is straightforward. Other subsets, such as the “Double negative” (DN, CD19+CD27-IgD-) population, are more complex with reports of differing functionality which could indicate a heterogeneous population. Recent advances in single-cell techniques enable an alternative route to characterize cells based on their transcriptome. To maximize immunological insight, we need to match prior data from phenotype-based studies with the finer granularity of the single-cell transcriptomic signatures. We also need to be able to define meaningful B cell subsets from single cell analyses performed on PBMCs, where the relative paucity of a B cell signature means that defining B cell subsets within the whole is challenging. Here we provide a reference single-cell dataset based on phenotypically sorted B cells and an unbiased procedure to better classify functional B cell subsets in the peripheral blood, particularly useful in establishing a baseline cellular landscape and in extracting significant changes with respect to this baseline from single-cell datasets. We find 10 different clusters of B cells and applied a novel, geometry-inspired, method to RNA velocity estimates in order to evaluate the dynamic transitions between B cell clusters. This indicated the presence of two main developmental branches of memory B cells. A T-independent branch that involves IgM memory cells and two DN subpopulations, culminating in a population thought to be associated with Age related B cells and the extrafollicular response. The other, T-dependent, branch involves a third DN cluster which appears to be a precursor of classical memory cells. In addition, we identify a novel DN4 population, which is IgE rich and closely linked to the classical/precursor memory branch suggesting an IgE specific T-dependent cell population.
- Published
- 2020
16. Synthesis, structure and DFT analysis of the THF solvate of 2-picolyllithium : a 2-picolyllithium solvate with significant carbanionic character
- Author
-
Etienne V. Brouillet, Alexander J. Stewart, Alan R. Kennedy, Stuart D. Robertson, Tobias Krämer, Robert E. Mulvey, and Stephen Towie
- Subjects
Nucleophilic addition ,010405 organic chemistry ,Atoms in molecules ,010402 general chemistry ,Resonance (chemistry) ,01 natural sciences ,Tautomer ,0104 chemical sciences ,Inorganic Chemistry ,chemistry.chemical_compound ,Crystallography ,Deprotonation ,chemistry ,Pyridine ,QD ,Natural bond orbital ,Methyl group - Abstract
Previous studies of different solvates of 2-methylpyridyllithium (2-picolyllithium) have uncovered electronic structures corresponding to aza-allyl and enamido resonance forms of the metallated pyridine-based compounds. Here, we report the synthesis and characterization of [2-CH2Li(THF)2C5H4N], a new THF solvate. X-ray crystallographic studies reveal a dimeric arrangement featuring a non-planar eight-membered [NCCLi]2 ring, in which the primary cation-anion interaction is between the central Li atom and the C atom of the deprotonated methyl group [length, 2.285(2) Å], suggesting a new carbanionic resonance structure for this 2-picolyllithium series. The significant carbanionic character of [2-CH2Li(THF)2C5H4N] was confirmed by gas-phase DFT calculations [B3LYP/6-311+G(d)] with the calculated electron density interrogated by means of quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analyses. For comparison these computational analyses were also performed on the literature structures of [2-CH2Li(2-Picoline)C5H4N] and [2-CH2Li(PMDETA)C5H4N]. In a reactivity study, [2-CH2Li(THF)2C5H4N] was found to undergo nucleophilic addition to pyridine to generate dipyridylmethane in a good yield.
- Published
- 2020
17. Influence of pilot hole diameter in cancellous screw fixation in a reduced density animal bone model
- Author
-
Alexander J. Stewart, Anthony W Miles, and James Fletcher
- Subjects
Materials science ,Bone density ,Swine ,medicine.medical_treatment ,Osteoporosis ,Bone Screws ,Biophysics ,Screw fixation ,03 medical and health sciences ,0302 clinical medicine ,Pilot hole ,Bone Density ,medicine ,Low density ,Animals ,Orthopedics and Sports Medicine ,Reduction (orthopedic surgery) ,030222 orthopedics ,030229 sport sciences ,medicine.disease ,Biomechanical Phenomena ,medicine.anatomical_structure ,Cancellous Bone ,Mechanical Tests ,Animal bone ,Cancellous bone ,Biomedical engineering - Abstract
Screw fixation in osteoporotic bone is clinically challenging. Screw failure rates are growing due to an increasing prevalence of osteoporosis. To address this, biomechanical models are needed to recreate the bone clinically encountered alongside the development of new operative techniques. The first aim of this study was to test whether the use of a smaller than recommended pilot-hole diameter improved pull-out strength for cancellous screws, with the second aim to create a model of low-density porcine bone for biomechanical testing.Thirty porcine tibiae were cut into transverse metaphyseal sections of 20 mm thickness. Bone density was altered using 0.15 M Hydrochloric acid, and measured and pre- and post-demineralisation using HRμCT. Seventy-two screw areas were randomised to either 2.5 mm or 1.5 mm pilot holes and to either be normal or reduced density. Maximum axial pull-out strength was measured.Demineralisation reduced bone density by 12% (p 0.0001) and 11% (p 0.0001) for 2.5 mm and 1.5 mm pilot hole diameters respectively. Pull-out strength reduced by 50% (p = 0.0001) and 44% (p 0.0001) following demineralisation for both 2.5 mm and 1.5 mm pilot hole diameters. Pull-out strength increased by 51% (p = 0.0008) when inserting screws into 1.5 mm pilot holes in low density bone, and by 28% (p = 0.027) in normal bone.Porcine bone can be demineralised to model low density cancellous bone. This novel model showed that pullout force is significantly reduced in lower density screw holes, but that this reduction can be mitigated by reducing pilot hole diameter for cancellous screws.
