Quantitative relationships between structure and antimicrobial activity of new “Soft” bisquaternary ammonium salts

New surface-active bisquaternary ammonium salts derived from bis-(2-dimethylaminoethyl) ester of glutaric acid are highly effective against representatives of Gram-positive, Gram-negative bacteria and yeasts. Relationships between structure, lipophilicity and antimicrobial effectiveness were demonstrated by quantitative structure-activity methodology. The nonlinear dependence of biological activity on the structure as well as lipophilicity (expressed as critical micelle concentration—CMC) was shown using Kubinyi’s bilinear model. The most effective compounds were those with the alkyl chain of 11–12 carbon atoms and with the CMC values around 0.7−1.0 mmol/L. These derivatives possessed higher antimicrobial activity particularly to Gram-negative bacteria. Part 45 of the seriesQuaternary Ammonium Salts; part 44: Brádlerová A.et al., Pharmazie, in press.     

New imidazoquinoxaline derivatives: Synthesis,biological evaluation on melanoma,effect on tubulin polymerization and structure–activity relationships

Microtubules are considered as important targets of anticancer therapy. EAPB0503 and its structural imidazo[1,2-a]quinoxaline derivatives are major microtubule-interfering agents with potent anticancer activity. In this study, the synthesis of several new derivatives of EAPB0503 is described, and the anticancer efficacy of 13 novel derivatives on A375 human melanoma cell line is reported. All new compounds show significant antiproliferative activity with IC₅₀ in the range of 0.077–122 μM against human melanoma cell line (A375). Direct inhibition of tubulin polymerization assay in vitro is also assessed. Results show that compounds 6b, 6e, 6g, and EAPB0503 highly inhibit tubulin polymerization with percentages of inhibition of 99%, 98%, 90%, and 84% respectively. Structure–activity relationship studies within the series are also discussed in line with molecular docking studies into the colchicine-binding site of tubulin.     

The effect of oxygen on the sporulation, δ-endotoxin synthesis and toxicity of Bacillus thuringiensis H14

Summary The sporulation and toxicity of Bacillus thuringiensis H14 were studied as a function of aeration. The fed-batch cultures carried out in the similar aeration conditions were followed in four different oxygen transfer rates containing 0, 20, 100 and 250 mmol/l/h. The percentage of total cells which had formed refractile spores in these four oxygen transfer rates were 100, 93, 84 and 48%, respectively. The highest rate of sporulation was observed in the absence of oxygen and the mature spores were the only population present under this condition at the end of culture. Sporulation in a large portion of cells failed under saturated oxygenation and either mature spores or vegetative cells were present at the end of culture. In the intermediate conditions, cells in different physiological states could be observed at the end of culture. It was found that the optimal conditions for spore yield and for δ-endotoxin yield were not the same, even though sporulation and δ-endotoxin formation proceed simultaneously during the fermentation process. The 130-kDa δ-endotoxin seemed to be more sensitive to aeration conditions. The higher toxicity against Culex pipiens was obtained under the saturated condition.     

Cutaneous thermal thresholds—the reproducibility of their measurements and the effect of gender

The present study evaluated the reproducibility of measurements of the forearm thresholds for warm (WT) and cold (CT) sensation, and their dependence on gender. The Middlesex Thermal Testing System was used for this purpose. CT did not differ between the five consecutive trials, whereas WT fell significantly. A minimum of two trial tests are therefore recommended prior to the assessment of WT. Furthermore, CT and WT were induced by significantly smaller skin temperature changes (lower thresholds) in females as compared to males. Should this gender specific difference in thermosensitivity also be observed in other skin regions, then females would be more sensitive to thermal stimulation than males.     

