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Biomedical subjects

A T Johnson

Publications and source records attributed to A T Johnson.

At least 19 recordsLinked to original sources
PubMed2006

Electron beam induced structural transformations of SWNTs and DWNTs grown on Si3N4/Si substrates.

Electron beam induced structural transformations are investigated in single-wall carbon nanotubes (SWNTs), double-wall carbon nanotubes (DWNTs) and crossed nanotube junctions. The nanotubes studied here are synthesized by the chemical vapor deposition method. The response of the nanotubes to an electron beam is found to be influenced by the presence of coatings of amorphous carbon, graphene fragments and structural defects on the tube surface. The dependence of structural modifications on electron beam irradiation dose is measured. While nanotubes with amorphous carbon, graphene fragment coverage and/or defects undergo rapid transformation leading to structure disintegration, those without such coverage or defects are more resistant to beam damage. In addition, it is shown that the amorphous carbon coverage on the double-wall nanotubes can be transformed into graphene layers during electron beam irradiation of coated nanotubes. Finally, the relative stability of nanotube side-wall and end-walls are investigated through sub-threshold energy and above threshold energy irradiation of a model system, C60-filled nanotubes (Peapods). The data indicates that electron beams could be used to join nanotubes end-to-end without damaging the side-walls.

Adsorption↗
PubMed2005

Controlled switching of optical emission energies in semiconducting single-walled carbon nanotubes.

We present scanning photoluminescence (PL) microscopy of freely suspended single-walled carbon nanotubes grown by chemically assisted vapor deposition (CVD) across micron-sized open apertures. Scans of the PL emission versus excitation position show unusual "holes"having subwavelength spatial features associated with abrupt blue shifts of the emission energy. By varying the excitation polarization, energy, intensity, and position, we demonstrate that optical switching in some nanotubes is controllable in a highly nonlinear manner by adjusting the nonequilibrium carrier density in the nanotube. Technologically important attributes include large spectral contrast between on/off states at room temperature, a dramatic response to small changes in light intensity near threshold, and the possibility that electrical charge injection could also be used to control emission energies.

Crystallization↗
PubMed2002

Role of single defects in electronic transport through carbon nanotube field-effect transistors.

The influence of defects on electron transport in single-wall carbon nanotube field-effect transistors (CNFETs) is probed by combined scanning gate microscopy (SGM) and scanning impedance microscopy (SIM). SGM images are used to quantify the depletion surface potential, and from this the Fermi level, at individual defects along the CNFET length. SIM is used to measure the voltage distribution along the CNFET. When the CNFET is in the conducting state, SIM reveals a uniform potential drop along its length, consistent with diffusive transport. In contrast, when the CNFET is "off," potential steps develop at the position of depleted defects. High-resolution imaging of a second set of weak defects is achieved in a new "tip-gated" SIM mode.

Journal Article↗
PubMed2002

Mapping the one-dimensional electronic States of nanotube peapod structures.

Arrays of C60 molecules nested inside single-walled nanotubes represent a class of nanoscale materials having tunable properties. We report electronic measurements of this system made with a scanning tunneling microscope and demonstrate that the encapsulated C60 molecules modify the local electronic structure of the nanotube. Our measurements and calculations also show that a periodic array of C60 molecules gives rise to a hybrid electronic band, which derives its character from both the nanotube states and the C60 molecular orbitals.

Journal Article↗
PubMed2000

Age-dependent prevalence of mutations at the GLC1A locus in primary open-angle glaucoma.

