Gears Based on Carbon Nanotubes

Gears based on carbon nanotubes (see figure) have been proposed as components of an emerging generation of molecular- scale machines and sensors. In comparison with previously proposed nanogears based on diamondoid and fullerene molecules, the nanotube-based gears would have simpler structures and are more likely to be realizable by practical fabrication processes. The impetus for the practical development of carbon-nanotube- based gears arises, in part, from rapid recent progress in the fabrication of carbon nanotubes with prescribed diameters, lengths, chiralities, and numbers of concentric shells. The shafts of the proposed gears would be made from multiwalled carbon nanotubes. The gear teeth would be rigid molecules (typically, benzyne molecules), bonded to the nanotube shafts at atomically precise positions. For fabrication, it may be possible to position the molecular teeth by use of scanning tunneling microscopy (STM) or other related techniques. The capability to position individual organic molecules at room temperature by use of an STM tip has already been demonstrated. Routes to the chemical synthesis of carbon-nanotube-based gears are also under investigation. Chemical and physical aspects of the synthesis of molecular scale gears based on carbon nanotubes and related molecules, and dynamical properties of nanotube- based gears, have been investigated by computational simulations using established methods of quantum chemistry and molecular dynamics. Several particularly interesting and useful conclusions have been drawn from the dynamical simulations performed thus far: The forces acting on the gears would be more sensitive to local molecular motions than to gross mechanical motions of the overall gears. Although no breakage of teeth or of chemical bonds is expected at temperatures up to at least 3,000 K, the gears would not work well at temperatures above a critical range from about 600 to about 1,000 K. Gear temperature could probably be controlled by use of coolant gases. For a given application, the gears would work well at temperatures below the critical range, provided that the rotational energy was less than the energy required to tilt the teeth through an angle of 20 . The predominant mechanism of gear failure would be slippage caused by tilting of teeth. Gears would resume functioning if the slipping gears were decelerated sufficiently

Measuring transversity densities in singly polarized hadron-hadron and lepton-hadron collisions

We show how the transverse polarization of a quark initiating a jet can be probed by the azimuthal distribution of two hadrons (of large $z$) in the jet. This permits a twist 2 asymmetry in hard processes when only one of the initial particles is polarized transversely. Applications to hadron-hadron and lepton-hadron scattering are discussed.Comment: 16 pages, LaTeX + EPSF, 2 postscript figures. PSU/TH/10

The Importance of Bcl-x L in the Survival of Human RPE Cells

PURPOSE: In normal eyes and in diseases such as age-related macular degeneration (AMD) and proliferative vitreoretinopathy (PVR), retinal pigment epithelial (RPE) cell survival is critically important. Bcl-x(L) has been shown to be among the most highly expressed survival factors in cultured human RPE cells. In the current study the effect of Bcl-x(L) blockade on human RPE cell survival was determined under normal conditions and after induced oxidative stress. METHODS: Cultured human RPE cells from three different donors were transfected with modified, 2'-O-methoxyethoxy Bcl-x(L)-mismatched control antisense oligonucleotides (ASOs), Bcl-x(L)-specific ASOs, and Bcl-x(L) splice switching oligonucleotides (SSOs), which shift the splicing pattern of Bcl-x pre-mRNA from Bcl-x(L) into Bcl-x(S), a proapoptotic factor. RNA and protein were harvested at various time points after transfection. Bcl-x(L) and Bcl-x(S) mRNA transcript levels were analyzed using gene-specific primers with reverse transcription-polymerase chain reaction. Bcl-x(L) protein levels were analyzed using Western blot. Cell viability was measured by WST-1 and lactate dehydrogenase (LDH) assays. The mode of cell death was determined with a cell death ELISA and an M30 assay. To study the effects of oxidative stress, the cells were stimulated after transfection with various concentrations of H(2)O(2.) Cell viability was analyzed by WST-1 (Roche, Indianapolis, IN) and LDH assays RESULTS: After Bcl-x(L)-specific ASO and SSO transfections, Bcl-x(L) mRNA and protein levels were significantly reduced. Bcl-x(S) levels were increased after transfection with SSO. By day 8 after plating, the cells transfected with Bcl-x(L)-specific ASO had significantly decreased viability, which was further reduced by day 10. The SSO had an even more potent effect. Cell viability was reduced on day 4 after plating and by day 10, less than 10% of the cells were viable. Apoptotic cell death occurred as early as day 4 after plating. H(2)O(2), used as a model oxidant, further enhanced cell death induced by Bcl-x(L)-specific ASO and SSO. CONCLUSIONS: Bcl-x(L) plays an important role in human RPE cell survival under normal conditions and when cells are exposed to oxidative stress. Treatment strategies that enhance Bcl-x(L) expression and/or prevent conversion of Bcl-x(L) to Bcl-x(S) may be useful in preventing RPE cell death in AMD. Treatments that reduce Bcl-x(L) and enhance Bcl-x(S) may be useful in inhibiting unwanted RPE cell proliferation in PVR

