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PubMed1982

Chemical modification potentiates the biological activities of 2-5A and its congeners.

Chemical modification of p5'A2'(p5'A2')np5'A by a periodate oxidation/Schiff base formation/borohydride reduction cycle gave a series of 2-5A analogues in which the ribose of the 2'-terminal nucleotide was transformed to an N-substituted morpholine (azahexapyranose). 2',5'-Oligoriboadenylate 5'-monophosphates bearing this modification were 5-10 times more potent as antagonists of the action of 2-5A or poly(I).poly(C) than was unmodified p5'A2'p5'A2'p5'A. Application of this modification to the tetramer triphosphate ppp5'A2'p5'A2'p5'A2'p5'A resulted in an analogue with 10 times the activity of ppp5'A2'p5'A2'p5'A (2-5A trimer triphosphate) as an inhibitor of protein synthesis or activator of the 2-5A-dependent endoribonuclease. This activator of the 2-5A-dependent endoribonuclease. This new 2-5A analogue, the most potent 2-5A derivative reported to date, inhibited translation in extracts of mouse L-cells programmed with encephalomyocarditis virus RNA at a concentration of 10(-10) M (concentration for half-maximal inhibition). All such N-substituted morpholine modified 2',5'-oligoriboadenylates were found to be extremely resistant to degradation by L-cell extracts under conditions where unmodified 2-5A or its derivatives were quickly destroyed. These data demonstrate the necessity for an intact terminal ribose ring for the action of the 2-5A phosphodiesterase. Thus, extensive chemical modification of 2' terminus of 2-5A may be possible without adversely affecting its biological activity while endowing it with other favorable properties such as resistance to degradation.

Adenine Nucleotides↗
PubMedDate not supplied

[Modification of the parent influenza virus nucleocapsid protein in infected cells].

The main structural nucleocapsid protein, NP, of parental influenza virus (WSN, HON1) was modified in the infected cells early after inoculation. The modification took place within ribonucleoprotein particles in the cytoplasm but was not observed within ribonucleoprotein particles in the nuclei. It occurred when the cells were incubated at 37 degrees C and not at 4 degrees C. The modified protein migrated slightly faster in SDS-containing polyacrylamide gels. Peptide mapping of NP protein labelled with 125I- of 14C-amino acids showed the modified form of NP not to contain at least two peptides but to contain one additional peptide as compared with the unmodified precursor. This suggested that the modification could be due both to proteolytic cleavage and to covalent modification of an amino acid residue. According to the latter suggestion, the intense phosphorylation of parental NP was observed in the cytoplasma of the infected cells when 32P was added for 30 min one hour postinfection. The nuclei of the infected cells early after infection contained more than half of parental ribonucleoprotein particles in which, however, unmodified NP was present. The possible significance of the observed modification of parental NP in the infectious cycle of influenza virus is discussed.

Animals↗
PubMed1980

[On the Polymorphism of barbiturates in powders and tablets. Part 4: the dissolution of barbital B and barbital A (modifications I and III and their release from tablets (author's transl)].

Two commercial brands of barbital (A: German Democratic Republic, modification III; B: Hungarian Peopl's Republic, modification I) were used to study the solubility and dissolution of the modifications. Crystals of these two substances were brought into the shape of tablets, the physical parameters and textural properties of which were determined. The effect of polymorphism on the release of these substances is discussed in the light of the results obtained from this investigation. The discussion will be continued and summarized in a subsequent paper, including further modifications.

Barbital↗
PubMed1980

Chemical modification of tryptophan residues in ribonuclease from a Rhizopus sp.

Tryptophan residues in ribonuclease from a Rhizopus sp. (RNase Rh) were modified by NBS, H2O2-dioxane, o-nitrophenylsulfenyl chloride (NPS-Cl) and the relation between the extent of modification and enzymatic activity was studied in each case. By extrapolation of the modified tryptophan residue-enzymatic activity curve to a completely inactive state, it was found that modification of 1-2 tryptophan residues is responsible for loss of enzymatic activity. RNase Rh was partly protected from modification by H2O2-dioxane (pH 8.4) and NPS-Cl (pH 3.5) when in the presence of 2'-AMP and the fluorescence emission spectrum of RNase Rh was quenched by adding 2'-AMP. It seems, therefore, that 1 or 2 tryptophan residues are involved in the active site of RNase Rh or are located near the active site. The solvent perturbation difference spectra of RNase Rh were measured using ethylene glycol and D2O as perturbants. The results indicated that 1.2 tryptophan residues for D2O and 1.9 tryptophan residues for ethylene glycol were exposed to the solvents. These data show that about 1.2-1.9 tryptophan residues are exposed to the solvent and their modification causes loss in enzymatic activity.

