Choindroitinase ABC I-Mediated Enhancement of Oncolytic Virus Spread and Anti Tumor Efficacy: A Mathematical Model

Oncolytic viruses are genetically engineered viruses that are designed to kill cancer cells while doing minimal damage to normal healthy tissue. After being injected into a tumor, they infect cancer cells, multiply inside them, and when a cancer cell is killed they move on to spread and infect other cancer cells. Chondroitinase ABC (Chase-ABC) is a bacterial enzyme that can remove a major glioma ECM component, chondroitin sulfate glycosoamino glycans from proteoglycans without any deleterious effects in vivo. It has been shown that Chase-ABC treatment is able to promote the spread of the viruses, increasing the efficacy of the viral treatment. In this paper we develop a mathematical model to investigate the effect of the Chase-ABC on the treatment of glioma by oncolytic viruses (OV). We show that the model''s predictions agree with experimental results for a spherical glioma. We then use the model to test various treatment options in the heterogeneous microenvironment of the brain. The model predicts that separate injections of OV, one into the center of the tumor and another outside the tumor will result in better outcome than if the total injection is outside the tumor. In particular, the injection of the ECM-degrading enzyme (Chase-ABC) on the periphery of the main tumor core need to be administered in an optimal strategy in order to infect and eradicate the infiltrating glioma cells outside the tumor core in addition to proliferative cells in the bulk of tumor core. The model also predicts that the size of tumor satellites and distance between the primary tumor and multifocal/satellite lesions may be an important factor for the efficacy of the viral therapy with Chase treatment.     

Secondary Rhythms of Cardiac Activity in Rat Ontogeny

Endogenous periodic oscillations of the heart beat rate are described in rat pups aged 3–4, 7–8, 10–11, 13–14, 21–22 days and 1.5 month after birth. These oscillations have all characteristic features established earlier for the secondary rhythms of endogenous contractile activity in the wall of various regions of the gastrointestinal tract and for bursts of spontaneous somatomotor excitation in the early postnatal ontogeny of rats: a multi-stage organization, inconstancy, irregularity of components. In frequency spectra of secondary oscillations of the heart rate obtained by means of fast Fourier transform of R–R intervals of the periodogram, age-related changes of the spectral frequency power are demonstrated in 4 ranges, 0.01–0.03, 0.03–0.1, 0.1–1.0, and 1.0–2.5 Hz, which correspond to the about-one-minute, decasecond, and about-one-second waves of the heart rhythm oscillations and to sinus arrhythmia. It is shown that the dominating frequencies of the secondary rhythms in each range do not have regular age-related changes, which is characteristic of all endogenous secondary rhythms.     

Seasonal activity budget of adult baltic ringed seals

Although ringed seals are important components in oceanic and fresh water ecosystems at high latitudes, little is known about how they exploit these harsh environments. Seasonal activity and diving behaviour of 19 adult Baltic ringed seals were studied by satellite telemetry. We elaborated an activity budget for ten months of the year, extending over the period from moult to the breeding season. Seals from three main regions showed explicit site fidelity and the distributions of animals tagged from different areas did not overlap, suggesting separate stocks. Both the mean duration and the mean depth of dives peaked in June and July. Seals spent 70% (females) to 85% (males) of their time diving in June and July which decreased to 50% in late autumn. Less than one percent of dives exceeded 10 min in females, while 10% of male dives lasted longer than 10 min in June to September. Less than one percent of dives lasted for more than 25 min. Both females and males were most active during day time and hauled out predominantly during the night. Activity patterns during the summer are suggested to be correlated to energy accumulation and prey availability. The information on seasonal activity budget is crucial for developing population energetic models where interactions between ringed seals and other trophic levels can be evaluated.     

Cardio- and hemodynamics of dogs during the development of postischemic shock reaction

Experiments on dogs have shown that tension of peripheral capacitive vessels decreased and development of the blood deposition reaction in the venous part of the vascular bed occurred immediately after beginning of long-ischemized tissue perfusion. This leads to limitation of venous blood return to the heart, decrease of the cardiac output and development of the system hypotension. Lowering in the perfusion coronary pressure induced limitation of the coronary blood flow and inhibition of the myocardial contractility. Indicated constriction of resistive vessels and dilatation of the capacitive ones may be due to an increase of the prostacyclin and thromboxane A2 blood levels. Described disturbances achieved their maximum 3 hours later and were accompanied by arterial hypoxemia, metabolic acidosis and hypercapnia.     

Ontogenetic features of psychophysiological mechanisms of perception of speech emotional component in musically gifted children

Cerebral mechanisms of musical abilities were explored in musically gifted children. For this purpose, psychophysiological characteristics of perception of emotional speech information were experimentally studied in samples of gifted and ordinary children. Forty six schoolchildren and forty eight musicians of three age groups (7-10, 11-13 and 14-17 years old) participated in the study. In experimental session, a test sentence was presented to a subject through headphones with two emotional intonations (joy and anger) and without emotional expression. A subject had to recognize the type of emotion. His/her answers were recorded. The analysis of variance revealed age- and gender-related features of emotional recognition: boys musicians led the schoolchildren of the same age by 4-6 years in the development of mechanisms of emotional recognition, whereas girls musicians were 1-3 years ahead. Musical education in girls induced the shift of predominant activities for emotional perception in the left hemisphere; in boys, on the contrary, initial distinct dominance of the left hemisphere was not retained in the process of further education.     