Chloroplast biogenesis — Correlation between structure and function

Chloroplast biogenesis is a multistage process leading to fully differentiated and functionally mature plastids. Complex analysis of chloroplast biogenesis was performed on the structural and functional level of its organization during the photoperiodic plant growth after initial growth of seedlings in the darkness. We correlated, at the same time intervals, the structure of etioplasts transforming into mature chloroplasts with the changes in the photosynthetic protein levels (selected core and antenna proteins of PSI and PSII) and with the function of the photosynthetic apparatus in two plant species: bean (Phaseolus vulgaris L.) and pea (Pisum sativum L). We selected these plant species since we demonstrated previously that the mature chloroplasts differ in the thylakoid organization. We showed that the protein biosynthesis as well as photosynthetic complexes formation proceeds gradually in both plants in spite of periods of darkness. We found that both steady structural differentiation of the bean chloroplast and reformation of prolamellar bodies in pea were accompanied by a gradual increase of the photochemical activity in both species. This article is part of a Special Issue entitled: Photosynthesis Research for Sustainability: from Natural to Artificial.     

Isolation, structure identification and SAR studies on thiosugar sulfonium salts, neosalaprinol and neoponkoranol, as potent α-glucosidase inhibitors

Two hitherto missing members of sulfonium salts family in Salacia genus plants as a new class of α-glucosidase inhibitors, neoponkoranol (7) and neosalaprinol (8), were isolated from the water extracts, and their structures were unambiguously identified. For further SAR studies on this series of sulfonium salts, several epimers of 7 and 8 were synthesized, and their inhibitory activities against rat small intestinal α-glucosidases were evaluated. Among them, 3'-epimer of 7 was found most potent in this class of molecules, and revealed as potent as currently used antidiabetics, voglibose and acarbose.     

Synthesis,antioxidant capacity,and structure–activity relationships of tri-O-methylnorbergenin analogues on tyrosinase inhibition

A series of tri-O-methylnorbergenin analogues 1–9 were synthesized and their antioxidant activities and inhibitory effects on tyrosinase were evaluated. Among tested analogues, compound 4 bearing cathechol moiety exhibited greater antioxidant activity and excellent inhibition on tyrosinase with IC₅₀ value of 9.1 μM, comparable to that of corresponding positive controls. The inhibition mechanism analysis of compound 4 demonstrated that it was a mixed-type inhibitor on tyrosinase. These results suggest that these compounds may serve as a useful clue for further designing and development of novel potential tyrosinase inhibitors.     

The relationships between XPC binding to conformationally diverse DNA adducts and their excision by the human NER system: Is there a correlation?

The first eukaryotic NER factor that recognizes NER substrates is the heterodimeric XPC-RAD23B protein. The currently accepted hypothesis is that this protein recognizes the distortions/destabilization caused by DNA lesions rather than the lesions themselves. The resulting XPC-RAD23B–DNA complexes serve as scaffolds for the recruitment of subsequent NER factors that lead to the excision of the oligonucleotide sequences containing the lesions. Based on several well-known examples of DNA lesions like the UV radiation-induced CPD and 6–4 photodimers, as well as cisplatin-derived intrastrand cross-linked lesions, it is generally believed that the differences in excision activities in human cell extracts is correlated with the binding affinities of XPC-RAD23B to these DNA lesions. However, using electrophoretic mobility shift assays, we have found that XPC-RAD23B binding affinities of certain bulky lesions derived from metabolically activated polycyclic aromatic hydrocarbon compounds such as benzo[a]pyrene and dibenzo[a,l]pyrene, are not directly, or necessarily correlated with NER excision activities observed in cell-free extracts. These findings point to features of XPC-RAD23B–bulky DNA adduct complexes that may involve the formation of NER-productive or unproductive forms of binding that depend on the structural and stereochemical properties of the DNA adducts studied. The pronounced differences in NER cleavage efficiencies observed in cell-free extracts may be due to differences in the successful recruitment of subsequent NER factors by the XPC-RAD23B–DNA adduct complexes, and/or in the verification step. These phenomena appear to depend on the structural and conformational properties of the class of bulky DNA adducts studied.     

