11 results on '"Geesaman BJ"'
Search Results
2. Human longevity and common variations in the LMNA gene: a meta-analysis.
- Author
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Conneely KN, Capell BC, Erdos MR, Sebastiani P, Solovieff N, Swift AJ, Baldwin CT, Budagov T, Barzilai N, Atzmon G, Puca AA, Perls TT, Geesaman BJ, Boehnke M, and Collins FS
- Subjects
- Age Factors, Aged, 80 and over, Case-Control Studies, Female, Haplotypes, Humans, Linkage Disequilibrium, Male, Polymorphism, Single Nucleotide, Lamin Type A genetics, Longevity genetics, Progeria genetics
- Abstract
A mutation in the LMNA gene is responsible for the most dramatic form of premature aging, Hutchinson-Gilford progeria syndrome (HGPS). Several recent studies have suggested that protein products of this gene might have a role in normal physiological cellular senescence. To explore further LMNA's possible role in normal aging, we genotyped 16 SNPs over a span of 75.4 kb of the LMNA gene on a sample of long-lived individuals (LLI) (US Caucasians with age ≥ 95 years, N=873) and genetically matched younger controls (N=443). We tested all common nonredundant haplotypes (frequency ≥ 0.05) based on subgroups of these 16 SNPs for association with longevity. The most significant haplotype, based on four SNPs, remained significant after adjustment for multiple testing (OR=1.56, P=2.5 × 10(-5) , multiple-testing-adjusted P=0.0045). To attempt to replicate these results, we genotyped 3619 subjects from four independent samples of LLI and control subjects from (i) the New England Centenarian Study (NECS) (N=738), (ii) the Southern Italian Centenarian Study (SICS) (N=905), (iii) France (N=1103), and (iv) the Einstein Ashkenazi Longevity Study (N= 702). We replicated the association with the most significant haplotype from our initial analysis in the NECS sample (OR=1.60, P=0.0023), but not in the other three samples (P > 0.15). In a meta-analysis combining all five samples, the best haplotype remained significantly associated with longevity after adjustment for multiple testing in the initial and follow-up samples (OR=1.18, P=7.5 × 10(-4) , multiple-testing-adjusted P=0.037). These results suggest that LMNA variants may play a role in human lifespan., (© 2012 The Authors. Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.)
- Published
- 2012
- Full Text
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3. Genetics of aging: implications for drug discovery and development.
- Author
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Geesaman BJ
- Subjects
- Aging drug effects, Animals, Diabetes Mellitus, Type 2 drug therapy, Disease Models, Animal, Humans, Insulin physiology, Insulin-Like Growth Factor I physiology, Longevity genetics, Paracrine Communication physiology, Aging genetics, Diabetes Mellitus, Type 2 genetics, Evolution, Molecular, Models, Biological
- Abstract
Aging is not a passive activity, but an actively regulated metabolic process. Specific genes have been identified that regulate aging, although aging, and consequently longevity, is only partially under genetic influence. It is also possible to increase life span by environmental modification; for example, caloric restriction can increase life span. Because human life span is long, directly studying aging in humans is impractical. Fortunately, significant insights into aging can be achieved by studying short-lived organisms, such as yeast, worms, and fruit flies. Many of the molecular pathways regulating aging in these lower organisms are conserved in mammals and overlap with pathways regulating metabolism. For example, an insulin-growth hormone signaling system has been implicated in regulating aging and longevity in both worms and mammals. Furthermore, the dysregulation of glucose homeostasis is a hallmark of aging in humans. In fact, type 2 diabetes, a disease of glucose homeostasis, can be conceptualized as a form of accelerated aging. Consistent with this, aging and diabetes are both common risk factors for a wide range of diseases. Because aging and diabetes are intimately related at a molecular level, diabetes may be able to provide the link between disease treatment (eg, diabetes) and the prevention of age-related diseases. If specific molecular pathways controlling the rate of aging can be modulated genetically, then perhaps they can be modulated pharmacologically. These insights may ultimately have an important impact on the discovery and development of drugs to both treat and prevent a wide range of diseases.
