One common structural feature of "words" in protein sequences and human texts.

Frequently discussed analogy between genetic and human texts is explored by comparison of alternation of polar and non-polar amino-acid residues in proteins and alternation of consonants and vowels in human texts. In human languages, the usage of possible combinations of consonants and vowels is influenced by pronounceability of the combinations. Similarly, oligopeptide composition of proteins is influenced by requirements of protein folding and stability. One special type of structure often present in proteins is amphipathic α-helices in which polar and non-polar amino acids alternate with the period 3.5 residues, not unlike alternation of consonants and vowels. In this study, we evaluated the contribution made by amphipathic alternations to the protein sequence texts (20-24%). Their proportion is lower than respective values for alternating words in human texts (57-89%). The proteomes (full sets of proteins for selected organisms) were transformed into ranked sequences of n-grams (words of length n), including periodical amphipathic structures. Similarly, human texts were transformed into sequences of alternating consonants and vowels. Analysis of the vocabularies shows that in both types of texts (human languages and proteins) the alternating words are dominant or highly preferred, thus, strengthening the analogy between these two types of texts. The contribution of amphipathic words in the upper parts of the ranked lists for 10 analyzed proteomes varies between 58 and 74%. In human texts respective values range between 90 and 100%.

Towards functional repertoire of the earliest proteins.

The conserved protein sequence motifs present in all prokaryotic proteomes, "omnipresent motifs," presumably, correspond to the earliest proteins of the Last Universal Cellular Ancestor, from which all the proteomes have descended. Fifteen proteomes, each representing one of the total 15 diverse phyla of 131 Eubacteria and Archea, from which the omnipresent elements have been originally derived, are exhaustively screened. All those proteins which harbor the omnipresent motifs are identified. Six "omnipresent" protein types are revealed which are located in all 15 proteomes: ABC cassettes, FtsH proteases, translation initiation factors, translation elongation factors, isoleucyl-tRNA synthases, and RNA polymerases ß'. In addition to the omnipresent motifs, these proteins also contain other highly conserved motifs, standing for additional modules of the proteins. Remarkably, the identified tentative earliest proteins are responsible for only three basic functions: supply of monomers (ABC transporters and proteases), protein synthesis (initiation and elongation factors, aminoacyl-tRNA synthases), and RNA synthesis (polymerases). No enzymes involved in metabolic activities are present in the list of the earliest proteins derived by this approach. Some of the omnipresent sequence motifs are found, indeed, in the metabolic enzymes (e.g. NTP binding motifs), but these enzymes do not make a sequence matching collection of 15 sequences, i.e. they are not omnipresent. Future analysis of less conserved sequence motifs may reveal at what degree of conservation (stage of evolution) the metabolic enzymes could have entered the scene.

A novel OmpY porin from Yersinia pseudotuberculosis: structure, channel-forming activity and trimer thermal stability.

A novel OmpY porin was predicted based on the Yersinia pseudotuberculosis genome analysis. Whereas it has the different genomic annotation such as "outer membrane protein N" (ABS46310.1) in str. IP 31758 or "outer membrane protein C2, porin" (YP_070481.1) in str. IP32953, it might be warranted to rename the OmpN/OmpC2 to OmpY, "outer membrane protein Y", where letter "Y" pertained to Yersinia. Both phylogenetic analysis and genomic localization clearly support that the OmpY porin belongs to a new group of general bacterial porins. The recombinant OmpY protein with its signal sequence was overexpressed in porin-deficient Escherichia coli strain. The mature rOmpY was shown to insert into outer membrane as a trimer. The OmpY porin, isolated from the outer membrane, was studied employing spectroscopic, electrophoretic and bilayer lipid membranes techniques. The far UV CD spectrum of rOmpY was essentially identical to that of Y. pseudotuberculosis OmpF. The near UV CD spectrum of rOmpY was weaker and smoother than that of OmpF. The rOmpY single-channel conductance was 180 ± 20 pS in 0.1 M NaCl and was lower than that of the OmpF porin. As was shown by electrophoretic and bilayer lipid membrane experiments, the rOmpY trimers were less thermostable than the OmpF trimers. The porins differed in the trimer-monomer transition temperature by about 20°C. The three-dimensional structural models of the Y. pseudotuberculosis OmpY and OmpF trimers were generated and the intra- and intermonomeric interactions stabilizing the porins were investigated. The difference in the thermal stability of OmpY and OmpF trimers was established to correlate with the difference in intermonomeric polar contacts.

Nucleosome positioning pattern derived from oligonucleotide compositions of genomic sequences.