Expression of three forms of melanoma growth stimulating activity (MGSA)/gro in human retinal pigment epithelial cells

PURPOSE: To characterize mRNA expression and protein production of the cytokine MGSA/gro in human retinal pigment epithelial (RPE) cells and to determine whether expression of MGSA/gro is modulated by serum and the cytokines interleukin 1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha), or transforming growth factor beta (TGF beta) mediators implicated in proliferative vitreoretinopathy (PVR). METHODS: Reverse-transcription polymerase chain reaction was used to determine the steady-state mRNA expression of three forms of MGSA/gro, alpha, beta, and gamma, by cultured human RPE cells in the presence or absence of recombinant IL-1 beta, TNF alpha, or TGF beta, or when serum-starved cells were re-fed with medium containing serum. Immunocytochemistry was used to characterize RPE cell-associated MGSA/gro protein, and immunoprecipitation of MGSA/gro from cell-conditioned medium was used to demonstrate MGSA/gro secretion. RESULTS: MGSA/gro mRNA was expressed minimally under basal conditions. Expression for all three forms of MGSA/gro mRNA was induced in a dose- and time-dependent manner after exposure to IL-1 beta, to a lesser extent after exposure to TNF alpha, but not after exposure to TGF beta. Serum induced MGSA/gro alpha and gamma transcripts, but not beta transcripts. Cell-associated MGSA/gro was identified on RPE cells grown in the absence of cytokines, but MGSA/gro was not secreted under these conditions. Exposure to IL-1 beta did not consistently cause increased cell-associated MGSA/gro; however, IL-1 beta induced secretion of MGSA/gro in a time-dependent manner. CONCLUSION: MGSA/gro is produced by human RPE in response to mediators implicated in PVR. Because MGSA/gro is a pleiotropic modulator of cell proliferation and inflammation, it may contribute to the intraocular wound healing response that characterizes PVR

Randomized Trial to Evaluate Tandospirone in Geographic Atrophy Secondary to Age-Related Macular Degeneration: The GATE Study

Purpose To determine the safety and efficacy of AL-8309B (tandospirone) in the management of patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD) and obtain standardized data on GA lesion growth progression. Design Prospective, controlled, double-masked, randomized, multicenter phase 3 clinical trial. Methods setting: Forty-eight clinical sites. patients: Patients with GA associated with AMD were enrolled. All patients were followed for a minimum of 30 months, and up to 36 months. intervention procedures: Patients were randomized (1:1:1) to receive AL-8309B ophthalmic solution 1.0%, 1.75%, or vehicle, administered as a twice-daily topical ocular drop. main outcome measures: The primary efficacy endpoint was mean annualized lesion enlargement from baseline as assessed with fundus autofluorescence (FAF) imaging. Results A total of 768 eyes of 768 patients were enrolled and treated with AL-8309B 1.0% (n = 250), AL-8309B 1.75% (n = 258), or vehicle (n = 260). An increase in mean lesion size was observed in both the AL-8309B and vehicle treatment groups, and growth rates were similar in all treatment groups. Annualized lesion growth rates were 1.73, 1.76, and 1.71 mm 2 for AL-8309B 1.0%, AL-8309B 1.75%, and vehicle, respectively. Conclusions AL-8309B 1.0% and 1.75% did not affect lesion growth in eyes with GA secondary to AMD. There were no clinically relevant safety issues identified for AL-8309B. The large natural history dataset from this study is a valuable repository for future comparisons

