Modeling hematopoietic system response caused by chronic exposure to ionizing radiation

A new model of the hematopoietic system response in humans chronically exposed to ionizing radiation describes the dynamics of the hematopoietic stem cell compartment as well as the dynamics of each of the four blood cell types (lymphocytes, neutrophiles, erythrocytes, and platelets). The required model parameters were estimated based on available results of human and experimental animal studies. They include the steady-state number of hematopoietic stem cells and peripheral blood cell lines in an unexposed organism, amplification parameters for each blood line, parameters describing proliferation and apoptosis, parameters of feedback functions regulating the steady-state numbers, and characteristics of radiosensitivity related to cell death and non-lethal cell damage. The model predictions were tested using data on hematological measurements (e.g., blood counts) performed in 1950–1956 in the Techa River residents chronically exposed to ionizing radiation since 1949. The suggested model of hematopoiesis is capable of describing experimental findings in the Techa River Cohort, including: (1) slopes of the dose–effect curves reflecting the inhibition of hematopoiesis due to chronic ionizing radiation, (2) delay in effect of chronic exposure and accumulated character of the effect, and (3) dose-rate patterns for different cytopenic states (e.g., leukopenia, thrombocytopenia).     

Is a compromise possible in Russia between animal advocates and researchers who use animals in harmful experiments?

The current situation relating to the use of laboratory animals in Russia, which is primarily characterised by the complete absence of legislation for their protection, is examined and discussed. This lack of regulation causes well-founded protests by animal protection organisations and a number of reputable politicians. It also has a negative influence on the quality of medical and biological research results that are obtained through the use of experimental animals in Russia. The opinion is expressed that the Russian scientific community should be able to build upon the experience of other countries - in particular, members of the European Union, where there is an effective system of self-control over the ethical and legislative regulation of animal-based research. It is suggested that, in Russia, the basic animal protection principles of the Three Rs should be introduced, when the decision on whether to finance scientific projects involving the use of animals is being made.     

Ligand displaces heat shock protein 90 from overlapping binding sites within the aryl hydrocarbon receptor ligand-binding domain

Hsp90 (heat shock protein of 90 kDa) is often found associated with functional domains of client proteins, including those for ligand binding, dimerization, DNA binding, and enzymatic activity. Although Hsp90 can maintain the conformation of functionally important domains prior to activation of the client protein, its specific binding site and the mechanism(s) of Hsp90 dissociation during activation are unknown. Here, we have identified and characterized residues involved in Hsp90 binding within the aryl hydrocarbon receptor (AhR) ligand-binding domain and demonstrate that they overlap with those involved in ligand binding. In agreement with this spatial model, ligand binding results in Hsp90 dissociation from the AhR Per-ARNT-Sim B fragment. Interestingly, whereas Hsp90-binding residues within the ligand-binding domain were not involved in Hsp90-dependent AhR protein stability, several of these residues are important for ligand-dependent AhR activation, and their mutation resulted in conversion of two AhR antagonists/partial agonists into full AhR agonists. These studies reveal co-localization of a tentative Hsp90-binding site with that for AhR ligand binding and provide the first molecular mechanism for Hsp90 dissociation in the activation of a client protein.     

Amperometric biosensors for detection of phenol using chemically modified electrodes containing immobilized bacteria

Eight strains of Pseudomonas were studied for development of phenol sensor. The immobilization of cells was performed by absorbing them on the working part of mediator-modified screen-printed electrodes (SPEs). Only three Pseudomonas strains were able to transfer electrons resulting from specific oxidation of phenol to the electrode by means of mediators; ferrocene, duroquinone and dimethyferrocene were successfully used with the strains 394 (p20), 74-III and 83-IV (working names), respectively. The lower limits for detection of phenol were 1 micro M for the strain 74-III and 10 micro M for the strain 83-IV and 394 (p20). Calibrations were obtained as the dependencies of logarithm of current changes (log deltaI) on logarithm of concentration (logC), log delta I vs. logC. Among all substrates tested (phenol, catechol, hydroquinone, ethanol, methanol, propanol, isopropanol, isobutanol, isoamylalcohol, acetate, glucose, xylose, vanillin, 2,4,6-trichlorphenol, 2,3,6-trichlorphenol, 4-hydroxy-3-methoxybenzoic acid, coumarin, pentafluorophenol), bacterial sensor demonstrated a good selectivity with respect to phenol and lower responses to catechol and hydroquinone (10-times lower). The dependence of signals on operating conditions was studied. The biosensor should be used during the day of preparation. The operational stability was satisfactory to perform up to 10 consecutive measurements. Low cost and very simple manufacturing procedure allow for bacterial sensor to be applied as disposable devices.     

