Despite considerable progress in genome- and proteome-based high-throughput screening methods and in rational drug design, the increase in approved drugs in the past decade did not match the increase of drug development costs. Network description and analysis not only gives a systems-level understanding of drug action and disease complexity, but can also help to improve the efficiency of drug design. We give a comprehensive assessment of the analytical tools of network topology and dynamics. The state-of-the-art use of chemical similarity, protein structure, protein-protein interaction, signaling, genetic interaction and metabolic networks in the discovery of drug targets is summarized. We propose that network targeting follows two basic strategies. The “central hit strategy” selectively targets central node/edges of the flexible networks of infectious agents or cancer cells to kill them. The “network influence strategy” works against other diseases, where an efficient reconfiguration of rigid networks needs to be achieved. It is shown how network techniques can help in the identification of single-target, edgetic, multi-target and allo-network drug target candidates. We review the recent boom in network methods helping hit identification, lead selection optimizing drug efficacy, as well as minimizing side-effects and drug toxicity. Successful network-based drug development strategies are shown through the examples of infections, cancer, metabolic diseases, neurodegenerative diseases and aging. Summarizing >1200 references we suggest an optimized protocol of network-aided drug development, and provide a list of systems-level hallmarks of drug quality. Finally, we highlight network-related drug development trends helping to achieve these hallmarks by a cohesive, global approach.

Diabetic patients who received a subconjunctival injection with triamcinolone acetonide at the end of cataract surgery had a lower macular thickness and macular volume at 6 and 12 weeks postoperatively than patients who did not. Intravitreal bevacizumab had no significant effect.

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During the last decade, network approaches became a powerful tool to describe protein structure and dynamics. Here we review the links between disordered proteins and the associated networks, and describe the consequences of local, mesoscopic and global network disorder on changes in protein structure and dynamics. We introduce a new classification of protein networks into 'cumulus-type', i.e., those similar to puffy (white) clouds, and 'stratus-type', i.e., those similar to flat, dense (dark) low-lying clouds, and relate these network types to protein disorder dynamics and to differences in energy transmission processes. In the first class, there is limited overlap between the modules, which implies higher rigidity of the individual units; there the conformational changes can be described by an 'energy transfer' mechanism. In the second class, the topology presents a compact structure with significant overlap between the modules; there the conformational changes can be described by 'multi-trajectories'; that is, multiple highly populated pathways. We further propose that disordered protein regions evolved to help other protein segments reach 'rarely visited' but functionally-related states. We also show the role of disorder in 'spatial games' of amino acids; highlight the effects of intrinsically disordered proteins (IDPs) on cellular networks and list some possible studies linking protein disorder and protein structure networks. # Mr. Zsolt Hoksza is a high school student of the Fazekas High School (www.fazekas.hu) in Budapest, Hungary, who started his research as a member of the EU Descartes Award winning High School Research Student organization (www.kutdiak.hu) founded by P.C. and offering research opportunities for several thousands of high school students since 1996. STRUCTURE AND DYNAMICS OF PROTEINS AS NETWORKS 2.A. Definition of protein structure networks.Protein structure networks (also called protein contact networks) form the basal layer of the cellular network hierarchy. At the residue level of coarse-graining, the nodes are amino acids, while links connect amino acids whose inter-distance is below a cut-off (usually 0.4 to 0.85 nm) in the native fold. Protein structure networks may have weighted links instead of distance cut-offs, and may discriminate between individual atoms (like αC or βC atoms). Covalent bonds may be included or excluded in the network representation [1-9].2.B. Key topological properties of protein structure networks. In the small world of protein structure networks any two amino acids are separated by only a few links, and the network diameter grows logarithmically with increasing number of amino acids. This smallworldness promotes the fast transmission of perturbations (conformational changes). Typically, protein structure networks have a Poisson degree distribution rather than the widely characteristic scale-free degree distribution. This means that they have fewer hubs than expected, and amino acid "mega-hubs", having an extremely large number of neighbors do not exist, whic...

BackgroundMacular edema is a common cause of visual loss at uveitic patients. The aim of our study was to investigate retinal and choroidal thickness at the macula in anterior (AU) and intermediate (IMU) uveitis and in healthy individuals using spectral domain optical coherence tomography (SD-OCT).MethodsCase-control study of 21 patients with AU and 23 patients with IMU and 34 age-matched healthy controls was performed with Spectralis SD-OCT (Heidelberg Engineering, Germany). High resolution SD-OCT scans and macular mapping were applied for automated measurement of retinal thickness. Standardized, masked manual measurement of the choroidal thickness was performed in the center of the ETDRS fields on enhanced depth imaging (EDI) scans. Evaluation of central retinal subfield thickness, 3 mm and 6 mm perifoveal rings was performed in the corresponding ETDRS zones in patient groups.ResultsThe mean central retinal subfield thickness was significantly higher in IMU (368.65 ± 115.88 μm, p = 0.0003), but not significantly different in AU (290.42 ± 26.37 μm p = 0.6617) compared to that of in controls (278.55 ± 18.31 μm). In both uveitis groups retina was significantly thicker in the 3 and 6 mm perifoveal rings than that of in controls (359 ± 15.24 μm in AU and 390.55 ± 70.90 μm in IMU vs 345,41 ± 15.28 μm in the control group, p = 0.0388 and p < 0.0001) in the 3 mm and (313.83 ± 16.63 μm in AU and 343.33 ± 57.29 μm in IMU vs 299 ± 13.82 μm in the control group, p = 0.0171 and p < 0.0001) in the 6 mm ring. Central choroidal thickness was 311.94 ± 60.48 μm in the control eyes, showed no significant difference in AU (312.61 ± 90.35 μm) and IMU (303.17 ± 93.66 μm) eyes, and was also similar at the perifoveal rings.ConclusionSignificant topographical changes could be detected in the macula of AU and IMU patients. Retinal thickness in the perifoveal rings was increased both in AU and IMU, but in the center only in IMU. Choroidal thickness seems to be unaffected by uveitis, even in the presence of macular edema, at least in the early stage of the inflammatory disease process.