Vaccination for protection of retinal ganglion cells against death from glutamate cytotoxicity and ocular hypertension: Implications for glaucoma

Our group recently demonstrated that autoimmune T cells directed against central nervous system-associated myelin antigens protect neurons from secondary degeneration. We further showed that the synthetic peptide copolymer 1 (Cop-1), known to suppress experimental autoimmune encephalomyelitis, can be safely substituted for the natural myelin antigen in both passive and active immunization for neuroprotection of the injured optic nerve. Here we attempted to determine whether similar immunizations are protective from retinal ganglion cell loss resulting from a direct biochemical insult caused, for example, by glutamate (a major mediator of degeneration in acute and chronic optic nerve insults) and in a rat model of ocular hypertension. Passive immunization with T cells reactive to myelin basic protein or active immunization with myelin oligodendrocyte glycoprotein-derived peptide, although neuroprotective after optic nerve injury, was ineffective against glutamate toxicity in mice and rats. In contrast, the number of surviving retinal ganglion cells per square millimeter in glutamate-injected retinas was significantly larger in mice immunized 10 days previously with Cop-1 emulsified in complete Freund's adjuvant than in mice injected with PBS in the same adjuvant (2,133 ± 270 and 1,329 ± 121, respectively, mean ± SEM; P < 0.02). A similar pattern was observed when mice were immunized on the day of glutamate injection (1,777 ± 101 compared with 1,414 ± 36; P < 0.05), but not when they were immunized 48 h later. These findings suggest that protection from glutamate toxicity requires reinforcement of the immune system by antigens that are different from those associated with myelin. The use of Cop-1 apparently circumvents this antigen specificity barrier. In the rat ocular hypertension model, which simulates glaucoma, immunization with Cop-1 significantly reduced the retinal ganglion cell loss from 27.8% ± 6.8% to 4.3% ± 1.6%, without affecting the intraocular pressure. This study may point the way to a therapy for glaucoma, a neurodegenerative disease of the optic nerve often associated with increased intraocular pressure, as well as for acute and chronic degenerative disorders in which glutamate is a prominent participant.

Protection of nonobese diabetic mice from autoimmune diabetes by reduction of islet mass before insulitis.

Nonobese diabetic mice spontaneously develop diabetes that is caused by autoimmune cell-mediated destruction of pancreatic beta cells. Here we report that surgical removal of 90% of pancreatic tissue before onset of insulitis induced a long-term diabetes-free condition in nonobese diabetic mice. Pancreatectomy after development of moderate insulitis had no effect on the course of diabetes. The effect of pancreatectomy was abrogated with subsequent development of diabetes by infusion of islet-cell-specific T lymphocytes and by transplantation of pancreatic islets. Lymphocytes from pancreatectomized diabetes-free mice exhibited low response to islet cells but responded normally to alloantigens. These results suggest that the islet cell mass plays a critical role in development of autoimmune diabetes.

Functional protection of dystrophic mouse (mdx) muscles after adenovirus-mediated transfer of a dystrophin minigene.

Fast skeletal muscles of mdx (X chromosome-linked muscular dystrophy) mice were injected after birth with a recombinant adenovirus containing a minidys- trophin gene, a 6.3-kbp cDNA coding for the N- and C-terminal ends of dystrophin. Adult muscles were challenged by forced lengthening during tetanic contractions. Stretch-induced mechanical and histological damages were much reduced in injected muscles, in direct proportion of the Miniber of fibers expressing minidystrophin. Damaged fibers were preferentially found among minidystrophin-negative regions. Minidystrostrophin confers an important functional and structural protection of limb muscles against high mechanical stress, even after a partial somatic gene transfer.

Protection of nonobese diabetic mice from diabetes by intranasal or subcutaneous administration of insulin peptide B-(9-23).

The observation that overt type I diabetes is often preceded by the appearance of insulin autoantibodies and the reports that prophylactic administration of insulin to biobreeding diabetes-prone (BB-DP) rats, nonobese diabetic (NOD) mice, and human subjects results in protection from diabetes suggest that an immune response to insulin is involved in the process of beta cell destruction. We have recently reported that islet-infiltrating cells isolated from NOD mice are enriched for insulin-specific T cells, that insulin-specific T cell clones are capable of adoptive transfer of diabetes, and that epitopes present on residues 9-23 of the B chain appear to be dominant in this spontaneous response. In the experiments described in this report, the epitope specificity of 312 independently isolated insulin-specific T cell clones was determined and B-(9-23) was found to be dominant, with 93% of the clones exhibiting specificity toward this peptide and the remainder to an epitope on residues 7-21 of the A chain. On the basis of these observations, the effect of either subcutaneous or intranasal administration of B-(9-23) on the incidence of diabetes in NOD mice was determined. The results presented here indicate that both subcutaneous and intranasal administration of B-(9-23) resulted in a marked delay in the onset and a decrease in the incidence of diabetes relative to mice given the control peptide, tetanus toxin-(830-843). This protective effect is associated with reduced T-cell proliferative response to B-(9-23) in B-(9-23)-treated mice.

Phosphinate analogs of D-, D-dipeptides: slow-binding inhibition and proteolysis protection of VanX, a D-, D-dipeptidase required for vancomycin resistance in Enterococcus faecium.