Nepafenac 0.3% after Cataract Surgery in Patients with Diabetic Retinopathy: Results of 2 Randomized Phase 3 Studies

Purpose To demonstrate the efficacy and safety of once-daily nepafenac 0.3% ophthalmic suspension versus vehicle, based on clinical outcomes, after cataract surgery in patients with diabetes. Design Two prospective, randomized, multicenter, double-masked, vehicle-controlled phase 3 studies. Participants Total, 615 patients in study 1 and 605 patients in study 2. Methods Patients were randomized (1:1) to topical nepafenac 0.3% or vehicle once-daily starting the day before surgery and continuing for 90 days thereafter. Main Outcome Measures Key efficacy variables were: patients (%) in whom macular edema (ME) developed (≥30% increase from preoperative baseline central subfield macular thickness) within 90 days after cataract surgery and the patients (%) with a best-corrected visual acuity (BCVA) improvement of ≥15 letters from preoperative baseline through day 14 maintained through day 90. Secondary end points included: patients (%) with a BCVA improvement of ≥15 letters from preoperative baseline through days 90 and 60 and safety over 3 months. Results A significantly lower percentage of patients demonstrated ME within 90 days after surgery with nepafenac 0.3% versus vehicle (study 1: 2.3% vs. 17.3%; P P = 0.001; pooled: 4.1% vs. 15.9%; P P P = 0.671) in study 2, and 55.4% versus 46.7% ( P = 0.003) in the pooled analysis. A greater percentage of patients treated with nepafenac 0.3% versus vehicle in study 1 and similar percentage in study 2 had a BCVA improvement of ≥15 letters from preoperative baseline through day 90 (77.2% vs. 67.7% [ P = 0.009] and 65.4% vs. 65.9% [ P = 0.888]) and through day 60 (76.2% vs. 64.7% [ P = 0.002] and 68.9% vs. 62.1% [ P = 0.092]). No unanticipated adverse events were observed. Conclusions These studies demonstrated the clinical benefits of nepafenac 0.3% over vehicle in reducing the risk of postoperative ME, with the integrated analysis showing improved BCVA after cataract surgery in patients with diabetic retinopathy, with no unanticipated safety events