Amino Acids↗
PubMedDate not supplied

[Actinophage restriction and modification by Streptomyces hygroscopicus and Str. levoris cultures].

The capability for restriction and modification was studied in the cultures of Streptomyces hygroscopicus 0477 and Streptomyces levoris 1331, 2340, 2144 toward the active against them temperate phage and three polyphages. All these cultures were found to be capable of the restriction and modification of the temperate phage. Certain differences in the restriction and modification were established between Str. levoris 1331 and the two other cultures of this species. The culture 1331 could modify the temperate phage only with respect to itself rather than the two other cultures. The phage growing on the culture 1331 was restricted not only by the culture 0477, but also by the strains of Str. levoris 2340 and 2144. At the same time, the phage growing on the strains 2340 and 2144 gave the identical effectiveness of inoculation on any of these cultures, as well as on the culture 1331, and was restricted to the same degree by the culture 0477. One of the examined polyphages 14/3 was not restricted by any of the tested cultures. Two other polyphages SH4 and p4 were restricted only by the culture 2144. However, the modification by this culture was not observed. Among the studied cultures of Str. levoris, the culture 2144 was most capable of the restriction.

Bacteriophages↗
PubMed1995

Modifications in cytokeratin and actin in cultured liver cells derived from griseofulvin-fed mice.

BACKGROUND: Hepatocytes from mice fed griseofulvin (GF) for 8 months form Mallory bodies (MBs), which represent a pathologic state of intermediate filaments (IFs). The cellular mechanisms that lead to MB formation are not known. EXPERIMENTAL DESIGN: This study was aimed to investigate if MB formation could be related to modification in cytokeratin (CK) metabolism. Primary cultures of hepatocytes from control and GF livers were studied. Immunofluorescence microscopy was used to study the organization of the cytoskeleton in these cells. The hepatocytes were labeled with [35S]methionine or [32P]orthophosphate to study, respectively, the level of amino acid incorporation into IF proteins (CK 8 and CK 18) and their phosphorylation levels. The response to the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate stimulation of the phosphorylation of CK 8 and CK 18 was also elicited in contrast to control hepatocytes. RESULTS: We found that there was a change in the organization of actin and the IF network in the hepatocytes from GF-treated animals. This was associated with an increase in labeled amino acid incorporation into CK 8 and CK 18 as well as in actin. Although there was no significant difference in the absolute level of CK phosphorylation, we found modifications in the phosphorylated isomers of CK 8, the more phosphorylated isomers becoming more prominent. The treatment of the hepatocytes with 12-O-tetradecanoyl-phorbol-13-acetate did not induce changes in the level of CK phosphorylation in GF-pretreated hepatocytes. CONCLUSIONS: These results suggest that the modification of the IF network and MB formation are the consequences of increased CK synthesis and the modification of phosphorylation. They could alter the normal interaction of the IFs with different cellular components, which results in conformational changes of CKs and the reorganization of the IF network to the form of MBs.

Actins↗
PubMedDate not supplied

Histopathological and ultrastructural modifications of the arthrosis articular cartilage.

Thirty samples of articular cartilage taken during the operation from patients with incipient arthrosis, arthrosis with radiological modifications and arthrosis under study for Rheumatoid Arthritis (RA) were investigated using histopathological (HE, VG, PAS-Alcian, Gömöri, Safranine O) and electronmicroscopic techniques. The control material was made of posttraumatic cartilage (Moore prosthesis). Histopathologically, the incipient arthrosis cartilage had superficial exfoliations associated with reduced saframinophilic tinctorial perichondrocytic activity. The arthrosic cartilage with typical radiological modifications was individualized at the synovia-cartilage junction by villous aspects of the synovia associated with perichondrocytic gaps, reduction of safraninophilia and modifications of reticuline-collagenic network. The arthrosic cartilage under study for RA revealed destructive fibrous modifications of the synovia and severe affection of the articular cartilage at synovia-cartilage junction. Electronmicroscopically, the ultrastructural affection was minimum in the incipient arthrosis cartilage developing to chondrocytic degeneration in arthrosis with radiological correspondent. Both histopathological and ultrastructural data emphasize the fact that arthrosis is associated with synovitis following a primitive degenerative process similar to rheumathoid synovitis in arthrosis under study for RA.

Biomarkers↗
PubMed1994

Effect of phosphorothioate modification of oligodeoxynucleotides on specific protein binding.

