Daniel Wilson - Academia.edu (original) (raw)

Papers by Daniel Wilson

Background: Plasmodium vivax malaria is a major public health challenge in Latin America, Asia an... more Background: Plasmodium vivax malaria is a major public health challenge in Latin America, Asia and Oceania, with 130-435 million clinical cases per year worldwide. Invasion of host blood cells by P. vivax mainly depends on a type I membrane protein called Duffy binding protein (PvDBP). The erythrocyte-binding motif of PvDBP is a 170 aminoacid stretch located in its cysteine-rich region II (PvDBP II), which is the most variable segment of the protein. Methods: To test whether diversifying natural selection has shaped the nucleotide diversity of PvDBP II in Brazilian populations, this region was sequenced in 122 isolates from six different geographic areas. A Bayesian method was applied to test for the action of natural selection under a population genetic model that incorporates recombination. The analysis was integrated with a structural model of PvDBP II , and T-and B-cell epitopes were localized on the 3-D structure. Results: The results suggest that: (i) recombination plays an important role in determining the haplotype structure of PvDBP II , and (ii) PvDBP II appears to contain neutrally evolving codons as well as codons evolving under natural selection. Diversifying selection preferentially acts on sites identified as epitopes, particularly on amino acid residues 417, 419, and 424, which show strong linkage disequilibrium. Conclusions: This study shows that some polymorphisms of PvDBP II are present near the erythrocyte-binding domain and might serve to elude antibodies that inhibit cell invasion. Therefore, these polymorphisms should be taken into account when designing vaccines aimed at eliciting antibodies to inhibit erythrocyte invasion.

Whole genome sequencing of bacteria has recently emerged as a cost-effective and convenient appro... more Whole genome sequencing of bacteria has recently emerged as a cost-effective and convenient approach for addressing many microbiological questions. Here we review the current status of clinical microbiology and how it has already begun to be transformed by the use of nextgeneration sequencing. We focus on three essential tasks: identifying the species of an isolate, testing its properties such as resistance to antibiotics and virulence, and monitoring the emergence and spread of bacterial pathogens. The application of next-generation sequencing will soon be sufficiently fast, accurate and cheap to be used in routine clinical microbiology practice, where it could replace many complex current techniques with a single, more efficient workflow.

Through an analysis of polymorphism within and divergence between species, we can hope to learn a... more Through an analysis of polymorphism within and divergence between species, we can hope to learn about the distribution of selective effects of mutations in the genome, changes in the fitness landscape that occur over time, and the location of sites involved in key adaptations that distinguish modern-day species. We introduce a novel method for the analysis of variation in selection pressures within and between species, spatially along the genome and temporally between lineages. We model codon evolution explicitly using a joint population genetics-phylogenetics approach that we developed for the construction of multiallelic models with mutation, selection, and drift. Our approach has the advantage of performing direct inference on coding sequences, inferring ancestral states probabilistically, utilizing allele frequency information, and generalizing to multiple species. We use a Bayesian sliding window model for intragenic variation in selection coefficients that efficiently combines information across sites and captures spatial clustering within the genome. To demonstrate the utility of the method, we infer selective pressures acting in Drosophila melanogaster and D. simulans from polymorphism and divergence data for 100 X-linked coding regions.

Population genetic methods: analytical techniques that primarily make inferences about the popula... more Population genetic methods: analytical techniques that primarily make inferences about the population from which a sample of molecular sequences were drawn, rather than the evolutionary tree of the samples themselves. Recombination: any process that results in the reassortment of genetic material among genomes. Recombination may either be homologous, where equivalent loci are involved, or nonhomologous, where material from different loci are involved. Recombination results in mosaic sequences. Standard neutral model: the simplest model in population genetics. The population is assumed to be of constant size, with no selection, and random mating (for sexual populations).

In bacteria, DNA sequence mismatches act as a barrier to recombination between distantly related ... more In bacteria, DNA sequence mismatches act as a barrier to recombination between distantly related organisms and can potentially promote the cohesion of species. We have performed computer simulations which show that the homology dependence of recombination can cause de novo speciation in a neutrally evolving population once a critical population size has been exceeded. Our model can explain the patterns of divergence and genetic exchange observed in the genus Salmonella, without invoking either natural selection or geographical population subdivision. If this model was validated, based on extensive sequence data, it would imply that the named subspecies of Salmonella enterica correspond to good biological species, making species boundaries objective. However, multilocus sequence typing data, analysed using several conventional tools, provide a misleading impression of relationships within S. enterica subspecies enterica and do not provide the resolution to establish whether new species are presently being formed.