The Importance of Bcl-x L in the Survival of Human RPE Cells

PURPOSE. In normal eyes and in diseases such as age-related macular degeneration (AMD) and proliferative vitreoretinopathy (PVR), retinal pigment epithelial (RPE) cell survival is critically important. Bcl-x L has been shown to be among the most highly expressed survival factors in cultured human RPE cells. In the current study the effect of Bcl-x L blockade on human RPE cell survival was determined under normal conditions and after induced oxidative stress. METHODS. Cultured human RPE cells from three different donors were transfected with modified, 2Ј-O-methoxyethoxy Bclx L -mismatched control antisense oligonucleotides (ASOs), Bclx L -specific ASOs, and Bcl-x L splice switching oligonucleotides (SSOs), which shift the splicing pattern of Bcl-x pre-mRNA from Bcl-x L into Bcl-x S , a proapoptotic factor. RNA and protein were harvested at various time points after transfection. Bcl-x L and Bcl-x S mRNA transcript levels were analyzed using genespecific primers with reverse transcription-polymerase chain reaction. Bcl-x L protein levels were analyzed using Western blot. Cell viability was measured by WST-1 and lactate dehydrogenase (LDH) assays. The mode of cell death was determined with a cell death ELISA and an M30 assay. To study the effects of oxidative stress, the cells were stimulated after transfection with various concentrations of H 2 O 2. Cell viability was analyzed by WST-1 (Roche, Indianapolis, IN) and LDH assays. RESULTS. After Bcl-x L -specific ASO and SSO transfections, Bcl-x L mRNA and protein levels were significantly reduced. Bcl-x S levels were increased after transfection with SSO. By day 8 after plating, the cells transfected with Bcl-x L -specific ASO had significantly decreased viability, which was further reduced by day 10. The SSO had an even more potent effect. Cell viability was reduced on day 4 after plating and by day 10, less than 10% of the cells were viable. Apoptotic cell death occurred as early as day 4 after plating. H 2 O 2 , used as a model oxidant, further enhanced cell death induced by Bcl-x L -specific ASO and SSO. CONCLUSIONS. Bcl-x L plays an important role in human RPE cell survival under normal conditions and when cells are exposed to oxidative stress. Treatment strategies that enhance Bcl-x L expression and/or prevent conversion of Bcl-x L to Bcl-x S may be useful in preventing RPE cell death in AMD. Treatments that reduce Bcl-x L and enhance Bcl-x S may be useful in inhibiting unwanted RPE cell proliferation in PVR. (Invest Ophthalmol Vis Sci. 2007;48:3846 -3853) DOI:10.1167/iovs.06-1145 A ge-related macular degeneration (AMD) is the leading cause of irreversible blindness in adults over the age of 65 in the United States and currently affects more than 1.75 million individuals. 1 The exact etiology of AMD is unknown and is probably multifactorial. However, it has been hypothesized that cumulative oxidative stress throughout life and associated RPE cell injury play an important role. In normal eyes, there is very little RPE cell turnover, and most RPE cells survive for an individual's lifetime. In geographic atrophy, an advanced form of AMD, RPE cells die by apoptotic and nonapoptotic mechanisms. 2,3 RPE cell death is accompanied by underlying choriocapillaris atrophy and overlying retinal thinning, ultimately resulting in decreased visual acuity. In our laboratory, we have examined the effect of nuclear transcription factor (NF)-B inhibition on tumor necrosis factor (TNF)-␣-induced apoptosis in human RPE cells. 7 NF-B is a transcription factor that controls a wide range of genes, including genes that regulate apoptosis. 8 TNF-␣ is a cytokine that regulates a variety of RPE cell activities, including cell attachment, spreading, chemotaxis, migration, and proliferation

Morphological assessment of the retina in uveitis

BACKGROUND: The objective of this study is to describe a system for color photograph evaluation in uveitis and report baseline morphologic findings for the Multicenter Uveitis Steroid Treatment (MUST) Trial. Four-hundred seventy-nine eyes of 255 subjects with intermediate, posterior, and panuveitis had stereoscopic color fundus photographs obtained by certified photographers and evaluated by certified graders using standardized procedures to evaluate morphologic characteristics of uveitis. The posterior pole was evaluated for macular edema, vitreoretinal interface abnormalities, and macular pigment disturbance/atrophy; the optic disk was assessed for edema, pallor, or glaucomatous changes. The presence of neovascularization, vascular occlusion, vascular sheathing, and tractional retinal changes was determined. A random subset of 77 images was re-graded to determine the percentage agreement with the original grading on a categorical scale. RESULTS: At baseline, 437/479 eyes had images available to grade. Fifty-three eyes were completely ungradable due to media opacity. Common features of intermediate and posterior/panuveitis were epiretinal membrane (134 eyes, 35 %), and chorioretinal lesions (140 eyes, 36 %). Macular edema was seen in 16 %. Optic nerve head and vascular abnormalities were rare. Reproducibility evaluation found exact agreement for the presence of chorioretinal lesions was 78 %, the presence and location of macular edema was 71 %, and the presence of epiretinal membrane was 71 %. Vertical cup-to-disk ratio measurement had intra-class correlation of 0.75. CONCLUSIONS: The MUST system for evaluating stereoscopic color fundus photographs describes the morphology of uveitis and its sequelae, in a standardized manner, is highly reproducible, and allows monitoring of treatment effect and safety evaluation regarding these outcomes in clinical trials

