Orally Active Multi-Functional Antioxidants Delay Cataract Formation in Streptozotocin (Type 1) Diabetic and Gamma-Irradiated Rats

Age-related cataract is a worldwide health care problem whose progression has been linked to oxidative stress and the accumulation of redox-active metals. Since there is no specific animal model for human age-related cataract, multiple animal models must be used to evaluate potential therapies that may delay and/or prevent cataract formation.Proof of concept studies were conducted to evaluate 4-(5-hydroxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 4) and 4-(5-hydroxy-4,6-dimethoxypyrimidin-2-yl)-N,N-dimethyl-3,5-dioxopiperazine-1-sulfonamide (compound 8), multi-functional antioxidants that can independently chelate redox metals and quench free radicals, on their ability to delay the progression of diabetic "sugar" cataracts and gamma radiation-induced cataracts. Prior to 15 Gy of whole head irradiation, select groups of Long Evans rats received either diet containing compound 4 or 8, or a single i.p. injection of panthethine, a radioprotective agent. Compared to untreated, irradiated rats, treatment with pantethine, 4 and 8 delayed initial lens changes by 4, 47, and 38 days, respectively, and the average formation of posterior subcapsular opacities by 23, 53 and 58 days, respectively. In the second study, select groups of diabetic Sprague Dawley rats were administered chow containing compounds 4, 8 or the aldose reductase inhibitor AL1576. As anticipated, treatment with AL1576 prevented cataract by inhibiting sorbitol formation in the lens. However, compared to untreated rats, compounds 4 and 8 delayed vacuole formation by 20 days and 12 days, respectively, and cortical cataract formation by 8 and 3 days, respectively, without reducing lenticular sorbitol. Using in vitro lens culture in 30 mM xylose to model diabetic "sugar" cataract formation, western blots confirmed that multi-functional antioxidants reduced endoplasmic reticulum stress.Multi-functional antioxidants delayed cataract formation in two diverse rat models. These studies provide a proof of concept that a general cataract treatment focused on reducing oxidative stress instead of a specific mechanism of cataractogenesis can be developed

Algorithmic Aspects of Heterogeneous Biological Networks Comparison ⋆

Abstract. Biological networks are commonly used to model molecular activity within the cell. Recent experimental studies have shown that the detection of conserved subnetworks across several networks, coming from different organisms, may allow the discovery of disease pathways and prediction of protein functions. There already exist automatic methods that allow to search for conserved subnetworks using networks alignment; unfortunately, these methods are limited to networks of same type, thus having the same graph representation. Towards overcoming this limitation, a unified framework for pairwise comparison and analysis of networks with different graph representations (in particular, a directed acyclic graph D and an undirected graph G over the same set of vertices) is presented in [4]. We consider here a related problem called k-DAGCC: given a directed graph D and an undirected graph G on the same set V of vertices, and an integer k, does there exist sets of vertices V1, V2,... Vk ′, k ′ ≤ k such that, for each 1 ≤ i ≤ k ′ , (i) D[Vi] is a DAG and (ii) G[Vi] is connected? Two variants of k-DAGCC are of interest: (a) the Vis must form a partition of V, or (b) the Vis must form a cover of V. We study the computational complexity of both variants of k-DAGCC and, depending on the constraints imposed on the input, provide several polynomial-time algorithms, hardness and inapproximability results.

Optimally orienting physical networks

Abstract. In a network orientation problem one is given a mixed graph, consisting of directed and undirected edges, and a set of source-target vertex pairs. The goal is to orient the undirected edges so that a maximum number of pairs admit a directed path from the source to the target. This problem is NP-complete and no approximation algorithms are known for it. It arises in the context of analyzing physical networks of protein-protein and protein-dna interactions. While the latter are naturally directed from a transcription factor to a gene, the direction of signal flow in protein-protein interactions is often unknown or cannot be measured en masse. One then tries to infer this information by using causality data on pairs of genes such that the perturbation of one gene changes the expression level of the other gene. Here we provide a first polynomial-size ilp formulation for this problem, which can be efficiently solved on current networks. We apply our algorithm to orient protein-protein interactions in yeast and measure our performance using edges with known orientations. We find that our algorithm achieves high accuracy and coverage in the orientation, outperforming simplified algorithmic variants that do not use information on edge directions. The obtained orientations can lead to better understanding of the structure and function of the network. Key words: network orientation, protein-protein interaction, proteindna interaction, integer linear program, mixed graph

Cataracts among Chernobyl clean-up workers: implications regarding permissible eye exposures

The eyes of a prospective cohort of 8,607 Chernobyl clean-up workers (liquidators) were assessed for cataract at 12 and 14 years after exposure. The prevalence of strictly age-related cataracts was low, as expected (only 3.9% had nuclear cataracts at either examination), since 90% of the cohort was younger than 55 years of age at first examination. However, posterior subcapsular or cortical cataracts characteristic of radiation exposure were present in 25% of the subjects. The data for Stage 1 cataracts, and specifically for posterior subcapsular cataracts, revealed a significant dose response. When various cataract end points were analyzed for dose thresholds, the confidence intervals all excluded values greater than 700 mGy. Linear-quadratic dose-response models yielded mostly linear associations, with weak evidence of upward curvature. The findings do not support the ICRP 60 risk guideline assumption of a 5-Gy threshold for "detectable opacities" from protracted exposures but rather point to a dose-effect threshold of under 1 Gy. Thus, given that cataract is the dose-limiting ocular pathology in current eye risk guidelines, revision of the allowable exposure of the human visual system to ionizing radiation should be considered

Dosimetry for a study of low-dose radiation cataracts among Chernobyl clean-up workers

A cohort of 8,607 Ukrainian Chernobyl clean-up workers during 1986-1987 was formed to study cataract formation after ionizing radiation exposure. Study eligibility required the availability of sufficient exposure information to permit the reconstruction of doses to the lens of the eye. Eligible groups included civilian workers, such as those who built the "sarcophagus" over the reactor, Chernobyl Nuclear Power Plant Workers, and military reservists who were conscripted for clean-up work. Many of the official doses for workers were estimates, because only a minority wore radiation badges. For 106 military workers, electron paramagnetic resonance (EPR) measurements of extracted teeth were compared with the recorded doses as the basis to adjust the recorded gamma-ray doses and provide estimates of uncertainties. Beta-particle doses to the lens were estimated with an algorithm devised to take into account the nature and location of Chernobyl work, time since the accident, and protective measures taken. A Monte Carlo routine generated 500 random estimates for each individual from the uncertainty distributions of the gamma-ray dose and of the ratio of beta-particle to gamma-ray doses. The geometric mean of the 500 combined beta-particle and gamma-ray dose estimates for each individual was used in the data analyses. The median estimated lens dose for the cohort was 123 mGy, while 4.4% received >500 mGy