- Published
- 2020
18. BRepertoire: a user-friendly web server for analysing antibody repertoire data
- Author
-
Catherine L. Townsend, Franca Fraternali, Christian Margreitter, Hui-Chun Lu, Deborah K. Dunn-Walters, and Alexander J. Stewart
- Subjects
0301 basic medicine ,Web server ,Statistical methods ,B-CELL ,Biology ,computer.software_genre ,03 medical and health sciences ,Antibody Repertoire ,Genetics ,Cluster Analysis ,Humans ,Use case ,Cluster analysis ,User Friendly ,Internet ,Information retrieval ,Repertoire ,Computational Biology ,High-Throughput Nucleotide Sequencing ,computer.file_format ,Genomics ,3. Good health ,030104 developmental biology ,ANTIBODIES ,Web Server Issue ,Table (database) ,Image file formats ,computer ,Software - Abstract
Antibody repertoire analysis by high throughput sequencing is now widely used, but a persisting challenge is enabling immunologists to explore their data to discover discriminating repertoire features for their own particular investigations. Computational methods are necessary for large-scale evaluation of antibody properties. We have developed BRepertoire, a suite of user-friendly web-based software tools for large-scale statistical analyses of repertoire data. The software is able to use data preprocessed by IMGT, and performs statistical and comparative analyses with versatile plotting options. BRepertoire has been designed to operate in various modes, for example analysing sequence-specific V(D)J gene usage, discerning physico-chemical properties of the CDR regions and clustering of clonotypes. Those analyses are performed on the fly by a number of R packages and are deployed by a shiny web platform. The user can download the analysed data in different table formats and save the generated plots as image files ready for publication. We believe BRepertoire to be a versatile analytical tool that complements experimental studies of immune repertoires. To illustrate the server’s functionality, we show use cases including differential gene usage in a vaccination dataset and analysis of CDR3H properties in old and young individuals. The server is accessible under http://mabra.biomed.kcl.ac.uk/BRepertoire.
- Published
- 2018
19. Radical and Ionic Mechanisms in Rearrangements of o-Tolyl Aryl Ethers and Amines Initiated by the Grubbs–Stoltz Reagent, Et3SiH/KOtBu
- Author
-
Alexander J. Stewart, Tell Tuttle, Krystian Kolodziejczak, and John A. Murphy
- Subjects
diarylmethanes ,Radical ,Reactive intermediate ,Pharmaceutical Science ,Truce–Smiles rearrangement ,carbanion ,DFT ,Medicinal chemistry ,dihydroacridines ,Analytical Chemistry ,chemistry.chemical_compound ,QD241-441 ,Deprotonation ,aryl substitution ,Drug Discovery ,potassium tert-butoxide ,QD ,Physical and Theoretical Chemistry ,Carbanion ,radical ,Grubbs–Stoltz reagent ,Chemistry ,Aryl ,Organic Chemistry ,electron transfer ,triethylsilane ,Chemistry (miscellaneous) ,Reagent ,Molecular Medicine ,Triethylsilane ,Methyl group - Abstract
Rearrangements of o-tolyl aryl ethers, amines, and sulfides with the Grubbs–Stoltz reagent (Et3SiH + KOtBu) were recently announced, in which the ethers were converted to o-hydroxydiarylmethanes, while the (o-tol)(Ar)NH amines were transformed into dihydroacridines. Radical mechanisms were proposed, based on prior evidence for triethylsilyl radicals in this reagent system. A detailed computational investigation of the rearrangements of the aryl tolyl ethers now instead supports an anionic Truce–Smiles rearrangement, where the initial benzyl anion can be formed by either of two pathways: (i) direct deprotonation of the tolyl methyl group under basic conditions or (ii) electron transfer to an initially formed benzyl radical. By contrast, the rearrangements of o-tolyl aryl amines depend on the nature of the amine. Secondary amines undergo deprotonation of the N-H followed by a radical rearrangement, to form dihydroacridines, while tertiary amines form both dihydroacridines and diarylmethanes through radical and/or anionic pathways. Overall, this study highlights the competition between the reactive intermediates formed by the Et3SiH/KOtBu system.
- Published
- 2021
20. Author response: Evolution of empathetic moral evaluation
- Author
-
Arunas L. Radzvilavicius, Joshua B. Plotkin, and Alexander J. Stewart
- Published
- 2019
21. Information gerrymandering and undemocratic decisions
- Author
-
Alexander J, Stewart, Mohsen, Mosleh, Marina, Diakonova, Antonio A, Arechar, David G, Rand, and Joshua B, Plotkin
- Subjects
Knowledge ,Bias ,Game Theory ,Decision Making ,Politics ,Humans ,Models, Theoretical ,Truth Disclosure ,Democracy ,Social Media ,Group Processes ,Social Networking - Abstract
People must integrate disparate sources of information when making decisions, especially in social contexts. But information does not always flow freely. It can be constrained by social networks
- Published
- 2018
22. Partitioning the environmental drivers of immunocompetence
- Author
-
Pascal I. Hablützel, Joseph A. Jackson, Alexander J. Stewart, Rebecca Synnott, Ida M. Friberg, Joanne Cable, and Numair Masud
- Subjects
Environmental Engineering ,010504 meteorology & atmospheric sciences ,Ecoimmunology ,Disease ,Gasterosteus ,010501 environmental sciences ,01 natural sciences ,Immune system ,biology.animal ,Animals ,Environmental Chemistry ,Waste Management and Disposal ,0105 earth and related environmental sciences ,biology ,Immunity ,Stickleback ,Vertebrate ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,Pollution ,Smegmamorpha ,Evolutionary biology ,Vertebrates ,bacteria ,Vital rates ,Immunocompetence - Abstract
By determining susceptibility to disease, environment-driven variation in immune responses can affect the health, productivity and fitness of vertebrates. Yet how the different components of the total environment control this immune variation is remarkably poorly understood. Here, through combining field observation, experimentation and modelling, we are able to quantitatively partition the key environmental drivers of constitutive immune allocation in a model wild vertebrate (three-spined stickleback, Gasterosteus aculeatus). We demonstrate that, in natural populations, thermal conditions and diet alone are sufficient (and necessary) to explain a dominant (seasonal) axis of variation in immune allocation. This dominant axis contributes to both infection resistance and tolerance and, in turn, to the vital rates of infectious agents and the progression of the disease they cause. Our results illuminate the environmental regulation of vertebrate immunity (given the evolutionary conservation of the molecular pathways involved) and they identify mechanisms through which immunocompetence and host-parasite dynamics might be impacted by changing environments. In particular, we predict a dominant sensitivity of immunocompetence and immunocompetence-driven host-pathogen dynamics to host diet shifts.