Availability of nucleosome positioning pattern(s) is crucial for chromatin studies. The matrix form of the pattern has been recently derived (I. Gabdank, D. Barash, E. N. Trifonov. J Biomol Struct Dyn 26, 403-412 (2009), and E. N. Trifonov. J Biomol Struct Dyn 27, 741-746 (2010)). In its simplified linear form it is described by the motif CGRAAATTTYCG. Oligonucleotide components of the motif (say, triplets GRA, RAA, AAA, etc.) would be expected to appear in eukaryotic sequences more frequently. In this work we attempted the reconstruction of the bendability patterns for 13 genomes by a novel approach-extension of highest frequency trinucleotides. The consensus of the patterns reconstructed on the basis of trinucleotide frequencies in 13 eukaryotic genomes is derived: CRAAAATTTTYG. It conforms to the earlier established sequence motif. The reconstruction, thus, attests to the universality of the nucleosome DNA bendability pattern.

[Etiological and prognostic aspects of renal failure in patients with prostatic adenoma].

The aim of our study was to assess the causes of renal failure in patients with prostatic adenoma (PA) and outcomes after draining of the urinary bladder. A retrospective study comprised 239 PA patients with a serum creatinine level over 120 mcmol/l. Outcomes were assessed after 3-5 day and 2.5 month bladder draining. The Spearman test was used for statistical analysis. We found that age, prostate volume, PA growth pattern, urinary tract infection, concomitant pathology (arterial hypertension, diabetes mellitus, atherosclerosis) do not correlate with a serum creatinine level. The presence of bilateral retention of the upper urinary tract was associated with a higher serum creatinine level. There is a significant correlation between lowering of a serum creatinine concentration after bladder draining and the level of upper urinary tract retention.

Single-base resolution nucleosome mapping on DNA sequences.

Nucleosome DNA bendability pattern extracted from large nucleosome DNA database of C. elegans is used for construction of full length (116 dinucleotide positions) nucleosome DNA bendability matrix. The matrix can be used for sequence-directed mapping of the nucleosomes on the sequences. Several alternative positions for a given nucleosome are typically predicted, separated by multiples of nucleosome DNA period. The corresponding computer program is successfully tested on best known experimental examples of accurately positioned nucleosomes. The uncertainty of the computational mapping is +/-1 base. The procedure is placed on publicly accessible server and can be applied to any DNA sequence of interest.

Chaperone Skp from Yersinia pseudotuberculosis exhibits immunoglobulin G binding ability.

A low-molecular-weight cationic protein that can bind human and rabbit immunoglobulins G has been isolated from Yersinia pseudotuberculosis cells. This immunoglobulin binding protein (IBP) interacts with IgG Fc-fragment, the association constant of the resulting complex being 3.1 microM(-1). MALDI-TOF mass spectrometry analysis of IBP revealed its molecular mass of 16.1 kDa, and capillary isoelectrofocusing analysis showed pI value of 9.2. N-Terminal sequence determination by Edman degradation revealed the sequence of the 15 terminal amino acid residues (ADKIAIVNVSSIFQ). Tryptic hydrolysate of IBP was subjected to MALDI-TOF mass spectrometry for proteolytic peptide profiling. Based on the peptide fingerprint, molecular mass, pI, and N-terminal sequence and using bioinformatic resources, IBP was identified as Y. pseudotuberculosis periplasmic chaperone Skp. Using the method of comparative modeling a spatial model of Skp has been built. This model was then used for modeling of Skp complexes with human IgG1 Fc-fragment by means of molecular docking.

Nucleosome DNA bendability matrix (C. elegans).

An original signal extraction procedure is applied to database of 146 base nucleosome core DNA sequences from C. elegans (S. M. Johnson et al. Genome Research 16, 1505-1516, 2006). The positional preferences of various dinucleotides within the 10.4 base nucleosome DNA repeat are calculated, resulting in derivation of the nucleosome DNA bendability matrix of 16x10 elements. A simplified one-line presentation of the matrix ("consensus" repeat) is ...A(TTTCCGGAAA)T.... All 6 chromosomes of C. elegans conform to the bendability pattern. The strongest affinity to their respective positions is displayed by dinucleotides AT and CG, separated within the repeat by 5 bases. The derived pattern makes a basis for sequence-directed mapping of nucleosome positions in the genome of C. elegans. As the first complete matrix of bendability available the pattern may serve for iterative calculations of the species-specific matrices of bendability applicable to other genomic sequences.

Sequence structure of hidden 10.4-base repeat in the nucleosomes of C. elegans.

By measuring prevailing distances between YY, YR, RR, and RY dinucleotides in the large database of the nucleosome DNA fragments from C. elegans, the consensus sequence structure of the nucleosome DNA repeat of C. elegans was reconstructed: (YYYYYRRRRR)n. An actual period was estimated to be 10.4 bases. The pattern is fully consistent with the nucleosome DNA patterns of other eukaryotes, as established earlier, and, thus, the YYYYYRRRRR repeat can be considered as consensus nucleosome DNA sequence repeat across eukaryotic species. Similar distance analysis for [A, T] dinucleotides suggested the related pattern (TTTYTARAAA)n where the TT and AA dinucleotides display rather out of phase behavior, contrary to the "AA or TT" in-phase periodicity, considered in some publications. A weak 5-base periodicity in the distribution of TA dinucleotides was detected.

