Hydrogen bonding analysis of phosphoric acid–N,N-dimethylformamide mixtures

Crizotinib is the most effective and the only drug that has been approved for the treatment of anaplastic lymphoma kinase (ALK)-positive lung cancer. Reports suggest that there is a development of an acquired resistance against crizotinib action due to the emergence of several mutations in the ALK gene and F1174L is one such mutation. In this study, we used molecular docking and molecular dynamics (MD) approach to decipher the effect of F1174L mutation in drug–target binding. Docking results suggest that crizotinib was found to adopt the most promising conformations to the native-type ALK by identifying the M1199 residue as a prospective partner for making a hydrogen bond as compared to the mutant-type ALK. MD results showed that the average atom, especially atoms of the native-type ALK-crizotinib complex, movements were less, displayed less fluctuation, fast convergence of energy, and changes in geometry. This shows the stable binding of crizotinib with the native-type ALK in comparison to the mutant-type ALK. We believe that this study could be useful for the logical design of stronger, more selective, and more consistent ALK inhibitor against drug-resistant F1174L mutation.     

Targeting c-Met Receptor Overcomes TRAIL-Resistance in Brain Tumors

Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) induced apoptosis specifically in tumor cells. However, with approximately half of all known tumor lines being resistant to TRAIL, the identification of TRAIL sensitizers and their mechanism of action become critical to broadly use TRAIL as a therapeutic agent. In this study, we explored whether c-Met protein contributes to TRAIL sensitivity. We found a direct correlation between the c-Met expression level and TRAIL resistance. We show that the knock down c-Met protein, but not inhibition, sensitized brain tumor cells to TRAIL-mediated apoptosis by interrupting the interaction between c-Met and TRAIL cognate death receptor (DR) 5. This interruption greatly induces the formation of death-inducing signaling complex (DISC) and subsequent downstream apoptosis signaling. Using intracranially implanted brain tumor cells and stem cell (SC) lines engineered with different combinations of fluorescent and bioluminescent proteins, we show that SC expressing a potent and secretable TRAIL (S-TRAIL) have a significant anti-tumor effect in mice bearing c-Met knock down of TRAIL-resistant brain tumors. To our best knowledge, this is the first study that demonstrates c-Met contributes to TRAIL sensitivity of brain tumor cells and has implications for developing effective therapies for brain tumor patients.     

Effect of additional disease (Comorbidity) on association of allergic rhinitis with KCNE4 gene rs12621643 variant

Analysis of association of allergic rhinitis with the KCNE4 gene rs12621643 variant was conducted in Russian residents of West Siberia (taking into account comorbidity with bronchial asthma). It was found that, among individuals without bronchial asthma, the frequencies of the KCNE4*G allele and KCNE4*G/G genotype are significantly higher in patients with rhinitis compared to individuals without it. At the same time, no association of rs12621643 with rhinitis was detected in the group of individuals with bronchial asthma. The data obtained indicate the association of the KCNE4 gene variability with allergic rhinitis, although the effect of this gene relative to the development of the disease can be leveled against a background of the manifestation of another atopic disease.     

The effect of neurospecific knockdown of candidate genes for locomotor behavior and sound production in Drosophila melanogaster

Molecular mechanisms underlying the functioning of central pattern generators (CPGs) are poorly understood. Investigations using genetic approaches in the model organism Drosophila may help to identify unknown molecular players participating in the formation or control of motor patterns. Here we report Drosophila genes as candidates for involvement in the neural mechanisms responsible for motor functions, such as locomotion and courtship song. Twenty-two Drosophila lines, used for gene identification, were isolated from a previously created collection of 1064 lines, each carrying a P element insertion in one of the autosomes. The lines displayed extreme deviations in locomotor and/or courtship song parameters compared with the whole collection. The behavioral consequences of CNS-specific RNAi-mediated knockdowns for 10 identified genes were estimated. The most prominent changes in the courtship song interpulse interval (IPI) were seen in flies with Sps2 or CG15630 knockdown. Glia-specific knockdown of these genes produced no effect on the IPI. Estrogen-induced knockdown of CG15630 in adults reduced the IPI. The product of the CNS-specific gene, CG15630 (a predicted cell surface receptor), is likely to be directly involved in the functioning of the CPG generating the pulse song pattern. Future studies should ascertain its functional role in the neurons that constitute the song CPG. Other genes (Sps2, CG34460), whose CNS-specific knockdown resulted in IPI reduction, are also worthy of detailed examination.     