- Published
- 2020
23. Half the story : thermal effects on within-host infectious disease progression in a warming climate
- Author
-
Martha Brown, Pascal I. Hablützel, Ida M. Friberg, Sophie Parker‐Norman, Joanne Cable, Anna G. Thomason, Hayley V. Watson, Anya V. Tober, Alexander J. Stewart, and Joseph A. Jackson
- Subjects
0106 biological sciences ,0301 basic medicine ,Systems analysis ,Disease ,Saprolegnia ,Biology ,Global Warming ,010603 evolutionary biology ,01 natural sciences ,Mesocosm ,Fish Diseases ,03 medical and health sciences ,Animals ,Environmental Chemistry ,Gasterosteus aculeatus ,General Environmental Science ,Global and Planetary Change ,Ecology ,Phenology ,Global warming ,Temperature ,Immunity ,Stickleback ,biology.organism_classification ,Smegmamorpha ,3. Good health ,030104 developmental biology ,13. Climate action ,Infectious disease (medical specialty) ,Ectotherm ,Seasons ,Immunocompetence - Abstract
Immune defense is temperature dependent in cold-blooded vertebrates (CBVs) and thus directly impacted by global warming. We examined whether immunity and within-host infectious disease progression are altered in CBVs under realistic climate warming in a seasonal mid-latitude setting. Going further, we also examined how large thermal effects are in relation to the effects of other environmental variation in such a setting (critical to our ability to project infectious disease dynamics from thermal relationships alone). We employed the three-spined stickleback and three ecologically relevant parasite infections as a “wild” model. To generate a realistic climatic warming scenario we used naturalistic outdoors mesocosms with precise temperature control. We also conducted laboratory experiments to estimate thermal effects on immunity and within-host infectious disease progression under controlled conditions. As experimental readouts we measured disease progression for the parasites and expression in 14 immune-associated genes (providing insight into immunophenotypic responses). Our mesocosm experiment demonstrated significant perturbation due to modest warming (+2°C), altering the magnitude and phenology of disease. Our laboratory experiments demonstrated substantial thermal effects. Prevailing thermal effects were more important than lagged thermal effects and disease progression increased or decreased in severity with increasing temperature in an infection-specific way. Combining laboratory-determined thermal effects with our mesocosm data, we used inverse modeling to partition seasonal variation in Saprolegnia disease progression into a thermal effect and a latent immunocompetence effect (driven by nonthermal environmental variation and correlating with immune gene expression). The immunocompetence effect was large, accounting for at least as much variation in Saprolegnia disease as the thermal effect. This suggests that managers of CBV populations in variable environments may not be able to reliably project infectious disease risk from thermal data alone. Nevertheless, such projections would be improved by primarily considering prevailing thermal effects in the case of within-host disease and by incorporating validated measures of immunocompetence.
- Published
- 2018
24. Bank voles (Myodes glareolus) and house mice (Mus musculus musculus; M. m. domesticus) in Europe are each parasitized by their own distinct species ofAspiculuris(Nematoda, Oxyurida)
- Author
-
Anna Bajer, Maciej Grzybek, Ann Lowe, Alexander J. Stewart, Philip D. Harris, Kurt J. Vandegrift, J. M. Behnke, Lesley R. Smales, and Alexis Ribas
- Subjects
Male ,Veterinary medicine ,Range (biology) ,Molecular Sequence Data ,Zoology ,DNA, Mitochondrial ,DNA, Ribosomal ,Electron Transport Complex IV ,Rodent Diseases ,Mice ,Oxyuroidea ,Genus ,Animals ,Microtus ,Phylogeny ,Oxyuriasis ,Base Sequence ,biology ,Arvicolinae ,Host (biology) ,Sequence Analysis, DNA ,DNA, Helminth ,biology.organism_classification ,Biological Evolution ,Europe ,Infectious Diseases ,Nematode ,Molecular phylogenetics ,Female ,Animal Science and Zoology ,Parasitology ,House mice ,Oxyurida - Abstract
SUMMARYThe molecular phylogeny and morphology of the oxyuroid nematode genusAspiculurisfrom voles and house mice has been examined. Worms collected fromMyodes glareolusin Poland, Eire and the UK are identified asAspiculuris tianjinensis, previously known only from China, while worms fromMus musculusfrom a range of locations in Europe and from laboratory mice, all conformed to the description ofAspiculuris tetraptera. Worms from voles and house mice are not closely related and are not derived from each other, withA. tianjinensisbeing most closely related toAspiculuris dinnikifrom snow voles and to an isolate fromMicrotus longicaudusin the Nearctic. BothA. tianjinensisandA. tetrapteraappear to represent recent radiations within their host groups; in voles, this radiation cannot be more than 2 million years old, while in commensal house mice it is likely to be less than 10 000 years old. The potential ofAspiculurisspp. as markers of host evolution is highlighted.
- Published
- 2015
25. Hook, Line and Infection
- Author
-
Alexander J. Stewart, Pieter van West, Chris F. Williams, Joanne Cable, Iain Barber, Joseph A. Jackson, Christophe Eizaguirre, and Rachel A. Paterson
- Subjects
0106 biological sciences ,0301 basic medicine ,biology ,ved/biology ,Three-spined stickleback ,business.industry ,Ecology (disciplines) ,ved/biology.organism_classification_rank.species ,Stickleback ,Zoology ,Gasterosteus ,biology.organism_classification ,010603 evolutionary biology ,01 natural sciences ,03 medical and health sciences ,Coldwater fish ,030104 developmental biology ,Parasitology ,Aquaculture ,Model organism ,business - Abstract
The three-spined stickleback (Gasterosteus aculeatus) is a model organism with an extremely well-characterized ecology, evolutionary history, behavioural repertoire and parasitology that is coupled with published genomic data. These small temperate zone fish therefore provide an ideal experimental system to study common diseases of coldwater fish, including those of aquacultural importance. However, detailed information on the culture of stickleback parasites, the establishment and maintenance of infections and the quantification of host responses is scattered between primary and grey literature resources, some of which is not readily accessible. Our aim is to lay out a framework of techniques based on our experience to inform new and established laboratories about culture techniques and recent advances in the field. Here, essential knowledge on the biology, capture and laboratory maintenance of sticklebacks, and their commonly studied parasites is drawn together, highlighting recent advances in our understanding of the associated immune responses. In compiling this guide on the maintenance of sticklebacks and a range of common, taxonomically diverse parasites in the laboratory, we aim to engage a broader interdisciplinary community to consider this highly tractable model when addressing pressing questions in evolution, infection and aquaculture.