- Published
- 2006
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4. Ageing and metabolism: drug discovery opportunities.
- Author
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Curtis R, Geesaman BJ, and DiStefano PS
- Subjects
- AMP-Activated Protein Kinases, Adipocytes drug effects, Aging genetics, Animals, Eating physiology, Humans, Insulin physiology, Life Expectancy, Metabolism genetics, Multienzyme Complexes physiology, Protein Serine-Threonine Kinases physiology, Aging drug effects, Aging physiology, Drug Design, Metabolism drug effects, Metabolism physiology
- Abstract
There has recently been significant progress in our understanding of the mechanisms that regulate ageing, and it has been shown that changes in single genes can dramatically extend lifespan and increase resistance to many diseases. Furthermore, many of these genes belong to evolutionarily conserved pathways that also control energy metabolism. In this review, we describe the shared molecular machinery that regulates ageing and energy metabolism. Although drugs to slow ageing face severe regulatory hurdles, it is likely that an understanding of ageing pathways will help to identify novel drug targets to treat metabolic disorders and other age-related diseases.
- Published
- 2005
- Full Text
- View/download PDF
5. Sarcomeric genes involved in reverse remodeling of the heart during left ventricular assist device support.
- Author
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Rodrigue-Way A, Burkhoff D, Geesaman BJ, Golden S, Xu J, Pollman MJ, Donoghue M, Jeyaseelan R, Houser S, Breitbart RE, Marks A, and Acton S
- Subjects
- Adult, Aged, Atrial Natriuretic Factor genetics, Atrial Natriuretic Factor metabolism, Blood Pressure genetics, Connective Tissue Growth Factor, Female, Heart Failure genetics, Heart Failure surgery, Heart Transplantation, Heart Ventricles metabolism, Heart Ventricles surgery, Humans, Immediate-Early Proteins genetics, Immediate-Early Proteins metabolism, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins metabolism, Male, Middle Aged, Myocardial Contraction genetics, Myosin Heavy Chains genetics, Myosin Heavy Chains metabolism, Natriuretic Peptide, Brain genetics, Natriuretic Peptide, Brain metabolism, Osteonectin genetics, Osteonectin metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Stroke Volume genetics, Transcription, Genetic genetics, Up-Regulation genetics, Heart-Assist Devices, Ventricular Remodeling genetics
- Abstract
Background: Left ventricular assist devices (LVADs) implanted in patients with severe congestive heart failure (CHF) as a bridge to transplantation have been shown to reverse chamber enlargement, regress cellular hypertrophy, and increase contractility. The purpose of this study was to gain a better understanding of the molecular changes associated with increased contractility after LVAD support., Methods: We took tissue sections from the left ventricular apex of 12 patients with CHF who were undergoing LVAD insertion (pre-LVAD) and from the LV free wall of those same patients before transplantation (post-LVAD). To control for sample-site differences, we obtained samples from the same regions in 7 patients with CHF who were undergoing transplantation without LVAD support and in 4 non- failing donor hearts. Gene expression was then probed on a custom DNA array containing 2,700 cardiac-enriched cDNA clones., Results: Calcium-handling genes were up-regulated by LVAD support, as previously reported. Sarcomeric genes were the other principle class of genes up-regulated by LVAD support, consistent with a possible restoration of sarcomere structure in reverse ventricular remodeling. However, a decrease in the fibrous component of the myocardium, also potentially involved in reverse remodeling, was not evident at the level of gene transcription because fibroblast markers were either unchanged or up-regulated. The remaining regulated genes did not fall into any defined functional class., Conclusions: Changes in the regulation of sarcomeric, calcium-handling, and fibroblast genes during LVAD support indicate a cardiac molecular adaptation to mechanical unloading. These molecular changes may play a role in the observed increase in contractile function during reverse remodeling.