A review on the relationships between plant genetic diversity and ecosystem functioning北大核心CSCD

The loss of genetic diversity is accelerating due to habitat loss and population reduction caused by global change and anthropologenic activities. For species-poor ecosystems, the effect of genetic diversity on ecosystem functioning may not be smaller than that of species diversity. Therefore, understanding the relationship between genetic diversity and ecosystem functioning (GD-EF) and its underlying mechanisms is important for biodiversity conservation, responses of ecosystems to environmental change and ecological restoration. Here, we reviewed the studies on the effects of plant genetic diversity on ecosystem structures (community structure of the higher tropic level) and ecosystem functions (primary production, nutrient cycling and ecosystem stability), and the mechanisms underlying these relationships. We also discussed the influence of functional diversity on GD-EF, the comparison of effects of the genetic and species diversity on ecosystem functioning, and the application of GD-EF in the ecological restorations. We finally pointed out the limitations in current studies to provide references for the future: (1) further studies on the mechanisms of GD-EF are needed; (2) no study has evaluated the influence of genetic diversity on maltifunctinarity; (3) the impacts of different measurements of genetic diversity on ecosystem functioning are unclear; (4) there are lack of long-time GD-EF studies and GD-EF studies conducted at multidimensional scales; (5) the relative importance of genetic diversity and other factors on ecosystem functioning in the nature is unclear. © 2018 Editorial Office of Chinese Journal of Plant Ecology. All Rights Reserved.     

Entropy and symmetry — their relation to thought processes in the biological system

This paper addresses the topic of the electrophysiology of thought processes in a biological system. A classification and criticism of definitions of intelligence is presented. The engenderment of intelligent regulations of behavior is seen to involve stipulations concerning the relation of metron to logon informational content (MacKay, 1950). The relationship is of a nature similar to that hidden behind the Maxwell demon (Maxwell, 1871), and to certain difficulties already faced in quantum mechanics. As thought structures observe conservation of variety under transformations, the conservation of entropy in thermodynamics is investigated. Conservation occurs in a Carnot cycle (Carnot, 1824) and only under a Lorenz transformation subject to a symmetry group formation. The symmetry group is topic neutral and could be applied to informational structures. The need for the informational equivalents of a Carnot cycle and Lorenz transformations is described. To depict the interaction of energy and structure, equivalents of Einstein's field equations are needed. The study of symmetry groups by electrophysiological methods is seen to be at least feasible.     

A note on sporadic nonperiodic oscillations in the activity of the endocrine system and on the endocrine—Nervous system feedback

By generalizing a previous paper on periodicities in the endocrine system (Bull. Math. Biophysics,30, 735–749, 1968), it is shown that nonperiodic, sporadic oscillations in the system are also possible. A procedure of describing the feedback mechanism between the endocrine system and the central nervous system is suggested. It is shown that the combined system: endocrine—CNS, also may show sporadic fluctuations.     

The influence of stochasticity,landscape structure and species traits on abundant–centre relationships

Species have been commonly hypothesized to have high population densities in geographic areas which correspond to either the centre of the species geographic range or climatic niche (abundant–centre hypothesis). However, there is mixed empirical support for this relationship, and little theoretical underpinning. We simulate a species spreading across a set of replicated artificial landscapes to examine the expected level of support for abundant–centre relationships in geographic and niche space. Species niche constraints were modeled as a single axis which was related directly to population growth rates. We found strong evidence for abundant–centre relationships when populations follow deterministic growth, dispersal is high, environmental noise is absent and intraspecific competition is low. However, the incorporation of ecological realism reduced the detectability of abundant–centre relationships considerably. Our results suggest that even in carefully constructed artificial landscapes designed to demonstrate abundant–centre dynamics, the incorporation of small amounts of demographic stochasticity, environmental heterogeneity or landscape structure can strongly influence the relationship between species population density and distance to species geographic range or niche centre. While some simulated relationships were of comparable strength to common empirical support for abundant–centre relationships, our results suggest that these relationships are expected to be fairly variable and weak.     