- Published
- 2017
26. Sexual antagonism drives the displacement of polymorphism across gene regulatory cascades
- Author
-
Alexander J. Stewart, Max Reuter, and Mark S. Hill
- Subjects
Male ,0106 biological sciences ,Evolution ,Population ,Locus (genetics) ,Biology ,010603 evolutionary biology ,01 natural sciences ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Gene expression ,Genetic variation ,Animals ,Gene Regulatory Networks ,Allele ,education ,Evolutionary dynamics ,Gene ,030304 developmental biology ,General Environmental Science ,Regulation of gene expression ,Sex Characteristics ,0303 health sciences ,education.field_of_study ,Binding Sites ,Polymorphism, Genetic ,General Immunology and Microbiology ,Reproduction ,General Medicine ,Mating Preference, Animal ,Adaptation, Physiological ,Sexual dimorphism ,Evolutionary biology ,Female ,General Agricultural and Biological Sciences - Abstract
Males and females have different reproductive roles and are often subject to contrasting selection pressures. This sexual antagonism can lead, at a given locus, to different alleles being favoured in each sex and, consequently, to genetic variation being maintained in a population. Although the presence of sexually antagonistic (SA) polymorphisms has been documented across a range of species, their evolutionary dynamics remain poorly understood. Here, we study SA selection on gene expression, which is fundamental to sexual dimorphism, via the evolution of regulatory binding sites. We show that for sites longer than 1 nucleotide, expression polymorphism is maintained only when intermediate expression levels are deleterious to both sexes. We then show that, in a regulatory cascade, expression polymorphism tends to become displaced over evolutionary time from the target of SA selection to upstream regulators. Our results have consequences for understanding the evolution of sexual dimorphism, and provide specific empirical predictions for the regulatory architecture of genes under SA selection.
- Published
- 2019
27. From extortion to generosity, evolution in the Iterated Prisoner’s Dilemma
- Author
-
Alexander J. Stewart and Joshua B. Plotkin
- Subjects
education.field_of_study ,Multidisciplinary ,Population ,Context (language use) ,Prisoner's dilemma ,Models, Psychological ,Biological Sciences ,Altruism (biology) ,Altruism ,Biological Evolution ,Microeconomics ,Tit for tat ,Superrationality ,Game Theory ,Economics ,Repeated game ,Humans ,Computer Simulation ,Cooperative Behavior ,education ,Game theory - Abstract
Recent work has revealed a new class of "zero-determinant" (ZD) strategies for iterated, two-player games. ZD strategies allow a player to unilaterally enforce a linear relationship between her score and her opponent's score, and thus to achieve an unusual degree of control over both players' long-term payoffs. Although originally conceived in the context of classical two-player game theory, ZD strategies also have consequences in evolving populations of players. Here, we explore the evolutionary prospects for ZD strategies in the Iterated Prisoner's Dilemma (IPD). Several recent studies have focused on the evolution of "extortion strategies," a subset of ZD strategies, and have found them to be unsuccessful in populations. Nevertheless, we identify a different subset of ZD strategies, called "generous ZD strategies," that forgive defecting opponents but nonetheless dominate in evolving populations. For all but the smallest population sizes, generous ZD strategies are not only robust to being replaced by other strategies but can selectively replace any noncooperative ZD strategy. Generous strategies can be generalized beyond the space of ZD strategies, and they remain robust to invasion. When evolution occurs on the full set of all IPD strategies, selection disproportionately favors these generous strategies. In some regimes, generous strategies outperform even the most successful of the well-known IPD strategies, including win-stay-lose-shift.
- Published
- 2013
28. Small groups and long memories promote cooperation
- Author
-
Joshua B. Plotkin, Alexander J. Stewart, and University of St Andrews. Applied Mathematics
- Subjects
0301 basic medicine ,Operations research ,Computer science ,QH301 Biology ,T-NDAS ,Decision Making ,Evolutionary game theory ,Models, Psychological ,Collective action ,Memory/physiology ,Article ,QH301 ,03 medical and health sciences ,Interpersonal relationship ,0302 clinical medicine ,Game Theory ,Memory ,Sociobiology ,Humans ,Interpersonal Relations ,QA Mathematics ,Cooperative Behavior ,QA ,Cognitive science ,Multidisciplinary ,Models, Statistical ,Decision Making/physiology ,030104 developmental biology ,Games, Experimental ,Construct (philosophy) ,Game theory ,030217 neurology & neurosurgery ,Social behavior - Abstract
Complex social behaviors lie at the heart of many of the challenges facing evolutionary biology, sociology, economics, and beyond. For evolutionary biologists the question is often how group behaviors such as collective action, or decision making that accounts for memories of past experience, can emerge and persist in an evolving system. Evolutionary game theory provides a framework for formalizing these questions and admitting them to rigorous study. Here we develop such a framework to study the evolution of sustained collective action in multi-player public-goods games, in which players have arbitrarily long memories of prior rounds of play and can react to their experience in an arbitrary way. We construct a coordinate system for memory-m strategies in iterated n-player games that permits us to characterize all cooperative strategies that resist invasion by any mutant strategy, and stabilize cooperative behavior. We show that, especially when groups are small, longer-memory strategies make cooperation easier to evolve, by increasing the number of ways to stabilize cooperation. We also explore the co-evolution of behavior and memory. We find that even when memory has a cost, longer-memory strategies often evolve, which in turn drives the evolution of cooperation, even when the benefits for cooperation are low.
