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Biomedical subjects

J M Harris

Publications and source records attributed to J M Harris.

At least 55 records · Page 3Linked to original sources
PubMed2000

Human leucocyte antigen-A2 increases risk of Alzheimer's disease but does not affect age of onset in a Scottish population.

The use of non-steroidal anti-inflammatory drugs has been associated with a reduced incidence of Alzheimer's disease (AD), suggesting that attenuation of the inflammatory response may be beneficial. Several, but not all, genetic association studies have shown human leucocyte antigen (HLA)-A2, a major histocompatibility complex class I antigen-binding transmembrane protein has an increased frequency in AD compared to controls, and in some reports is associated with a lowered age of onset. We further investigated the role of HLA-A2 in an independent sample of AD cases, including a large early onset cohort. The results of this current study and meta analysis of all studies available to date support previous evidence of an excess of HLA-A2 in AD, but found no evidence of a relationship with age of onset.

Age Distribution↗
PubMed2000

Hormone status selects for spontaneous somatic androgen receptor variants that demonstrate specific ligand and cofactor dependent activities in autochthonous prostate cancer.

We have used the autochthonous transgenic adenocarcinoma of mouse prostate (TRAMP) model to investigate the relationship between somatic mutation in the androgen receptor (AR) and the emergence of androgen-independent prostate cancer. Here we report the identification, isolation, and characterization of distinct classes of AR variants from spontaneous prostate tumors in the TRAMP model. Using cDNA cloning, single stranded conformation polymorphism and sequencing strategies, 15 unique somatic mutations in the AR were identified in prostate tumors obtained from eight TRAMP mice between 24 and 29 weeks of age. At least one mutation was isolated from each mouse. All mutations were single base substitutions, 10 were missense and 5 were silent. Nine mutations in the AR were identified in tumors of four mice that were castrated at 12 weeks of age. Interestingly, the majority of mutations (seven out of nine, 78%) identified in the androgen-independent tumors colocalized in the AR transactivation domain. The remaining mutations colocalized in the AR ligand binding domain. In general, the AR variants demonstrated promoter-, cell-, and cofactor-specific activities in response to various hormones. All AR variants isolated in this study maintained strong sensitivity for androgens, and four AR variants isolated from castrated mice demonstrated increased activities in the absence of ligand. The K638M and F677S variants demonstrated increased activities in response to androgen, and K638M also demonstrated increased response to estradiol. In the presence of AR coactivator ARA70 the E231G variant demonstrated increased activity in response to both androgen and estradiol. However, in the presence of AR coactivator ARA160 the E231G variant was selectively responsive to androgen. Collectively these analyses not only indicate that somatic mutations in the AR gene occur spontaneously in TRAMP tumors but also how changes in the hormonal environment may drive the selection of spontaneous somatic mutations that provide a growth advantage.

Animals↗
PubMed2000

The transcriptional factor LBP-1c/CP2/LSF gene on chromosome 12 is a genetic determinant of Alzheimer's disease.

Although the varepsilon4 allele of the apolipoprotein E gene appears as an important biological marker for Alzheimer's disease (AD) susceptibility, other genetic determinants are clearly implicated in the AD process. Here, we propose that a genetic variation in the transcriptional factor LBP-1c/CP2/LSF gene, located close to the LRP locus, is a genetic susceptibility factor for AD. We report an association between a non-coding polymorphism (G-->A) in the 3'-untranslated region of this gene and sporadic AD in French and British populations and a similar trend in a North American population. The combined analysis of these three independent populations provides evidence of a protective effect of the A allele (OR = 0.58, 95% CI 0.44-0.75). We describe a potential biologically relevant role for the A allele whereby it reduces binding to nuclear protein(s). The absence of the A allele was associated with a lower LBP-1c/CP2/LSF gene expression in lymphocytes from AD cases compared with controls. Our data suggest that polymorphic variation in the implication of the LBP-1c/CP2/LSF gene may be important for the pathogenesis of AD, particularly since LBP-1c/CP2/LSF interacts with proteins such as GSKbeta, Fe65 and certain factors involved in the inflammatory response.

3' Untranslated Regions↗
PubMed2000

Enantioselective syntheses of isoaltholactone, 3-epi-altholactone, and 5-hydroxygoniothalamin.

A flexible enantioselective route to highly functionalized alpha, beta-unsaturated delta-lactones has allowed for the syntheses of the styryllactones: isoaltholactone, 3-epi-altholactone, and 5-hydroxygoniothalamin in 10%, 5%, and 13% overall yields from furfural, respectively. This approach derives its asymmetry by applying the Sharpless catalytic asymmetric dihydroxylation to vinylfuran. The resulting diols are produced in high enantioexcess and can be stereoselectively transformed into alpha,beta-unsaturated delta-lactones via a short highly diastereoselective oxidation and reduction sequence.

