Ultra-low supply voltage crystal quartz oscillator.

In this paper, an ultra-low-voltage crystal quartz oscillator is proposed. The design of the proposed oscillator is essentially based on using a HEMT operating in an unsaturated dc regime and a quartz resonator as a resonant impedance transformer. The 25 MHz prototype shows steady oscillations at the supply voltage of less than 17 mV and the power consumption as low as 300 nW, i.e., 1-2 orders of magnitude lower than the other to-date oscillators. This approach is good for building ultra-low consumption radio devices including those working at low temperatures.

[Sequencing and analysis of the resistome of Streptomyces fradiae ATCC19609 in order to develop a test system for screening of new antimicrobial agents].

The paper provides the annotation and data on sequencing the antibiotic resistance genes in Streptomyces fradiae strain ATCC19609, highly sensitive to different antibiotics. Genome analysis revealed four groups of genes that determined the resistome of the tested strain. These included classical antibiotic resistance genes (nine aminoglycoside phosphotransferase genes, two beta-lactamase genes, and the genes of puromycin N-acetyltransferase, phosphinothricin N-acetyltransferase, and aminoglycoside acetyltransferase); the genes of ATP-dependent ABC transporters, involved in the efflux of antibiotics from the cell (MacB-2, BcrA, two-subunit MDR1); the genes of positive and negative regulation of transcription (whiB and padR families); and the genes of post-translational modification (serine-threonine protein kinases). A comparative characteristic of aminoglycoside phosphotransferase genes in S. fradiae ATCC19609, S. lividans TK24, and S. albus J1074, the causative agent of actinomycosis, is provided. The possibility of using the S. fradiae strain ATCC19609 as the test system for selection of the macrolide antibiotic oligomycin A derivatives with different levels of activity is demonstrated. Analysis of more than 20 semisynthetic oligomycin A derivatives made it possible to divide them into three groups according to the level of activity: inactive (>1 nmol/disk), 10 substances; with medium activity level (0.05­1 nmol/disk), 12 substances; and more active (0.01­0.05 nmol/disk), 2 substances. Important for the activity of semisynthetic derivatives is the change in the position of the 33rd carbon atom in the oligomycin A molecule.

Hybrid Antibiotics Based on Azithromycin and Glycopeptides: Synthesis and Antibacterial Activity.

A series of hybrid antibiotics on the basis of azithromycin and glycopeptides with the glycopeptide molecule attached via the aminoalkylcarbamoyl spacer to 11-position of the macrolide was synthesized. All the synthesized compounds demonstrated equal or superior to azithromycin and vancomycin antibacterial activity against 7 tested strains of grampositive bacteria. The new hybrid antibiotics were more active than azithromycin or vancomycin against S.pneumoniae ATCC 49619. Some of the compounds were active against E.faecium and E.faecalis strains resistant to vancomycin.

[Design of Novel Carboxamides of Eremomycin and Vancomycin with 4- or 3-Amino Methyl Phenyl Boric Acid and Their Investigation].

Amidation of the end carboxyl group of eremomycin and vancomycin by pinacolinic 4- or 3-amino methyl phenyl boron acids esters in the presence of the condensing reagent PyBOP resulted in formation of novel carboxamides of the antibiotics (IIIa-VIa). After elimination of the pinacolinic group under mild hydrolysis in weak acid aqueous medium there formed the respective derivatives with a residue of the nonprotected boric acid (III-VI). It was shown that the activity of the 4-substituted derivatives of the borole-containing eremomycin and vancomycin practically was the same as that of the initial antibiotics, while higher than that of the respective 3-substituted derivatives of the borole-containing derivatives against 8 strains of grampositive bacteria.

[Antimicrobial Properties of Eremoxylarin A Produced by Ascomycete of Sordariomycetes in Submerged Culture].

The fungal strain INA 01108 producing antibiotic substances with broad spectrum of antibacterial activity was isolated from the natural environment. By the morphological characteristics and DNA analysis it was shown to belong to Ascomycetes of Sordariomycetes. In submerged culture the strain produced at least four antibiotics. The major component of them was identified as eremophilane-type sesquiterpene eremoxylarin A. Eremoxylarin A is effective in vitro against grampositive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin group glycopeptide antibiotics resistant Leuconostoc mesenteroides VKPM B-4177. The efficacy and toxicity of eremoxylarin A was determined on a murine staphylococcal sepsis model. The dose of 6.25 mg/kg provided 100% recovery and survival of the animals, while the dose of 3.12 mg/kg was close to the ED50. The chemical structure of eremoxylarin A allows to modify the antibiotic and such studies may be relevant to design a less toxic derivative without loss of the valuable antimicrobial properties.

