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Thomas E Johnson

Publications and source records attributed to Thomas E Johnson.

At least 19 recordsLinked to original sources
PubMed2007

Dietary restriction in the nematode Caenorhabditis elegans.

The nematode Caenorhabditis elegans has proved to be an excellent model organism for the study of development and aging. Many aging mutants have been discovered in the past two decades, and much has been discovered about the physiology of long-lived mutants. It therefore seems surprising that dietary restriction (DR) has not been extensively studied using C. elegans. The main reason for this is the lack of an ideal method to subject C. elegans to DR. However, several authors have tried to study the effect of DR on the metabolism and physiology of C. elegans, and epistasis-type interaction studies have been carried out in order to detect genes that might be involved in DR effects. These studies show that DR life extension is not caused by a reduced metabolic rate, consistent with results in other species. Moreover, the well-known insulin/IGF-1 pathway seems not to mediate life-extending effects. One possibility is that target of rapamycin signaling mediates the effects of DR on life span in C. elegans.

Aging↗
PubMed2006

Recent results: biomarkers of aging.

This communication reviews recent papers attempting to identify Biomarkers of Aging (BoA). A BoA is a biological parameter that will predict functional capability at some later age. Few, if any, BoA have been found and this review describes the recent search for BoA. Among others that have been put forward are IL6 and other markers of inflammation, allostatic load, and corticosterone, which have been described primarily in humans. Work in model systems as well as theoretical work are also reviewed.

Aged↗
PubMed2006

Hormesis and aging in Caenorhabditis elegans.

Hormesis has emerged as an important manipulation for the study of aging. Although hormesis is manifested in manifold combinations of stress and model organism, the mechanisms of hormesis are only partly understood. The increased stress resistance and extended survival caused by hormesis can be manipulated to further our understanding of the roles of intrinsic and induced stress resistance in aging. Genes of the dauer/insulin/insulin-like signaling (IIS) pathway have well-established roles in aging in Caenorhabditis elegans. Here, we discuss the role of some of those genes in the induced stress resistance and induced life extension attributable to hormesis. Mutations in three genes (daf-16, daf-18, and daf-12) block hormetically induced life extension. However, of these three, only daf-18 appears to be required for a full induction of thermotolerance induced by hormesis, illustrating possible separation of the genetic requirements for stress resistance and life extension. Mutations in three other genes of this pathway (daf-3, daf-5, and age-1) do not block induced life extension or induced thermotolerance; daf-5 mutants may be unusually sensitive to hormetic conditions.

Aging↗
PubMed2006

Murine weight loss exhibits significant genetic variation during dietary restriction.

We present genetic analyses of murine weight loss during dietary restriction (DR) for females eating 60% ad libitum (AL). We examined 5 cohorts across 81 different strains (22 strains tested twice) that included the LXS and LSXSS recombinant inbred strains, the LXS parental strains ILS and ISS, and the classical inbreds 129S6, A, BALB/c, C57BL/6, C3H, and DBA. Weight loss exhibited highly significant genetic variation, with DR body weights ranging from approximately 60 to approximately 85% of AL body weight. This variation was not explained by the strain differences in absolute food intake, feces calorie content, motor activity, or AL body fat. Heritability was 40-50%, and several provisional quantitative trait loci were mapped. This variation can be used to test whether weight loss correlates with the health benefits of DR, independently of the reduction in calories. The genetic variation also implies the existence of genes that would be novel therapeutic targets, distinct from genes affecting AL body weight or body fat, for enhancing (or mitigating) weight loss during food restriction.

Adipose Tissue↗
PubMed2006

Confirmation and fine mapping of ethanol sensitivity quantitative trait loci, and candidate gene testing in the LXS recombinant inbred mice.

In previous studies, we have mapped quantitative trait loci (QTLs) for hypnotic sensitivity to ethanol using a small recombinant inbred (RI) panel and a large F(2) backcross. Alcohol sensitivity is a major predictor of long-term risk for alcoholism. We remapped hypnotic sensitivity using a new set of 75 RI strains, the LXS, derived from Inbred Long Sleep and Inbred Short Sleep strains. We expected to improve mapping resolution in the QTL regions and to identify novel QTLs for loss of the righting reflex due to ethanol. We used three common mapping algorithms (R/qtl, QTL Cartographer, and WebQTL) to map QTLs in the LXS, and we compared the results. Most mapping studies use only a single algorithm, an approach that may result in failure to identify minor QTLs. We confirmed most of our previously reported QTLs, although one major QTL from earlier work (Lore2) failed to replicate, possibly because it represented multiple linked genes separated by recombination in the RI strains. We also report narrowed confidence intervals, based on mapping with a new genetic resource of more than 4000 polymorphic single-nucleotide polymorphism markers. These narrowed confidence intervals will facilitate candidate gene identification and assessment of overlap with human regions specifying risk for alcoholism. Finally, we present an approach for using these RI strains to assess evidence for candidate genes in the narrowed intervals, and we apply this method to a strong candidate, the serotonin transporter.

Alcoholism↗
PubMed2006

Mouse genetic models in alcohol research.