Importance of disturbance history on net primary productivity in the world's most productive forests and implications for the global carbon cycle

Analysis of growth and biomass turnover in natural forests of Eucalyptus regnans, the world's tallest angiosperm, reveals it is also the world's most productive forest type, with fire disturbance an important mediator of net primary productivity (NPP). A comprehensive empirical database was used to calculate the averaged temporal pattern of NPP from regeneration to 250 years age. NPP peaks at 23.1 ± 3.8 (95% interquantile range) Mg C ha^?1 year^?1 at age 14 years, and declines gradually to about 9.2 ± 0.8 Mg C ha^?1 year^?1 at 130 years, with an average NPP over 250 years of 11.4 ± 1.1 Mg C ha^?1 year^?1, a value similar to the most productive temperate and tropical forests around the world. We then applied the age‐class distribution of E. regnans resulting from relatively recent historical fires to estimate current NPP for the forest estate. Values of NPP were 40% higher (13 Mg C ha^?1 year^?1) than if forests were assumed to be at maturity (9.2 Mg C ha^?1 year^?1). The empirically derived NPP time series for the E. regnans estate was then compared against predictions from 21 global circulation models, showing that none of them had the capacity to simulate a post‐disturbance peak in NPP, as found in E. regnans. The potential importance of disturbance impacts on NPP was further tested by applying a similar approach to the temperate forests of conterminous United States and of China. Allowing for the effects of disturbance, NPP summed across both regions was on average 11% (or 194 Tg C/year) greater than if all forests were assumed to be in a mature state. The results illustrate the importance of accounting for past disturbance history and growth stage when estimating forest primary productivity, with implications for carbon balance modelling at local to global scales.     

Ethnic and Geographical Aspects of the Prevalence of the Polymorphic Variants of Genes Associated with Tuberculosis

Specificity of the structure of gene pools of different ethno-territorial groups of the human population can underlie the epidemiological features of the spread of tuberculosis (TB) and the structure of the genetic component of the susceptibility to the disease. The variability of 62 genetic variants potentially associated with the risk of the development of TB in the Russian population of the city of Tomsk has been studied and the differentiation of various ethno-territorial groups of the world by these markers has been assessed. The studied sample comprised 445 Russian residents of the city of Tomsk without bronchopulmonary pathology. For comparison, the data on the variability of the genetic markers of interest in 26 populations from the 1000 Genomes Project was involved. In the Tomsk population, only the ancestral allele was found for seven of the 58 SNPs studied; the allele frequencies for 36 markers were within the limits of the values seen in other European populations; for 12 SNPs, the observed frequencies were closer to populations with a significant Mongoloid component. By the total of the SNPs, the Tomsk population, despite the geographical distance from the rest of the European populations, did not differ from them (in genetic distances and G_st statistics), although it had some features of the gene pool. Intergroup differentiation of the world populations by these SNPs reflects mainly interracial differences. The greatest differences in the genetic structure between the studied populations were seen for the markers localized in intergenic regions. Statistically significant differences were found when comparing the levels of the average expected heterozygosity between groups of “L4 carrier populations” of mycobacteria and “non-L4” populations, which indicates the impact of the prevalence of different pathogenic lineages of M. tuberculosis on the formation of population specificity of the allelic frequencies.     

Cultural monuments and nature conservation: a review of the role of kurgans in the conservation and restoration of steppe vegetation

Steppe is among the most endangered biomes of the world, especially in Eastern Europe, where more than 90 % of original steppes have been destroyed due to conversion into croplands, afforestation and other human activities. Currently, steppe vegetation is often restricted to places unsuitable for ploughing, such as ancient burial mounds called kurgans. The aim of our study was to collect and synthesise existing knowledge on kurgans by a review of research papers and grey literature. The proportion of kurgans covered by steppe vegetation increases from west to east and from lowlands to uplands. Despite their small size, kurgans act as biodiversity hotspots and harbour many red-listed species. High overall species richness and a high proportion of grassland specialists are maintained by a pronounced fine-scale environmental heterogeneity. The main factors threatening the biodiversity of kurgans are intensified agriculture and construction works. We conclude that kurgans can play a crucial role in preserving steppe vegetation, especially in intensively used agricultural landscapes in the western part of the steppe zone. Despite the vital role of kurgans in sustaining steppe vegetation, we identified serious knowledge gaps on their distribution, vegetation, flora and fauna and their potential role in steppe restoration.     

Correlation Networks from Flows. The Case of Forced and Time-Dependent Advection-Diffusion Dynamics

Complex network theory provides an elegant and powerful framework to statistically investigate different types of systems such as society, brain or the structure of local and long-range dynamical interrelationships in the climate system. Network links in climate networks typically imply information, mass or energy exchange. However, the specific connection between oceanic or atmospheric flows and the climate network’s structure is still unclear. We propose a theoretical approach for verifying relations between the correlation matrix and the climate network measures, generalizing previous studies and overcoming the restriction to stationary flows. Our methods are developed for correlations of a scalar quantity (temperature, for example) which satisfies an advection-diffusion dynamics in the presence of forcing and dissipation. Our approach reveals that correlation networks are not sensitive to steady sources and sinks and the profound impact of the signal decay rate on the network topology. We illustrate our results with calculations of degree and clustering for a meandering flow resembling a geophysical ocean jet.