Cosmic topology. Part II. Eigenmodes, correlation matrices, and detectability of orientable Euclidean manifolds

If the Universe has non-trivial spatial topology, observables depend on both the parameters of the spatial manifold and the position and orientation of the observer. In infinite Euclidean space, most cosmological observables arise from the amplitudes of Fourier modes of primordial scalar curvature perturbations. Topological boundary conditions replace the full set of Fourier modes with specific linear combinations of selected Fourier modes as the eigenmodes of the scalar Laplacian. We present formulas for eigenmodes in orientable Euclidean manifolds with the topologies $E_1$ - $E_6$, $E_{11}$, $E_{12}$, $E_{16}$, and $E_{18}$ that encompass the full range of manifold parameters and observer positions, generalizing previous treatments. Under the assumption that the amplitudes of primordial scalar curvature eigenmodes are independent random variables, for each topology we obtain the correlation matrices of Fourier-mode amplitudes (of scalar fields linearly related to the scalar curvature) and the correlation matrices of spherical-harmonic coefficients of such fields sampled on a sphere, such as the temperature of the cosmic microwave background (CMB). We evaluate the detectability of these correlations given the cosmic variance of the observed CMB sky. We find that topologies where the distance to our nearest clone is less than about 1.2 times the diameter of the last scattering surface of the CMB give a correlation signal that is larger than cosmic variance noise in the CMB. This implies that if cosmic topology is the explanation of large-angle anomalies in the CMB, then the distance to our nearest clone is not much larger than the diameter of the last scattering surface. We argue that the topological information is likely to be better preserved in three-dimensional data, such as will eventually be available from large-scale structure surveys.Comment: 79 pages, 9 figure

Safety and Efficacy of Risuteganib in Intermediate Non-exudative Age-Related Macular Degeneration

Purpose : Risuteganib is a small synthetic peptide that regulates select integrin functions involved in the pathogenesis of dry age-related macular degeneration (AMD). This study evaluated the safety and efficay of risuteganib for the treatment of dry AMD. Methods : Randomized, double-masked, placebo-controlled Phase 2 study in eyes with intermediate dry AMD presenting with best-corrected visual acuity (BCVA) between 20/40-20/200 was conducted across multiple centers in the United States. Patients were randomized to receive either intravitreal 1.0mg risuteganib or sham injection at baseline. At week 16, patients in the risuteganib group received a second dose and the sham group crossed over and receive a single dose of 1.0mg risuteganib. The primary endpoint was the percentage of population with ≥ 8 letters BCVA gain from baseline to week 28 in 1.0mg risuteganib vs baseline to week 12 for sham. Results : Forty-five patients were enrolled in the study. At baseline, mean patient age was 78.8 and 75.9 years and mean baseline BCVA was 67.1 and 64.4 letters in the sham and risuteganib groups, respectively. The primary endpoint was met; 48% of patients in the risuteganib group at week 28 and 7% of patients in the sham group at week 12 gained > 8 letters from baseline (p=0.013). Of the risuteganib treated patients, 20% gained > 15 letters at week 28; no patients in the sham group at week 12 had this gain. On a post-hoc masked analysis by 2 independent reading centers, greater outer retinal and photoreceptor thickness and volume and smaller ellipsoid zone defect area in the central 1 mm zone at baseline were associated with increased BCVA response to risuteganib. Risuteganib demonstrated a good safety profile in this study. Conclusions : Risuteganib showed significant benefit over sham in patients with dry AMD with respect to proportion of patients gaining > 8 letters of BCVA from baseline. Furthermore, post hoc analysis provides preliminary insights into baseline anatomic features that may help to determine likelihood of BCVA response to risuteganib. These findings will be confirmed in an upcoming larger trial