[New antibiotics produced by Bacillus subtilis strains].

Two Bacillus subtilis strains isolated from the fruiting body of a basidiomycete fungus Pholiota squarrosa exhibited a broad range of antibacterial activity, including those against methicillin-resistant Staphylococcus aureus INA 00761 (MRSA) and Leuconostoc mes6nteroides VKPM B-4177 resistant to glycopep-> tide antibiotics, as well as antifungal activity. The strains were identified as belonging to the "B. subtilis" com- plex based on their morphological and physiological characteristics, as well as by sequencing of the 16S rRNA gene fragments. Both strains (INA 01085 and INA 01086) produced insignificant amounts of polyene antibiotics (hexaen and pentaen, respectively). Strain INA 01086 produced also a cyclic polypeptide antibiotic containing Asp, Gly, Leu, Pro, Tyr, Thr, Trp, and Phe, while the antibiotic of strain INA 01085 contained, apart from these, two unidentified nonproteinaceous amino acids. Both polypeptide antibiotics were new compounds efficient against gram-positive bacteria and able to override the natural bacterial antibiotic resistance.

[Unusual amidation reaction of Asn-containing glycopeptide antibiotics using the coupling reagent PyBOP].

The coupling reagent PyBOP is widely used for the synthesis of different peptides and their amides, particularly for carboxamides of glycopeptide antibiotics of vancomycin or teicoplanin groups. The amidation reaction of the peptide core of the glycopeptide antibiotic eremomycin (I) with highly reactive amines in the presence of PyBOP is usually not accompanied by the formation of side products. However, the amidation of I with bulky amines (e.g., decyl amine and adamantyl amine) in the presence of PyBOP and Et3N or di-(i-Pr)2EtN (pH - 8.5) yielded N-unsubstituted carboxamide of eremomycin (Ia) as an admixture. The reaction of (I) or vancomycin (II) with an excess of PyBOP and Et3N (pH - 8.5) without addition of an amine or ammonia gave a mixture of products which contained higher amounts of the corresponding N-unsubstituted carboxamides (-20%). The structures of the samples of Ia and vancomycin amide (IIa) were proved by 1H NMR and ESI MS methods and confirmed by comparing with the authentic samples.

Synthesis and study of antibacterial activities of antibacterial glycopeptide antibiotics conjugated with benzoxaboroles.

BACKGROUND: The ability of boron-containing compounds to undergo a number of novel binding interactions with drug target functional groups has recently been described. In an extension of this work, we have incorporated a boron-containing scaffold, the benzoxaborole, into several glycopeptides antibiotics. The aim of this work is to exploit the inherent reactivity of boron to gain additional interactions with the bacterial cell wall components to improve binding affinity and to thereby overcome resistance. RESULTS: Three antibacterial glycopeptides (vancomycin, eremomycin and teicoplanin aglycone) have been selected for the construction of a series of 12 new benzoxaborole-glycopeptide conjugates. The hybrid antibiotics, in which the benzoxaborole and glycopeptide moieties were separated by a linker, exhibited excellent antibacterial activity against Gram-positive bacteria, including those with intermediate susceptibility to glycopeptides. Some analogs also demonstrated activity against vancomycin-resistant enterococci. CONCLUSION: Conjugation of antibiotics with benzoxaborole derivatives provides antibiotics with new and useful properties. Teicoplanin aglycone-benzoxaborole derivatives overcome resistance of Gram-positive bacteria to vancomycin.

Note: Ultra-high frequency ultra-low dc power consumption HEMT amplifier for quantum measurements in millikelvin temperature range.

We have presented theory and experimentally demonstrated an efficient method for drastically reducing the power consumption of the rf/microwave amplifiers based on HEMT in unsaturated dc regime. Conceptual one-stage 10 dB-gain amplifier showed submicrowatt level of the power consumption (0.95 µW at frequency of 0.5 GHz) when cooled down to 300 mK. Proposed technique has a great potential to design the readout amplifiers for ultra-deep-cooled cryoelectronic quantum devices.