VanX is a D-Ala-D-Ala dipeptidase that is essential for vancomycin resistance in Enterococcus faecium. Contrary to most proteases and peptidases, it prefers to hydrolyze the amino substrate but not the related kinetically and thermodynamically more favorable ester substrate D-Ala-D-lactate. The enzymatic activity of VanX was previously found to be inhibited by the phosphinate analogs of the proposed tetrahedral intermediate for hydrolysis of D-Ala-D-Ala. Here we report that such phosphinates are slow-binding inhibitors. D-3-[(1-Aminoethyl)phosphinyl]-D-2-methylpropionic acid I showed a time-dependent onset of inhibition of VanX and a time-dependent return to uninhibited steady-state rates upon dilution of the enzyme/inhibitor mixture. The initial inhibition constant Ki after immediate addition of VanX to phosphinate I to form the E-I complex is 1.5 microM but is then lowered by a relatively slow isomerization step to a second complex, E-I*, with a final K*i of 0.47 microM. This slow-binding inhibition reflects a Km/K*i ratio of 2900:1. The rate constant for the slow dissociation of complex E-I* is 0.24 min-1. A phosphinate analog with an ethyl group replacing what would be the side chain of the second D-alanyl residue in the normal tetrahedral adduct gives a K*i value of 90 nM. Partial proteolysis of VanX reveals two protease-sensitive loop regions that are protected by the intermediate analog phosphinate, indicating that they may be part of the VanX active site.

Through the Eyes of Visitors: Understanding the Contexts of the Visitor Photo Study at the Denver Museum of Nature & Science

This case study describes the analysis of the Visitor Photo Study, a study in which visitors to the Denver Museum of Nature & Science documented their visit through pictures. The origins, implementation, and findings of the Visitor Photo Study are considered within the contexts of the fields of Community-Based Research (Strand, Marullo, Cutforth, Stoecker, & Donohue, 2003b), Visual Studies (Marshall & Rossman, 2011; Pink, 2007), and Visitor Studies (Visitor Studies Association, 2012). This study considers the extent to which the principles and elements of each of these fields were present in the Visitor Photo Study, which elements were not fully realized or were missing from the study, and ways in which the Visitor Photo Study extends each of these fields. The value of this type of analysis and implications for museums, faculty, and students are also discussed.

The Minoans and their interpretations of nature in comparison with succeeding cultures

"Some of the finest interpretations ot nature ever to be expressed by an were painted by the Minoan fresco artists of Crete. Discovered only since the turn of the 20th century, the Kinoan Bronze Age civilization was amazingly progressive and notably modern. Apparently, the Minoans gained their high standard of living mainly through economic prosperity and secarity provided by a great navy. Arts, architecture and craft relice uncovered have been numerous, well-preserved and invaluable sources of historical knowledge"

Internet Civil Liberties in the U.S. and the Protection of the Modern Terrorist

This capstone examines the civil liberties of the modern terrorist and explicates the right to freedom of speech for terrorist organizations and their use of the internet. Terrorist organizations use the internet to promote ideas, recruit members, organize the flow of information, and coordinate actions. During the war on terror the US Patriot Act became law allowing for U.S. government censorship and surveillance of internet traffic and many believe these acts are a threat to civil liberties. Terrorist organizations have the right to express their views, however unpopular, and censoring or restricting web sites diminishes civil liberties for all, which democracies and liberal societies are founded upon.

The select works of Antony van Leeuwenhoek : containing his microscopical discoveries in many of the works of nature / translated from the Dutch and Latin editions published by the author, by Samuel Hoole.

2 (text)

The select works of Antony van Leeuwenhoek : containing his microscopical discoveries in many of the works of nature / translated from the Dutch and Latin editions published by the author, by Samuel Hoole.

1 (text)

A general system of nature, through the three grand kingdoms of animals, vegetables, and minerals, systematically divided into their several classes, orders, genera, species, and varieties, with their habitations, manners, economy, structure and peculiarities. /

v. 7 (1806)

Modernist Ecology: Modernism and the Reimagination of Nature

Countering the trend in contemporary ecocriticism to advance realism as an environmentally responsible mode of representation, this essay argues that the anti-realist aesthetics of literary modernism were implicitly “ecological.” In order to make this argument I distinguish between contemporary and modernist ecological culture (both of which I differentiate in turn from ecological science); while the former is concerned primarily with the practical reform characteristic of what we now call “environmentalism,” the latter demanded an all-encompassing reimagination of the relationship between humanity and nature. “Modernist ecology,” as I call it, attempted to envision this change, which would be ontological or metaphysical rather than simply social, through thematically and formally experimental works of art. Its radical vision, suggestive in some ways of today’s “deep” ecology, repudiated modern accounts of nature as a congeries of inert objects to be manipulated by a sovereign subject, and instead foregrounded the chiasmic intertexture of the subject/object relationship. In aesthetic modernism we encounter not “objective” nature, but “nature-being” – a blank substratum beneath the solid contours of what philosopher Kate Soper calls “lay nature” – the revelation of which shatters historical constructions of nature and alone allows for radical alternatives. This essay looks specifically at modernist ecology as it appears in the works of W. B. Yeats, D. H. Lawrence, and Samuel Beckett, detailing their attempts to envision revolutionary new ecologies, but also their struggles with the limited capacity of esoteric modernist art to effect significant ecological change on a collective level.