Adaptive Mutations in the JC Virus Protein Capsid Are Associated with Progressive Multifocal Leukoencephalopathy (PML)

PML is a progressive and mostly fatal demyelinating disease caused by JC virus infection and destruction of infected oligodendrocytes in multiple brain foci of susceptible individuals. While JC virus is highly prevalent in the human population, PML is a rare disease that exclusively afflicts only a small percentage of immunocompromised individuals including those affected by HIV (AIDS) or immunosuppressive drugs. Viral- and/or host-specific factors, and not simply immune status, must be at play to account for the very large discrepancy between viral prevalence and low disease incidence. Here, we show that several amino acids on the surface of the JC virus capsid protein VP1 display accelerated evolution in viral sequences isolated from PML patients but not in sequences isolated from healthy subjects. We provide strong evidence that at least some of these mutations are involved in binding of sialic acid, a known receptor for the JC virus. Using statistical methods of molecular evolution, we performed a comprehensive analysis of JC virus VP1 sequences isolated from 55 PML patients and 253 sequences isolated from the urine of healthy individuals and found that a subset of amino acids found exclusively among PML VP1 sequences is acquired via adaptive evolution. By modeling of the 3-D structure of the JC virus capsid, we showed that these residues are located within the sialic acid binding site, a JC virus receptor for cell infection. Finally, we go on to demonstrate the involvement of some of these sites in receptor binding by demonstrating a profound reduction in hemagglutination properties of viral-like particles made of the VP1 protein carrying these mutations. Collectively, these results suggest that a more virulent PML causing phenotype of JC virus is acquired via adaptive evolution that changes viral specificity for its cellular receptor(s)

Identification of RIP1 kinase as a specific cellular target of necrostatins

Necroptosis is a cellular mechanism of necrotic cell death induced by apoptotic stimuli in the form of death domain receptor engagement by their respective ligands under conditions where apoptotic execution is prevented. Although it occurs under regulated conditions, necroptotic cell death is characterized by the same morphological features as unregulated necrotic death. Here we report that necrostatin-1, a previously identified small-molecule inhibitor of necroptosis, is a selective allosteric inhibitor of the death domain receptor–associated adaptor kinase RIP1 in vitro. We show that RIP1 is the primary cellular target responsible for the antinecroptosis activity of necrostatin-1. In addition, we show that two other necrostatins, necrostatin-3 and necrostatin-5, also target the RIP1 kinase step in the necroptosis pathway, but through mechanisms distinct from that of necrostatin-1. Overall, our data establish necrostatins as the first-in-class inhibitors of RIP1 kinase, the key upstream kinase involved in the activation of necroptosis

Adaptive Mutations in the JC Virus Protein Capsid Are Associated with Progressive Multifocal Leukoencephalopathy (PML)

PML is a progressive and mostly fatal demyelinating disease caused by JC virus infection and destruction of infected oligodendrocytes in multiple brain foci of susceptible individuals. While JC virus is highly prevalent in the human population, PML is a rare disease that exclusively afflicts only a small percentage of immunocompromised individuals including those affected by HIV (AIDS) or immunosuppressive drugs. Viral- and/or host-specific factors, and not simply immune status, must be at play to account for the very large discrepancy between viral prevalence and low disease incidence. Here, we show that several amino acids on the surface of the JC virus capsid protein VP1 display accelerated evolution in viral sequences isolated from PML patients but not in sequences isolated from healthy subjects. We provide strong evidence that at least some of these mutations are involved in binding of sialic acid, a known receptor for the JC virus. Using statistical methods of molecular evolution, we performed a comprehensive analysis of JC virus VP1 sequences isolated from 55 PML patients and 253 sequences isolated from the urine of healthy individuals and found that a subset of amino acids found exclusively among PML VP1 sequences is acquired via adaptive evolution. By modeling of the 3-D structure of the JC virus capsid, we showed that these residues are located within the sialic acid binding site, a JC virus receptor for cell infection. Finally, we go on to demonstrate the involvement of some of these sites in receptor binding by demonstrating a profound reduction in hemagglutination properties of viral-like particles made of the VP1 protein carrying these mutations. Collectively, these results suggest that a more virulent PML causing phenotype of JC virus is acquired via adaptive evolution that changes viral specificity for its cellular receptor(s)

Electric and Hydraulic Properties of Carbon Felt Immersed in Different Dielectric Liquids