[Forecasting parameters of acute chemical toxicity according to in vitro conformation changes of proteins].

The authors analyze experimental data on in vitro effects induced by chemicals that were used throughout MEIC toxicologic studies in ovalbumin and acetylcholinesterase of human RBC. Influence on proteins is compared to acute toxicity caused by the chemicals in humans and various cell lines. The conclusion is that the method is prospective for screening of acute chemical toxicity signs in humans.

[Nitric oxide donor increases the effectiveness of cytostatic therapy and inhibits the development of drug resistance]. / Donor oksida azota povyshaet éffektivnost' tsitostaticheskoi terapii i zaderzhivaet razvitie lekarstvennoi rezistentnosti.

The investigation has established a potential of low-dosage chemotherapy with cytostatics when used in combination with nitric oxide (NO) donor. Such regimen resulted in more animals being cured of leukemias P388 and L1210 and longer survival. Similar effect was reported with transplantable intracerebral leukemia P388 in which case mean survival after cyclophosphamide plus NO-donor was three times as high as that after cyclophosphamide alone. Combination therapy also promoted animetastatic effect: melanoma B16 inhibition by cyclophosphamide alone was 50% vs. 80% after cyclophosphamide plus NO-donor. NO-donor inhibited development of drug resistance to cyclophosphamide.

Nitric oxide donor increases the efficiency of cytostatic therapy and retards the development of drug resistance.

The potentiality to increase the chemotherapeutic effectiveness of some cytostatics in low, subtherapeutic doses in combination with nitric oxide (NO) donor has been shown. This type of combined therapy results in significant increase in life span and number of survivors among mice bearing leukemias P388 and L-1210. A similar effect was observed for intracerebral leukemia P388 transplantation. In this case the life span of mice treated with cyclophosphamide and NO donor increased by three times in comparison to therapy with cyclophosphamide alone. The coinjection of nitric oxide donor and cytostatics improved the antimetastatic activity of the cytostatics: the index of melanoma B16 metastasis inhibition at the cyclophosphamide monotherapy is 50%; on addition of NO donor the index is over 80%. Comparative studies of NO donor (organic nitrate) and a similar compound in which ONO(2) moieties were replaced by OH groups demonstrated that the presence of NO(2) is required for adjuvant activity of compounds and confirmed that nitric oxide modifies the antitumor effects of cytostatics. It is shown also that nitric oxide donor retards the development of drug resistance to cyclophosphamide.

O-glycosides of N-hydroxyindoles.

First O-glycosides of N-hydroxyindole were synthesized by the interaction of the indoles containing electron withdrowing substituents with acyl halogenoses in the presence of alkaline reagents. 1-O-beta-D-Glucopyranosides of 1-hydroxy-5-(or 6)-nitroindoles, 1-O-beta-D-ribofuranoside of 1-hydroxy-5-nitroindole and also 1-[(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)oxy]-2-methoxycarbonylindole were obtained. 1-[(2,3,4,6-Tetra-O-acetyl-beta-D-glucopyranosyl)-oxy]-6-nitro-indole was transformed into 1-[(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)-oxy]indole.

The formation of 2-hydroxy-4-hydroxymethyl-3-(indol-3-yl)-cyclopent-2-enone derivatives from ascorbigens.

A facile preparation is described of 3-(indol-3-yl)-2-hydroxy-4-hydroxymethylcyclopent-2-enone and its N-derivatives in 15-40% yields by the degradation of ascorbigen or its N-derivatives in a warm solution of L-ascorbic acid through a sequential domino reaction. The same cyclopentenone derivatives were obtained in 30-40% yields by the condensation of (N-alkylindol-3-yl)glycolic acids with ascorbic acid. 2,6-Dihydroxy-1-(indol-3-yl)hexa-1,4-diene-3-one and 2-hydroxy-4-hydroxymethyl-5-(indol-3-yl)cyclopent-2-enone were identified as intermediates in this reaction.