Models of molecular evolution that incorporate the ratio of nonsynonymous to synonymous polymorph... more Models of molecular evolution that incorporate the ratio of nonsynonymous to synonymous polymorphism (d N /d S ratio) as a parameter can be used to identify sites that are under diversifying selection or functional constraint in a sample of gene sequences. However, when there has been recombination in the evolutionary history of the sequences, reconstructing a single phylogenetic tree is not appropriate, and inference based on a single tree can give misleading results. In the presence of high levels of recombination, the identification of sites experiencing diversifying selection can suffer from a false-positive rate as high as 90%. We present a model that uses a population genetics approximation to the coalescent with recombination and use reversible-jump MCMC to perform Bayesian inference on both the d N /d S ratio and the recombination rate, allowing each to vary along the sequence. We demonstrate that the method has the power to detect variation in the d N /d S ratio and the recombination rate and does not suffer from a high false-positive rate. We use the method to analyze the porB gene of Neisseria meningitidis and verify the inferences using prior sensitivity analysis and model criticism techniques.

Infection, Genetics and …, 2009

Clinical radiology, 2001

RefDoc, THE reference in scientific document supply / Refdoc, la référence en fourniture de docum... more RefDoc, THE reference in scientific document supply / Refdoc, la référence en fourniture de documents scientifiques ...

Radiology, 2003

To compare the accuracy of four breath-hold magnetic resonance (MR) imaging sequences to establis... more To compare the accuracy of four breath-hold magnetic resonance (MR) imaging sequences to establish the most effective superparamagnetic iron oxide (SPIO)-enhanced sequence for detection of colorectal hepatic metastases. Thirty-one patients with colorectal hepatic metastases underwent T1-weighted gradient-echo (GRE) and T2-weighted fast spin-echo (FSE) MR imaging before and after SPIO enhancement. Four sequences were optimized for lesion detection: T2-weighted FSE, multiecho data image combination (MEDIC), T2-weighted GRE with an 11-msec echo time (TE), and T2-weighted GRE with a 15-msec TE. Images were reviewed independently by three blinded observers. The accuracy of each sequence was measured by using alternative free-response receiver operating characteristic analysis. All results were correlated with findings at surgery, intraoperative ultrasonography, or histopathologic examination. Differences between the mean results of the three observers were measured by using the Student t test. Postcontrast T2-weighted GRE sequences were the most accurate and were significantly superior to postcontrast T2-weighted FSE and unenhanced sequences alone (P <.05). For all lesions that were malignant or smaller than 1 cm, respectively, mean accuracies of postcontrast sequences were 0.082 and 0.64 for T2-weighted FSE, 0.90 and 0.78 for MEDIC, 0.92 and 0.80 for GRE with an 11-msec TE, 0.93 and 0.82 for GRE with a 15-msec TE, and 0.81 and 0.62 for unenhanced sequences. Optimized SPIO-enhanced T2-weighted GRE combined with unenhanced T2-weighted FSE MR sequences were the most sensitive. Breath-hold FSE postcontrast sequences offer no improvement in sensitivity compared with unenhanced sequences alone.

Molecular Biology and …, 2009

Responsible for the majority of bacterial gastroenteritis in the developed world, Campylobacter j... more Responsible for the majority of bacterial gastroenteritis in the developed world, Campylobacter jejuni is a pervasive pathogen of humans and animals, but its evolution is obscure. In this paper, we exploit contemporary genetic diversity and empirical evidence to piece ...

PLoS …, 2008

Campylobacter jejuni is the leading cause of bacterial gastro-enteritis in the developed world. I... more Campylobacter jejuni is the leading cause of bacterial gastro-enteritis in the developed world. It is thought to infect 2–3 million people a year in the US alone, at a cost to the economy in excess of US $4 billion. C. jejuni is a widespread zoonotic pathogen that is carried by ...

The common zoonotic pathogen Campylobacter coli is an important cause of bacterial gastroenteriti... more The common zoonotic pathogen Campylobacter coli is an important cause of bacterial gastroenteritis worldwide but its evolution is incompletely understood. Using multilocus sequence type (MLST) data of 7 housekeeping genes from a national survey of Campylobacter in Scotland (2005/6), and a combined population genetic-phylogenetics approach, we investigated the evolutionary history of C. coli. Genealogical reconstruction of isolates from clinical infection, farm animals and the environment, revealed a three-clade genetic structure. The majority of farm animal, and all disease causing genotypes belonged to a single clade (clade 1) which had comparatively low synonymous sequence diversity, little deep branching genetic structure, and a higher number of shared alleles providing evidence of recent clonal decent. Calibration of the rate of molecular evolution, based on within-species genetic variation, estimated a more rapid rate of evolution than in traditional estimates. This placed the divergence of the clades at less than 2500 years ago, consistent with the introduction of an agricultural niche having had an effect upon the evolution of the C. coli clades. Attribution of clinical isolate genotypes to source, using an asymmetric island model, confirmed that strains from chicken and ruminants, and not pigs or turkeys, are the principal source of human C. coli infection. Taken together these analyses are consistent with an evolutionary scenario describing the emergence of agriculture-associated C. coli lineage that is an important human pathogen.

