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Biomedical subjects

J Rogers

Publications and source records attributed to J Rogers.

At least 109 records · Page 6Linked to original sources
PubMed1999

Sequence and analysis of chromosome 4 of the plant Arabidopsis thaliana.

The higher plant Arabidopsis thaliana (Arabidopsis) is an important model for identifying plant genes and determining their function. To assist biological investigations and to define chromosome structure, a coordinated effort to sequence the Arabidopsis genome was initiated in late 1996. Here we report one of the first milestones of this project, the sequence of chromosome 4. Analysis of 17.38 megabases of unique sequence, representing about 17% of the genome, reveals 3,744 protein coding genes, 81 transfer RNAs and numerous repeat elements. Heterochromatic regions surrounding the putative centromere, which has not yet been completely sequenced, are characterized by an increased frequency of a variety of repeats, new repeats, reduced recombination, lowered gene density and lowered gene expression. Roughly 60% of the predicted protein-coding genes have been functionally characterized on the basis of their homology to known genes. Many genes encode predicted proteins that are homologous to human and Caenorhabditis elegans proteins.

Animals↗
PubMed1999

A ribozyme that lacks cytidine.

The RNA-world hypothesis proposes that, before the advent of DNA and protein, life was based on RNA, with RNA serving as both the repository of genetic information and the chief agent of catalytic function. An argument against an RNA world is that the components of RNA lack the chemical diversity necessary to sustain life. Unlike proteins, which contain 20 different amino-acid subunits, nucleic acids are composed of only four subunits which have very similar chemical properties. Yet RNA is capable of a broad range of catalytic functions. Here we show that even three nucleic-acid subunits are sufficient to provide a substantial increase in the catalytic rate. Starting from a molecule that contained roughly equal proportions of all four nucleosides, we used in vitro evolution to obtain an RNA ligase ribozyme that lacks cytidine. This ribozyme folds into a defined structure and has a catalytic rate that is about 10(5)-fold faster than the uncatalysed rate of template-directed RNA ligation.

Base Sequence↗
PubMed1999

Contributions of residues of pancreatic phospholipase A2 to interfacial binding, catalysis, and activation.

Primary rate and equilibrium parameters for 60 site-directed mutants of bovine pancreatic phospholipase A2 (PLA2) are analyzed so incremental contributions of the substitution of specific residues can be evaluated. The magnitude of the change is evaluated so a functional role in the context of the N- and C-domains of PLA2 can be assigned, and their relationship to the catalytic residues and to the i-face that makes contact with the interface. The effect of substitutions and interfacial charge is characterized by the equilibrium dissociation constant for dissociation of the bound enzyme from the interface (Kd), the dissociation constant for dissociation of a substrate mimic from the active site of the bound enzyme (KL), and the interfacial Michaelis constants, KM and kcat. Activity is lost (>99.9%) on the substitution of H48 and D49, the catalytic residues. A more than 95% decrease in kcat is seen with the substitution of F5, I9, D99, A102, or F106, which form the substrate binding pocket. Certain residues, which are not part of the catalytic site or the substrate binding pocket, also modulate kcat. Interfacial anionic charge lowers Kd, and induces kcat activation through K56, K53, K119, or K120. Significant changes in KL are seen by the substitution of N6, I9, F22, Y52, K53, N71, Y73, A102, or A103. Changes in KM [=(k2+k-1)/k1] are attributed to kcat (=k2) and KL (=k-1/k1). Some substitutions change more than one parameter, implying an allosteric effect of the binding to the interface on KS, and the effect of the interfacial anionic charge on kcat. Interpreted in the context of the overall structure, results provide insights into the role of segments and domains in the microscopic events of catalytic turnover and processivity, and their allosteric regulation. We suggest that the interfacial recognition region (i-face) of PLA2, due to the plasticity of certain segments and domains, exercises an allosteric control on the substrate binding and chemical step.

Animals↗
PubMed1999

Effectiveness of ciprofloxacin microspheres in eradicating bacterial biofilm.