Epigenetic nucleosomes: Alu sequences and CG as nucleosome positioning element.

Alu sequences carry periodical pattern with CG dinucleotides (CpG) repeating every 31-32 bases. Similar distances are observed in distribution of DNA curvature in crystallized nucleosomes, at positions +/-1.5 and +/-4.5 periods of DNA from nucleosome DNA dyad. Since CG elements are also found to impart to nucleosomes higher stability when positioned at +/-1.5 sites, it suggests that CG dinucleotides may play a role in modulation of the nucleosome strength when the CG elements are methylated. Thus, Alu sequences may harbor special epigenetic nucleosomes with methylation-dependent regulatory functions. Nucleosome DNA sequence probe is suggested to detect locations of such regulatory nucleosomes in the sequences.

Sequence-directed mapping of nucleosome positions.

A nucleosome DNA sequence probe is designed that combines recently derived RR/YY counter-phase and AA/TT in-phase periodical patterns. A simple nucleosome mapping procedure is introduced for prediction of the nucleosome positions in the sequence of interest, to serve as a guide for experimental studies of the chromatin structure.

Protein sequence modules.

Conserved protein sequence segments are commonly believed to correspond to functional sites in the protein sequence. A novel approach is proposed to profile the changing degree of conservation along the protein sequence, by evaluating the occurrence frequencies of all short oligopeptides of the given sequence in a large proteome database. Thus, a protein sequence conservation profile can be plotted for every protein. The profile indicates where along the sequences the potential functional (conserved) sites are located. The corresponding oligopeptides belonging to the sites are very frequent across many prokaryotic species. Analysis of a representative set of such profiles reveals a common feature of all examined proteins: they consist of sequence modules represented by the peaks of conservation. Typical size of the modules (peak-to-peak distance) is 25-30 amino acid residues.

Homology models of the Yersinia pseudotuberculosis and Yersinia pestis general porins and comparative analysis of their functional and antigenic regions.

The amino acid sequences of the Yersinia pseudotuberculosis porin (YPS) and Y. pestis porin (YPT) have recently deduced but their three-dimensional structures were not known. These sequences were analyzed using the servers 3D-PSSM and PredPort. The YPS and YPT porins were shown to have a high degree of identity (above 50%) in primary and secondary structures. The three-dimensional models of the Yersinia pseudotuberculosis porin (YPS) and Y. pestis porin (YPT) were obtained using the homology modeling approach, SWISS-MODEL Protein Modeling Server and 3-D structure of PhoE porin from E. coli as template. The superposition of the Calpha-atoms of the monomers of the Yersinia porins and PhoE porin gave a root mean square deviations of 0.47 A and 0.43 A for YPS and YPT respectively. Yersinia porins were found to be very similar in their three-dimensional structure to other non-specific enterobacterial porins, having the same features of overall fold and disposition of loop L3. The intrinsic structures of the monomer pores of YPS and YPT were investigated and their conductances were predicted with the program HOLE. The good correspondence between the theoretical and experimental magnitudes of YPS conductance was found. The Yersinia porins were determined to be unusual in containing the substitution, Glu replaced by Val, in a highly conserved pentapeptide (Pro-Glu-Phe-Gly-Gly-Asp), located in the loop L3 tip that disturbs the functionally important cluster of the acidic amino acids in the constriction site. Comparative analysis of structural organization of YPS and E. coli OmpF porin in the regions involved in subunit association and pore lumen was performed. The YPS porin functional properties were predicted. The differences between these porins in polar interactions playing a significant role in stabilization of the porin trimers were found and discussed in term of the variations in trimer stability. The Yersinia porins were shown to have the highest degree of the structural similarity. The differences between the porins were observed in their external loops. Their loops L6 and loops L8 showed 71.4 and 52.9% of sequence identity, respectively. The arrangement of charged residues clustered in the channel external vestibule of these porins was found to be also different suggesting the possible differences in their functional properties. The surface exposed regions of Yersinia porins involved in their potential sequential antigenic determinants were compared. The structural basis of their cross reactivity and antigenic differences is discussed.

The triplet code from first principles.