Patterns of genetic diversity within populations of human pathogens, shaped by the ecology of hos... more Patterns of genetic diversity within populations of human pathogens, shaped by the ecology of host-microbe interactions, contain important information about the epidemiological history of infectious disease. Exploiting this information, however, requires a systematic approach that distinguishes the genetic signal generated by epidemiological processes from the effects of other forces, such as recombination, mutation, and population history. Here, a variety of quantitative techniques were employed to investigate multilocus sequence information from isolate collections of Neisseria meningitidis, a major cause of meningitis and septicemia world wide. This allowed quantitative evaluation of alternative explanations for the observed population structure. A coalescent-based approach was employed to estimate the rate of mutation, the rate of recombination, and the size distribution of recombination fragments from samples from diseaseassociated and carried meningococci obtained in the Czech Republic in 1993 and a global collection of diseaseassociated isolates collected globally from 1937 to 1996. The parameter estimates were used to reject a model in which genetic structure arose by chance in small populations, and analysis of molecular variation showed that geographically restricted gene flow was unlikely to be the cause of the genetic structure. The genetic differentiation between disease and carriage isolate collections indicated that, whereas certain genotypes were overrepresented among the disease-isolate collections (the ''hyperinvasive'' lineages), disease-associated and carried meningococci exhibited remarkably little differentiation at the level of individual nucleotide polymorphisms. In combination, these results indicated the repeated action of natural selection on meningococcal populations, possibly arising from the coevolutionary dynamic of hostpathogen interactions.

The distribution of serogroups and multilocus sequence types (STs) in collections of disease-asso... more The distribution of serogroups and multilocus sequence types (STs) in collections of disease-associated and carried meningococci from the period 1991 to 2000 in three European countries (the Czech Republic, Greece, and Norway) was investigated. A total of 314 patient isolates and 353 isolates from asymptomatic carriers were characterized. The frequency distributions of serogroups and clone complexes differed among countries and between disease and carrier isolate collections. Highly significant differentiation was seen at each housekeeping locus. A marked positive association of serogroup C with disease was evidenced. The ST-11 complex was strongly positively associated with disease; associations for other clone complexes were weaker. The genetic diversity of the clone complexes differed. A single ST dominated the ST-11 clone complex, while the ST-41/44 complex exhibited greater levels of diversity. These data robustly demonstrated differences in the distribution of meningococcal genotypes in disease and carrier isolates and among countries. Further, they indicated that differences in genotype diversity and pathogenicity exist between meningococcal clone complexes.

The evolution of the human immunodeficiency virus (HIV-1) during chronic infection involves the r... more The evolution of the human immunodeficiency virus (HIV-1) during chronic infection involves the rapid, continuous turnover of genetic diversity. However, the role of natural selection, relative to random genetic drift, in governing this process is unclear. We tested a stochastic model of genetic drift using partial envelope sequences sampled longitudinally in 28 infected children. In each case the Bayesian posterior (empirical) distribution of coalescent genealogies was estimated using Markov chain Monte Carlo methods. Posterior predictive simulation was then used to generate a null distribution of genealogies assuming neutrality, with the null and empirical distributions compared using four genealogy-based summary statistics sensitive to nonneutral evolution. Because both null and empirical distributions were generated within a coalescent framework, we were able to explicitly account for the confounding influence of demography. From the distribution of corrected P-values across patients, we conclude that empirical genealogies are more asymmetric than expected if evolution is driven by mutation and genetic drift only, with an excess of lowfrequency polymorphisms in the population. This indicates that although drift may still play an important role, natural selection has a strong influence on the evolution of HIV-1 envelope. A negative relationship between effective population size and substitution rate indicates that as the efficacy of selection increases, a smaller proportion of mutations approach fixation in the population. This suggests the presence of deleterious mutations. We therefore conclude that intrahost HIV-1 evolution in envelope is dominated by purifying selection against low-frequency deleterious mutations that do not reach fixation. Sequence data from this article have been deposited with the EMBL/ GenBank Data Libraries under accession nos. AY823998-AY824946.