Electroconductive carbon felt (CF) material, having a permeable structure and significant electroconductive surface, is widely used for electrodes in numerous electrochemical applications such as redox flow batteries, fuel cells, electrochemical desalination apparatus, etc. The internal structure of CF is composed of different lengths of carbon filaments bonded together. This structure creates a large number of stochastically oriented and stochastically linked channels that have different lengths and cross sections. Therefore, the CF hydraulic permeability is similar to that of porous media and is determined by the internal empty volume and arrangement of carbon fibers. Its electroconductivity is ensured by the conductivity of the carbon filaments and by the electrical interconnections between fibers. Both of these properties (permeability and electrical conductivity) are extremely important for the efficient functioning of electrochemical devices. However, their influences counter each other during CF compressing. Increasing the stress on a felt element provides supplementary electrical contacts of carbon filaments, which lead to improved electrical conductivity. Thus, the active surface of the felt electrode is increased, which also boosts redox chemical reactions. On the other hand, compressed felt possesses reduced hydrodynamic permeability as a result of a diminished free volume of porous media and intrinsic channels. This causes increasing hydrodynamic expenditures of electrolyte pumping through electrodes and lessened cell (battery) efficiency. The designer of specific electrochemical systems has to take into account both of these properties when selecting the optimal construction for a cell. This article presents the results of measurements and novel approximating expressions of electrical and hydraulic characteristics of a CF during its compression. Since electrical conductivity plays a determining role in providing electrochemical reactions, it was measured in dry conditions and when the CF was immersed in several non-conductive liquids. The choice of such liquids prevented side effects of electrolyte ionic conductivity impact on electrical resistivity of the CF. This gave an opportunity to determine the influences of dielectric parameters of electrolytes to increase or decrease the density of interconnectivity of carbon fibers either between themselves or between them and electrodes. The experiments showed the influence of liquid permittivity on the conductivity of CF, probably by changing the density of fiber interconnections inside the felt

Rural development in Stavropol Krai: Assessment based on statistics and local perception

The article classifies rural territorial entities using the systems approach, which is based on identifying their key subsystems—natural, social, and economic. The study aims to develop and implement a procedure for creating a multi-aspect assessment range of rural development levels relying on the combined use of multivariate statistical analysis and the computational and expert comparison of objective and subjective structured information. The grouping of rural territorial entities carried out on this basis is intended to identify a pattern representing their targeted development, taking into account both the existing social and economic situation in the territory and its perception by the population. Methodological approaches to classify territorial rural units according to their level of rural development usually lack a systemic perspective and a subjective dimension to include the rural inhabitant perspectives. Using only expert opinions does not allow it to be reflected adequately enough. The comparison between the objective and subjective assessments of the natural, social, and economic conditions of rural territorial entities serves as the basis for identifying three groups of development patterns. Results were obtained through the combined application methods—cluster analysis and multidimensional scaling. The first one was used for an objective ranking of municipal districts in the region using official statistical data, while the second method was used for structuring the rural survey results. The main study result is the procedure for the multi-aspect grouping of rural areas, which enables the objective and subjective assessment of their key subsystems—economic, social, and natural—to be integrated into a single assessment tool. Its application helps establish a range of general patterns representing rural development. The study results can be used in the creation and updating of object- and subject-differentiated programs for the development of rural territorial entities

Rural development in Stavropol Krai: Assessment based on statistics and local perception

The article classifies rural territorial entities using the systems approach, which is based on identifying their key subsystems—natural, social, and economic. The study aims to develop and implement a procedure for creating a multi-aspect assessment range of rural development levels relying on the combined use of multivariate statistical analysis and the computational and expert comparison of objective and subjective structured information. The grouping of rural territorial entities carried out on this basis is intended to identify a pattern representing their targeted development, taking into account both the existing social and economic situation in the territory and its perception by the population. Methodological approaches to classify territorial rural units according to their level of rural development usually lack a systemic perspective and a subjective dimension to include the rural inhabitant perspectives. Using only expert opinions does not allow it to be reflected adequately enough. The comparison between the objective and subjective assessments of the natural, social, and economic conditions of rural territorial entities serves as the basis for identifying three groups of development patterns. Results were obtained through the combined application methods—cluster analysis and multidimensional scaling. The first one was used for an objective ranking of municipal districts in the region using official statistical data, while the second method was used for structuring the rural survey results. The main study result is the procedure for the multi-aspect grouping of rural areas, which enables the objective and subjective assessment of their key subsystems—economic, social, and natural—to be integrated into a single assessment tool. Its application helps establish a range of general patterns representing rural development. The study results can be used in the creation and updating of object- and subject-differentiated programs for the development of rural territorial entities