Limitations of Peptide Retro-inverso Isomerization in Molecular Mimicry

A retro-inverso peptide is made up of d-amino acids in a reversed sequence and, when extended, assumes a side chain topology similar to that of its parent molecule but with inverted amide peptide bonds. Despite their limited success as antigenic mimicry, retro-inverso isomers generally fail to emulate the protein-binding activities of their parent peptides of an α-helical nature. In studying the interaction between the tumor suppressor protein p53 and its negative regulator MDM2, Sakurai et al. (Sakurai, K., Chung, H. S., and Kahne, D. (2004) J. Am. Chem. Soc. 126, 16288–16289) made a surprising finding that the retro-inverso isomer of p53(15–29) retained the same binding activity as the wild type peptide as determined by inhibition enzyme-linked immunosorbent assay. The authors attributed the unusual outcome to the ability of the d-peptide to adopt a right-handed helical conformation upon MDM2 binding. Using a battery of biochemical and biophysical tools, we found that retro-inverso isomerization diminished p53 (15,–29) binding to MDM2 or MDMX by 3.2–3.3 kcal/mol. Similar results were replicated with the C-terminal domain of HIV-1 capsid protein (3.0 kcal/mol) and the Src homology 3 domain of Abl tyrosine kinase (3.4 kcal/mol). CD and NMR spectroscopic as well as x-ray crystallographic studies showed that d-peptide ligands of MDM2 invariably adopted left-handed helical conformations in both free and bound states. Our findings reinforce that the retro-inverso strategy works poorly in molecular mimicry of biologically active helical peptides, due to inherent differences at the secondary and tertiary structure levels between an l-peptide and its retro-inverso isomer despite their similar side chain topologies at the primary structure level.     

Principles of formalizing a quantitative evaluation of the genetic danger of chemical compounds for man

Specific characteristics of the mutagenic effect of chemicals, which must be taken into account in developing the test system to assess the potential genetic risk caused by chemical substances, are considered. The organizational principles of the procedures currently available for testing and ranking chemicals by their mutagenic and carcinogenic hazard to humans are discussed. The use of selective information suggested by Wiener and Shannon as an efficiency measure of testing and estimating the potential genetic hazard of chemical substances is substantiated. The feasibility of this approach was demonstrated by testing the efficiency of the battery of two short-term in vitro tests as an example. It was shown that selective information is able to serve as an integral universal criterion of the efficiency of testing, if either one test or the test battery were used.     

Mid-Holocene environmental and human dynamics in northeastern China reconstructed from pollen and archaeological data

A pollen record from the Taishizhuang site (40°21.5′N, 115°49.5′E) located in the transitional forest-steppe zone near the present-day limit of the summer monsoon is used to reconstruct vegetation and climate. Quantitative biome reconstruction suggests that between ca. 5700 and 4400 cal. years B.P. temperate deciduous forest dominated the vegetation cover around the Taishizhuang site. After that time the landscape became more open and the scores of the steppe biome were always higher than those of the temperate deciduous forest except for two oscillations dated to ca. 4000 cal. years B.P. and ca. 3500 cal. years B.P. However, ca. 3400-2100 cal. years B.P. the common vegetation became steppe and the landscape was more open in comparison with the previous time interval. The results of the pollen-based precipitation reconstruction suggest that annual precipitation was ca. 550-750 mm (ca. 100-300 mm higher than present) during the mid-Holocene ‘forest phase’, and ca. 450-650 mm during the following ‘forest-steppe phase’. From ca. 3400 cal. years B.P. during the ‘steppe phase’ annual precipitation was similar to modern values (ca. 300-500 mm). Archaeological records from 100 sites prove the habitation of northeastern China during the prehistoric and early historic periods from ca. 8200 cal. years B.P., but do not provide evidence of the use of wood resources intensive enough to influence the regional vegetation development and to leave traces in the pollen assemblages. Both archaeological and palaeoenvironmental data support the conclusion that changes in pollen composition in northeastern China between 5700 and 2100 cal. years B.P. reflect natural variations in precipitation and not major deforestation caused by humans.     

Flora Europaea Notulae Systematicae ad Floram Europaeam spectantes No. 20 Corrigenda et Addenda

Following the publication of the last of the series of Flora Europaea Notulae, No. 20 in the Botanical Journal of the Linnean Society , 76: 297–384 (1978), a number of additions or alterations have been drawn to our attention. These are published in continuation.     

Population genetic analysis of the association between the BRCA1 and P53 gene polymorphisms and the risk of sporadic breast cancer

Polymorphism of two tumor-suppressor genes, BRCA1 and P53, was examined. DNA was extracted from blood leukocytes of the women affected with breast cancer (N = 151) and of the women with no clinical symptoms of tumor diseases (N = 191). Typing of the polymorphic variants was performed using PCR-RFLP method. It was demonstrated that the genetic structure of the patient group (taking into consideration BRCA1 and P53 polymorphic variants) differed from that of the control group. The group of genotypes, found exclusively among the patients, as well as the group of "resistant" genotypes revealed predominantly among the controls, was described. Detection of the genotype A1A1 B1B1 S1S1 C1C1 F1F1 J2J2, whose frequency in control group was eight times higher than in the patient group, was an additional confirmation of the existence of "resistant" genotypes. These findings point to the association between the combinations of the BRCA1 and P53 allelic variants and the risk of breast cancer.     

The ecology and prevalence of arboviruses on the territory of the Saratov Region

The territorial spread of Tahyna, Batai, Sindbis, West Nile fever and Crimean-Congo hemorrhagic fever viruses throughout the Saratov region in 1998 - 2000 was analyzed. The characteristics of the epizootic activity of the natural foci of these arboviruses in different landscape zones (temperate forest-steppes, steppes and semi-deserts) were calculated. The species composition of small mammals, the natural reservoirs of the causative agents of arbovirus infections, was determined.     

Microbiological processes in a high-temperature oil field

Thermophilic sulfate-reducing bacteria (SRB) oxidizing lactate, butyrate, and C12-C16 n-alkanes of oil at a temperature of 90 degrees C were isolated from samples of water and oil originating from oil reservoirs of the White Tiger high-temperature oil field (Vietnam). At the same time, no thermophiles were detected in the injected seawater, which contained mesophilic microorganisms and was the site of low-temperature processes of sulfate reduction and methanogenesis. Thermophilic SRB were also found in samples of liquid taken from various engineering reservoirs used for oil storage, treatment, and transportation. These samples also contained mesophilic SRB, methanogens, aerobic oil-oxidizing bacteria, and heterotrophs. Rates of bacterial production of hydrogen sulfide varied from 0.11-2069.63 at 30 degrees C and from 1.18-173.86 at 70 degrees C micrograms S/(1 day); and those of methane production, varied from 58.4-100 629.8 nl CH4/(1 day) (at 30 degrees C). The sulfur isotopic compositions of sulfates contained in reservoir waters and of hydrogen sulfide of the accompanying gas indicate that bacterial sulfate reduction might be effective in the depth of the oil field.