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The review is devoted to unsolvable problems of biology. 1) Problems unsolvable due to stochastic mutations occurring during DNA replication that make it impossible to create two identical organisms or even two identical complex cells (Sverdlov, E. D. (2009) Biochemistry (Moscow), 74, 939–944) and to “defeat” cancer. 2) Problems unsolvable due to multiple interactions in complex systems leading to the appearance of unpredictable emergent properties that prevent establishment of unambiguous relationships between the genetic architecture and phenotypic manifestation of the genome and make impossible to predict with certainty responses of the organism, its parts, or pathological processes to external factors. 3) Problems unsolvable because of the uncertainty principle and observer effect in biology, due to which it is impossible to obtain adequate information about cells in their tissue microenvironment by isolating and analyzing individual cells. In particular, we cannot draw conclusions on the properties of stem cells in their niches based on the properties of stem cell cultures. A strategy is proposed for constructing the pattern most closely approximated to the relationship of genotypes with their phenotypes by designing networks of intermediate phenotypes (endophenotypes).

Multifunctional activity of the PDX1 gene product is reviewed. The PDX1 protein is unique in that being expressed exclusively in the pancreas it exhibits various functional activities in this organ both during embryonic development and during induction and progression of pancreatic cancer. Hence, PDX1 belongs to the family of master regulators with multiple and often antagonistic functions.

AbstractThe mechanisms of excitation of low-frequency unstable combustion of a methane–air mixture in full-scale low-emission combustors are experimentally studied. Experimental investigations of the flow characteristics without combustion in low-emission combustors shows that the central zone of reverse flows can serve as a source of regular hydrodynamic pressure oscillations in a wide range of flow regimes. A model of low-frequency unstable combustion is proposed. The model is based on hydrodynamic instability of the flow in the central zone of reverse flows, which can excite low-frequency regimes of unstable combustion. Methods for suppressing thermohydrodynamic instability of combustion are developed. Based on the proposed model and with the use of methods that ensure suppression of combustion instability, a low-emission combustor with a stable process of combustion in the entire range of its operation conditions is created and tested, which confirms the feasibility of the proposed approach.

Here, we put forward the hypothesis on the mechanism of functioning of cancer stem cells, provided that they exist. The hypothesis is based on the following postulates. 1) Paracrine exchange between cancer and stromal cells is efficient only if they are in a close contact and form a synapse-like cleft between them for the cell–cell crosstalk. The concentration of paracrine signaling molecules in the cleft is high because of the cleft small volume. 2) Cancer stem cells per se do not exist. Instead, there are cancer stem complexes formed by cancer cells tightly bound to stromal cells (portable niches) that exchange paracrine signals. 3) Cancer stem complex is a complex system with newly emerged properties, such as a stemness and resistance to external impacts, including therapeutic interventions. 4) The stemness manifests itself as the ability of cancer cells within the complex to divide asymmetrically: one daughter cell remains in the complex forming a renewed stem complex, whereas the other daughter cell detaches from the complex and transforms in a non-stem cell capable of differentiation. 5) An increased resistance of a cancer stem complex is due to the integration of its intrinsic defense systems through the exchange of paracrine signals, i.e., represents a microresistance at the cell level. 6) Cancer stem complexes can stochastically dissociate with the formation of non-stem cancer cells. Partially differentiated non-stem cancer cells are able to stochastically bind to the stromal component, dedifferentiate under the action of paracrine signals, and form new cancer stem complexes. Therefore, a tumor is a flexible system existing in the pseudo-equilibrium state. Such systems comply with the Le Chatelier’s principle stating that an equilibrium system under the action of external factors activates the processes antagonistic to the changes (homeostasis). This promotes tumor resistance at the level of cell populations, i.e., the macroresistance. 7) The portable niche travels with the cancer cell during metastasis. We propose a general therapeutic strategy targeting the contacts between cancer and stromal cells. The disruption of these contacts should lead to the destruction of cancer stem complexes and elimination of tumors.