Background: Genetic diversity of the human immunodeficiency virus type 1 (HIV-1) population withi... more Background: Genetic diversity of the human immunodeficiency virus type 1 (HIV-1) population within an individual is lost during transmission to a new host. The demography of transmission is an important determinant of evolutionary dynamics, particularly the relative impact of natural selection and genetic drift immediately following HIV-1 infection. Despite this, the magnitude of this population bottleneck is unclear. Results: We use coalescent methods to quantify the bottleneck in a single case of homosexual transmission and find that over 99% of the env and gag diversity present in the donor is lost. This was consistent with the diversity present at seroconversion in nine other horizontally infected individuals. Furthermore, we estimated viral diversity at birth in 27 infants infected through vertical transmission and found there to be no difference between the two modes of transmission. Conclusion: Assuming the bottleneck at transmission is selectively neutral, such a severe reduction in genetic diversity has important implications for adaptation in HIV-1, since beneficial mutations have a reduced chance of transmission.

Clinical …, 2002

The aim of present study was to determine which brain regions are involved in the conscious perce... more The aim of present study was to determine which brain regions are involved in the conscious perception of sound motion in humans. Methods: Six kinds of sound stimuli were studied. Two static sound stimuli with durations of 100 or 1000 ms remained at a fixed position during the stimulation period. Four moving sound stimuli with duration of 100 or 1000 ms were moving from left to right, or right to left, during the stimulation period. Evoked magnetic fields were recorded using a 151-channel whole cortex magnetoencephalographic system. Results: The response identified in all sound stimuli was M100. Responses identified only in moving sound stimuli were M180, M280 and M680. Contour maps and dipoles overlapped on magnetic resonance imaging indicated that both the M100 and M680 responses were generated in the superior temporal cortex (left and right), while M180 and M280 were generated in the parietal cortex (right). Conclusions: The results of this MEG study indicated that the right parietal cortex was involved in sound motion processing. We hypothesize that the right parietal cortex, in association with the left and right superior temporal cortex, forms a network to process sound motion information.

Journal of Monetary Economics, 2004

We look at disaggregated imports of various types of equipment to make inferences on cross-countr... more We look at disaggregated imports of various types of equipment to make inferences on cross-country differences in the composition of equipment investment. We make three contributions. First, we document strikingly large differences in investment composition. ...

…, 1993

Immunosuppression after transplantation is complicated by hypertension and nephrotoxicity, reflec... more Immunosuppression after transplantation is complicated by hypertension and nephrotoxicity, reflecting widespread vasoconstriction associated with CsA. FK506 is a novel alternative immunosuppressive agent, structurally unrelated to CsA. These studies compared systemic and renal vascular changes developing in the initial 4 weeks after liver transplantation in patients treated with FK506 (plus PRED) and CsA (plus PRED and AZA). We studied arterial pressure, cardiac index (pulsed doppler ultrasound), and systemic resistance index (SVRI) before and weekly after liver transplant in 32 patients treated with CsA (2 mg/kg initial dose plus PRED; median dose at week 4, 30 mg/day) and 14 patients treated with FK506 (0.15 mg/kg/day initial dose and PRED; mean week 4 dose, 12.5). Renal plasma flow and glomerular filtration rate (GFR) were measured by clearance of para-amino hippurate and 125-iothalamate. Renin activity, aldosterone, and urinary prostanoids were measured by RIA. Pretransplant pressures and hemodynamics reflected low SVRI and increased cardiac index typical of end-stage liver disease. After transplantation, SVRI and pressures rose in both groups, but after week 2, SVRI was lower in patients treated with FK506. This was associated with less prevalent clinical hypertension during the subsequent 4 months (4/14 FK506 (28%) vs. 25/32 (78%) CsA, P < 0.01). By contrast, renal blood flow and GFR fell in both treatment groups similarly, whereas renal vascular resistance rose. Urinary 6-keto-PG-F1-alpha was suppressed in all transplant recipients, but to a greater degree in FK506-treated patients. This value correlated directly to post-transplant GFR (r = 0.48, P < 0.001). These data indicate that FK506-based immunosuppression differs from CsA by inducing less systemic vasoconstriction and hypertension. Renal vasoconstrictive effects were at least as great as those seen with CsA, however, and indicate that nephrotoxicity will remain a common feature to both regimens.

…, 2003

Ribosomes, the universal cellular organelles catalyzing the translation of genetic code into prot... more Ribosomes, the universal cellular organelles catalyzing the translation of genetic code into proteins, are protein/RNA assemblies, of a molecular weight 2.5 mega Daltons or higher. They are built of two subunits that associate for performing protein biosynthesis. The large ...