The Last Frontier: Catch Records of White Sharks (Carcharodon carcharias) in the Northwest Pacific Ocean

White sharks are highly migratory apex predators, globally distributed in temperate, sub-tropical, and tropical waters. Knowledge of white shark biology and ecology has increased recently based on research at known aggregation sites in the Indian, Atlantic, and Northeast Pacific Oceans; however, few data are available for the Northwest Pacific Ocean. This study provides a meta-analysis of 240 observations of white sharks from the Northwest Pacific Ocean between 1951 and 2012. Records comprise reports of bycatch in commercial fisheries, media accounts, personal communications, and documentation of shark-human interactions from Russia (n = 8), Republic of Korea (22), Japan (129), China (32), Taiwan (45), Philippines (1) and Vietnam (3). Observations occurred in all months, excluding October-January in the north (Russia and Republic of Korea) and July-August in the south (China, Taiwan, Philippines, and Vietnam). Population trend analysis indicated that the relative abundance of white sharks in the region has remained relatively stable, but parameterization of a 75% increase in observer effort found evidence of a minor decline since 2002. Reliably measured sharks ranged from 126–602 cm total length (TL) and 16–2530 kg total weight. The largest shark in this study (602 cm TL) represents the largest measured shark on record worldwide. For all countries combined the sex ratio was non-significantly biased towards females (1∶1.1; n = 113). Of 60 females examined, 11 were confirmed pregnant ranging from the beginning stages of pregnancy (egg cases) to near term (140 cm TL embryos). On average, 6.0±2.2 embryos were found per litter (maximum of 10) and gestation period was estimated to be 20 months. These observations confirm that white sharks are present in the Northwest Pacific Ocean year-round. While acknowledging the difficulties of studying little known populations of a naturally low abundance species, these results highlight the need for dedicated research to inform regional conservation and management planning.     

Formulation of the Microbicide INP0341 for In Vivo Protection against a Vaginal Challenge by Chlamydia trachomatis

The salicylidene acylhydrazide (SA) compounds have exhibited promising microbicidal properties. Previous reports have shown the SA compounds, using cell cultures, to exhibit activity against Chlamydia trachomatis, herpes simplex virus and HIV-1. In addition, using an animal model of a vaginal infection the SA compound INP0341, when dissolved in a liquid, was able to significantly protect mice from a vaginal infection with C. trachomatis. To expand upon this finding, in this report INP0341 was formulated as a vaginal gel, suitable for use in humans. Gelling agents (polymers) with inherent antimicrobial properties were chosen to maximize the total antimicrobial effect of the gel. In vitro formulation work generated a gel with suitable rheology and sustained drug release. A formulation containing 1 mM INP0341, 1.6 wt% Cremophor ELP (solubility enhancer) and 1.5 wt% poly(acrylic acid) (gelling and antimicrobial agent), was chosen for studies of efficacy and toxicity using a mouse model of a vaginal infection. The gel formulation was able to attenuate a vaginal challenge with C. trachomatis, serovar D. Formulations with and without INP0341 afforded protection, but the inclusion of INP0341 increased the protection. Mouse vaginal tissue treated with the formulation showed no indication of gel toxicity. The lack of toxicity was confirmed by in vitro assays using EpiVaginal tissues, which showed that a 24 h exposure to the gel formulation did not decrease the cell viability or the barrier function of the tissue. Therefore, the gel formulation described here appears to be a promising vaginal microbicide to prevent a C. trachomatis infection with the potential to be expanded to other sexually transmitted diseases.     

Post-translational modifications in MeHg-induced neurotoxicity

Mercury (Hg) exposure remains a major public health concern due to its widespread distribution in the environment. Organic mercurials, such as MeHg, have been extensively investigated especially because of their congenital effects. In this context, studies on the molecular mechanism of MeHg-induced neurotoxicity are pivotal to the understanding of its toxic effects and the development of preventive measures. Post-translational modifications (PTMs) of proteins, such as phosphorylation, ubiquitination, and acetylation are essential for the proper function of proteins and play important roles in the regulation of cellular homeostasis. The rapid and transient nature of many PTMs allows efficient signal transduction in response to stress. This review summarizes the current knowledge of PTMs in MeHg-induced neurotoxicity, including the most commonly PTMs, as well as PTMs induced by oxidative stress and PTMs of antioxidant proteins. Though PTMs represent an important molecular mechanism for maintaining cellular homeostasis and are involved in the neurotoxic effects of MeHg, we are far from understanding the complete picture on their role, and further research is warranted to increase our knowledge of PTMs in MeHg-induced neurotoxicity.