PURPOSE: To screen a population with primary open-angle glaucoma for mutations in the gene that encodes the trabecular meshwork inducible glucocorticoid response protein (TIGR), also known as myocilin (MYOC). METHODS: Ophthalmologic information was collected for study subjects with primary open-angle glaucoma and their relatives. Mutation screening of 74 primary open-angle glaucoma probands was conducted by sequencing TIGR/MYOC coding sequence and splice sites. RESULTS: In 23 families we detected 13 nonsynonymous sequence changes, nine of which appear to be mutations likely to cause or contribute to primary open-angle glaucoma. Two mutations, Arg272Gly and Ile499Ser, and one nonsynonymous sequence variant, Asn57Asp, are novel. We found mutations in nine of 25 juvenile glaucoma probands (36%) and two of 49 adult-onset glaucoma probands (4%). Age classification of families rather than individual probands revealed mutations in three of nine families with strictly juvenile primary open-angle glaucoma (33%), and no mutations in 39 families with strictly adult-onset primary open-angle glaucoma (0%). In families with mixed-onset primary open-angle glaucoma containing both juvenile primary open-angle glaucoma and adult-onset primary open-angle glaucoma cases, we found mutations in eight of 26 families (31%). CONCLUSIONS: Our data suggest that Gly252Arg, Arg272Gly, Glu323Lys, Gln368STOP, Pro370Leu, Thr377Met, Val426Phe, Ile477Asn, and Ile499Ser are likely to play roles that cause or contribute to the etiology of autosomal dominant primary open-angle glaucoma. Our finding of more TIGR/MYOC mutations in families with mixed-onset primary open-angle glaucoma than in the families with strictly adult-onset primary open-angle glaucoma implies that the presence of relatives with juvenile primary open-angle glaucoma in a family could be used as a basis for identifying a subset of the population with adult-onset primary open-angle glaucoma with higher prevalence of TIGR/MYOC mutations. To address this issue, and to refine estimations of mutation prevalence in these age-defined subpopulations, prospective study of a larger population ascertained entirely through adult-onset primary open-angle glaucoma probands will be needed.

Adolescent↗
PubMed1999

High affinity retinoic acid receptor antagonists: analogs of AGN 193109.

A series of high affinity retinoic acid receptor (RAR) antagonists were prepared based upon the known antagonist AGN 193109 (2). Introduction of various phenyl groups revealed a preference for substitution at the para-position relative to the meta-site. Antagonists with the highest affinities for the RARs possessed hydrophobic groups, however, the presence of polar functionality was also well tolerated.

Naphthalenes↗
PubMed1999

Identification of the AP1-antagonism domain of retinoic acid receptors.

Retinoids are therapeutically effective in the treatment of psoriasis, photoaging, acne, and certain cancers. Some of the therapeutic actions of retinoids can be ascribed to retinoic acid receptor (RAR)-mediated antagonism of AP1-dependent gene expression. The increased activity of transcription factor AP1, a complex of oncoproteins Jun and Fos, is associated with cell growth and proliferation. Retinoids, on the other hand, inhibit cell proliferation and affect differentiation, activities that possibly stem from an antagonism of AP1-mediated gene expression by RARs. To gain insight into the molecular mechanism of RAR-AP1 interaction, we have identified the regions of the RAR required for AP1 antagonism. We demonstrate that the AP1 antagonism domain of RAR is a complex of the core of the DNA binding domain and the hydrophobic zipper region. Further, both monomeric RAR and RAR-RXR heterodimers inhibit the expression of an AP1 reporter. CREB binding protein (CBP) has been described as a cofactor for AP1, various nuclear hormone receptor proteins including RARs, and certain other transcription factors and is required for their transactivation properties. Therefore, CBP has been proposed as a common limiting cofactor that can account for inhibition of AP1-dependent gene expression by RARs. Interestingly, however, our results along with previously reported observations suggest that in addition to CBP, there may be other limiting cofactor(s) responsible for mutual transrepression of RAR and AP1.

Binding Sites↗
PubMed1999

Synthesis and biological activity of high-affinity retinoic acid receptor antagonists.

This article reports the synthesis and biological activity of new high affinity retinioic acid receptor (RAR) antagonists. The effect of introducing heteroatoms in the bicyclic ring system of the potent dihydronaphthalene RAR antagonist 8, and the variation of the pendant aromatic group on the ability of these compounds to function as RAR antagonists is discussed. The use of binding, transcriptional, and in vivo assays revealed that the 2,2-dimethylthiochromene analogue 59, and the 2,2-dimethylchromene derivative 85, were the most effective in blocking retinoid agonist induced activity.