Background: Plasmodium vivax malaria is a major public health challenge in Latin America, Asia an... more Background: Plasmodium vivax malaria is a major public health challenge in Latin America, Asia and Oceania, with 130-435 million clinical cases per year worldwide. Invasion of host blood cells by P. vivax mainly depends on a type I membrane protein called Duffy binding protein (PvDBP). The erythrocyte-binding motif of PvDBP is a 170 aminoacid stretch located in its cysteine-rich region II (PvDBP II), which is the most variable segment of the protein. Methods: To test whether diversifying natural selection has shaped the nucleotide diversity of PvDBP II in Brazilian populations, this region was sequenced in 122 isolates from six different geographic areas. A Bayesian method was applied to test for the action of natural selection under a population genetic model that incorporates recombination. The analysis was integrated with a structural model of PvDBP II , and T-and B-cell epitopes were localized on the 3-D structure. Results: The results suggest that: (i) recombination plays an important role in determining the haplotype structure of PvDBP II , and (ii) PvDBP II appears to contain neutrally evolving codons as well as codons evolving under natural selection. Diversifying selection preferentially acts on sites identified as epitopes, particularly on amino acid residues 417, 419, and 424, which show strong linkage disequilibrium. Conclusions: This study shows that some polymorphisms of PvDBP II are present near the erythrocyte-binding domain and might serve to elude antibodies that inhibit cell invasion. Therefore, these polymorphisms should be taken into account when designing vaccines aimed at eliciting antibodies to inhibit erythrocyte invasion.

Whole genome sequencing of bacteria has recently emerged as a cost-effective and convenient appro... more Whole genome sequencing of bacteria has recently emerged as a cost-effective and convenient approach for addressing many microbiological questions. Here we review the current status of clinical microbiology and how it has already begun to be transformed by the use of nextgeneration sequencing. We focus on three essential tasks: identifying the species of an isolate, testing its properties such as resistance to antibiotics and virulence, and monitoring the emergence and spread of bacterial pathogens. The application of next-generation sequencing will soon be sufficiently fast, accurate and cheap to be used in routine clinical microbiology practice, where it could replace many complex current techniques with a single, more efficient workflow.

Through an analysis of polymorphism within and divergence between species, we can hope to learn a... more Through an analysis of polymorphism within and divergence between species, we can hope to learn about the distribution of selective effects of mutations in the genome, changes in the fitness landscape that occur over time, and the location of sites involved in key adaptations that distinguish modern-day species. We introduce a novel method for the analysis of variation in selection pressures within and between species, spatially along the genome and temporally between lineages. We model codon evolution explicitly using a joint population genetics-phylogenetics approach that we developed for the construction of multiallelic models with mutation, selection, and drift. Our approach has the advantage of performing direct inference on coding sequences, inferring ancestral states probabilistically, utilizing allele frequency information, and generalizing to multiple species. We use a Bayesian sliding window model for intragenic variation in selection coefficients that efficiently combines information across sites and captures spatial clustering within the genome. To demonstrate the utility of the method, we infer selective pressures acting in Drosophila melanogaster and D. simulans from polymorphism and divergence data for 100 X-linked coding regions.

Population genetic methods: analytical techniques that primarily make inferences about the popula... more Population genetic methods: analytical techniques that primarily make inferences about the population from which a sample of molecular sequences were drawn, rather than the evolutionary tree of the samples themselves. Recombination: any process that results in the reassortment of genetic material among genomes. Recombination may either be homologous, where equivalent loci are involved, or nonhomologous, where material from different loci are involved. Recombination results in mosaic sequences. Standard neutral model: the simplest model in population genetics. The population is assumed to be of constant size, with no selection, and random mating (for sexual populations).

In bacteria, DNA sequence mismatches act as a barrier to recombination between distantly related ... more In bacteria, DNA sequence mismatches act as a barrier to recombination between distantly related organisms and can potentially promote the cohesion of species. We have performed computer simulations which show that the homology dependence of recombination can cause de novo speciation in a neutrally evolving population once a critical population size has been exceeded. Our model can explain the patterns of divergence and genetic exchange observed in the genus Salmonella, without invoking either natural selection or geographical population subdivision. If this model was validated, based on extensive sequence data, it would imply that the named subspecies of Salmonella enterica correspond to good biological species, making species boundaries objective. However, multilocus sequence typing data, analysed using several conventional tools, provide a misleading impression of relationships within S. enterica subspecies enterica and do not provide the resolution to establish whether new species are presently being formed.

