Unsupervised learning of aging principles from longitudinal data.

Age is the leading risk factor for prevalent diseases and death. However, the relation between age-related physiological changes and lifespan is poorly understood. We combined analytical and machine learning tools to describe the aging process in large sets of longitudinal measurements.

Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis.

CLN7 neuronal ceroid lipofuscinosis is an inherited lysosomal storage neurodegenerative disease highly prevalent in children. CLN7/MFSD8 gene encodes a lysosomal membrane glycoprotein, but the biochemical processes affected by CLN7-loss of function are unexplored thus preventing development of potential treatments. Here, we found, in the Cln7 mouse model of CLN7 disease, that failure in autophagy causes accumulation of structurally and bioenergetically impaired neuronal mitochondria.

Targeting PFKFB3 alleviates cerebral ischemia-reperfusion injury in mice.

The glycolytic rate in neurons is low in order to allow glucose to be metabolized through the pentose-phosphate pathway (PPP), which regenerates NADPH to preserve the glutathione redox status and survival. This is controlled by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3), the pro-glycolytic enzyme that forms fructose-2,6-bisphosphate, a powerful allosteric activator of 6-phosphofructo-1-kinase. In neurons, PFKFB3 protein is physiologically inactive due to its proteasomal degradation.

New Fluorescent Reporter Systems for Evaluation of the Expression of E- and N-Cadherins.

During metastatic growth, cells of solid tumors undergo phenotypical changes related to epithelial-mesenchymal transition. Epithelial-mesenchymal transition is regarded as a potential target for prospective antitumor drugs. Fluorescent reporter systems for evaluation of the expression of markers of epithelial and mesenchymal status (E- and N-cadherins) were created.

The Use of Human Liver Cell Model and Cytochrome P450 Substrate-Inhibitor Panel for Studies of Dasatinib and Warfarin Interactions.

The possibility of interactions between warfarin and dasatinib and their interactions with other drugs metabolized by cytochrome P450 isoform CYP3A4 was demonstrated using a previously created cytochrome P450 substrate-inhibitor panel for preclinical in vitro studies of drug biotransformation on a 3D histotypical microfluidic cell model of human liver (liver-on-a-chip technology). Dasatinib and warfarin are inhibitors of CYP2C19 isoform and hence, can interfere the drugs metabolized by this isoform. Our findings are in line with the data obtained on primary culture of human hepatocytes and suggest that the model can be used in preclinical in vitro studies of drugs.

Development of a Specific Substrate-Inhibitor Panel (Liver-on-a-Chip) for Evaluation of Cytochrome P450 Activity.

We developed a cytochrome P450 substrate-inhibitor panel for preclinical in vitro evaluation of drugs in a 3D histotypical microfluidic cell model of human liver (liver-on-a-chip technology). The concentrations of substrates and inhibitors were optimized to ensure reliable detection of the principal metabolites by HPLC-mass-spectroscopy. The selected specific substrate-inhibitor pairs, namely bupropion/2-phenyl-2-(1-piperidinyl)propane) for evaluation of CYP2B6B activity, tolbutamide/sulfaphenazole for CYP2C9, omeprazole/(+)-N-benzylnirvanol for CYP2C19, and testosterone/ketoconazole for CYP3A4, enable reliable evaluation of the drug metabolism pathway.

Effect of Circulation Parameters on Functional Status of HepaRG Spheroids Cultured in Microbioreactor.

We studied the relationship between microcirculation parameters and functional status of HepaRG cells in spheroids and chose an optimal regimen within the physiologically permissible limits of mechanical impact for the cells that maintains the expression of functional genes of the liver.

Maintenance of High Cytochrome P450 Expression in HepaRG Cell Spheroids in DMSO-Free Medium.

We studied the effects of DMSO and fibroblasts during HepaRG cell spheroid formation and conditions of their subsequent culturing on the levels of mRNA of the major cytochromes P450. A protocol of spheroid formation from differentiated HepaRG cells and their culturing in serum- and DMSO-free medium is developed.

The abietane diterpenoid parvifloron D from Plectranthus ecklonii is a potent apoptotic inducer in human leukemia cells.

Background: Abietane diterpenes have attracted much attention because they display a wide range of biological activities, including antitumor activities. These compounds are the most diverse of the diterpenoids isolated from species of Plectranthus. Naturally occurring diterpene parvifloron D is the main phytochemical constituent of Plectranthus ecklonii.

Synthesis and effects on cell viability of flavonols and 3-methyl ether derivatives on human leukemia cells.

Flavonoids are polyphenolic compounds which display an array of biological activities and are considered potential antitumor agents. Here we evaluated the antiproliferative activity of selected synthetic flavonoids against human leukemia cell lines. We found that 4'-bromoflavonol (flavonol 3) was the most potent.

[Methodic approaches to evaluation of microclimate at workplace, with application of various types of protective clothing against occupational hazards].

Studies of heat state of human involved into physical work in heating environment and having various protective clothing on demonstrated value of the protective clothing in modifying thermal load on the body and possible decrease of this load through air temperature and humidity correction, shorter stay at workplace. The authors presented hygienic requirements to air temperatures range in accordance with allowable body heating degree, suggested mathematic model to forecast integral parameter of human functional state in accordance with type of protective clothing applied. The article also covers necessity of upper air temperature limit during hot season, for applying protective clothing made of materials with low air permeability and hydraulic conductivity.

[Occupational microclimate. Results and prospects of research].