The treatment of cultures of planktonic cells and aged biofilm cells of P. aeruginosa and S. aureus with ciprofloxacin (CFX) microspheres of poly(l-lactic acid) (PLA) has been investigated using a modified, open in vitro chemostat system. The kinetics of release of CFX as a function of drug loading and the dose of microspheres were correlated with the rate and extent of killing and eradication of the planktonic cells and biofilm cells cultured on pieces of silicone tubing in the chemostat, respectively. At 71% w/w drug loading, a minimum dose of 7 mg of CFX in microspheres was required to sustain CFX concentration for about 10 h above the minimum inhibitory concentration (MIC) in order to completely eradicate the cells of either bacteria. In contrast, peak concentrations obtained from an equivalent dose of free CFX decreased to low values within 30 min and the bacteria cells were not eradicated. Lower microsphere loadings of CFX were ineffective at the same dose. Thus, this study has identified the formulation requirements for PLA microspheres to sustain CFX concentrations above the MIC for several days in order to eradicate bacteria, particularly aged biofilm cells, in the open chemostat in which the drug is being continually diluted, or similarly at a site of administration, for example, in the peritoneal cavity.

Anti-Infective Agents↗
PubMed1999

Quantitative trait linkage mapping in anthropology.

Recent years have seen rapid progress in several areas of both biomedical and anthropological genetics. While genetic analyses have come to play a significant role in biological anthropology, there has been little use of modern methods for linkage mapping of quantitative trait loci (QTLs). It is now feasible to design research studies to investigate the quantitative genetics of complex phenotypes that are of primary importance to traditional questions in biological anthropology. Complex traits such as functionally significant morphological features, physiological characteristics or aspects of behavior can be examined to estimate the influence of genetic variation on within-species phenotypic variation. In addition, new methods for mapping quantitative trait loci provide opportunities to identify the regions within chromosomes that contain the functional genes of interest. This review summarizes molecular genetic and statistical genetic approaches to QTL mapping, and presents examples of how this approach can expand the scope of anthropological genetics to include mapping and identifying individual genes that influence complex phenotypic traits relevant to fundamental questions in biological anthropology.

Animals↗
PubMed1999

Cytogenetic and fertility studies of a rheboon, rhesus macaque (Macaca mulatta) x baboon (Papio hamadryas) cross: further support for a single karyotype nomenclature.

Historically, two different numbering systems have been used to describe the baboon and macaque karyotypes. However, G-banding studies and, more recently, fluorescence in situ hybridization results have shown that the two karyotypes are virtually identical. To confirm this hypothesis, cytogenetic analysis of an unusual animal, a rheboon, was undertaken. The rheboon reported here, an 18-year-old male, is the only long-term survivor of 26 pregnancies resulting from matings between female baboons (Papio hamadryas) and male rhesus macaques (Macaca mulatta). A G-banded karyotype was prepared from the rheboon and compared with the karyotypes of the two parental species. Spectral karyotyping (SKY) was carried out on the rheboon chromosomes, and the results were compared with SKY studies reported for the baboon and with CISS (chromosome in situ suppression) studies in the rhesus macaque. No differences were detected in any of the rheboon's pairs of autosomes, reinforcing the apparent identity of the two parental karyotypes. Based on these results, we argue that a single karyotyping system should be adopted for the two species. Fertility studies were initiated to determine if the rheboon is sterile, as are most hybrid animals. Two semen ejaculates were devoid of sperm. A testicular biopsy revealed hypoplasia of the seminiferous tubules with few Leydig cells and large lumena. Meiotic arrest occurred during meiosis I, resulting in absence of mature spermatozoa. Thus, the testicular and meiotic findings in the rheboon were similar to those observed in other hybrids, even though the parental karyotypes appear identical.

Animals↗
PubMed1999

Microsatellite polymorphisms in Bolivian squirrel monkeys (Saimiri boliviensis).

Two different approaches were used to identify new microsatellite polymorphisms among captive Bolivian squirrel monkeys (Saimiri boliviensis). In the first case, PCR primers for published human microsatellite loci were screened using genomic DNA from squirrel monkeys. Six polymorphic loci were identified using DNA samples from 19 unrelated individuals. The average heterozygosity among these six loci is 0.73. In the second set of experiments, a DNA library was created from Saimiri genomic DNA, and clones were selected from that library by screening with probes containing di-, tri-, and tetranucleotide repeats. Six novel microsatellites were identified this way, with an average heterozygosity of 0.59. Primer pairs for these six cloned microsatellites were also screened using a series of DNA samples from ten other platyrrhine species to assess the potential utility of these loci in other taxa. This study provides 12 new DNA polymorphisms that will be useful for various studies of this genus and demonstrates that both approaches can be used to develop new DNA polymorphisms in platyrrhine species.