Models of molecular evolution that incorporate the ratio of nonsynonymous to synonymous polymorph... more Models of molecular evolution that incorporate the ratio of nonsynonymous to synonymous polymorphism (d N /d S ratio) as a parameter can be used to identify sites that are under diversifying selection or functional constraint in a sample of gene sequences. However, when there has been recombination in the evolutionary history of the sequences, reconstructing a single phylogenetic tree is not appropriate, and inference based on a single tree can give misleading results. In the presence of high levels of recombination, the identification of sites experiencing diversifying selection can suffer from a false-positive rate as high as 90%. We present a model that uses a population genetics approximation to the coalescent with recombination and use reversible-jump MCMC to perform Bayesian inference on both the d N /d S ratio and the recombination rate, allowing each to vary along the sequence. We demonstrate that the method has the power to detect variation in the d N /d S ratio and the recombination rate and does not suffer from a high false-positive rate. We use the method to analyze the porB gene of Neisseria meningitidis and verify the inferences using prior sensitivity analysis and model criticism techniques.

Infection, Genetics and …, 2009

Clinical radiology, 2001

RefDoc, THE reference in scientific document supply / Refdoc, la référence en fourniture de docum... more RefDoc, THE reference in scientific document supply / Refdoc, la référence en fourniture de documents scientifiques ...

Radiology, 2003

To compare the accuracy of four breath-hold magnetic resonance (MR) imaging sequences to establis... more To compare the accuracy of four breath-hold magnetic resonance (MR) imaging sequences to establish the most effective superparamagnetic iron oxide (SPIO)-enhanced sequence for detection of colorectal hepatic metastases. Thirty-one patients with colorectal hepatic metastases underwent T1-weighted gradient-echo (GRE) and T2-weighted fast spin-echo (FSE) MR imaging before and after SPIO enhancement. Four sequences were optimized for lesion detection: T2-weighted FSE, multiecho data image combination (MEDIC), T2-weighted GRE with an 11-msec echo time (TE), and T2-weighted GRE with a 15-msec TE. Images were reviewed independently by three blinded observers. The accuracy of each sequence was measured by using alternative free-response receiver operating characteristic analysis. All results were correlated with findings at surgery, intraoperative ultrasonography, or histopathologic examination. Differences between the mean results of the three observers were measured by using the Student t test. Postcontrast T2-weighted GRE sequences were the most accurate and were significantly superior to postcontrast T2-weighted FSE and unenhanced sequences alone (P <.05). For all lesions that were malignant or smaller than 1 cm, respectively, mean accuracies of postcontrast sequences were 0.082 and 0.64 for T2-weighted FSE, 0.90 and 0.78 for MEDIC, 0.92 and 0.80 for GRE with an 11-msec TE, 0.93 and 0.82 for GRE with a 15-msec TE, and 0.81 and 0.62 for unenhanced sequences. Optimized SPIO-enhanced T2-weighted GRE combined with unenhanced T2-weighted FSE MR sequences were the most sensitive. Breath-hold FSE postcontrast sequences offer no improvement in sensitivity compared with unenhanced sequences alone.

Molecular Biology and …, 2009

Responsible for the majority of bacterial gastroenteritis in the developed world, Campylobacter j... more Responsible for the majority of bacterial gastroenteritis in the developed world, Campylobacter jejuni is a pervasive pathogen of humans and animals, but its evolution is obscure. In this paper, we exploit contemporary genetic diversity and empirical evidence to piece ...

PLoS …, 2008

Campylobacter jejuni is the leading cause of bacterial gastro-enteritis in the developed world. I... more Campylobacter jejuni is the leading cause of bacterial gastro-enteritis in the developed world. It is thought to infect 2–3 million people a year in the US alone, at a cost to the economy in excess of US $4 billion. C. jejuni is a widespread zoonotic pathogen that is carried by ...

The common zoonotic pathogen Campylobacter coli is an important cause of bacterial gastroenteriti... more The common zoonotic pathogen Campylobacter coli is an important cause of bacterial gastroenteritis worldwide but its evolution is incompletely understood. Using multilocus sequence type (MLST) data of 7 housekeeping genes from a national survey of Campylobacter in Scotland (2005/6), and a combined population genetic-phylogenetics approach, we investigated the evolutionary history of C. coli. Genealogical reconstruction of isolates from clinical infection, farm animals and the environment, revealed a three-clade genetic structure. The majority of farm animal, and all disease causing genotypes belonged to a single clade (clade 1) which had comparatively low synonymous sequence diversity, little deep branching genetic structure, and a higher number of shared alleles providing evidence of recent clonal decent. Calibration of the rate of molecular evolution, based on within-species genetic variation, estimated a more rapid rate of evolution than in traditional estimates. This placed the divergence of the clades at less than 2500 years ago, consistent with the introduction of an agricultural niche having had an effect upon the evolution of the C. coli clades. Attribution of clinical isolate genotypes to source, using an asymmetric island model, confirmed that strains from chicken and ruminants, and not pigs or turkeys, are the principal source of human C. coli infection. Taken together these analyses are consistent with an evolutionary scenario describing the emergence of agriculture-associated C. coli lineage that is an important human pathogen.

