Jayakrishna Ambati | University of Kentucky (original) (raw)

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Papers by Jayakrishna Ambati

Research paper thumbnail of Heuristic combinatorial optimization by simulated Darwinian evolution: a polynomial time algorithm for the Traveling Salesman Problem

Formal Aspects of Computing, 1992

A genetic algorithm simulating Darwinian evolution is proposed to yield near-optimal solutions to... more A genetic algorithm simulating Darwinian evolution is proposed to yield near-optimal solutions to the Traveling Salesman Problem. Noting that Darwinian evolution is itself an optimization process, we propose a heuristic algorithm that incorporates the tenets of natural selection. The time complexity of this algorithm is equivalent to the fastest sorting scheme! Computer simulations indicate rapid convergence is maintained even with increasing problem complexity. This methodology can be adapted to tackle a host of other combinatorial problems.

Research paper thumbnail of Macrophage Depletion Inhibits Experimental Choroidal Neovascularization

Research paper thumbnail of Transscleral Delivery of Bioactive Protein to the Choroid and Retina

To investigate the feasibility of transscleral drug delivery to the choroid and retina.

Research paper thumbnail of Diffusion of High Molecular Weight Compounds through Sclera

To determine the in vitro permeability of the sclera to high molecular weight compounds and the r... more To determine the in vitro permeability of the sclera to high molecular weight compounds and the relationship between scleral permeability and molecular size.

Research paper thumbnail of VEGF164-mediated Inflammation Is Required for Pathological, but Not Physiological, Ischemia-induced Retinal Neovascularization

Journal of Experimental Medicine, 2003

Hypoxia-induced VEGF governs both physiological retinal vascular development and pathological ret... more Hypoxia-induced VEGF governs both physiological retinal vascular development and pathological retinal neovascularization. In the current paper, the mechanisms of physiological and pathological neovascularization are compared and contrasted. During pathological neovascularization, both the absolute and relative expression levels for VEGF 164 increased to a greater degree than during physiological neovascularization. Furthermore, extensive leukocyte adhesion was observed at the leading edge of pathological, but not physiological, neovascularization. When a VEGF 164 -specific neutralizing aptamer was administered, it potently suppressed the leukocyte adhesion and pathological neovascularization, whereas it had little or no effect on physiological neovascularization. In parallel experiments, genetically altered VEGF 164 -deficient (VEGF 120/188 ) mice exhibited no difference in physiological neovascularization when compared with wild-type (VEGF ϩ / ϩ ) controls. In contrast, administration of a VEGFR-1/Fc fusion protein, which blocks all VEGF isoforms, led to significant suppression of both pathological and physiological neovascularization. In addition, the targeted inactivation of monocyte lineage cells with clodronateliposomes led to the suppression of pathological neovascularization. Conversely, the blockade of T lymphocyte-mediated immune responses with an anti-CD2 antibody exacerbated pathological neovascularization. These data highlight important molecular and cellular differences between physiological and pathological retinal neovascularization. During pathological neovascularization, VEGF 164 selectively induces inflammation and cellular immunity. These processes provide positive and negative angiogenic regulation, respectively. Together, new therapeutic approaches for selectively targeting pathological, but not physiological, retinal neovascularization are outlined.

Research paper thumbnail of An animal model of age-related macular degeneration in senescent Ccl2- or Ccr2-deficient mice

Nature Medicine, 2003

AMD is the principal cause of irreversible, registered legal blindness on three continents 1 . It... more AMD is the principal cause of irreversible, registered legal blindness on three continents 1 . It is characterized by progressive degeneration of the retina, RPE and underlying choroid (the highly vascular tissue beneath the RPE), which results in severe vision loss. The earliest clinically visible abnormality in AMD is the accumulation of drusen (lipoproteinaceous deposits) in the extracellular matrix between the RPE and the choroid. Drusen deposition is a significant risk factor for progression to CNV, the exudative hallmark of late AMD, and vision loss. To date, there is no animal model of drusen deposition or spontaneously occurring CNV resembling that seen in patients with AMD.

Research paper thumbnail of Age-Related Macular Degeneration: Etiology, Pathogenesis, and Therapeutic Strategies

Survey of Ophthalmology, 2003

Age-related macular degeneration is the principal cause of registered legal blindness among those... more Age-related macular degeneration is the principal cause of registered legal blindness among those aged over 65 in the United States, western Europe, Australia, and Japan. Despite intensive research, the precise etiology of molecular events that underlie age-related macular degeneration is poorly understood. However, investigations on parallel fronts are addressing this prevalent public health problem. Sophisticated biochemical and biophysical techniques have refined our understanding of the pathobiology of drusen, geographic atrophy, and retinal pigment epithelial detachments. Epidemiological identification of risk factors has facilitated an intelligent search for underlying mechanisms and fueled clinical investigation of behavior modification. Gene searches have not only brought us to the cusp of identifying the culpable gene loci in age-related macular degeneration, but also localized genes responsible for other macular dystrophies. Recent and ongoing investigations, often cued by tumor biology, have revealed an important role for various growth factors, particularly in the neovascular form of the condition. Transgenic and knockout studies have provided important mechanistic insights into the development of choroidal neovascularization, the principal cause of vision loss in age-related macular degeneration. This in turn has culminated in preclinical and clinical trials of directed molecular interventions. 293, 2003. Ć 2003 by Elsevier Inc. All rights reserved.) Key words. age-related macular degeneration • choroidal neovascularization • drusen • macular dystrophies

Research paper thumbnail of Heuristic combinatorial optimization by simulated Darwinian evolution: a polynomial time algorithm for the Traveling Salesman Problem

Formal Aspects of Computing, 1992

A genetic algorithm simulating Darwinian evolution is proposed to yield near-optimal solutions to... more A genetic algorithm simulating Darwinian evolution is proposed to yield near-optimal solutions to the Traveling Salesman Problem. Noting that Darwinian evolution is itself an optimization process, we propose a heuristic algorithm that incorporates the tenets of natural selection. The time complexity of this algorithm is equivalent to the fastest sorting scheme! Computer simulations indicate rapid convergence is maintained even with increasing problem complexity. This methodology can be adapted to tackle a host of other combinatorial problems.