C1 and N5 derivatives of cerpegin: Synthesis of a new series based on structure–activity relationships to optimize their inhibitory effect on 20S proteasome

Thirty-two new derivatives of cerpegin (1,1,5-trimethylfuro[3,4-c]pyridine-3,4-dione) were designed and synthesized in high yield by a new method, combining several C¹ and N⁵ substituents. All compounds were tested for their inhibitory effect on the CT-L, T-L and PA proteolytic activities of a purified mammalian 20S proteasome. Only one molecule inhibited both CT-L and PA activities. Sixteen molecules specifically inhibited PA at the micromolar range, out of which fourteen had IC₅₀ values around 5 μM and two had IC₅₀ values closer to 2 μM. Except in one case, neither calpain I nor cathepsin B was inhibited. In silico docking suggests a unique mode of binding of the most efficient compounds to the β1 catalytic site (PA activity) in relation to the chemical nature of C¹ substituents.     

Double-enkephalins—Synthesis,activity on guinea-pig ileum,and analgesic effect

We have synthesized enkephalin analogues in which C-terminal methionine or leucine residues are replaced by a second active fragment of the enkephalin analogue. Synthesis of two compounds is described: in one, two fragments of a D-Ala²-enkephalin analogue are connected by a -NH-NH-bridge, and in the other, three methylene groups are incorporated between the amino groups. The first compound is a very potent inhibitor of electrically induced contractions of guinea-pig ileum and produces a strong analgesia when administered intraperitoneally in mice. The second compound is less active on the ileum and fails to produce analgesia after systemic injection. The double-enkephalins may interact with μ-receptors.     

Study of the inhibitory effect of fatty acids on the interaction between DNA and polymerase β

The binding of human DNA polymerase β (pol β) to DNA template-primer duplex and single-stranded DNA in the absence or presence of pol β inhibitors has been studied using a surface plasmon resonance biosensor. Two fatty acids, linoleic acid and nervonic acid, were used as potent pol β inhibitors. In the interaction between pol β and DNA, pol β could bind to ssDNA in a single binding mode, but bound to DNA template-primer duplexes in a parallel mode. Both pol β inhibitors prevented the binding of pol β to the single strand overhang and changed the binding from parallel to single mode. The affinities of pol β to the template-primer duplex region in the presence of nervonic acid or linoleic acid were decreased by 20 and 5 times, respectively. The significant inhibitory effect of nervonic acid on the pol β-duplex interaction was due to both a 2-fold decrease in the association rate and a 9-fold increase in the dissociation rate. In the presence of linoleic acid, no significant change of association rate was observed, and the decrease in binding affinity of pol β to DNA was mainly due to 7-fold increase in the dissociation rate. Published in Russian in Biokhimiya, 2009, Vol. 74, No. 7, pp. 1000–1006. These authors contributed equally.     

Impacts of methamidophos, copper, and their combinations on bacterial community structure and function in black soil

The potential ecotoxicologial risks of methamidophos, copper, and their combinations on microbial community of black soil ecosystem in the Northeast China were assessed in species richness and structures by using 16S rDNA-PCR-DGGE analysis approach, and functional characteristics at community levels by using BIOLOGGN system analysis method as well as two conventional methods(DHA and SIR). All results of DGGE banding fingerprint pat-terns(amplified by bacterial specific 16S rDNA V3 high variable region universal primer) indicated that the species richness of bacterial community in tested soil was significantly decreased to different extents by using different concentrations of single methamidophos, copper, especially some of their combinations had worse effects than their corresponding single factors. In addition, the structures of soil bacterial community had been disturbed under all stresses applied in this study because of the enrichment of some species and the disappearance of other species from the b