Patterns of genetic diversity within populations of human pathogens, shaped by the ecology of hos... more Patterns of genetic diversity within populations of human pathogens, shaped by the ecology of host-microbe interactions, contain important information about the epidemiological history of infectious disease. Exploiting this information, however, requires a systematic approach that distinguishes the genetic signal generated by epidemiological processes from the effects of other forces, such as recombination, mutation, and population history. Here, a variety of quantitative techniques were employed to investigate multilocus sequence information from isolate collections of Neisseria meningitidis, a major cause of meningitis and septicemia world wide. This allowed quantitative evaluation of alternative explanations for the observed population structure. A coalescent-based approach was employed to estimate the rate of mutation, the rate of recombination, and the size distribution of recombination fragments from samples from diseaseassociated and carried meningococci obtained in the Czech Republic in 1993 and a global collection of diseaseassociated isolates collected globally from 1937 to 1996. The parameter estimates were used to reject a model in which genetic structure arose by chance in small populations, and analysis of molecular variation showed that geographically restricted gene flow was unlikely to be the cause of the genetic structure. The genetic differentiation between disease and carriage isolate collections indicated that, whereas certain genotypes were overrepresented among the disease-isolate collections (the ''hyperinvasive'' lineages), disease-associated and carried meningococci exhibited remarkably little differentiation at the level of individual nucleotide polymorphisms. In combination, these results indicated the repeated action of natural selection on meningococcal populations, possibly arising from the coevolutionary dynamic of hostpathogen interactions.

The distribution of serogroups and multilocus sequence types (STs) in collections of disease-asso... more The distribution of serogroups and multilocus sequence types (STs) in collections of disease-associated and carried meningococci from the period 1991 to 2000 in three European countries (the Czech Republic, Greece, and Norway) was investigated. A total of 314 patient isolates and 353 isolates from asymptomatic carriers were characterized. The frequency distributions of serogroups and clone complexes differed among countries and between disease and carrier isolate collections. Highly significant differentiation was seen at each housekeeping locus. A marked positive association of serogroup C with disease was evidenced. The ST-11 complex was strongly positively associated with disease; associations for other clone complexes were weaker. The genetic diversity of the clone complexes differed. A single ST dominated the ST-11 clone complex, while the ST-41/44 complex exhibited greater levels of diversity. These data robustly demonstrated differences in the distribution of meningococcal genotypes in disease and carrier isolates and among countries. Further, they indicated that differences in genotype diversity and pathogenicity exist between meningococcal clone complexes.

The evolution of the human immunodeficiency virus (HIV-1) during chronic infection involves the r... more The evolution of the human immunodeficiency virus (HIV-1) during chronic infection involves the rapid, continuous turnover of genetic diversity. However, the role of natural selection, relative to random genetic drift, in governing this process is unclear. We tested a stochastic model of genetic drift using partial envelope sequences sampled longitudinally in 28 infected children. In each case the Bayesian posterior (empirical) distribution of coalescent genealogies was estimated using Markov chain Monte Carlo methods. Posterior predictive simulation was then used to generate a null distribution of genealogies assuming neutrality, with the null and empirical distributions compared using four genealogy-based summary statistics sensitive to nonneutral evolution. Because both null and empirical distributions were generated within a coalescent framework, we were able to explicitly account for the confounding influence of demography. From the distribution of corrected P-values across patients, we conclude that empirical genealogies are more asymmetric than expected if evolution is driven by mutation and genetic drift only, with an excess of lowfrequency polymorphisms in the population. This indicates that although drift may still play an important role, natural selection has a strong influence on the evolution of HIV-1 envelope. A negative relationship between effective population size and substitution rate indicates that as the efficacy of selection increases, a smaller proportion of mutations approach fixation in the population. This suggests the presence of deleterious mutations. We therefore conclude that intrahost HIV-1 evolution in envelope is dominated by purifying selection against low-frequency deleterious mutations that do not reach fixation. Sequence data from this article have been deposited with the EMBL/ GenBank Data Libraries under accession nos. AY823998-AY824946.