Antineoplastic Agents↗
PubMed2000

Syntheses of four D- and L-hexoses via diastereoselective and enantioselective dihydroxylation reactions.

An expeditious approach to various protected hexoses has been developed by the use of the Sharpless catalytic asymmetric dihydroxylation reaction. Applying the Sharpless catalytic asymmetric dihydroxylation reaction on vinylfuran, diols with high enantioexcess are produced. The resulting diols can be stereoselectively transformed into either protected D- or L-mannose in five steps and approximately 39% yield from furfural. Similarly, both D- and L-talose and gulose have been synthesized in 19% overall yields, respectively. Using a modified strategy, both protected D- and L-gulo- and allo-sugar-delta-lactones were synthesized in eight steps and approximately 20%, overall yield from furfural.

Furaldehyde↗
PubMed2000

Irreversible inhibition of type I dehydroquinase by substrates for type II dehydroquinase.

Mechanistic differences between type I and type II dehydroquinases have been exploited in the design of type specific inhibitors. (2R)-2-Bromo-3-dehydroquinic acid (3), (2R)-2-fluoro-3-dehydroquinic acid (5) and 2-bromo-3-dehydroshikimic acid (4), all excellent substrates for type II dehydroquinase, are shown to be irreversible inhibitors of type I dehydroquinase.

Enzyme Inhibitors↗
PubMed2000

Expression and cytoplasmic localisation of deoxyuridine triphosphate pyrophosphatase encoded by a human endogenous retrovirus.

Many lentiviruses encode a dUTPase which may protect against toxic misincorporation of dUTP into cDNA during reverse transcription. However, the primate lentiviruses HIV and SIV do not express a dUTPase. Significantly, the host genomes of these lentiviruses contain a multicopy endogenous retrovirus which is absent in non-primate genomes. In humans, this endogenous retrovirus is known as HERV-K and encodes a potential dUTPase sequence. Previously, we have suggested that HIV infection is complemented by a cytosolic dUTPase derived from the dUTPase gene encoded by HERV-K. This study demonstrates expression of HERV-K dUTPase transcripts and protein in human cell lines using RT-PCR and western blot analysis. Immunocytochemistry showed that HERV-K dUTPase was predominantly located in cell cytoplasm when transiently expressed in COS-1 cells. These data provide substantiation and support for the hypothesis above and is the first documentation of expression of an enzyme of nucleotide metabolism expressed by an endogenous retrovirus.

Blotting, Western↗
PubMed2000

Risk factors for bronchial hyperresponsiveness in workers exposed to acid anhydrides.

Risk factors for bronchial hyperresponsiveness have previously been established in the general community. In settings where occupational asthma is a risk, it has not been established whether occupational sensitization or measures of exposure are important. Bronchial responsiveness to histamine was measured in a cohort of 506 workers exposed to acid anhydrides. Skin-prick tests were performed with conjugates of phthalic, maleic and trimellitic anhydride with human serum albumin and with common inhalant allergens. Employment and smoking histories were recorded. Occupational exposure was measured using personal air samplers and estimates of past exposure made by retrospective exposure assessment. Three hundred and seventy workers (73%) had bronchial responsiveness measured (median age 39 yrs, range 18-77) and 46 (12%) of these were hyperresponsive (provocative dose causing a 20% fall in forced expiratory volume in one second (FEV1; PD20) < or = 8 micromol). Twelve (3%) of these responsive workers had a skin-prick test reaction to an acid anhydride conjugate, 124 (34%) to a common inhalant allergen, and 148 (40%) were current smokers. Multivariate analysis showed that occupational sensitization, sensitization to a common inhalant allergen, age, and pack-years of smoking were independent risk factors for bronchial hyperresponsiveness. Of these only occupational sensitization was completely independent of baseline FEV1. It is concluded that sensitization to acid anhydrides is a significant risk factor for bronchial hyperresponsiveness. However, measures of personal acid anhydride exposure were not associated with bronchial hyperresponsiveness.

Adolescent↗
PubMed2000

Comparing contrast-modulated and luminance-modulated masking: effects of spatial frequency and phase.