Animal models offer several advantages for the study of complex human disorders such as alcoholism. No animal model replicates all aspects of alcoholism but different components of the disorder can be investigated using various rodent models. In this article, we review a select subset of the most widely used mouse genetic models in alcohol research. Different genetically defined strains and stocks of mice are useful for genetic, physiologic, behavioral and pharmacological studies of this devastating disorder. In the past decade, numerous genomic regions associated with a tendency for various behavioral components of alcoholism have been identified; recent applications of new methods are shedding light on quantitative trait genes. Many of the underlying genes should be identified in the near future.

Alcoholism↗
PubMed2006

Visualizing hidden heterogeneity in isogenic populations of C. elegans.

Age-specific mortality levels off at advanced ages in many species; one explanation for this phenomenon is provided by the population heterogeneity theory. Although mortality at advanced ages can be well fit by heterogeneity models, population heterogeneity remains theoretical, lacking much direct evidence to support the existence of unobserved heterogeneity. Here, we provide direct evidence to support the heterogeneity theory by using isogenic population of worms of Caenorhabditis elegans. We measure the ability of individual worms to respond to a heat stress using an HSP-16.2 promoter that has been attached to GFP, a fluorescent marker that can be assessed in living animals. Worms differ substantially in their response; worms with high response have a long lifespan, and worms with low response to stress have a short life. Each of these classes results from a mix of two distinct, heterogeneous classes of worms and the addition of more classes does not result in a better fit.

Aging↗
PubMed2006

Expression profiling identifies novel candidate genes for ethanol sensitivity QTLs.

The Inbred Long Sleep (ILS) and Inbred Short Sleep (ISS) mouse strains have a 16-fold difference in duration of loss of the righting response (LORR) following administration of a sedative dose of ethanol. Four quantitative trait loci (QTLs) have been mapped in these strains for this trait. Underlying each of these QTLs must be one or more genetic differences (polymorphisms in either gene coding or regulatory regions) influencing ethanol sensitivity. Because prior studies have tended to focus on differences in coding regions, genome-wide expression profiling in cerebellum was used here to identify candidate genes for regulatory region differences in these two strains. Fifteen differentially expressed genes were found that map to the QTL regions and polymorphisms were identified in the promoter regions of four of these genes by direct sequencing of ILS and ISS genomic DNA. Polymorphisms in the promoters of three of these genes, Slc22a4, Rassf2, and Tax1bp3, disrupt putative transcription factor binding sites. Slc22a4 and another candidate, Xrcc5, have human orthologs that map to genomic regions associated with human ethanol sensitivity in genetic linkage studies. These genes represent novel candidates for the LORR phenotype and provide new targets for future studies into the neuronal processes underlying ethanol sensitivity.

Animals↗
PubMed2006

An atypical presentation of adenoid cystic carcinoma of the lacrimal gland.

PURPOSE: To report a case of lacrimal gland adenoid cystic carcinoma (ACC) with an atypical initial presentation and to postulate an anatomical explanation for this unusual biologic behavior. DESIGN: Interventional case report. METHODS: An orbital magnetic resonance imaging study of a 58-year-old man who complained of progressive diplopia and orbital discomfort disclosed a soft tissue mass in the left cavernous sinus and orbital apex. The left lacrimal gland and the contiguous bone appeared normal. RESULTS: Biopsy of the intracranial mass revealed ACC of unknown origin which was judged to be unresectable. He underwent two cycles of intraarterial cytoreductive chemotherapy followed by a left medial maxillectomy with sphenoethmoidectomy, orbital exenteration, and chemoradiation. ACC tumor cells were identified in nerve fiber bundles surrounding and within the lacrimal gland. CONCLUSIONS: In patients presenting with an infiltrative mass in the cavernous sinus or orbital apex, metastatic disease from an occult lacrimal gland primary should be considered, even with a normal-appearing lacrimal gland.

Carcinoma, Adenoid Cystic↗
PubMed2006

The quest for genetic determinants of human longevity: challenges and insights.

Twin studies show that genetic differences account for about a quarter of the variance in adult human lifespan. Common polymorphisms that have a modest effect on lifespan have been identified in one gene, APOE, providing hope that other genetic determinants can be uncovered. However, although variants with substantial beneficial effects have been proposed to exist and several candidates have been put forward, their effects have yet to be confirmed. Human studies of longevity face numerous theoretical and logistical challenges, as the determinants of lifespan are extraordinarily complex. However, large-scale linkage studies of long-lived families, longitudinal candidate-gene association studies and the development of analytical methods provide the potential for future progress.

Alleles↗
PubMed2006

daf-16 protects the nematode Caenorhabditis elegans during food deprivation.