Alleles↗
PubMed1999

Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer's disease.

We have characterized amyloid beta peptide (Abeta) concentration, Abeta deposition, paired helical filament formation, cerebrovascular amyloid angiopathy, apolipoprotein E (ApoE) allotype, and synaptophysin concentration in entorhinal cortex and superior frontal gyrus of normal elderly control (ND) patients, Alzheimer's disease (AD) patients, and high pathology control (HPC) patients who meet pathological criteria for AD but show no synapse loss or overt antemortem symptoms of dementia. The measures of Abeta deposition, Abeta-immunoreactive plaques with and without cores, thioflavin histofluorescent plaques, and concentrations of insoluble Abeta, failed to distinguish HPC from AD patients and were poor correlates of synaptic change. By contrast, concentrations of soluble Abeta clearly distinguished HPC from AD patients and were a strong inverse correlate of synapse loss. Further investigation revealed that Abeta40, whether in soluble or insoluble form, was a particularly useful measure for classifying ND, HPC, and AD patients compared with Abeta42. Abeta40 is known to be elevated in cerebrovascular amyloid deposits, and Abeta40 (but not Abeta42) levels, cerebrovascular amyloid angiopathy, and ApoE4 allele frequency were all highly correlated with each other. Although paired helical filaments in the form of neurofibrillary tangles or a penumbra of neurites surrounding amyloid cores also distinguished HPC from AD patients, they were less robust predictors of synapse change compared with soluble Abeta, particularly soluble Abeta40. Previous experiments attempting to relate Abeta deposition to the neurodegeneration that underlies AD dementia may have failed because they assayed the classical, visible forms of the molecule, insoluble neuropil plaques, rather than the soluble, unseen forms of the molecule.

Aged↗
PubMed1999

The effects of dental wear on third molar eruption and on the curve of Spee in human archaeological dentitions.

The abrasiveness of food is a key determinant in the rate of physiological attrition (dental wear) in humans. With increasing food processing through time, the rate of physiological dental wear in human teeth has decreased markedly. Many consider such wear to be beneficial to oral health and that insufficient wear may result in impaction of the third molars. If enhanced extraoral food processing provides an evolutionary advantage, then it is possible that agenesis of the redundant third molar may follow. One of the aims here was to examine impaction and agenesis of the third molars in four populations of varying antiquity and hence varying dental-wear rates. Paradoxically, whilst there is a decrease in the rate of dental wear with modernity, there is also an increasing prevalence of advanced dental wear due to prolongation of the lifespan of the human dentition. As the effect of dental wear on the curve of Spee was unknown, a second aim was to examine it in an archaeological population with a high rate of dental wear. The results showed an increase in non-eruption and impaction of the third molars with modernity, but did not demonstrate a significant increase in the rate of agenesis. The time period over which impaction and agenesis could be discerned was of the order of 600 years and this may not be sufficient to observe adaptive changes at the genetic level in humans. In molar teeth there was no clear indication of maintenance of the curve of Spee with dental wear. This has potential implications on the design of prostheses for the worn dentition.

Adult↗
PubMed1999

Selection, evolution of behavior and animal models in behavioral neuroscience.

We investigated whether genetic differences in various forms of intraspecific aggression and anxiety in four different genetic lines of mice (i.e. wild, outbred Swiss-CD1, inbred DBA/2 and inbred C57/BL6N) may reflect modifications in behavioral strategy. Experiments 1 and 2 used ethologically based paradigms to analyze aggressive and anxiety responses both in social (i.e. aggression) and non-social (i.e. novel environment exploration) contexts. In Experiment 3, an anxiolytic drug (chlordiazepoxide (CDP)) was used to examine possible differences in proximal mechanisms underlying anxiety-related behaviors. The data show that intrasexual aggression, infanticide and maternal aggressions are related and covarying. Genetic lines with the highest levels of intermale attack (i.e. Wild and Swiss-CD1) also have highest levels of infanticide, interfemale attack and maternal aggression but, interestingly, the lowest levels of anxiety. In fact, exploratory behavior is lower and risk assessment behavior markedly higher in DBA/2 and C57/BL6N mice (i.e. the less aggressive strains) compared to Swiss and Wild genetic lines. Although reproductive status influences anxiety levels in female mice, our findings show that (contrary to previous studies) lactating mice are more anxious than virgin females in terms of risk assessment activities. These data demonstrate the importance of studying behavior in a more ecologically-relevant context which emphasizes the function of behavior in a specific situation. Moreover, differential strain sensitivity to the behavioral effects of CDP suggests that genetic lines of mice may differ in the underlying mechanisms mediating behavior. It is therefore possible that artificial selection of different genotypes has resulted in differences in proximate mechanisms modulating the levels of aggression and anxiety, thereby leading to modification of social behavior. Overall, the results presented here suggest that subtle genetic alterations in specific underlying neural mechanisms are likely to cause profound effects on behavioral responses and their adaptive significance. Implications for behavioral neuroscience research that seeks to understand both the proximal and ultimate mechanisms of behavior are discussed.