Histogenesis of the taste buds of the vallate papilla in the in the rat in the postnatal stages of development

The developing taste buds of vallate papillae were studied with electron microscope in rats during the first 7 days after birth. Two types of cells--light and dark--are identified in the taste buds of a one day old animal. The apical parts of dark cells are characterized by numerous dark granules. A distinguishing feature of light cells is the presence of synaptic contacts with afferent intragemmal nerves. On the 4th day of development on the top of the apical parts of the cell, a microvillar apparatus is seen to form, which does not yet communicate with the oral cavity. On the 7th day, basal cells appear in the taste buds. Some of these cells are seen mitotically dividing. The differentiated microvillar apparatus now communicates with oral cavity. The structure of the taste buds is getting similar to that in the adults. The structural and functional peculiarities of the developing taste buds are discussed in association with the period of ontogenesis under consideration.     

Assessment of Caspian Seal By-Catch in an Illegal Fishery Using an Interview-Based Approach

The Caspian seal (Pusa caspica) has declined by more than 90% since 1900 and is listed as endangered by IUCN. We made the first quantitative assessment of Caspian seal by-catch mortality in fisheries in the north Caspian Sea by conducting semi-structured interviews in fishing communities along the coasts of Russia (Kalmykia, Dagestan), Kazakhstan and Turkmenistan. We recorded a documented minimum by-catch of 1,215 seals in the survey sample, for the 2008–2009 fishing season, 93% of which occurred in illegal sturgeon fisheries. Due to the illegal nature of the fishery, accurately quantifying total fishing effort is problematic and the survey sample could reflect less than 10% of poaching activity in the north Caspian Sea. Therefore total annual by-catch may be significantly greater than the minimum documented by the survey. The presence of high by-catch rates was supported independently by evidence of net entanglement from seal carcasses, during a mass stranding on the Kazakh coast in May 2009, where 30 of 312 carcasses were entangled in large mesh sturgeon net remnants. The documented minimum by-catch may account for 5 to 19% of annual pup production. Sturgeon poaching therefore not only represents a serious threat to Caspian sturgeon populations, but may also be having broader impacts on the Caspian Sea ecosystem by contributing to a decline in one of the ecosystem’s key predators. This study demonstrates the utility of interview-based approaches in providing rapid assessments of by-catch in illegal small-scale fisheries, which are not amenable to study by other methods.     

Ouabain is a potent promoter of growth and activator of ERK1/2 in ouabain-resistant rat renal epithelial cells

Endogenous cardiotonic steroids (ECS) are putative ligands of the inhibitory binding site of the membrane sodium pump (Na+, K+-ATPase). There is growing evidence that cardiotonic steroids may promote the growth of cardiac and vascular myocytes, including evidence indicating growth stimulation at concentrations in the same range as circulating ECS concentrations. We investigated four parameters to determine whether ouabain, a proposed ECS, promotes growth of immortalized rat proximal tubule epithelial cells: cell count by hemocytometer; metabolic activity as reflected in the mitochondrial conversion of the tetrazolium salt, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, to its formazan product (MA); DNA synthesis reflected as bromodeoxyuridine incorporation (DNA); and mitosis reflected as histone phosphorylation state detected using anti-phosphohistone 3 antibody (HP). Maximum stimulatory responses were observed at 1 nm ouabain (MA, 20.3% increase, p < 0.01; DNA, 28.4% increase, p < 0.001; HP, maximum response at 0.5 h, 50% increase, p < 0.001). We observed that growth stimulation was associated with stimulation of ERK1/2 phosphorylation (ERK-P), and both growth and ERK-P could be blocked by the MEK inhibitor (U0126, 100 nm). Western blot analysis revealed that the only alpha isoform of Na+, K+-ATPase that could be detected in these cultures was the highly ouabain-resistant alpha1 isoform. Measurement of ouabain inhibition of ion transport in these cultures using 86Rb+ uptake revealed the predominance of the expected ouabain-resistant isoform (IC50 = 24 microm) and an additional minor ( approximately 15%) ouabain-sensitive inhibition with IC50 approximately 30 pm. Similar bimodal transport inhibition curves were obtained in freshly dissected rat proximal tubules. These results indicate that renal epithelial cells may be a sensitive target of the ERK1/2-activating and growth-promoting effects of ouabain even in the presence of ouabain-resistant Na+, K+-ATPase.     

Comparative study of the brain of developed and underdeveloped neonatal rodents of the Muridae family

Morphological studies have been made of the neocortical and archicortical structures in the spiny mouse Acomys cahirinus, the only maturely born species from the family Muridae. The data obtained reveal highly developed hippocampus as compared to the neocortex in this mouse, in contrast to relationships found in other mice and rats.