- Published
- 2005
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6. Haplotype-based identification of a microsomal transfer protein marker associated with the human lifespan.
- Author
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Geesaman BJ, Benson E, Brewster SJ, Kunkel LM, Blanché H, Thomas G, Perls TT, Daly MJ, and Puca AA
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Apolipoproteins E genetics, Biomarkers, Carrier Proteins physiology, Case-Control Studies, Chromosomes, Human, Pair 4 genetics, Cohort Studies, Female, Genetic Linkage, Humans, Longevity physiology, Male, Microsomes metabolism, Middle Aged, Polymorphism, Single Nucleotide, Carrier Proteins genetics, Haplotypes genetics, Longevity genetics
- Abstract
We previously reported a genomewide linkage study for human longevity using 308 long-lived individuals (LLI) (centenarians or near-centenarians) in 137 sibships and identified statistically significant linkage within chromosome 4 near microsatellite D4S1564. This interval spans 12 million bp and contains approximately 50 putative genes. To identify the specific gene and gene variants impacting lifespan, we performed a haplotype-based fine-mapping study of the interval. The resulting genetic association study identified a haplotype marker within microsomal transfer protein as a modifier of human lifespan. This same variant was tested in a second cohort of LLI from France, and although the association was not replicated, there was evidence for statistical distortion in the form of Hardy-Weinberg disequilibrium. Microsomal transfer protein has been identified as the rate-limiting step in lipoprotein synthesis and may affect longevity by subtly modulating this pathway. This study provides proof of concept for the feasibility of using the genomes of LLI to identify genes impacting longevity.
- Published
- 2003
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7. The dependence of motion repulsion and rivalry on the distance between moving elements.
- Author
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Matthews N, Geesaman BJ, and Qian N
- Subjects
- Convergence, Ocular physiology, Humans, Vision, Binocular physiology, Distance Perception physiology, Motion Perception physiology
- Abstract
We investigated the extent to which motion repulsion and binocular motion rivalry depend on the distance between moving elements. The stimuli consisted of two sets of spatially intermingled, finite-life random dots that moved across each other. The distance between the dots moving in different directions was manipulated by spatially pairing the dot trajectories with various precisions. Data from experiment 1 indicated that motion repulsion occurred reliably only when the average distance between orthogonally moving elements was at least 21.0 arc min. When the dots were precisely paired, a single global direction intermediate to the two actual directions was perceived. This result suggests that, at a relatively small spatial scale, interaction between different directions favors motion attraction or coherence, while interaction at a somewhat larger scale generates motion repulsion. Similarly, data from experiment 2 indicated that binocular motion rivalry was significantly diminished by spatially pairing the dots, which moved in opposite directions in the two eyes. This supports the recent proposal that rivalry occurs at or after the stage of binocular convergence, since monocular cells could not have directly responded to our interocular pairing manipulation. Together, these findings suggest that the neural mechanisms underlying motion perception are highly sensitive to the fine spatial relationship between moving elements.
- Published
- 2000
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8. Perceptual learning on orientation and direction discrimination.
- Author
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Matthews N, Liu Z, Geesaman BJ, and Qian N
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- Discrimination, Psychological physiology, Humans, Space Perception physiology, Learning, Visual Perception physiology
- Abstract
Two experiments were conducted to determine the extent to which perceptual learning transfers between orientation and direction discrimination. Naive observers were trained to discriminate orientation differences between two single-line stimuli, and direction differences between two single-moving-dot stimuli. In the first experiment, observers practiced the orientation and direction tasks along orthogonal axes in the fronto-parallel plane. In the second experiment, a different group of observers practiced both tasks along a single axis. Perceptual learning was observed on both tasks in both experiments. Under the same-axis condition, the observers' orientation sensitivity was found to be significantly elevated after the direction training, indicating a transfer of learning from direction to orientation. There was no evidence of transfer in any other cases tested. In addition, the rate of learning on the orientation task was much higher than the rate on the direction task. The implications of these findings on the neural mechanisms subserving orientation and direction discrimination are discussed.