Inhibition of either the insulin-like or target of rapamycin (TOR) pathways in the nematode Caenorhabditis elegans extends life span. Here, we demonstrate that starvation and inhibition of the C. elegans insulin receptor homolog (daf-2) elicits a daf-16-dependent up-regulation of a mitochondrial superoxide dismutase (sod-3). We also find that although heat and oxidative stress result in nuclear localization of the DAF-16 protein, these stressors do not activate a SOD-3 reporter, suggesting that nuclear localization alone may not be sufficient for transcriptional activation of DAF-16. We show that inhibition of either TOR activity or key components of the cognate translational machinery (eIF-4G and EIF-2B homologs) increases life span by both daf-16-dependent and -independent mechanisms. Finally, we demonstrate that at least one nematode hexokinase is localized to the mitochondria. We propose that the increased life spans conferred by alterations in both the TOR and insulin-like pathways function by inappropriately activating food-deprivation pathways.

Adaptation, Physiological↗
PubMed2006

DNA microarray and proteomic strategies for understanding alcohol action.

This article summarizes the proceedings of a symposium presented at the 2005 annual meeting of the Research Society on Alcoholism in Santa Barbara, California. The organizer was James M. Sikela, and he and Michael F. Miles were chairs. The presentations were (1) Genomewide Surveys of Gene Copy Number Variation in Human and Mouse: Implications for the Genetics of Alcohol Action, by James M. Sikela; (2) Regional Differences in the Regulation of Brain Gene Expression: Relevance to the Detection of Genes Associated with Alcohol-Related Traits, by Robert Hitzemann; (3) Identification of Ethanol Quantitative Trait Loci Candidate Genes by Expression Profiling in Inbred Long Sleep/Inbred Short Sleep Congenic Mice, by Robnet T. Kerns; and (4) Quantitative Proteomic Analysis of AC7-Modified Mice, by Kathleen J. Grant.

Alcoholism↗
PubMed2006

Applicability of ACR breast dosimetry methodology to a digital mammography system.

Determination of mean glandular dose (MGD) to breast tissue is an essential aspect of mammography equipment evaluations and exposure controls. The American College of Radiology (ACR) Quality Control Manual outlines the procedure for MGD determination in screen-film mammography based upon conversions of entrance skin exposures (ESEs) measured with an ionization chamber (IC). The development of digital mammography has increased with the demand for improved object resolution and tissue contrast. This change in image receptor from screen-film to a solid-state detector has led to questions about the applicability of the ACR MGD methodology to digital mammography. This research has validated the applicability of the ACR MGD methodology to digital mammography in the GE digital mammography system Senographe 2000D. MGD was determined using light output measurements from thermoluminescent dosimeters (MGDTL), exposure measurements from an IC (MGD(IC)) and conversion factors from the ACR Mammography Quality Control Manual. MGD(TL) and MGD(IC) data indicate that there is a statistically significant difference between the two measurements with the Senographe 2000D. However, the applicability of the ACR's methodology was validated by calculating MGD at various depths in a 50/50 breast phantom. Additionally, the results of backscatter measurements from the image receptors of both mammography modalities indicate there is a difference (all P values < 0.001) in the radiation backscattered from each image receptor.

Algorithms↗
PubMed2006

Creation of an innovative laser incident reporting form for improved trend analysis using the Delphi technique.

With expanding numbers of laser applications, there is greater potential for laser radiation exposures. Proper surveillance and evaluation of laser incidents can lead to better injury prevention and more efficient medical treatment. Current laser incident databases do not provide sufficient information for surveillance and analysis of laser trends. A laser incident reporting form (LIRF) was created for U.S. Air Force applications by using the Delphi technique. To create the LIRF, four expert panels were formed by 40 health and safety professionals experienced with laser systems and medical evaluation of laser incidents. After three rounds of surveys, the final LIRF contained 100 data collection fields identifying the most valuable items for injury trend analysis. Although the LIRF was initially developed to collect USAF laser incident information, it could potentially act as the cornerstone for a new system serving the entire military system.

Data Collection↗
PubMed2006

Response of lightly and highly pigmented porcine skin (Sus scrofa domestica) to single 3.8-microm laser radiation pulses.

The purpose of this study was to determine the effect of melanin on skin response to single 3.8-microm, 8-micros laser pulses and the difference in lesion formation thresholds. Our hypothesis was that pigmentation would play a significant role in skin energy absorption at 3.8 microm. Previous studies comparing pigmented and lightly pigmented porcine skin with human skin found that compared with Yorkshire pigs, Yucatan minipigs were a superior model for laser skin exposure because of their higher pigmentation levels. In the current study, 10 pigs under general anesthesia were exposed to 3.8-microm laser pulses ranging from 0.01 J/cm2 to 93 J/cm2. Gross examinations and skin biopsies were done 24 h after laser exposure, and histologic examinations were conducted on these tissue samples. The 24-h effective dose (ED50) was determined to be 4.5 J/cm2 for Yucatan mini-pigs and 2.6 J/cm2 for Yorkshire pigs. As deposited energy was increased, the lesion presentation progressed from desiccation of the superficial layer of epidermis (4 J/cm2) to desiccation with inflammatory centers (14 J/cm2), and finally to replacement of inflammatory areas with an epidermal ulcerated central area (=21 J/cm2). Therefore we found no statistical difference between the 24-h ED50 of the 2 breeds of pigs, nor was there any difference in histologic presentation at 24 h postexposure.

Animals↗