- Published
- 2016
- Full Text
- View/download PDF
29. Evolutionary consequences of behavioral diversity
- Author
-
Joshua B. Plotkin, Alexander J. Stewart, Todd L. Parsons, University College of London [London] (UCL), Laboratoire de Probabilités et Modèles Aléatoires (LPMA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania, and University of Pennsylvania [Philadelphia]
- Subjects
0301 basic medicine ,Physics - Physics and Society ,Punishment (psychology) ,Fitness landscape ,FOS: Physical sciences ,Physics and Society (physics.soc-ph) ,01 natural sciences ,Microeconomics ,03 medical and health sciences ,0103 physical sciences ,Economics ,Quantitative Biology - Populations and Evolution ,010306 general physics ,Multidisciplinary ,Ecology ,Stochastic game ,Populations and Evolution (q-bio.PE) ,Public good ,Social relation ,[MATH.MATH-PR]Mathematics [math]/Probability [math.PR] ,Social dynamics ,030104 developmental biology ,PNAS Plus ,FOS: Biological sciences ,Game theory ,Diversity (business) - Abstract
Iterated games provide a framework to describe social interactions among groups of individuals. Recent work stimulated by the discovery of "zero-determinant" strategies has rapidly expanded our ability to analyze such interactions. This body of work has primarily focused on games in which players face a simple binary choice, to "cooperate" or "defect". Real individuals, however, often exhibit behavioral diversity, varying their input to a social interaction both qualitatively and quantitatively. Here we explore how access to a greater diversity of behavioral choices impacts the evolution of social dynamics in finite populations. We show that, in public goods games, some two-choice strategies can nonetheless resist invasion by all possible multi-choice invaders, even while engaging in relatively little punishment. We also show that access to greater behavioral choice results in more "rugged " fitness landscapes, with populations able to stabilize cooperation at multiple levels of investment, such that choice facilitates cooperation when returns on investments are low, but hinders cooperation when returns on investments are high. Finally, we analyze iterated rock-paper-scissors games, whose non-transitive payoff structure means unilateral control is difficult and zero-determinant strategies do not exist in general. Despite this, we find that a large portion of multi-choice strategies can invade and resist invasion by strategies that lack behavioral diversity -- so that even well-mixed populations will tend to evolve behavioral diversity., Comment: 26 pages, 4 figures
- Published
- 2016
30. Collapse of cooperation in evolving games
- Author
-
Alexander J. Stewart and Joshua B. Plotkin
- Subjects
Physics::Physics and Society ,Computer Science::Computer Science and Game Theory ,Genotype ,Evolutionary game theory ,Peace war game ,Strong reciprocity ,Outcome (game theory) ,ComputingMethodologies_ARTIFICIALINTELLIGENCE ,Microeconomics ,Superrationality ,Game Theory ,Reward ,Memory ,Economics ,Quantitative Biology::Populations and Evolution ,Humans ,Interpersonal Relations ,Cooperative Behavior ,Quantitative Biology - Populations and Evolution ,Multidisciplinary ,Bacteria ,Stochastic game ,Populations and Evolution (q-bio.PE) ,Prisoner's dilemma ,Biological Sciences ,Biological Evolution ,FOS: Biological sciences ,Mutation ,Recreation ,Game theory - Abstract
Game theory provides a quantitative framework for analyzing the behavior of rational agents. The Iterated Prisoner's Dilemma in particular has become a standard model for studying cooperation and cheating, with cooperation often emerging as a robust outcome in evolving populations. Here we extend evolutionary game theory by allowing players' strategies as well as their payoffs to evolve in response to selection on heritable mutations. In nature, many organisms engage in mutually beneficial interactions, and individuals may seek to change the ratio of risk to reward for cooperation by altering the resources they commit to cooperative interactions. To study this, we construct a general framework for the co-evolution of strategies and payoffs in arbitrary iterated games. We show that, as payoffs evolve, a trade-off between the benefits and costs of cooperation precipitates a dramatic loss of cooperation under the Iterated Prisoner's Dilemma; and eventually to evolution away from the Prisoner's Dilemma altogether. The collapse of cooperation is so extreme that the average payoff in a population may decline, even as the potential payoff for mutual cooperation increases. Our work offers a new perspective on the Prisoner's Dilemma and its predictions for cooperation in natural populations; and it provides a general framework to understand the co-evolution of strategies and payoffs in iterated interactions., 33 pages, 13 figures
- Published
- 2014
31. Under-dominance constrains the evolution of negative autoregulation in diploids
- Author
-
Robert M. Seymour, Andrew Pomiankowski, Max Reuter, Alexander J. Stewart, and University of St Andrews. Applied Mathematics
- Subjects
Molecular Networks (q-bio.MN) ,Gene regulatory network ,Cellular homeostasis ,Saccharomyces cerevisiae/genetics ,0302 clinical medicine ,Homeostasis ,Autoregulation ,Gene Regulatory Networks ,Quantitative Biology - Molecular Networks ,Biology (General) ,Regulation of gene expression ,Genetics ,0303 health sciences ,Ecology ,biology ,QR Microbiology ,Drosophila melanogaster ,Computational Theory and Mathematics ,Modeling and Simulation ,Monte Carlo Method ,Research Article ,QH301-705.5 ,Saccharomyces cerevisiae ,Transcription Factors/genetics ,QH426 Genetics ,Molecular Dynamics Simulation ,Evolution, Molecular ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Escherichia coli ,Animals ,Humans ,Quantitative Biology - Genomics ,Quantitative Biology - Populations and Evolution ,Biology ,Molecular Biology ,Transcription factor ,QH426 ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Genomics (q-bio.GN) ,Evolutionary Biology ,Binding Sites ,Models, Genetic ,Human evolutionary genetics ,fungi ,Populations and Evolution (q-bio.PE) ,biology.organism_classification ,Diploidy ,QR ,Escherichia coli/genetics ,Gene Expression Regulation ,FOS: Biological sciences ,Mutation ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
Regulatory networks have evolved to allow gene expression to rapidly track changes in the environment as well as to buffer perturbations and maintain cellular homeostasis in the absence of change. Theoretical work and empirical investigation in Escherichia coli have shown that negative autoregulation confers both rapid response times and reduced intrinsic noise, which is reflected in the fact that almost half of Escherichia coli transcription factors are negatively autoregulated. However, negative autoregulation is rare amongst the transcription factors of Saccharomyces cerevisiae. This difference is surprising because E. coli and S. cerevisiae otherwise have similar profiles of network motifs. In this study we investigate regulatory interactions amongst the transcription factors of Drosophila melanogaster and humans, and show that they have a similar dearth of negative autoregulation to that seen in S. cerevisiae. We then present a model demonstrating that this stiking difference in the noise reduction strategies used amongst species can be explained by constraints on the evolution of negative autoregulation in diploids. We show that regulatory interactions between pairs of homologous genes within the same cell can lead to under-dominance — mutations which result in stronger autoregulation, and decrease noise in homozygotes, paradoxically can