Animals↗
PubMed1999

Syntactic-semantic tagging as a mediator between linguistic representations and formal models: an exercise in linking SNOMED to GALEN.

Natural language understanding applications are good candidates to solve the knowledge acquisition bottleneck when designing large scale concept systems. However, a necessary condition is that systems are built that transform sentences into a meaning representation that is independent of the subtleties of linguistic structure that nevertheless underly the way language works. The Cassandra II syntactic-semantic tagging system fulfills this goal partially. Within the GALEN-IN-USE project, it is used to transform linguistic representations of surgical procedure expressions into conceptual representations. In this paper, the proctology chapter of the SNOMED V3.1 procedure axis was used as a testbed to evaluate the usefulness of this approach. A quantitative and qualitative analysis of the data obtained is presented, showing that the Cassandra system can indeed complement the manual modelling efforts being conducted in the GALEN-IN-USE project. The different requirements related to linguistic modelling versus conceptual modelling can partly be accounted for by using an interface ontology, of which the fine tuning will however remain an important effort.

Artificial Intelligence↗
PubMed1999

Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda.

Spondyloepiphyseal dysplasia tarda (SEDL; MIM 313400) is an X-linked recessive osteochondrodysplasia that occurs in approximately two of every one million people. This progressive skeletal disorder which manifests in childhood is characterized by disproportionate short stature with short neck and trunk, barrel chest and absence of systemic complications. Distinctive radiological signs are platyspondyly with hump-shaped central and posterior portions, narrow disc spaces, and mild to moderate epiphyseal dysplasia. The latter usually leads to premature secondary osteoarthritis often requiring hip arthroplasty. Obligate female carriers are generally clinically and radiographically indistinguishable from the general population, although some cases have phenotypic changes consistent with expression of the gene defect. The SEDL gene has been localized to Xp22 (refs 8,9) in the approximately 2-Mb interval between DXS16 and DXS987 (ref. 10). Here we confirm and refine this localization to an interval of less than 170 kb by critical recombination events at DXS16 and AFMa124wc1 in two families. In one candidate gene we detected three dinucleotide deletions in three Australian families which effect frameshifts causing premature stop codons. The gene designated SEDL is transcribed as a 2.8-kb transcript in many tissues including fetal cartilage. SEDL encodes a 140 amino acid protein with a putative role in endoplasmic reticulum (ER)-to-Golgi vesicular transport.

Adolescent↗
PubMed1999

A spontaneous corneal change in juvenile Wistar rats.

Corneal changes were seen in a shipment of male and female Charles River Wistar (Crl:(WI)BR) albino rats aged 33 days. Seventeen weeks later, varying degrees of corneal roughness were observed ophthalmoscopically in 40 of 43 males and 26 of 29 females. Corneal lesions, described clinically as multiple punctate or particulate opacities, were most often bilateral and located paracentrally. Histologically, lesions were observed in only 21 of 40 males and in 15 of 26 females which had shown clinical changes. The lesions consisted of basophilic particulate material, which occasionally formed linear plaques, lining the basement membrane of the corneal epithelium. Ultrastructurally, irregularly distributed electron-dense deposits, occasionally assuming a concentric laminar appearance, were observed. X-ray microanalysis revealed that the granules consisted predominantly of calcium and phosphorus, with trace amounts of iron, zinc, sodium and aluminium. These mineral deposits in the corneas of Wistar rats were similar to those described in other species. Awareness of this spontaneously occurring disease in Wistar rats is of importance in relation to toxicological investigations in which the cornea may be a target organ.

Aging↗