[Indole derivatives in vegetables of the family Cruciferae]. / Indol'nye soedineniia v ovoshchakh semeistva Krestotsvetnykh (Cruci ferae)

The chemical background of the biological activities of vegetables of the Cruciferae family is considered. These vegetables contain alkaloids of the glucobrassicin group that are decomposed by the enzyme myrosinase (thioglucosidase, EC 3.2.3.1) released upon damage to the plant cells. This results in several indole derivatives, with ascorbigen and indole-3-carbinol predominating. In the gastrointestinal tract, these compounds form 5H,11H-indolo[3,2-b]carbazole, natural ligand of the aromatic hydrocarbon receptor (Ah receptor) and a functional analogue of 2,3,7,8-tetrachlorodibenzo-p-dioxin, a dangerous xenobiotic. The indolocarbazole-Ah receptor complex activates the gene of CYP1A1, an isoenzyme of cytochrome P450-dependent monoamine oxidase, which enhances the 2-hydroxylation (inactivation) of estrogens. In its turn, the resulting lowered level of estrogens inhibits the growth of hormone-dependent tumors or prevents their appearance. The mechanism of xenobiotic inactivation, underlying the anticarcinogenic action of food products including vegetables of Cruciferae family and some homogeneous indole compounds, is similar. Some other effects of nutrient indole compounds, e.g., the inhibition of expression of the cyclin-dependent kinase 6 (CDK6) by indole-3-carbinol that leads to the cell cycle arrest in G1 phase, are also considered. Analysis of the biological effects of the Cruciferae diet has helped start clinical studies of indole-3-carbinol as an antitumor and anticarcinogenic remedy for patients with a high risk of tumor diseases.

Polyfunctional indole-3-carbinol derivatives: 1-(indol-3-yl)glycerols and related compounds, beta-hydroxytryptamines and ascorbigens. Chemistry and biological properties.

Earlier interaction of indole-3-carbinols with L-ascorbic acid and chemical and biological properties of formed 2-skatylderivatives of L-ascorbic acid (ascorbigens) were discussed. In this presentation the properties and stereochemistry of products of interaction of polyfunctional biologically important indole-3-carbinols (indoleglycerol analogs and beta-hydroxytryptamine derivatives) with L-ascorbic acid are investigated. Biological significance of this reaction is discussed.

The clastogenic and mutagenic effects of ascorbigen and 1'-methylascorbigen.

Ascorbigen, which occurs naturally in the human diet, and a synthetic analogue (1'-methylascorbigen), were assayed for cytotoxic and clastogenic activities in a SV40-transformed Indian Muntjac cell line (SVM), and for mutagenic activity in the Ames test using Salmonella typhimurium strains TA98 and TA100. Ascorbigen had no effect upon the clonal survival of SVM at concentrations below 0.21 mg/ml and did not induce either chromosome aberrations or sister-chromatid exchanges (SCEs) at any concentration tested up to the maximum compatible with the assay conditions; nor did it induce mutations in either Salmonella strain. In contrast, 1'-methylascorbigen was an order of magnitude more cytotoxic, demonstrating a Dq of 0.03 mg/ml, and whilst it too was not found to induce chromosome aberrations it did induce SCEs in SVM (although only at highly cytotoxic doses) and mutations in the Ames test.

Ascorbigen and other indole-derived compounds from Brassica vegetables and their analogs as anticarcinogenic and immunomodulating agents.

Searches for the natural compounds that determine the anticarcinogenic properties of a cruciferous-vegetable diet, revealed the products of alkaloid glucobrassicin biotransformations; among these, ascorbigen, an indole-containing derivative of L-ascorbic acid, was found to be the most abundant. Study of chemical properties of ascorbigen showed that it is capable of different transformations in acidic (including gastric juice) and slightly alkaline (including blood) media. The stable and unstable products of ascorbigen transformation determine the biological properties of the compound. The most important product of ascorbigen transformation in gastric juice is 5,11-dihydroindolo[3,2-b]-carbazole, with a binding affinity to the Ah receptor only 3.7 x 10(-2) lower than that of tetrachlorodibenzodioxin. This compound may be responsible for modifying P450 enzyme activities. Ascorbigen and its analogs are available synthetically. Their biological evaluation showed that some of the compounds of these series are immunomodulators. The most active is N-methylascorbigen, which demonstrates therapeutic effects (inhibition of tumor growth, protection of animals from bacterial and viral infections). The immunomodulatory activity of natural ascorbigen may be an additional factor of importance for the anticarcinogenic properties of a cruciferous-vegetable diet.