cause increased noise in heterozygotes. This severely limits a diploid's ability to evolve negative autoregulation as a noise reduction mechanism. Our work offers a simple and general explanation for a previously unexplained difference between the regulatory architectures of E. coli and yeast, Drosophila and humans. It also demonstrates that the effects of diploidy in gene networks can have counter-intuitive consequences that may profoundly influence the course of evolution., Author Summary All genes have to deal with intrinsic noise, and a variety of mechanisms have evolved to reduce it. One important mechanism of noise reduction for transcription factors is negative autoregulation, in which a gene product represses its own rate of transcription. Negative auotregulation occurs frequently in E. coli but, we find, occurs much more rarely in S. cerevisiae, D. melanogaster and humans. Whilst there are a great many important differences in the genetic architectures of these organisms, they tend to share, with the exception of negative autoregulation, similar profiles of network motifs. This makes the discrepancy in the degree of negative autoregulation all the more striking, as it lacks any obvious explanation. Our study presents a potential explanation, by comparing the evolvability of negative autoregulation as a noise reduction mechanism in haploids and diploids. We show that, in diploids, mutations that increase the strength of negative autoregulation at one gene copy often increase overall noise in gene expression. This results in under-dominance, in which heterozygotes are less fit than homozygotes. The result is that the evolution of negative autoregulation in diploids is significantly constrained. We verify our results using a combination of detailed molecular simulations and evolutionary simulations
- Published
- 2012
32. The population genetics of cooperative gene regulation
- Author
-
Joshua B. Plotkin, Andrew Pomiankowski, Robert M. Seymour, Alexander J. Stewart, and University of St Andrews. Applied Mathematics
- Subjects
0106 biological sciences ,Evolution, molecular ,Selection, genetic ,genetic structures ,Evolution ,Mutation rate ,QH301 Biology ,Gene regulatory network ,Cooperativity ,QH426 Genetics ,Models, genetic ,Biology ,Genetics, population/methods ,010603 evolutionary biology ,01 natural sciences ,Gene regulatory networks ,Evolution, Molecular ,QH301 ,03 medical and health sciences ,Mutation Rate ,QH359-425 ,Protein binding ,Gene Regulatory Networks ,Selection, Genetic ,Evolutionary dynamics ,QH426 ,Gene ,Transcription factor ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Gene expression regulation ,Regulation of gene expression ,0303 health sciences ,Binding Sites ,Models, Genetic ,Binding sites/genetics ,Transcription factors/metabolism ,Cooperative binding ,DNA binding site ,Genetics, Population ,Gene Expression Regulation ,Evolutionary biology ,Algorithms ,Research Article ,Protein Binding ,Transcription Factors - Abstract
JBP and AJS acknowledge funding from the Burroughs Wellcome Fund, the David and Lucile Packard Foundation, the James S. McDonnell Foundation, the Alfred P. Sloan Foundation, grant #D12AP00025 from the U.S. Department of the Interior and Defense Advanced Research Projects Agency, and grant RFP-12-16 from the Foundational Questions in Evolutionary Biology Fund. AP acknowledges grants from the Natural Environment Research Council (NE/G00563X/1) and the Engineering and Physical Sciences Research Council (EP/F500351/1, EP/I017909/1). AJS also acknowledges an EPSRC PhD Plus fellowship. Background: Changes in gene regulatory networks drive the evolution of phenotypic diversity both within and between species. Rewiring of transcriptional networks is achieved either by changes to transcription factor binding sites or by changes to the physical interactions among transcription factor proteins. It has been suggested that the evolution of cooperative binding among factors can facilitate the adaptive rewiring of a regulatory network. Results: We use a population-genetic model to explore when cooperative binding of transcription factors is favored by evolution, and what effects cooperativity then has on the adaptive re-writing of regulatory networks. We consider a pair of transcription factors that regulate multiple targets and overlap in the sets of target genes they regulate. We show that, under stabilising selection, cooperative binding between the transcription factors is favoured provided the amount of overlap between their target genes exceeds a threshold. The value of this threshold depends on several population-genetic factors: strength of selection on binding sites, cost of pleiotropy associated with protein-protein interactions, rates of mutation and population size. Once it is established, we find that cooperative binding of transcription factors significantly accelerates the adaptive rewiring of transcriptional networks under positive selection. We compare our qualitative predictions to systematic data on Saccharomyces cerevisiae transcription factors, their binding sites, and their protein-protein interactions. Conclusions: Our study reveals a rich set of evolutionary dynamics driven by a tradeoff between the beneficial effects of cooperative binding at targets shared by a pair of factors, and the detrimental effects of cooperative binding for non-shared targets. We find that cooperative regulation will evolve when transcription factors share a sufficient proportion of their target genes. These findings help to explain empirical pattens in datasets of transcription factors in Saccharomyces cerevisiae and, they suggest that changes to physical interactions between transcription factors can play a critical role in the evolution of gene regulatory networks. Publisher PDF
- Published
- 2012
33. Why transcription factor binding sites are ten nucleotides long
- Author
-
Joshua B. Plotkin, Sridhar Hannenhalli, and Alexander J. Stewart
- Subjects
Mutation rate ,Population ,Plasma protein binding ,Biology ,Investigations ,Models, Biological ,Evolution, Molecular ,Mutation Rate ,Bacterial transcription ,Genetics ,Animals ,Humans ,Computer Simulation ,Binding site ,Nucleotide Motifs ,education ,Transcription factor ,education.field_of_study ,Binding Sites ,Reproduction ,Robustness (evolution) ,DNA ,DNA binding site ,Genetics, Population ,Algorithms ,Protein Binding ,Transcription Factors - Abstract
Gene expression is controlled primarily by transcription factors, whose DNA binding sites are typically 10 nt long. We develop a population-genetic model to understand how the length and information content of such binding sites evolve. Our analysis is based on an inherent trade-off between specificity, which is greater in long binding sites, and robustness to mutation, which is greater in short binding sites. The evolutionary stable distribution of binding site lengths predicted by the model agrees with the empirical distribution (5–31 nt, with mean 9.9 nt for eukaryotes), and it is remarkably robust to variation in the underlying parameters of population size, mutation rate, number of transcription factor targets, and strength of selection for proper binding and selection against improper binding. In a systematic data set of eukaryotic and prokaryotic transcription factors we also uncover strong relationships between the length of a binding site and its information content per nucleotide, as well as between the number of targets a transcription factor regulates and the information content in its binding sites. Our analysis explains these features as well as the remarkable conservation of binding site characteristics across diverse taxa.