Animals↗
PubMed1999

Respiratory resistance measured by an airflow perturbation device.

The airflow perturbation device (APD) is an instrument for the measurement of respiratory resistance. The APD is small, lightweight, fast and requires no special breathing manoeuvres. Airflow perturbation determines resistance by superimposing a periodic signal onto spontaneous breathing with a variable resistance device. Respiratory impedance is the ratio of magnitude of pressure perturbation to magnitude of flow perturbation, and respiratory resistance is the in-phase portion of respiratory impedance. The APD was tested to determine its responses to repeated resistance measurements and to changes in resistance. A mechanical model test showed that the APD could detect increased resistance levels, but overestimated resistance when resistance increased with flow. Tests with human subjects showed that the APD gave results consistent from day to day, was able to detect added resistances, and gave resistance values correlated with airway resistance values obtained by body plethysmography. Accelerometers placed on the chests of the subjects showed that perturbations extend to the chest surface. Thus, the APD must measure total respiratory resistance.

Airway Resistance↗
PubMed1999

Type-specific contributions to chromosome size differences in Escherichia coli.

The Escherichia coli genome varies in size from 4.5 to 5.5 Mb. It is unclear whether this variation may be distributed finely throughout the genome or is concentrated at just a few chromosomal loci or on plasmids. Further, the functional correlates of size variation in different genome copies are largely unexplored. We carried out comparative macrorestriction mapping using rare-restriction-site alleles (made with the Tn10dRCP2 family of elements, containing the NotI, BlnI, I-CeuI, and ultra-rare-cutting I-SceI sites) among the chromosomes of laboratory E. coli K-12, newborn-sepsis-associated E. coli RS218, and uropathogenic E. coli J96. These comparisons showed just a few large accessory chromosomal segments accounting for nearly all strain-to-strain size differences. Of 10 sepsis-associated and urovirulence genes, previously isolated from the two pathogens by scoring for function, all were colocalized exclusively with one or more of the accessory chromosomal segments. The accessory chromosomal segments detected in the pathogenic strains from physical, macrorestriction comparisons may be a source of new virulence genes, not yet isolated by function.

Alleles↗
PubMed1998

GLC1A mutations point to regions of potential functional importance on the TIGR/MYOC protein.

