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Biomedical subjects

Jonathan Arnold

Publications and source records attributed to Jonathan Arnold.

11 recordsLinked to original sources
PubMed2006

Discovery of a significant optical chromatographic difference between spores of Bacillus anthracis and its close relative, Bacillus thuringiensis.

A significant difference between two closely related Bacillus spores has been discovered using optical chromatography. This difference can be harnessed for the separation of microscopic particles using opposing laser and fluid flow forces. Particles of different size, composition, and shape experience different optical and fluid forces and come to rest at unique equilibrium positions where the two forces balance. Separations in excess of 600 mum have been observed between Bacillus anthracis Sterne strain and its genetic relative, Bacillus thuringiensis. These findings open new possibilities for detection and characterization of the biological warfare agent, B. anthracis, the causative agent of anthrax, the deadly mammalian disease. The large optical separation between these species is surprising given their close genetic relationship but may be explained by differences in their shape and exosporium morphology, which may result in differences in fluid drag force. The observation of large differences due to less common variables indicates the complex nature of the force balance in optical chromatography, which may in the future be used to separate and characterize microbiological samples. In general, the discovery of such large differences between such closely related biological species suggests new possibilities for the separation and characterization of microorganisms using the full range of emerging techniques that employ radiation pressure (optical filtering, laser tweezers, optical chromatography, etc.).

Bacillus anthracis↗
PubMed2005

Exact sample sizes needed to detect dependence in 2 x 3 tables.

Many medical and biological studies entail classifying a number of observations according to two factors, where one has two and the other three possible categories. This is the case of, for example, genetic association studies of complex traits with single-nucleotide polymorphisms (SNPs), where the a priori statistical planning, analysis, and interpretation of results are of critical importance. Here, we present methodology to determine the minimum sample size required to detect dependence in 2 x 3 tables based on Fisher's exact test, assuming that neither of the two margins is fixed and only the grand total N is known in advance. We provide the numerical tools necessary to determine these sample sizes for desired power, significance level, and effect size, where only the computational time can be a limitation for extreme parameter values. These programs can be accessed at . This solution of the sample size problem for an exact test will permit experimentalists to plan efficient sampling designs, determine the extent of statistical support for their hypotheses, and gain insight into the repeatability of their results. We apply this solution to the sample size problem to three empirical studies, and discuss the results with specified power and nominal significance levels.

DNA, Mitochondrial↗
PubMed2005

Competitive coexistence of two Pneumocystis species.

Pneumocystis are fungal pathogens of mammalian lungs that can cause lethal pneumonia in immunocompromised hosts. In some mammals, coinfections of genetically distinct Pneumocystis populations have been identified, but the nature of their interaction and its significance are unknown. Two species that infect rats, Pneumocystis carinii and Pneumocystis wakefieldiae, were studied over a 6-year period, representing approximately 700 generations of Pneumocystis. Population densities of each species were analyzed within the framework of the Lotka-Volterra competition model, which revealed the two species were in competition and predicted competitive exclusion of one species. However, stable coexistence was observed in 460 replicate populations. Selected extrinsic factors that might mitigate the extinction were evaluated. Logistic-regression analyses showed that higher relative humidity and higher organism lung burdens were associated with infections comprised of P. carinii alone, while lower temperatures and an increased rat census were associated with the presence of P. wakefieldiae. PCR and immunofluorescent analysis of rat lung tissue showed that both species were present within the same alveoli, excluding habitat heterogeneity as a mechanism of coexistence. These data suggest that P. carinii and P. wakefieldiae were in competitive coexistence, which was influenced in part by extrinsic factors. To our knowledge, this is the first report to evaluate interactions of pathogenic fungal species within a mammalian host using ecological models.

Acquired Immunodeficiency Syndrome↗
PubMed2005

The human commensal yeast, Candida albicans, has an ancient origin.

Candida albicans, the primary causative agent of candidiasis, is a ubiquitous member of the human flora and is capable of causing severe invasive disease. Despite its importance as a human pathogen, little is known concerning those factors creating and maintaining genetic diversity within the species and how extant strains reflect their evolutionary history. Based on nucleotide polymorphism frequencies, we estimated the time to a most recent common ancestor for the species to be about 3-16 million years, with variation due to molecular clock calibration. As C. albicans genotypes have broad geographic associations, this suggests that the origins of DNA sequence variation in extant populations coincided with early hominid evolution. This is consistent with an emerging view of a genetically complex organism that is able to survive under host immunity as an obligate commensal species.

Candida albicans↗
PubMed2004

Essential eukaryotic core.

The AIDs-related fungal pathogen Pneumocystis carinii is unusual in having a remarkably compact genome of 7.7 megabase pairs (mbp) whose small size presents the opportunity to identify the essential eukaryotic core of genes. The essential eukaryotic core is defined to be a collection of essential genes shared by all eukaryotes. Sequencing the 3' ends of more than 5500 cDNAs from P. carinii allowed us to identify about 200 genes shared with its nearest known but distant relative, Schizosaccharomyces pombe and also Saccharomyces cerevisiae, and with homologs known to be essential in S. pombe or S. cerevisae. As the cDNA library contains about one half of the P. carinii genes, the size of the essential eukaryotic core (approximately 400) is slightly larger than the prokaryotic core (265-350) being identified by studies of the bacterial pathogen Mycoplasma genitalium. The collection of genes in the essential eukaryotic core may prove useful in identifying new broad spectrum antifungal drug targets.