- Published
- 1999
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9. The effect of complex motion pattern on speed perception.
- Author
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Geesaman BJ and Qian N
- Subjects
- Humans, Psychometrics, Psychophysics, Rotation, Time Factors, Motion Perception physiology, Optical Illusions physiology, Pattern Recognition, Visual physiology
- Abstract
We recently reported a new motion illusion where dots in expanding random dot patterns appear to move faster than those in rotation patterns despite having the same physical speed distributions. In the current paper, we compared expansion and rotation motion to translational motion and found that the perceived dot speed in translation patterns was between that of expansion and rotation. We also explored contraction motion and found subjects perceived dots in contracting patterns as moving slightly faster than those in expanding patterns and much faster than those in rotating patterns. Finally, we found that stimulus presentation order in a trial plays an important role in determining the magnitude of the speed illusion--the effect is greater when the subjectively faster stimulus is viewed second (e.g., expansion after rotation). The dependence on stimulus order is greatest when comparing complex motion patterns with large subjective speed differences. This phenomenon is unlikely to be explained in terms of channel fatigue or adaptation.
- Published
- 1998
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10. A novel speed illusion involving expansion and rotation patterns.
- Author
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Geesaman BJ and Qian N
- Subjects
- Humans, Pattern Recognition, Visual physiology, Psychophysics, Rotation, Time Factors, Motion Perception physiology, Optical Illusions physiology
- Abstract
Using random dot stimuli well controlled for dot speed, we found that the moving features in expanding patterns appear to move faster than those in rotating patterns. The illusion is well correlated with the strength of the global motion signal. For example, in displays where the number of motion directions defining the patterns is reduced, the magnitude of the illusion decreases. Similarly, the strength of the effect diminishes as dot density is reduced. In patterns where only wedge-shaped segments of the stimuli are left exposed, the difference in perceived speed increases with the angular size of the wedge. Stimulus placement relative to the fixation point has little effect on the persistence of this phenomenon-expansion patterns appear to contain elements of greater speed, independent of stimulus eccentricity. These results argue against a local explanation for this perceptual illusion, suggesting that the global motion pattern of the stimulus, per se, is responsible.
- Published
- 1996
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11. The analysis of complex motion patterns by form/cue invariant MSTd neurons.
- Author
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Geesaman BJ and Andersen RA
- Subjects
- Animals, Cues, Macaca mulatta, Photic Stimulation, Visual Pathways physiology, Motion, Visual Cortex physiology, Visual Perception physiology
- Abstract
Several groups have proposed that area MSTd of the macaque monkey has a role in processing optical flow information used in the analysis of self motion, based on its neurons' selectivity for large-field motion patterns such as expansion, contraction, and rotation. It has also been suggested that this cortical region may be important in analyzing the complex motions of objects. More generally, MSTd could be involved in the generic function of complex motion pattern representation, with its cells responsible for integrating local motion signals sent forward from area MT into a more unified representation. If MSTd is extracting generic motion pattern signals, it would be important that the preferred tuning of MSTd neurons not depend on the particular features and cues that allow these motions to be represented. To test this idea, we examined the diversity of stimulus features and cues over which MSTd cells can extract information about motion patterns such as expansion, contraction, rotation, and spirals. The different classes of stimuli included: coherently moving random dot patterns, solid squares, outlines of squares, a square aperture moving in front of an underlying stationary pattern of random dots, a square composed entirely of flicker, and a square of nonFourier motion. When a unit was tuned with respect to motion pattern producing the most vigorous response in a neuron was nearly the same for each class. Although preferred tuning was invariant, the magnitude and width of the tuning curves often varied between classes. Thus, MSTd is form/cue invariant for complex motions, making it an appropriate candidate for analysis of object motion as well as motion introduced by observer translation.
- Published
- 1996
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