AbstractThis paper presents an analysis of the hydrodynamic and physicochemical characteristics of flow and combustion in a low-emission combustor (LEC) that differs from other combustors in design and lean fuel–air combustion modes. The influence of the composition and residence time of the mixture in the LEC on NO\\(_x\\) and CO emissions is considered. A LEC operation concept and demonstrator have been developed that provide NO\\(_x\\) and CO emissions below 5 ppm, which is 2–5 times lower than that in available LECs. The results of experimental studies of the LEC demonstrator with varying flame temperature, pressure, and residence time in the LEC confirm the validity of the proposed solutions.

Stimulation of BxPC-3, Panc-1, and MIA PaCA-2 pancreatic cancer cells with EGF, HGF, FGF-1, FGF-2, FGF-7, and FGF-10 growth factors caused changes in the expression of master genes regulating pancreatic development (SOX9, HNF3b, GATA-4, GATA-6, and HES1). This, in turn, caused changes in the expression profile of important transcription factors, embryonic development regulators. It was also found that the master genes belonging to the same family may cause opposite effects (suppression or enhancement of expression of a particular transcriptional regulator) in the same cell line.

A new and highly effective method, termed suppression subtractive hybridization (SSH), has been developed for the generation of subtracted cDNA libraries. It is based primarily on a recently described technique called suppression PCR and combines normalization and subtraction in a single procedure. The normalization step equalizes the abundance of cDNAs within the target population and the subtraction step excludes the common sequences between the target and driver populations. In a model system, the SSH technique enriched for rare sequences over 1,000-fold in one round of subtractive hybridization. We demonstrate its usefulness by generating a testis-specific cDNA library and by using the subtracted cDNA mixture as a hybridization probe to identify homologous sequnces in a human Y chromosome cosmid library. The human DNA inserts in the isolated cosmids were further confirmed to be expressed in a testis-specific manner. These results suggest that the SSH technique is applicable to many molecular genetic and positional cloning studies for the identification of disease, developmental, tissue-specific, or other differentially expressed genes.

The fibroblast activation protein (FAP) is selectively expressed in cancer-associated fibroblasts (CAFs) and facilitates tumor progression, which makes this protein an attractive therapeutic target. There are difficulties in obtaining CAFs for studying the function and suppression of FAP. In this work, the expression level of FAP was determined by PCR assay in 25 human cell lines and 8 surgical samples of tumor stroma. The expression of FAP was observed in all tumor stroma samples and in four cell lines: NGP-127, SJCRH30, SJSA-1, and A375. The level of FAP expression in NGP-127, SJCRH30, and SJSA-1 lines as well as in CAFs of patients was comparable, which makes these cell lines a possible model for studying FAP.

We show characteristic morphological changes corresponding to epithelial–mesenchymal transition (EMT) program fulfillment in PANC1 cell line stimulated with TGFβ1. Our results support downregulation of E-cadherin protein. We show 5- and 28-fold increase in SNAI1 and SNAI2 expression levels and 25- and 15-fold decrease in CDH1 and KRT8 expression levels, respectively, which confirms the EMT-program fulfillment. We demonstrate downregulation of expression of pancreatic master genes SOX9 , FOXA2 , and GATA4 (2-, 5-, and 4-fold, respectively) and absence of significant changes in HES1, NR5A2 , and GATA6 expression levels in the cells stimulated with TGFβ1. Our results indicate the absence of induction of expression of PTF1A, PDX1, HNF1b, NEUROG3, RPBJL, NKX6.1 , and ONECUT1 genes, which are inactive in PANC1 cell line after the EMT stimulated by TGFβ1.

We sequenced 1500-bp genomic DNA regions upstream from the survivin gene (BIRC5). DNA was isolated from human placenta and tumors of patients with diagnosed squamous cancer of the lung that showed high-level BIRC5 gene expression. We have revealed four new promoter allelic variants differing in single nucleotide substitutions, one variant with two nucleotide substitutions, and a variant with a TAAA tetranucleotide insertion. All promoter variants displayed low activity in cells with functionally active p53 protein and high activity in cell lines characterized by low level or absence of p53 protein function. The activity of the promoters with single nucleotide substitutions was comparable to that of the wild-type promoter, whereas two nucleotide substitutions markedly reduced the activity. We also demonstrated the functional significance of a putative Sp1 transcription factor-binding site at (-63...-54) upstream from the transcription initiation site. Mutation within this sequence led to a sharp decrease of promoter activity. The functional architecture of the survivin promoter is discussed based on results known from the literature and those obtained here.