Oxidative stress inhibits the mitochondrial import of preproteins and leads to their degradation

The mitochondrion depends upon the import of cytosolically synthesized preproteins for most of the proteins that comprise its structural elements and metabolic pathways. Here we have examined the influence of redox conditions on mitochondrial preprotein import and processing by mammalian mitochondria. Paraquat pretreatment of isolated mitochondria inhibited the subsequent import preornithine transcarbamylase (pOTC) in vitro. In intact cells oxidizing conditions led to decreased levels of mature OTC and accumulation of its preprotein. Implicating a mitochondrial import lesion, the fluorescence of pOTC-GFP (a protein in which the presequence of pOTC was fused to green fluorescent protein) transfected cells was decreased by paraquat treatment while cytosolic wild-type GFP remained largely unaffected. The accumulation of preproteins was enhanced by proteasome inhibitors. We observed that precursor proteins that failed to be imported, due to oxidizing conditions or an intrinsically slower import rate, are susceptible to degradation. Inhibition of the proteasome was also found to lead to higher levels of the translocase outer membrane protein 20 (Tom20) and to the perinuclear accumulation of mitochondria. These studies indicate that cellular redox conditions influence mitochondrial import, which, in turn, affects mitochondrial protein levels. A role for the proteasome in this process and in general mitochondrial function was also indicated.     

Correction of the stomach blood flow as a mechanism of anti-ulcer effects of short proline-containing peptides

Intraperitoneal administration of the PGP did not change basal mucosal blood flow, whereas the PG and GP significantly decreased it. Ethanol and Indomethacin caused a rapid and stable decrease in the blood flow. Administration of the PGP prior to ethanol abolished this effect. Injections of the PGP and PG following Indomethacin administration prevented reduction of the mucosal blood flow. Administration of the GP did not change the blood flow decrease induced with Indomethacin. The mucosal blood flow correction seems to be one of the possible mechanisms of the PGP and PG antiulcer effect. The effect seems to be realised through a change in the CNS activity.     

Studies of the impurity pellet ablation in the high-temperature plasma of magnetic confinement devices

The ablation of impurity pellets in tokamak and stellarator plasmas is investigated. Different mechanisms for shielding the heat fluxes from the surrounding plasma to the pellet surface are discussed. A model for impurity pellet ablation is developed that can account for both neutral and electrostatic shielding. It is shown that the experimental values of the impurity pellet ablation rate are well described by the neutral gas shielding model over a wide range of plasma temperatures and densities. Taking into account the electrostatic shielding leads to worse agreement between the predictions of the model and the experimental data; this result still remains unclear. Scaling laws are obtained that allow one to estimate the local ablation rate of impurity pellets made of various materials over a wide range of plasma parameters in the neutral gas shielding model.     

The role of the cardiac-pulmonary blood volume in the changes in left ventricle output during stimulation of the afferent fibers of somatic nerves

Stimulation of tibial nerve afferent fibers has revealed heterogeneous shifts of left ventricular output, as well as pulmonary artery and posterior vena cava blood flow in anesthetized cats. Uniform changes in left ventricular output and pulmonary artery blood flow were noted in the majority of cases, with venous return most often exceeding pulmonary artery blood flow. beta-adrenoreceptor blockade failed to influence changes in pulmonary artery blood flow. It is concluded that the increase in pulmonary artery blood flow depends on the rise in venous return, but not on neurogenic influence upon the right ventricle. The reduction in left ventricular output is the result of decreased right ventricular outflow due to its overload caused by pulmonary vasoconstriction.     

The Route of HIV Escape from Immune Response Targeting Multiple Sites Is Determined by the Cost-Benefit Tradeoff of Escape Mutations

Cytotoxic T lymphocytes (CTL) are a major factor in the control of HIV replication. CTL arise in acute infection, causing escape mutations to spread rapidly through the population of infected cells. As a result, the virus develops partial resistance to the immune response. The factors controlling the order of mutating epitope sites are currently unknown and would provide a valuable tool for predicting conserved epitopes. In this work, we adapt a well-established mathematical model of HIV evolution under dynamical selection pressure from multiple CTL clones to include partial impairment of CTL recognition, , as well as cost to viral replication, . The process of escape is described in terms of the cost-benefit tradeoff of escape mutations and predicts a trajectory in the cost-benefit plane connecting sequentially escaped sites, which moves from high recognition loss/low fitness cost to low recognition loss/high fitness cost and has a larger slope for early escapes than for late escapes. The slope of the trajectory offers an interpretation of positive correlation between fitness costs and HLA binding impairment to HLA-A molecules and a protective subset of HLA-B molecules that was observed for clinically relevant escape mutations in the Pol gene. We estimate the value of from published experimental studies to be in the range (0.01–0.86) and show that the assumption of complete recognition loss () leads to an overestimate of mutation cost. Our analysis offers a consistent interpretation of the commonly observed pattern of escape, in which several escape mutations are observed transiently in an epitope. This non-nested pattern is a combined effect of temporal changes in selection pressure and partial recognition loss. We conclude that partial recognition loss is as important as fitness loss for predicting the order of escapes and, ultimately, for predicting conserved epitopes that can be targeted by vaccines.     

Analysis of geographic centrality and genetic diversity in the declining grasshopper species Bryodemella tuberculata (Orthoptera: Oedipodinae)

Human-induced ecological and climatic changes have led to the decline and even local extinction of many formerly widely distributed temperate and cold-adapted species. Determining the exact causes of this decline remains difficult. Bryodemella tuberculata was a widely distributed orthopteran species before the mid-19th century. Since then, many European populations have suffered drastic declines and are now considered extinct or critically endangered. We used ecological niche modelling based on a large dataset of extant and extinct occurrence data to investigate whether poor climatic suitability in the periphery of its global range was a possible cause of the local extinction of the European populations of B. tuberculata. We also used population genetics based on the COI marker to estimate and compare the genetic diversity of extant populations. We found that Europe still provides highly suitable habitats close to the climatic optimum, contradicting the assumption of climate change as major driver of this decline. Instead, changes in land-cover and other anthropogenic modifications of the habitats at the local scale seem to be the major reasons for local extinctions. Genetic analysis suggests Central Asia as center of diversity with a stable population size, whereas the effective sizes of the remaining European populations are decreasing. We found European genetic lineages nested within Central Asian lineages, suggesting a Central Asian source distribution area. Our results suggest that the declining European populations represent relics of a formerly wider distribution, which was fragmented by changes in land-use. These relics are now threatened by limited connectivity and small effective population sizes. Specific conservation actions, such as the restoration of former or potential new habitats, and translocation of individuals from extant populations to these restored sites may help slow, stall, or even revert the extinction process.