The article covers results of studies conducted over last 15 years and aimed to elaboration of requirements to integral parameters of microclimate at workplace, its evaluation and regulation, prophylactic measures against body overcooling and overheating. The authors present methods to evaluate combined effects of physical factors (noise, vibration, microclimate) and to assess microclimate with consideration of factors determining body thermal load (energy expenditure, duration of stay at workplace, heat insulation of clothes and thermo-physical parameters of its materials). Mathematic models of forecasting cold and heat stress are presented, as well as requirements to heat insulation for individual protective means against cold and methods to calculate it.

Antiproliferative activity of abietane diterpenoids against human tumor cells.

In the present study, the cytotoxicity of 30 diterpenoids with an abietane or a halimane skeleton was determined against five human tumor cell lines (HL-60, U937, Molt-3, SK-MEL-1, and MCF-7). Diterpenoids containing an abietane skeleton including taxodone (1) and taxodione (2), as well as the semisynthetic derivatives 12, 14, 15, 17, and 22, were the most cytotoxic compounds for human leukemia cells. Overexpression of the protective mitochondrial proteins Bcl-2 and Bcl-x(L) did not confer resistance to abietane diterpene-induced cytotoxicity.

Astragalin heptaacetate-induced cell death in human leukemia cells is dependent on caspases and activates the MAPK pathway.

Flavonoids are naturally occurring polyphenolic compounds and are among the most promising anticancer agents. Here we demonstrate that the flavonoid derivative astragalin heptaacetate (AHA) induces cell death. This was prevented by the non-specific caspase inhibitors z-VAD-fmk and Q-VD-OPH, and reduced by the selective caspase-4 inhibitor z-LEVD-fmk.

[Isolation and properties of cysteine protease from Serratia proteamaculans 94].

A new cysteine protease (SpCP) with a molecular mass of about 50 kDa and optimal functioning at pH 8.0 was isolated from the culture medium of a Serratia proteamaculans 94 psychrotolerant strain using affinity and gel permeation chromatography. The enzyme N terminal amino acid sequence (SPVEEAEGDGIVLDV-) exhibits a reliable similarity to N terminal sequences of gingipains R, cysteine proteases from Polphyromonas gingivalis.

MicroRNA in schizophrenia: genetic and expression analysis of miR-130b (22q11).

MicroRNAs (miRNAs) are a class of small regulatory RNAs that control a level of expression of protein encoding genes. Their role in brain pathologies is unknown. We made a first attempt to carry out a genetic study coupled with gene expression analysis of microRNA in human neuropsychiatric pathology.

[Physiologic and hygienic principles underlying creation of clothes protecting against cold].

The article presents principles underlying creation of clothes protecting against cold, in accordance with specific usage conditions (ambient air temperature and speed, ergonomic traits and metabolic level of work, duration of cold exposure). The authors listed requirements to thermal protection of clothes and to separate entities (hat, gloves, shoes) in relation to various climate regions. Major steps of creation and evaluation of the clothes are demonstrated.

[Method evaluating heat isolation for individual device suit designed to protect workers from coldness].

Based on results of personal research and of foreign studies, the authors present a method to calculate heat isolation for individual protective means set necessary for human heat state preservation in real working conditions. The method includes surface temperature measurements with consideration of cooling degree and energy consumption, calculation of separate elements of heat balance and density of "net" heat flow in correlation with cooling duration. Calculating heat isolation, the authors considered influence of wind speed on its value and air-resistance of outer clothing.

[Comparative evaluation of methods accepted by Russian and international standards to assess total resistance of special cold-proof clothing set].

Experimental studies helped to compare methods determining and calculating total heat resistance of clothing sets accepted by Russian and international standards. Findings are that difference in the total heat resistance values calculated on humans and on dummies in relatively still air and quiet conditions is caused by measurement technique applied. Significant difference in the total heat resistance values calculated in windy conditions or during walk require further research aimed to study influence of those factors on clothes' heat resistance.

[Cold stress and its prophylaxis].

The authors present criteria of cold stress and their relationships with thermoregulatory strain, ability to work and some health state parameters. Findings are unfavorable influence of human cooling and adaptation to cold on vibration disease development. The article covers requirements to heat-proof properties of clothing set, to duration of exposure to cold in various climate areas of Russian Federation.

[Physiological-occupational requirements with reference to clothes protecting workers from low temperature and methods for the evaluation of heat insulation].

The authors specified a method regulating clothes production in accordance with physiologic and hygienic requirements that result from particular utilization conditions (ambient temperature, motion speed, energy expenditure, duration of exposure to cold). The article represents criteria for allowable heat state of human, requirements to heat insulation of clothes set and items (hat, mittens, and shoes) for various climate areas, for allowable duration of exposure to cold.

Determination of heat loss from the feet and insulation of the footwear.

This study compared the methods of determining the footwear insulation on human participants and the thermal foot model. Another purpose was to find the minimal number of measurement points on the human foot that is needed for insulation calculation. Bare foot was tested at 3 ambient temperatures on 6 participants.

[The evaluation of skin temperature points and heat flow in the area of the foot for the measurement of the footwear heat insulation].

Analyzing results of the personal experiments, the authors present methodology to minimize number of sites for measurement of foot skin temperature and heat flow. Average foot temperature could be reliably measured through one or several sites. The studies revealed informativeness of each among 11 measurement sites and helped to specify corresponding equations for evaluation of foot heat conditions and heat insulation.