The masking of a sinusoidal test grating by contrast-modulated (CM) gratings could, in principle, be attributable to the presence of a distortion product, injected into the stimulus during some nonlinear transformation at an early level of visual processing (e.g. Nachmias, 1989 Vision Research 29 137-142). If so, CM gratings and luminance-modulated (LM) gratings of similar effective contrast and spatial frequency should mask the detection of sinusoids in a similar fashion. We compared the effects of masking by 1 cycle deg-1 CM gratings [both simple beats (8 + 9 cycles deg-1) and amplitude-modulated gratings (8 + 9 + 10 cycles deg-1)], with those of masking by 1 cycle deg-1 LM gratings of low contrast. We found that: (i) CM and low-contrast LM grating masks yielded similar spatial-frequency tuning functions around the modulation frequency of 1 cycle deg-1; (ii) low-contrast LM gratings masked the detection of test sinusoids in a highly phase-dependent fashion, while masking by CM gratings did not vary systematically with relative spatial phase. The results suggest that masking produced by CM gratings cannot simply be explained by the presence of a distortion product at the beat or modulation frequency.

Contrast Sensitivity↗
PubMed2000

Detecting binocular 3D motion in static 3D noise: no effect of viewing distance.

Relative binocular disparity cannot tell us the absolute 3D shape of an object, nor the 3D trajectory of its motion, unless the visual system has independent access to how far away the object is at any moment. Indeed, as the viewing distance is changed, the same disparate retinal motions will correspond to very different real 3D trajectories. In this paper we were interested in whether binocular 3D motion detection is affected by viewing distance. A visual search task was used, in which the observer is asked to detect a target dot, moving in 3D, amidst 3D stationary distractor dots. We found that distance does not affect detection performance. Motion-in-depth is consistently harder to detect than the equivalent lateral motion, for all viewing distances. For a constant retinal motion with both lateral and motion-in-depth components, detection performance is constant despite variations in viewing distance that produce large changes in the direction of the 3D trajectory. We conclude that binocular 3D motion detection relies on retinal, not absolute, visual signals.

Distance Perception↗
PubMed2000

The effects of dot density and motion coherence on perceptual fading of a target in noise.

A peripherally presented target embedded in dynamic texture perceptually disappears (or 'fills-in') after around 10 s of steady fixation. This phenomenon was investigated for a target containing moving dots. The effects of manipulating the coherence of the motion within the target and the density of dots across the whole screen were explored. Coherence thresholds for the detection of a target at different dot densities were recorded for comparison. Fading occurred faster as either motion coherence or dot density was reduced. Coherence thresholds for target detection were unaffected by manipulations of dot density. There appeared to be no relationship between the stimulus exposure time needed for fading and the coherence threshold for detection of a target. The results suggest that the time taken for a target to fade is not a simple function of its motion detection threshold.

Adaptation, Ocular↗
PubMed2000

Structure-function analysis of the Rev-erbA and RVR ligand-binding domains reveals a large hydrophobic surface that mediates corepressor binding and a ligand cavity occupied by side chains.

Rev-erbA/RVR are closely related orphan nuclear receptors (NRs) functioning as dominant transcriptional silencers through an association with the nuclear receptor corepressor N-CoR. In contrast with ligand-regulated NRs, Rev-erbA/RVR lack the ligand-binding domain (LBD) C-terminal activation helix, H12. In the case of retinoid acid receptor and thyroid hormone receptor, ligand binding is thought to reposition H12, causing corepressor dissociation and coactivator recruitment, thus leading to transcriptional activation. Here we present homology models of the Rev-erbA/RVR LBDs, which show that the putative ligand cavity is occupied by side chains, suggesting the absence of endogenous ligands. Modeling also revealed a very hydrophobic surface due to the absence of H12, exposing residues from H3, loop 3-4, H4, and H11. Mutation of specific residues from this surface severely impaired the in vitro and in vivo interaction of the Rev-erbA/RVR LBD with the receptor-interacting domain of the corepressors N-CoR or its splice variant RIP13delta1, reinforcing the view of the physical association of N-CoR with a LBD surface encompassing H3-H4 and H11. Furthermore, mutations in the LBD surface significantly reduced the ability of Rev-erbA and RVR to function as repressors of transcription. Interestingly, a hydrophobic surface comprised of H3-H4 and H12 in liganded NRs mediates the interaction with coactivators. Hence, it appears that corepressors and coactivators bind to overlapping surfaces of NR LBDs, the conformational change associated with H12 upon ligand binding resulting in a switch from a corepressor- to a coactivator-binding surface.

Amino Acid Sequence↗
PubMed2000

Binocular three-dimensional motion detection: contributions of lateral motion and stereomotion.

When an object moves along a trajectory in three-dimensional (3-D) space, there are potentially two orthogonal components that could be used to detect its motion: stereomotion resulting from the difference or disparity between the images in the right and left eyes, and lateral motion from the sum or average of the image motions in the right and left eyes. Using a suprathreshold search task for a target moving amid 3-D distractors, we found a range of 3-D trajectories for which increasing the stereomotion component did not improve detection. However, with larger stereomotion components, performance improved. The addition of random-motion noise to only the lateral motion component adversely affected the detection of both lateral motion and stereomotion. These data suggest that the visual system uses the average of the monocular image motions for the detection of a range of 3-D trajectories. In addition, a mechanism sensitive to the changing disparity may also be used but only for a very restricted range of 3-D motions.