PURPOSE: The aim of this study was to screen affected members of glaucoma families for mutations in the Trabecular Meshwork Inducible Glucocorticoid Response (TIGR) gene also known by the name myocilin (MYOC) or by combined names such as TIGR/MYOC. Our primary objectives were (1) to identify mutations responsible for glaucoma in members of three families for which we have shown linkage between chromosome 1 GLC1A-region markers and the primary open angle glaucoma (POAG) phenotype, and (2) to determine the relationship of these and other mutations to key points of predicted function and structure of the TIGR/MYOC protein. METHODS: DNA sequence determination was used to identify sequence changes in sections of the TIGR/MYOC gene that were PCR-amplified from genomic DNA from the probands of three previously-reported GLC1A juvenile-onset POAG families, UM:JG1, UM:JG3, UM:GL57, and unmapped family UM:JG5. Allele-specific oligonucleotide hybridization was used to screen for the identified mutations in PCR-amplified DNA from individual members of each pedigree and from a panel of 11 additional juvenile glaucoma family probands, 42 adult POAG family probands, and 43 normal individuals. Computerized algorithms were used to identify functional motifs and predict structures of normal and mutant forms of the protein. RESULTS: Sequence changes were found that alter amino acids in the olfactomedin-like domain near the carboxy terminal end of the TIGR protein in affected members of families UM:JG1 (Pro370Leu), UM:JG3 (Val426Phe), UM:GL57 (Glu323Lys) and UM:JG5 (Gly252Arg). Co-segregation of glaucoma and Pro370Leu, Val426Phe, and Gly252Arg in known GLC1A families suggests that these are mutations. Although the Gly252Arg substitution observed in UM:JG5 is non-conservative, it was not possible to distinguish whether it is a mutation or a polymorphism. None of the sequence changes described in these families were observed in other juvenile glaucoma cases in this study, nor in any of the POAG or phenotypically normal individuals tested here. Analysis of amino acid sequence changes resulting from mutations described in this and other works demonstrate localization of many mutations in the vicinity of predicted functional motifs in the olfactomedin-like domain. Identification of rat latrophilin (LPH1/CIRL) as a new member of the olfactomedin-like protein family to which TIGR/MYOC belongs suggests that the region of olfactomedin homology is a protein domain that can occur in different protein contexts. CONCLUSIONS: Location of mutations described in this and previous work suggests that some specific predicted protein motifs in the olfactomedin-like domain may be important to TIGR/MYOC function. In some cases, the role of TIGR/MYOC in the etiology of glaucoma may result from alteration of the sequences recognized by modifying enzymes such as casein kinase II. In other cases altered protein folding may affect access of enzymes to their target sequences on TIGR/MYOC. Although modifications and structures discussed here are predicted rather than proven, they provide a useful theoretical framework for design of subsequent experiments. Alterations to protein folding and predicted modification motifs cannot explain the pathogenic mechanisms of all of the known TIGR/MYOC glaucoma mutations.

Adult↗
PubMed1998

Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene (GLC1A)

BACKGROUND: A substantial proportion of cases of glaucoma have a genetic basis. Mutations causing glaucoma have been identified in the chromosome 1 open-angle glaucoma gene (GLC1A), which encodes a 57-kd protein known as myocilin. The normal role of this protein and the mechanism by which mutations cause glaucoma are not known. METHODS: We screened 716 patients with primary open-angle glaucoma and 596 control subjects for sequence changes in the GLC1A gene. RESULTS: We identified 16 sequence variations that met the criteria for a probable disease-causing mutation because they altered the predicted amino acid sequence and they were found in one or more patients with glaucoma, in less than 1 percent of the control subjects. These 16 mutations were found in 33 patients (4.6 percent). Six of the mutations were found in more than 1 subject (total, 99). Clinical features associated with these six mutations included an age at diagnosis ranging from 8 to 77 years and maximal recorded intraocular pressures ranging from 12 to 77 mm Hg. CONCLUSIONS: A variety of mutations in the GLC1A gene are associated with glaucoma. The spectrum of disease can range from juvenile glaucoma to typical late-onset primary open-angle glaucoma.

Age of Onset↗
PubMed1998

Generating the Snellen Chart by computer.

The Snellen Chart is the eye chart that is commonly used to measure visual acuity. The chart has combinations of nine different letters in eleven different lines, each smaller than the one above. Repeated measures of visual acuity may result in chart memorization and false information. Thus, a computer program was written to produce randomized multiple versions of Snellen eye charts. The chart may be changed at some distance from the computer in order to hear subject letter identifications during exercise testing. Different sized letters can also be produced so that the distance from the subject to the chart can vary.

Humans↗
PubMed1998

Respirator performance ratings for speech intelligibility.