Research paper thumbnail of Macrophage Depletion Inhibits Experimental Choroidal Neovascularization

Research paper thumbnail of Transscleral Delivery of Bioactive Protein to the Choroid and Retina

To investigate the feasibility of transscleral drug delivery to the choroid and retina.

Research paper thumbnail of Diffusion of High Molecular Weight Compounds through Sclera

To determine the in vitro permeability of the sclera to high molecular weight compounds and the r... more To determine the in vitro permeability of the sclera to high molecular weight compounds and the relationship between scleral permeability and molecular size.

Research paper thumbnail of VEGF164-mediated Inflammation Is Required for Pathological, but Not Physiological, Ischemia-induced Retinal Neovascularization

Journal of Experimental Medicine, 2003

Hypoxia-induced VEGF governs both physiological retinal vascular development and pathological ret... more Hypoxia-induced VEGF governs both physiological retinal vascular development and pathological retinal neovascularization. In the current paper, the mechanisms of physiological and pathological neovascularization are compared and contrasted. During pathological neovascularization, both the absolute and relative expression levels for VEGF 164 increased to a greater degree than during physiological neovascularization. Furthermore, extensive leukocyte adhesion was observed at the leading edge of pathological, but not physiological, neovascularization. When a VEGF 164 -specific neutralizing aptamer was administered, it potently suppressed the leukocyte adhesion and pathological neovascularization, whereas it had little or no effect on physiological neovascularization. In parallel experiments, genetically altered VEGF 164 -deficient (VEGF 120/188 ) mice exhibited no difference in physiological neovascularization when compared with wild-type (VEGF ϩ / ϩ ) controls. In contrast, administration of a VEGFR-1/Fc fusion protein, which blocks all VEGF isoforms, led to significant suppression of both pathological and physiological neovascularization. In addition, the targeted inactivation of monocyte lineage cells with clodronateliposomes led to the suppression of pathological neovascularization. Conversely, the blockade of T lymphocyte-mediated immune responses with an anti-CD2 antibody exacerbated pathological neovascularization. These data highlight important molecular and cellular differences between physiological and pathological retinal neovascularization. During pathological neovascularization, VEGF 164 selectively induces inflammation and cellular immunity. These processes provide positive and negative angiogenic regulation, respectively. Together, new therapeutic approaches for selectively targeting pathological, but not physiological, retinal neovascularization are outlined.

Research paper thumbnail of An animal model of age-related macular degeneration in senescent Ccl2- or Ccr2-deficient mice

Nature Medicine, 2003

AMD is the principal cause of irreversible, registered legal blindness on three continents 1 . It... more AMD is the principal cause of irreversible, registered legal blindness on three continents 1 . It is characterized by progressive degeneration of the retina, RPE and underlying choroid (the highly vascular tissue beneath the RPE), which results in severe vision loss. The earliest clinically visible abnormality in AMD is the accumulation of drusen (lipoproteinaceous deposits) in the extracellular matrix between the RPE and the choroid. Drusen deposition is a significant risk factor for progression to CNV, the exudative hallmark of late AMD, and vision loss. To date, there is no animal model of drusen deposition or spontaneously occurring CNV resembling that seen in patients with AMD.

Research paper thumbnail of Age-Related Macular Degeneration: Etiology, Pathogenesis, and Therapeutic Strategies

Survey of Ophthalmology, 2003

Age-related macular degeneration is the principal cause of registered legal blindness among those... more Age-related macular degeneration is the principal cause of registered legal blindness among those aged over 65 in the United States, western Europe, Australia, and Japan. Despite intensive research, the precise etiology of molecular events that underlie age-related macular degeneration is poorly understood. However, investigations on parallel fronts are addressing this prevalent public health problem. Sophisticated biochemical and biophysical techniques have refined our understanding of the pathobiology of drusen, geographic atrophy, and retinal pigment epithelial detachments. Epidemiological identification of risk factors has facilitated an intelligent search for underlying mechanisms and fueled clinical investigation of behavior modification. Gene searches have not only brought us to the cusp of identifying the culpable gene loci in age-related macular degeneration, but also localized genes responsible for other macular dystrophies. Recent and ongoing investigations, often cued by tumor biology, have revealed an important role for various growth factors, particularly in the neovascular form of the condition. Transgenic and knockout studies have provided important mechanistic insights into the development of choroidal neovascularization, the principal cause of vision loss in age-related macular degeneration. This in turn has culminated in preclinical and clinical trials of directed molecular interventions. 293, 2003. Ć 2003 by Elsevier Inc. All rights reserved.) Key words. age-related macular degeneration • choroidal neovascularization • drusen • macular dystrophies