Temporal order ("chronology") of appearance of amino acids and their respective codons on evolutionary scene is reconstructed. A consensus chronology of amino acids is built on the basis of 60 different criteria each offering certain temporal order. After several steps of filtering the chronology vectors are averaged resulting in the consensus order: G, A, D, V, P, S, E, (L, T), R, (I, Q, N), H, K, C, F, Y, M, W. It reveals two important features: the amino acids synthesized in imitation experiments of S. Miller appeared first, while the amino acids associated with codon capture events came last. The reconstruction of codon chronology is based on the above consensus temporal order of amino acids, supplemented by the stability and complementarity rules first suggested by M. Eigen and P. Schuster, and on the earlier established processivity rule. At no point in the reconstruction the consensus amino-acid chronology was in conflict with these three rules. The derived genealogy of all 64 codons suggested several important predictions that are confirmed. The reconstruction of the origin and evolutionary history of the triplet code becomes, thus, a powerful research tool for molecular evolution studies, especially in its early stages.

[Evolution of the genetic code and earliest proteins. Reconstruction from the current sequences]. / Evoliutsiia geneticheskogo koda i drevneishikh belkov. Vossozdanie kartiny na osnovanii sovremennykh posledovatel'nostei.

One would expect that present-day protein sequences have changed many times during their evolution, at every point, so that there is no chance to recognize in the sequences any traces of their ancient organization. It turns out to be not true. Massive analysis of complete genomes of bacteria allows one to derive, according to very specific predictions, distinct features of very early sequences and to outline the history of evolution protein. Modern proteins appear to have evolved from short peptides of mixed sequences of two alphabet types. They were then closed to sequences of optimal size from which modern folds/domains and multidomain proteins were formed. The reconstruction of amino acid and codon chronology is described. A specific idea on the nature and evolutionary significance of gene splicing is suggested. The gene splicing, while obeying the rules of basic structural organization of proteins, offers accessibility to regions of sequence space that could not be reached by mutational changes typical for prokaryotes.

[Segmented genome: elementary units of genome structure]. / Segmentirovannyi genom. Elementarnye edinitsy genoma.

Numerous observations, measurements and calculations strongly indicate that both eukaryotic and prokaryotic genomes are built as linear arrays of units of rather uniform size, about 400 base pairs. The units are likely to correspond to early individual genes that existed, presumably, in form of DNA circles. Their combinatorial fusion resulted eventually in formation of the early segmented genomes. The segmented structure of the genomes is, apparently, still maintained by some structural selection pressures. Some of the units can be recognized in the sequences by characteristic sequence motifs at the borders of the units. Identification and characterization of the units, their mapping on the genomes should become an important prerequisite of genome comparisons and genome evolution studies.

[Proteomic code]. / Proteomnyi kod.

On the basis of recent fundamentally novel developments in the protein structure a proteomic code is suggested, that would potentially allow to describe sequence, structure, and function of proteins by a spectrum of elementary loop-n-lock units. All major characteristics of the nearly standard units are described, and first five "codons" of the proteomic code are presented with their respective unique sequences, structures, and functions. More such codons are to be discovered, and the general procedure for their identification is described.

Protein folding: looping from hydrophobic nuclei.

Protein structure can be viewed as a compact linear array of nearly standard size closed loops of 25-30 amino acid residues (Berezovsky et al., FEBS Letters 2000; 466: 283-286) irrespective of details of secondary structure. The end-to-end contacts in the loops are likely to be hydrophobic, which is a testable hypothesis. This notion could be verified by direct comparison of the loop maps with Kyte and Doolittle hydropathicity plots. This analysis reveals that most of the ends of the loops are hydrophobic, indeed. The same conclusion is reached on the basis of positional autocorrelation analysis of protein sequences of 23 fully sequenced bacterial genomes. Hydrophobic residues valine, alanine, glycine, leucine, and isoleucine appear preferentially at the 25-30 residues distance one from another. These observations open a new perspective in the understanding of protein structure and folding: a consecutive looping of the polypeptide chain with the loops ending primarily at hydrophobic nuclei.

[Psychopharmacotherapy of out-patient with dementia]. / Ambulatornaia psikhofarmakoterapiia bol'nykh, stradaiushchikh dementsiei.

A treatment of 285 out-patients with different types of dementia and concomitant behavioral and psychiatric disorders has been conducted in gerontopsychiatric unit of Moscow mental out-patient clinic No. 10. The sample analyzed consisted of 88 (31%) men and 197 (69%) women, aged from 60 to 98 (mean 74.5 +/- 6.4) years. Each patient had an epidemiological record registering demographical and clinical details as well as information on the drugs and doses prescribed, etc. Tranquillizers and hypnotics used separately or in combination with other drugs were prescribed to 60% of the patients, neuroleptics--to 37%, vasotropics and nootropics--to 35%, antidepressants--to 16%, antiparkinsonic drugs--to 8%, anticolvunsants--3%. Most frequently different drugs have been used in combination (58% of the cases) and in 33% cases--as monotherapy. Only in 9% of the patients psychotropics have not been prescribed. The choice of psychotropics was dependent on the patient age and disease severity. At older age and severe dementia neuroleptics were prescribed to the patients more frequently.