Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion

Deregulation of the Rb and p53 Pathways in Uveal Melanoma

Uveal melanoma is the most common primary eye cancer, yet its molecular pathogenesis is poorly understood. In this study, we investigated the immunohistochemical expression of proteins in the Rb and p53 tumor suppressor pathways in 33 uveal melanomas from enucleated eyes. Strong nuclear staining for Rb was present in most tumors. However, a few cases displayed weak nuclear staining and strong cytoplasmic staining (possibly indicating Rb mutation), and this aberrant staining correlated strongly with failed radiotherapy or thermotherapy before enucleation. Staining for cyclin D1 was positive in most tumors and was associated with advanced age and larger tumor size, which are both poor prognostic factors. Generally, immunostaining for p53 was weak (suggesting a lack of p53 mutations), although p53 positivity correlated strongly with staining for phosphorylated Rb, supporting the notion that inappropriate phosphorylation of Rb can induce p53. Strong immunostaining for MDM2, which can functionally block p53 activity, was observed in most tumors and correlated significantly with female sex. Strong cytoplasmic staining was observed for Bcl2, which can inhibit both p53-dependent and -independent apoptosis. We conclude that Rb and p53 are mutated infrequently in uveal melanoma, but their respective pathways may be functionally inactivated

Genetics and Age-Related Macular Degeneration: A Practical Review for Clinicians

Age-related macular degeneration (AMD) is a multifactorial genetic disease, with at least 52 identifiable associated gene variants at 34 loci, including variants in ( ) and ( ). Genetic factors account for up to 70% of disease variability. However, population-based genetic risk scores are generally more helpful for clinical trial design and stratification of risk groups than for individual patient counseling. There is some evidence of pharmacogenetic influences on various treatment modalities used in AMD patients, including Age-Related Eye Disease Study (AREDS) supplements, photodynamic therapy (PDT), and anti-vascular endothelial growth factor (anti-VEGF) agents. However, there is currently no convincing evidence that genetic information plays a role in routine clinical care

Genetics and diabetic retinopathy

There are many reasons to suspect a genetic influence on the development and progression of diabetic retinopathy, including substantial variability in disease severity among patients with similar risk factors. Linkage studies have suggested associations with chromosomes 1, 3, 12 and others. The most studied individual genes are those encoding vascular endothelial growth factor, aldose reductase, and the receptor for advanced glycation end products, all of which have shown statistically significant associations in multiple series from various parts of the world. At this time, no definite genetic associations with diabetic retinopathy have been consistently reported. This may be due to small sample sizes, differences in study design, underlying genetic differences between study populations, or other factors. As we continue to collect data, these relationships may become more clear

Longterm tolerance to retinal ischemia by repetitive hypoxic preconditioning: role of HIF-1alpha and heme oxygenase-1. Invest Ophthalmol Vis Sci.

PURPOSE. To determine whether the duration of ischemic tolerance in the retina could be extended by repetitive presentations of the preconditioning stimulus and to begin to elucidate the mechanistic underpinnings of the resultant novel phenotype. METHODS. Adult male Swiss-Webster ND4 mice were repeatedly preconditioned with systemic hypoxia (RHP) over 12 days; 4 weeks later, the mice were subjected to 30 minutes of unilateral retinal ischemia. Protection was quantified morphologically and functionally 1 week after ischemia by histologic analyses and scotopic electroretinography, respectively. Temporal expression patterns of hypoxia-inducible factor (HIF)-1␣ and heme oxygenase (HO)-1 were measured in response to RHP and after retinal ischemia by immunoblot analysis and immunohistochemistry. RESULTS. Morphologic and functional protection against ischemiainduced reductions in retinal layer thicknesses and layer cell counts, and a-and b-wave amplitudes, was documented for at least 4 weeks after RHP. There was no evidence of tissue injury or dysfunction by RHP alone. Temporally associated with this period of long-term tolerance (LTT) to retinal ischemia were sustained increases in retinal levels of HIF-1␣ and HO-1 protein lasting at least 1 and 4 weeks, respectively, after the last RHP stimulus. CONCLUSIONS. A novel form of sustained retinal ischemic tolerance is described, wherein endogenous adaptive responses triggered by repeated hypoxia afford protection against injury many weeks after the preconditioning stimulus. HIF-1␣ -mediated, long-lasting increases in retinal HO-1 expression may contribute to the LTT phenotype. Further elucidation of the genetic and molecular basis of such adaptive plasticity could provide therapeutic targets for preventing and/or treating a variety of ischemic retinopathies. (Invest Ophthalmol Vis Sci