- Published
- 2012
34. Extortion and cooperation in the Prisoner’s Dilemma
- Author
-
Alexander J. Stewart and Joshua B. Plotkin
- Subjects
Non-cooperative game ,Multidisciplinary ,Prisoners ,Prisoner's dilemma ,Rational agent ,Deadlock (game theory) ,Models, Psychological ,Dilemma ,Superrationality ,Extortion ,Game Theory ,Commentaries ,Humans ,Psychology ,Social psychology ,Game theory ,Law and economics - Abstract
The two-player Iterated Prisoner's Dilemma game is a model for both sentient and evolutionary behaviors, especially including the emergence of cooperation. It is generally assumed that there exists no simple ultimatum strategy whereby one player can enforce a unilateral claim to an unfair share of rewards. Here, we show that such strategies unexpectedly do exist. In particular, a player X who is witting of these strategies can (i) deterministically set her opponent Y's score, independently of his strategy or response, or (ii) enforce an extortionate linear relation between her and his scores. Against such a player, an evolutionary player's best response is to accede to the extortion. Only a player with a theory of mind about his opponent can do better, in which case Iterated Prisoner's Dilemma is an Ultimatum Game.
- Published
- 2012
35. Environmental robustness and the adaptability of populations
- Author
-
Alexander J, Stewart, Todd L, Parsons, and Joshua B, Plotkin
- Subjects
Population Density ,Phenotype ,Genotype ,Models, Genetic ,Adaptation, Biological ,Genetic Variation ,Environment ,Selection, Genetic - Abstract
Recent work has shown that genetic robustness can either facilitate or impede adaptation. But the impact of environmental robustness on adaptation remains unclear. Environmental robustness helps ensure that organisms consistently develop the same phenotype in the face of "environmental noise" during development. Under purifying selection, those genotypes that express the optimal phenotype most reliably will be selectively favored. The resulting reduction in genetic variation tends to slow adaptation when the population is faced with a novel target phenotype. However, environmental noise sometimes induces the expression of an alternative advantageous phenotype, which may speed adaptation by genetic assimilation. Here, we use a population-genetic model to explore how these two opposing effects of environmental noise influence the capacity of a population to adapt. We analyze how the rate of adaptation depends on the frequency of environmental noise, the degree of environmental robustness in the population, the distribution of environmental robustness across genotypes, the population size, and the strength of selection for a newly adaptive phenotype. Over a broad regime, we find that environmental noise can either facilitate or impede adaptation. Our analysis uncovers several surprising insights about the relationship between environmental noise and adaptation, and it provides a general framework for interpreting empirical studies of both genetic and environmental robustness.
- Published
- 2012
36. Degree dependence in rates of transcription factor evolution explains the unusual structure of transcription networks
- Author
-
Alexander J. Stewart, Andrew Pomiankowski, and Robert M. Seymour
- Subjects
Genetics ,Regulation of gene expression ,Binding Sites ,General Immunology and Microbiology ,Models, Genetic ,Robustness (evolution) ,General Medicine ,Biology ,Degree distribution ,General Biochemistry, Genetics and Molecular Biology ,Evolution, Molecular ,Gene Expression Regulation ,Transcription (biology) ,Evolutionary biology ,Gene Duplication ,Gene duplication ,Mutation ,Rate of evolution ,General Agricultural and Biological Sciences ,Transcription factor ,Gene ,Gene Deletion ,General Environmental Science ,Transcription Factors ,Research Article - Abstract
Transcription networks have an unusual structure. In both prokaryotes and eukaryotes, the number of target genes regulated by each transcription factor, its out -degree, follows a broad tailed distribution. By contrast, the number of transcription factors regulating a target gene, its in -degree, follows a much narrower distribution, which has no broad tail. We constructed a model of transcription network evolution through trans - and cis -mutations, gene duplication and deletion. The effects of these different evolutionary processes on the network structure are enough to produce an asymmetrical in - and out -degree distribution. However, the parameter values required to replicate known in - and out -degree distributions are unrealistic. We then considered variation in the rate of evolution of a gene dependent upon its position in the network. When transcription factors with many regulatory interactions are constrained to evolve more slowly than those with few interactions, the details of the in - and out -degree distributions of transcription networks can be fully reproduced over a range of plausible parameter values. The networks produced by our model depend on the relative rates of the different evolutionary processes. By determining the circumstances under which the networks with the correct degree distributions are produced, we are able to assess the relative importance of the different evolutionary processes in our model during evolution.
- Published
- 2009
37. Educational needs of dental trainers
- Author
-
Alexander J. Stewart
- Subjects
Medical education ,business.industry ,Teaching ,education ,Primary care ,Work in process ,Key issues ,Feedback ,Work (electrical) ,Scotland ,ComputingMilieux_COMPUTERSANDEDUCATION ,Medicine ,Humans ,Clinical Competence ,Curriculum ,business ,General Dentistry ,Education, Dental ,Needs Assessment - Abstract
The development of a curriculum for trainers in dental primary care, and its use in an assessment of their educational needs, was described in a previous paper1. This paper describes work in progress, which seeks to address the key issues raised by the earlier work.
