Diet and subsistence in Bronze Age pastoral communities from the southern Russian steppes and the North Caucasus.

The flanks of the Caucasus Mountains and the steppe landscape to their north offered highly productive grasslands for Bronze Age herders and their flocks of sheep, goat, and cattle. While the archaeological evidence points to a largely pastoral lifestyle, knowledge regarding the general composition of human diets and their variation across landscapes and during the different phases of the Bronze Age is still restricted. Human and animal skeletal remains from the burial mounds that dominate the archaeological landscape and their stable isotope compositions are major sources of dietary information. Here, we present stable carbon and nitrogen isotope data of bone collagen of 105 human and 50 animal individuals from the 5th millennium BC to the Sarmatian period, with a strong focus on the Bronze Age and its cultural units including Maykop, Yamnaya, Novotitorovskaya, North Caucasian, Catacomb, post-Catacomb and late Bronze Age groups. The samples comprise all inhumations with sufficient bone preservation from five burial mound sites and a flat grave cemetery as well as subsamples from three further sites. They represent the Caucasus Mountains in the south, the piedmont zone and Kuban steppe with humid steppe and forest vegetation to its north, and more arid regions in the Caspian steppe. The stable isotope compositions of the bone collagen of humans and animals varied across the study area and reflect regional diversity in environmental conditions and diets. The data agree with meat, milk, and/or dairy products from domesticated herbivores, especially from sheep and goats having contributed substantially to human diets, as it is common for a largely pastoral economy. This observation is also in correspondence with the faunal remains observed in the graves and offerings of animals in the mound shells. In addition, foodstuffs with elevated carbon and nitrogen isotope values, such as meat of unweaned animals, fish, or plants, also contributed to human diets, especially among communities living in the more arid landscapes. The regional distinction of the animal and human data with few outliers points to mobility radii that were largely concentrated within the environmental zones in which the respective sites are located. In general, dietary variation among the cultural entities as well as regarding age, sex and archaeologically indicated social status is only weakly reflected. There is, however, some indication for a dietary shift during the Early Bronze Age Maykop period.

Virtual screening, synthesis and biological evaluation of DNA intercalating antiviral agents.

This paper describes computer-aided design of new anti-viral agents against Vaccinia virus (VACV) potentially acting as nucleic acid intercalators. Earlier obtained experimental data for DNA intercalation affinities and activities against Vesicular stomatitis virus (VSV) have been used to build, respectively, pharmacophore and QSAR models. These models were used for virtual screening of a database of 245 molecules generated around typical scaffolds of known DNA intercalators. This resulted in 12 hits which then were synthesized and tested for antiviral activity against VaV together with 43 compounds earlier studied against VSV. Two compounds displaying high antiviral activity against VaV and low cytotoxicity were selected for further antiviral activity investigations.

Anti-Inflammatory Effects and Joint Protection in Collagen-Induced Arthritis after Treatment with IQ-1S, a Selective c-Jun N-Terminal Kinase Inhibitor.

c-Jun N-terminal kinases (JNKs) participate in many physiologic and pathologic processes, including inflammatory diseases. We recently synthesized the sodium salt of IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime) and demonstrated that it is a high-affinity JNK inhibitor and inhibits murine delayed-type hypersensitivity. Here we show that IQ-1S is highly specific for JNK and that its neutral form is the most abundant species at physiologic pH. Molecular docking of the IQ-1S syn isomer into the JNK1 binding site gave the best pose, which corresponded to the position of cocrystallized JNK inhibitor SP600125 (1,9-pyrazoloanthrone). Evaluation of the therapeutic potential of IQ-1S showed that it inhibited matrix metalloproteinase 1 and 3 gene expression induced by interleukin-1ß in human fibroblast-like synoviocytes and significantly attenuated development of murine collagen-induced arthritis (CIA). Treatment with IQ-1S either before or after induction of CIA resulted in decreased clinical scores, and joint sections from IQ-1S-treated CIA mice exhibited only mild signs of inflammation and minimal cartilage loss compared with those from control mice. Collagen II-specific antibody responses were also reduced by IQ-1S treatment. By contrast, the inactive ketone derivative 11H-indeno[1,2-b]quinoxalin-11-one had no effect on CIA clinical scores or collagen II-specific antibody titers. IQ-1S treatment also suppressed proinflammatory cytokine and chemokine levels in joints and lymph node cells. Finally, treatment with IQ-1S increased the number of Foxp3(+)CD4(+)CD25(+) regulatory T cells in lymph nodes. Thus, IQ-1S can reduce inflammation and cartilage loss associated with CIA and can serve as a small-molecule modulator for mechanistic studies of JNK function in rheumatoid arthritis.

Synthesis and biological activity of 7H-benzo[4,5]indolo[2,3-b]-quinoxaline derivatives.

New 7-(2-aminoethyl)-7H-benzo[4,5]indolo[2,3-b]quinoxalines (13-20) were synthesized with high yields starting from 3H-benzo[e]indole-1,2-dione. These compounds were screened for the cytotoxicity, anti-viral activity, interferon inducing ability and DNA affinity compared with the corresponding 6-(2-aminoethyl)-6H-indolo[2,3-b]quinoxaline derivatives (1-12). It was shown, that compounds 13-20 bind to DNA stronger (lg Кa=6.23-6.87) than compounds 1-12 (lg Кa=5.57-5.89). Anti-viral activity is significantly reduced with annulations of benzene ring in Indoloquinoxaline moiety 13-20.

Synthesis, cytotoxicity, antiviral activity and interferon inducing ability of 6-(2-aminoethyl)-6H-indolo[2,3-b]quinoxalines.

New 6-(2-aminoethyl)-6H-indolo[2,3-b]quinoxalines were synthesized with high yields using bromoethylisatin and 6-(2-bromoethyl)-6H-indolo[2,3-b]quinoxaline as intermediates. These compounds were screened for the cytotoxicity, antiviral activity and interferon inducing ability. It was shown, that tested 6-(2-aminoethyl)-6H-indolo[2,3-b]quinoxalines are low toxic potent interferon inducers and antivirals. Morpholine and 4-methyl-piperidine derivatives appeared as the most active antivirals and the least cytotoxic in the investigated series.

Synthesis and affinity to DNA of phenylbenzoimidazoles and benzoimidazo[1,2-c]quinazolines.

Novel N-(benzoimidazophenyl)dialkylaminoalkylamides and 6-dialkylaminoalkylbenzoimidazo[1,2-c]quinazolines were prepared as potential interferon inducers and antiviral agents. They were screened for the DNA affinity by the ethidium bromide displacement assay. It was shown that the lg K(a) values of the compounds containing tetracyclic benzoimidazo[1,2-c]quinazoline fragment are approximately one order magnitude greater than those of the corresponding acyclic phenylbenzoimidazole derivatives.