Metabolome-Wide Association Study of Primary Open Angle Glaucoma

PURPOSE. To determine if primary open-angle glaucoma (POAG) patients can be differentiated from controls based on metabolic characteristics. METHODS. We used ultra-high resolution mass spectrometry with C18 liquid chromatography for metabolomic analysis on frozen plasma samples from 72 POAG patients and 72 controls. Metabolome-wide Spearman correlation was performed to select differentially expressed metabolites (DEM) correlated with POAG. We corrected P values for multiple testing using Benjamini and Hochberg false discovery rate (FDR). Hierarchical cluster analysis (HCA) was used to depict the relationship between participants and DEM. Differentially expressed metabolites were matched to the METLIN metabolomics database; both DEM and metabolites significantly correlating with DEM were analyzed using MetaboAnalyst to identify metabolic pathways altered in POAG. RESULTS. Of the 2440 m/z (mass/charge) features recovered after filtering, 41 differed between POAG cases and controls at FDR ¼ 0.05. Hierarchical cluster analysis revealed these DEM to associate into eight clusters; three of these clusters contained the majority of the DEM and included palmitoylcarnitine, hydroxyergocalciferol, and high-resolution METLIN matches to sphingolipids, other vitamin D-related metabolites, and terpenes. MetaboAnalyst also indicated likely alteration in steroid biosynthesis pathways. CONCLUSIONS. Global ultrahigh resolution metabolomics emphasized the importance of altered lipid metabolism in POAG. The results suggest specific metabolic processes, such as those involving palmitoylcarnitine, sphingolipids, vitamin D-related compounds, and steroid precursors, may contribute to POAG status and merit more detailed study with targeted methods

Metabolome-Wide Association Study of Neovascular Age-Related Macular Degeneration

<div><p>Purpose</p><p>To determine if plasma metabolic profiles can detect differences between patients with neovascular age-related macular degeneration (NVAMD) and similarly-aged controls.</p><p>Methods</p><p>Metabolomic analysis using liquid chromatography with Fourier-transform mass spectrometry (LC-FTMS) was performed on plasma samples from 26 NVAMD patients and 19 controls. Data were collected from mass/charge ratio (<i>m/z</i>) 85 to 850 on a Thermo LTQ-FT mass spectrometer, and metabolic features were extracted using an adaptive processing software package. Both non-transformed and log2 transformed data were corrected using Benjamini and Hochberg False Discovery Rate (FDR) to account for multiple testing. Orthogonal Partial Least Squares-Discriminant Analysis was performed to determine metabolic features that distinguished NVAMD patients from controls. Individual <i>m/z</i> features were matched to the Kyoto Encyclopedia of Genes and Genomes database and the Metlin metabolomics database, and metabolic pathways associated with NVAMD were identified using MetScape.</p><p>Results</p><p>Of the 1680 total <i>m/z</i> features detected by LC-FTMS, 94 unique <i>m/z</i> features were significantly different between NVAMD patients and controls using FDR (q = 0.05). A comparison of these features to those found with log2 transformed data (n = 132, q = 0.2) revealed 40 features in common, reaffirming the involvement of certain metabolites. Such metabolites included di- and tripeptides, covalently modified amino acids, bile acids, and vitamin D-related metabolites. Correlation analysis revealed associations among certain significant features, and pathway analysis demonstrated broader changes in tyrosine metabolism, sulfur amino acid metabolism, and amino acids related to urea metabolism.</p><p>Conclusions</p><p>These data suggest that metabolomic analysis can identify a panel of individual metabolites that differ between NVAMD cases and controls. Pathway analysis can assess the involvement of certain metabolic pathways, such as tyrosine and urea metabolism, and can provide further insight into the pathophysiology of AMD.</p></div