Adult↗
PubMed2000

IDSs reconsider the viability of risk contracting.

As financial success with risk contracting continues to elude many IDSs, some of these organizations have started questioning their overall mission as risk-bearing entities. To determine whether to continue to assume risk, an IDS should consider its market environment, the commitment of its provider constituents to the organization, its core competencies, the likelihood of success with risk contracting, and alternatives. To determine its future course, the IDS should engage in a strategic-planning process that includes all IDS stakeholders. Such a process can help build consensus regarding the IDS's market characteristics and benefits of IDS membership; determine the IDS's appropriate roles, services, and functions; and evaluate resources required to pursue the desired strategy. The process should include planning for various possible future scenarios, and results should be communicated to all IDS provider constituents.

Catchment Area, Health↗
PubMed1999

Forced MyHCIIB expression following targeted genetic manipulation of conditionally immortalized muscle precursor cells.

The ability to carry out gene targeting in somatic stem cells while maintaining their stem cell characteristics would have important implications for gene therapy and for the analysis of gene function. Using mouse myoblasts, we have explored this possibility by attempting to alter the promoter of a myosin heavy chain gene (MyHCIIB) characteristic of physiologically "fast" muscle so as to force its unscheduled expression in physiologically "slow" muscle fibers. Conditionally immortalized muscle precursor cells were transfected with a gene targeting construct designed to replace the MyHCIIB promoter with that for the carbonic anhydrase III gene (CAIII), which is highly expressed in slow muscle. A potentially targeted clone was isolated and differentiated in culture to form myotubes which expressed MyHCIIB. Cells from the same clone were injected into both slow and fast muscle of host mice, where they contributed to fiber formation. In slow muscle, the fibers derived from this clone did not express MyHCIIB; this may reflect an instability of the targeted MyHCIIB locus and/or a failure of the hybrid promoter to function in slow fibers in vivo. Nonetheless, we have demonstrated that a "promoter knock-in" gene targeting procedure can be used to generate unique MyHCIIB-expressing myotubes in culture and that conditionally immortalized myoblasts can be subjected to extensive passaging and genetic manipulation without losing their ability to form fibers in culture and in vivo.

Animals↗
PubMed1999

Photoimmobilization of organophosphorus hydrolase within a PEG-based hydrogel.

Organophosphorous hydrolase (OPH) was physically and covalently immobilized within photosensitive polyethylene glycol (PEG)-based hydrogels. The hydroxyl ends of branched polyethylene glycol (b-PEG, four arms, MW = 20,000) were modified with cinnamylidene acetate groups to give water-soluble, photosensitive PEG macromers (b-PEG-CA). The b-PEG-CA macromers underwent photocrosslinking reaction and formed gels upon UV irradiation (>300 nm) in the presence of erythrosin B. Native OPH was pegylated with cinnamylidene-terminated PEG chains (MW = 3400) to be covalently linked with the b-PEG-CA macromers during photogelation. The effect of pegylation on the stability of the enzyme was determined. Furthermore, the effect of enzyme concentration, wavelength of irradiation, and photosensitizer on the stability of the entrapped enzyme was also investigated. The pegylated OPH was more stable than the native enzyme, and the OPH-containing gels exhibited superior stability than the soluble enzyme preparations.

Aryldialkylphosphatase↗
PubMed1999

Direct evidence for thymic function in adult humans.

The understanding of human thymic function and evaluation of its contribution to T cell homeostasis are matters of great importance. Here we report the development of a novel assay to quantitate the frequency and diversity of recent thymic emigrants (RTEs) in the peripheral blood of humans. Such cells were defined by the presence of T cell receptor (TCR) rearrangement deletion circles (DCs), episomal byproducts of TCR-beta V(D)J rearrangement. DCs were detected in T cells in the thymus, cord blood, and adult peripheral blood. In the peripheral blood of adults aged 22 to 76 years, their frequency was highest in the CD4(+)CD45RA(+) CD62L(+) subpopulation of naive T cells. TCR DCs were also observed in other subpopulations of peripheral blood T cells, including those with the CD4(+)CD45RO(-)CD62L(+) and CD4(+)CD45RO(+)CD62L(+) phenotypes. RTEs were observed to have more than one Vbeta rearrangement, suggesting that replenishment of the repertoire in the adult is at least oligoclonal. These results demonstrate that the normal adult thymus continues to contribute, even in older individuals, a diverse set of new T cells to the peripheral circulation.

Adult↗