Background: Genetic diversity of the human immunodeficiency virus type 1 (HIV-1) population withi... more Background: Genetic diversity of the human immunodeficiency virus type 1 (HIV-1) population within an individual is lost during transmission to a new host. The demography of transmission is an important determinant of evolutionary dynamics, particularly the relative impact of natural selection and genetic drift immediately following HIV-1 infection. Despite this, the magnitude of this population bottleneck is unclear. Results: We use coalescent methods to quantify the bottleneck in a single case of homosexual transmission and find that over 99% of the env and gag diversity present in the donor is lost. This was consistent with the diversity present at seroconversion in nine other horizontally infected individuals. Furthermore, we estimated viral diversity at birth in 27 infants infected through vertical transmission and found there to be no difference between the two modes of transmission. Conclusion: Assuming the bottleneck at transmission is selectively neutral, such a severe reduction in genetic diversity has important implications for adaptation in HIV-1, since beneficial mutations have a reduced chance of transmission.

Clinical …, 2002

The aim of present study was to determine which brain regions are involved in the conscious perce... more The aim of present study was to determine which brain regions are involved in the conscious perception of sound motion in humans. Methods: Six kinds of sound stimuli were studied. Two static sound stimuli with durations of 100 or 1000 ms remained at a fixed position during the stimulation period. Four moving sound stimuli with duration of 100 or 1000 ms were moving from left to right, or right to left, during the stimulation period. Evoked magnetic fields were recorded using a 151-channel whole cortex magnetoencephalographic system. Results: The response identified in all sound stimuli was M100. Responses identified only in moving sound stimuli were M180, M280 and M680. Contour maps and dipoles overlapped on magnetic resonance imaging indicated that both the M100 and M680 responses were generated in the superior temporal cortex (left and right), while M180 and M280 were generated in the parietal cortex (right). Conclusions: The results of this MEG study indicated that the right parietal cortex was involved in sound motion processing. We hypothesize that the right parietal cortex, in association with the left and right superior temporal cortex, forms a network to process sound motion information.

Journal of Monetary Economics, 2004

We look at disaggregated imports of various types of equipment to make inferences on cross-countr... more We look at disaggregated imports of various types of equipment to make inferences on cross-country differences in the composition of equipment investment. We make three contributions. First, we document strikingly large differences in investment composition. ...

…, 1993

Immunosuppression after transplantation is complicated by hypertension and nephrotoxicity, reflec... more Immunosuppression after transplantation is complicated by hypertension and nephrotoxicity, reflecting widespread vasoconstriction associated with CsA. FK506 is a novel alternative immunosuppressive agent, structurally unrelated to CsA. These studies compared systemic and renal vascular changes developing in the initial 4 weeks after liver transplantation in patients treated with FK506 (plus PRED) and CsA (plus PRED and AZA). We studied arterial pressure, cardiac index (pulsed doppler ultrasound), and systemic resistance index (SVRI) before and weekly after liver transplant in 32 patients treated with CsA (2 mg/kg initial dose plus PRED; median dose at week 4, 30 mg/day) and 14 patients treated with FK506 (0.15 mg/kg/day initial dose and PRED; mean week 4 dose, 12.5). Renal plasma flow and glomerular filtration rate (GFR) were measured by clearance of para-amino hippurate and 125-iothalamate. Renin activity, aldosterone, and urinary prostanoids were measured by RIA. Pretransplant pressures and hemodynamics reflected low SVRI and increased cardiac index typical of end-stage liver disease. After transplantation, SVRI and pressures rose in both groups, but after week 2, SVRI was lower in patients treated with FK506. This was associated with less prevalent clinical hypertension during the subsequent 4 months (4/14 FK506 (28%) vs. 25/32 (78%) CsA, P < 0.01). By contrast, renal blood flow and GFR fell in both treatment groups similarly, whereas renal vascular resistance rose. Urinary 6-keto-PG-F1-alpha was suppressed in all transplant recipients, but to a greater degree in FK506-treated patients. This value correlated directly to post-transplant GFR (r = 0.48, P < 0.001). These data indicate that FK506-based immunosuppression differs from CsA by inducing less systemic vasoconstriction and hypertension. Renal vasoconstrictive effects were at least as great as those seen with CsA, however, and indicate that nephrotoxicity will remain a common feature to both regimens.

…, 2003

Ribosomes, the universal cellular organelles catalyzing the translation of genetic code into prot... more Ribosomes, the universal cellular organelles catalyzing the translation of genetic code into proteins, are protein/RNA assemblies, of a molecular weight 2.5 mega Daltons or higher. They are built of two subunits that associate for performing protein biosynthesis. The large ...