- Published
- 2003
38. An assessment of the educational needs of dental trainers, based on an outcome-based curriculum
- Author
-
Alexander J, Stewart and Janet, Clarkson
- Subjects
Scotland ,Surveys and Questionnaires ,Mentors ,Humans ,Clinical Competence ,Curriculum ,Education, Dental, Graduate ,Needs Assessment - Abstract
To develop a curriculum for dental trainers and use it as a basis for an assessment of their learning needs.A selected group of dental trainers in Scotland using a nominal group technique produced a list of learning outcomes for trainers. Outcomes were categorised as essential for all trainers, desirable for intermediate trainer development or optional for experienced trainers. The format of an outcome-based curriculum for medical teachers was adopted and a draft dental version produced, 'The effective dental trainer". This was finalised after further consultation and used to devise a needs assessment questionnaire which was sent to all Scottish dental trainers.The response rate was 100%. The list of learning outcomes considered to be essential was extensive and most trainers reported high levels of confidence and ability in core outcomes. Few statistically significant differences between the responses given by new, intermediate and experienced trainers were found.The limitations of self-reported learning needs in response to a questionnaire are highlighted by the small number of differences in confidence and ability reported by trainers with varied experience. A more meaningful assessment of learning needs could come from educational appraisal of all trainers, which is currently taking place.
- Published
- 2002
39. The evolution of complex gene regulation by low-specificity binding sites
- Author
-
Alexander J. Stewart and Joshua B. Plotkin
- Subjects
Molecular Networks (q-bio.MN) ,Computational biology ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Evolution, Molecular ,Gene expression ,Quantitative Biology - Genomics ,Quantitative Biology - Molecular Networks ,Gene Regulatory Networks ,Binding site ,Quantitative Biology - Populations and Evolution ,Gene ,Research Articles ,Binding selectivity ,General Environmental Science ,Genomics (q-bio.GN) ,Regulation of gene expression ,Binding Sites ,Models, Genetic ,General Immunology and Microbiology ,Populations and Evolution (q-bio.PE) ,General Medicine ,DNA binding site ,Gene Expression Regulation ,FOS: Biological sciences ,Mutation ,General Agricultural and Biological Sciences - Abstract
Transcription factor binding sites vary in their specificity, both within and between species. Binding specificity has a strong impact on the evolution of gene expression, because it determines how easily regulatory interactions are gained and lost. Nevertheless, we have a relatively poor understanding of what evolutionary forces determine the specificity of binding sites. Here we address this question by studying regulatory modules composed of multiple binding sites. Using a population-genetic model, we show that more complex regulatory modules, composed of a greater number of binding sites, must employ binding sites that are individually less specific, compared to less complex regulatory modules. This effect is extremely general, and it hold regardless of the regulatory logic of a module. We attribute this phenomenon to the inability of stabilising selection to maintain highly specific sites in large regulatory modules. Our analysis helps to explain broad empirical trends in the yeast regulatory network: those genes with a greater number of transcriptional regulators feature by less specific binding sites, and there is less variance in their specificity, compared to genes with fewer regulators. Likewise, our results also help to explain the well-known trend towards lower specificity in the transcription factor binding sites of higher eukaryotes, which perform complex regulatory tasks, compared to prokaryotes.
- Published
- 2013
40. Seasonal immunoregulation in a naturally-occurring vertebrate
- Author
-
Martha Brown, Ida M. Friberg, Joseph A. Jackson, Alexander J. Stewart, Justin A. Pachebat, Anna G. Thomason, and Pascal I. Hablützel
- Subjects
0301 basic medicine ,Ecoimmunology ,Three-spined stickleback ,Teleost ,Zoology ,Wildlife ,Adaptive Immunity ,Biology ,Immunomodulation ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Immunity ,biology.animal ,Genetics ,Animals ,Gene Regulatory Networks ,14. Life underwater ,Genome ,Innate immune system ,Gene Expression Profiling ,Toll-Like Receptors ,Immunoregulation ,Stickleback ,Vertebrate ,Seasonality ,RNAseq ,biology.organism_classification ,Acquired immune system ,Immunity, Innate ,030104 developmental biology ,Gene Expression Regulation ,Organ Specificity ,Vertebrates ,Seasons ,Research Article ,Genome-Wide Association Study ,Signal Transduction ,030215 immunology ,Biotechnology - Abstract
Background Fishes show seasonal patterns of immunity, but such phenomena are imperfectly understood in vertebrates generally, even in humans and mice. As these seasonal patterns may link to infectious disease risk and individual condition, the nature of their control has real practical implications. Here we characterize seasonal dynamics in the expression of conserved vertebrate immunity genes in a naturally-occurring piscine model, the three-spined stickleback. Results We made genome-wide measurements (RNAseq) of whole-fish mRNA pools (n = 36) at the end of summer and winter in contrasting habitats (riverine and lacustrine) and focussed on common trends to filter habitat-specific from overarching temporal responses. We corroborated this analysis with targeted year-round whole-fish gene expression (Q-PCR) studies in a different year (n = 478). We also considered seasonal tissue-specific expression (6 tissues) (n = 15) at a third contrasting (euryhaline) locality by Q-PCR, further validating the generality of the patterns seen in whole fish analyses. Extremes of season were the dominant predictor of immune expression (compared to sex, ontogeny or habitat). Signatures of adaptive immunity were elevated in late summer. In contrast, late winter was accompanied by signatures of innate immunity (including IL-1 signalling and non-classical complement activity) and modulated toll-like receptor signalling. Negative regulators of T-cell activity were prominent amongst winter-biased genes, suggesting that adaptive immunity is actively down-regulated during winter rather than passively tracking ambient temperature. Network analyses identified a small set of immune genes that might lie close to a regulatory axis. These genes acted as hubs linking summer-biased adaptive pathways, winter-biased innate pathways and other organismal processes, including growth, metabolic dynamics and responses to stress and temperature. Seasonal change was most pronounced in the gill, which contains a considerable concentration of T-cell activity in the stickleback. Conclusions Our results suggest major and predictable seasonal re-adjustments of immunity. Further consideration should be given to the effects of such responses in seasonally-occurring disease. Electronic supplementary material The online version of this article (doi:10.1186/s12864-016-2701-7) contains supplementary material, which is available to authorized users.
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.