Base Sequence↗
PubMed2003

Mapping by sequencing the Pneumocystis genome using the ordering DNA sequences V3 tool.

A bioinformatics tool called ODS3 has been created for mapping by sequencing. The tool allows the creation of integrated genomic maps from genetic, physical mapping, and sequencing data and permits an integrated genome map to be stored, retrieved, viewed, and queried in a stand-alone capacity, in a client/server relationship with the Fungal Genome Database (FGDB), and as a web-browsing tool for the FGDB. In that ODS3 is programmed in Java, the tool promotes platform independence and supports export of integrated genome-mapping data in the extensible markup language (XML) for data interchange with other genome information systems. The tool ODS3 is used to create an initial integrated genome map of the AIDS-related fungal pathogen, Pneumocystis carinii. Contig dynamics would indicate that this physical map is approximately 50% complete with approximately 200 contigs. A total of 10 putative multigene families were found. Two of these putative families were previously characterized in P. carinii, namely the major surface glycoproteins (MSGs) and HSP70 proteins; three of these putative families (not previously characterized in P. carinii) were found to be similar to families encoding the HSP60 in Schizosaccharomyces pombe, the heat-shock psi protein in S. pombe, and the RNA synthetase family (i.e., MES1) in Saccharomyces cerevisiae. Physical mapping data are consistent with the 16S, 5.8S, and 26S rDNA genes being single copy in P. carinii. No other fungus outside this genus is known to have the rDNA genes in single copy.

Computational Biology↗
PubMed2003

Long-term outcome of spinal cord stimulation and hardware complications.

Spinal cord stimulation (SCS) is a treatment modality for medically intractable chronic pain. This study reports an 11-year experience with SCS assessing long-term pain relief and specifically evaluating complications and revisions. It took the form of a retrospective review of medical/surgical records with a postal questionnaire. The subjects were 102 patients with medically intractable chronic pain who underwent SCS implantation between 1989 and 2000. There were 64 revision operations carried out on 35 patients. These comprised electrode replacement/repositioning (29), generator replacement (23), cable failure (3) and implant removal (5). Five (4.9%) implants became infected and 2 required removal. Clinician-reported pain relief was substantial in 69 (68%) patients. This study adds to the weight of evidence that patients undergoing SCS derive significant benefits in terms of pain relief. However, revision rates remain high due to technical and biological factors.

Adolescent↗
PubMed2002

Population structure of Candida albicans, a member of the human flora, as determined by microsatellite loci.

This study examines the macrogeographic population structure of Candida albicans, a yeast commensal of humans, through a population genetic analysis of 5 microsatellite loci in 13 cities. The populations were predominantly clonal with some recombination. About 5% of the genetic variation is between populations and the overall pattern is one of intermediate differentiation. We did not find a single widespread genotype but instead found high, macrogeographic gene flow in these clinical populations; the most common genotype was limited to Atlanta and San Francisco. Homogeneity is evident within large geographic regions, such as Europe, Asia, and the USA, and isolation by distance accounted for 39% of the variation observed. Overall gene flow for a member of the human flora is variable but can be extensive, with an average of 4.5 migrants per generation (N(m)). Eastern hemisphere populations were less divergent than those of the Americas and Caribbean, consistent with the expansion of humans out of the eastern hemisphere.

Alleles↗
PubMed2002

Parallel Monte Carlo methods for physical mapping of chromosomes.

Reconstructing a physical map of a chromosome from a genomic library presents a central computational problem in genetics. Physical map reconstruction in the presence of errors is a problem of high computational complexity. Parallel Monte Carlo methods for a maximum likelihood estimation-based approach to physical map reconstruction are presented. The estimation procedure entails gradient descent search for determining the optimal spacings between probes for a given probe ordering. The optimal probe ordering is determined using a simulated Monte Carlo algorithm. A two-tier parallelization strategy is proposed wherein the gradient descent search is parallelized at the lower level and the simulated Monte Carlo algorithm is simultaneously parallelized at the higher level. Implementation and experimental results on a network of shared-memory symmetric multiprocessors (SMPs) are presented.

Algorithms↗
PubMed1999

Towards understanding the evolution of the human commensal yeast Candida albicans.

Allelic frequencies and relationships for one dimorphic locus and three unlinked polymorphic loci have been determined for 114 unrelated isolates of Candida albicans, including 14 laboratory reference strains and 50 strains from each of two geographic regions. Although there was no indication of geographical partitioning, there were significant correlations for specific allelic pairs among loci and little evidence that any alleles were in Hardy-Weinberg equilibrium. This gives additional support for the concept that the primary mode of genetic inheritance in this species is clonal, with other intracellular genetic events playing a lesser role in the creation of genomic diversity. Through inference of this and other known attributes of closely related Candida species, such as sequence analysis of IS1 and the ITS2 (internal transcribed spacer 2) region of the rDNA cistron, the deduced phylogeny suggests an evolutionarily recent origin for many frequently isolated strains. This finding will be of interest in the context of understanding pathogenicity and drug resistance in this human commensal yeast.

Alleles↗