A respirator degrades speech intelligibility and thus interferes with the ability of the wearer to communicate. The magnitude of this degradation is not well-studied and can vary as a function of numerous parameters. This study investigated the performance degradation of speech intelligibility in low-level noise for different speaker-listener distances and message sets (single words or predictable sentences) that occurred while wearing a respirator compared with not wearing a respirator. Thirteen speaker-listener pairs with normal hearing and speech were used. Speaker-listener separation distances were 0.61, 1.22, 1.83, 2.44, 3.05, and 3.66 m (2, 4, 6, 8, 10, and 12 ft) for the respirator condition and 1.22, 2.44, 3.05, 6.1, 9.15, and 12.2 m (4, 8, 10, 20, 30, and 40 ft) for the no-respirator condition. The means of the scores were used to determine the speech performance rating for both the single-word and sentence comprehension tests. The performance rating expresses the percentage of performance that can be expected while wearing a respirator compared with not wearing a respirator. Scores were interpolated linearly at distances at which no data were obtained. As expected, the speech performance rating was higher for the sentence comprehension test than for the single-word comprehension test at each distance. At a distance of 12.2 m, the speech performance rating for the sentence comprehension was 70%. For the single-word comprehension test, the speech performance rating was zero for distances greater than 9.1 m.

Adolescent↗
PubMed1998

The use of a retinoid receptor antagonist in a new model to study vitamin A-dependent developmental events.

Multiple fetal anomalies occur in vitamin A deficient animals as well as in retinoic acid receptor gene 'knockout' mice, indicating that retinoic acid (an active metabolite of vitamin A) performs some essential functions in normal development. Additional approaches are needed to probe directly the stages and sites in the embryo where a presence of endogenous retinoic acid is indispensable. We have employed a new strategy for this purpose which involved an intervention in retinoic acid receptor (RAR)-dependent functions at specific developmental stages by means of a highly effective RAR antagonist, AGN 193109. We report that in an in vitro cell differentiation bioassay, AGN 193109 completely reversed the inhibitory action of a potent RAR agonist, AGN 190121. In pregnant mice, a single oral 1 mg/kg dose of the antagonist given on 8 day post coitum (dpc) produced a severe craniofacial anomaly (median cleft face or frontonasal dysplasia) and eye malformations in virtually all exposed fetuses. On the other hand, treatment on 11 dpc, a time in development when RARs are strategically expressed in the limb bud primordium, no limb anomalies could be induced by the antagonist. Even after a high dose of 100 mg/kg, limb development progressed normally in spite of the fact that measurable concentrations of the antagonist were present. Because retinoids are long known to influence skin morphology, we next monitored the effects of the antagonist on skin development. When given late in gestation, on 14 dpc, we found that the antagonist delayed differentiation and maturation of the fetal skin and hair follicles. We conclude that this model provides a convenient and pertinent system which enables us to seek and clarify true functions of retinoic acid and its cognate receptors in embryogenesis and in adult animals.

Animals↗
PubMed1997

Identification of highly potent retinoic acid receptor alpha-selective antagonists.

The syntheses and full retinoid receptor characterization of a novel series of retinoic acid receptor alpha (RAR alpha) antagonists, 1-5, are described. These compounds bind with high affinity to RAR alpha but were completely inactive in gene transactivation. They were also potent and effective antagonists of retinoic acid (RA) induced gene transcription at RAR alpha. Compounds 1-5 exhibited varying degrees of selectivity for RAR alpha relative to RAR beta/gamma, with compound 5 being the most selective in both binding and functional antagonism assays. These compounds will be invaluable tools in delineating the physiological roles of RAR alpha in development and in the adult animal and may themselves be useful therapeutic agents in human diseases associated with RAR alpha.

Animals↗
PubMed1997

Sweat rate inside a full-facepiece respirator.

The accumulation of sweat inside a full-facepiece respirator mask and the rise in facial skin temperature can be important factors for acceptability of respirators worn in the heat. This study questioned how much sweat would have to be removed from a respirator (if a design to remove accumulated sweat were possible). Results from 20 subjects sitting in a warm, humid environment (35 degrees C and 90% relative humidity) for 90 minutes indicated that the average value was about 0.203 g sweat/min from the face, head, and neck, with most of that coming from the neck region. Men were found to have higher sweating rates than women. The results indicate that a large amount of sweat could accumulate inside the mask over a typical 8-hour day. Average facial skin temperature was found to rise about 2 degrees C over the 90-minutes test, and this rise could likely be the cause of the very uncomfortable rating given to the respirator.

Equipment Design↗