Phosphorothioate modification of internucleoside linkages is widely used to prevent degradation of oligodeoxynucleotide (ODN) therapeutic agents in serum and cells. This modification generally increases ODN potency, but in many instances it is associated with an increase of poorly understood nonspecific effects. In this study, we have found that both cellular retention and nonspecific protein binding are dependent upon the extent of the oligonucleotide's modification. Flow cytometry of cells treated with fluorescein-labeled single-stranded (ss) or double-stranded (ds) ODNs demonstrated that fully phosphorothioate-modified ODNs exhibit much greater cellular association than 3'-terminally modified ODNs (with three 3'-terminal phosphorothioate linkages). Additionally, gel shift assays with either ss- or ds-probes showed that fully phosphorothioate-modified ODNs also exhibit much greater cytoplasmic and nuclear protein binding than either 3'-terminally modified or unmodified ODNs. However, gel shift competition assays showed that transcription factor binding by fully phosphorothioate-modified ds-ODNs was completely nonspecific relative to 3'-terminally modified and unmodified ds-ODNs. These results suggest that the benefits derived from full phosphorothioate modification of ODNs may be negated by increases of nonspecific protein binding and associated sequence-independent effects.

3T3 Cells↗
PubMed1994

Interaction of EcoP1 modification methylase with S-adenosyl-L-methionine: a UV-crosslinking study.

EcoP1 modification methylase was radioactively labeled when incubated with S-adenosyl-L-[methyl-3H]methionine in the presence of ultraviolet light. Crosslinking of the enzyme as detected by electrophoresis on sodium dodecyl sulfate-polyacrylamide gel followed by fluorography and autoradiography, was shown to be specific by a number of criteria. More importantly, EcoP1 modification methylase was also radioactively labeled with S-adenosyl-L-[carboxyl-14C]methionine demonstrating that labeling involved binding of the entire AdoMet molecule rather than methylation of the protein. Further, c2 EcoP1 mutant DNA modification methylases which show negligible or very little methylation activity, correspondingly formed a weak or no adduct upon crosslinking. These results suggest that photolabeling of EcoP1 DNA modification methylase occurs at the AdoMet binding site.

Carbon Radioisotopes↗
PubMed1994

Life expectancy following dietary modification or smoking cessation. Estimating the benefits of a prudent lifestyle.

OBJECTIVE: To evaluate the maximum benefits of dietary modification or smoking cessation to the life expectancy of North American adults. DESIGN: Using a computer model, we estimated the change in life expectancy for men and women following risk factor modification. We then estimated the total number of adults who would be targeted by national guidelines and the total person-years of life that would be saved. PATIENTS: Men and women aged 30 to 74 years who were free of coronary heart disease. INTERVENTIONS: Smoking cessation or serum cholesterol-reducing diets with 8% to 10% saturated fat and 240 to 300 mg of daily cholesterol, respectively. RESULTS: On average, dietary modification would reduce serum cholesterol levels from 0.45 mmol/L (17.4 mg/dL) to 0.75 mmol/L (29.1 mg/dL) in men and 0.12 mmol/L (4.6 mg/dL) to 0.55 mmol/L (21.4 mg/dL) in women, thereby increasing life expectancy by 0.03 to 0.4 year and 0.01 to 0.16 year, respectively. Smoking cessation would increase life expectancy from 2.59 to 4.43 years among men and from 2.6 to 3.68 years among women. Among adult Canadians, dietary modification would save 373,000 to 683,000 person-years of life. The majority of these benefits would occur among men who start dieting at ages 30 to 59 years. Smoking cessation would add more than 4 million person-years of life to the Canadian population. The relative impact of either intervention among American adults would be similar to these Canadian estimates. CONCLUSIONS: Younger men, aged 30 to 59 years, might live slightly longer after dietary change, but among women and older men the average benefits would be negligible. The benefits of smoking cessation are more uniform across age and sex and are substantially greater than those predicted for dietary change.

Adult↗
PubMed1993

The role of modification of lipoproteins and of the immune system in early atherogenesis.

Not only the plasma cholesterol level, but also postsecretory modifications of lipoproteins appear to be of influence in atherogenesis. Evidence that several forms of modification, especially oxidation, occur in vivo is rapidly accumulating, although their clinical relevance remains uncertain. Modification of lipoproteins has been demonstrated in persons with such well-known risk factors of premature atherosclerosis as smoking, diabetes mellitus and hyperlipidaemia. Because there is a relation between the amount of natural antioxidants in the plasma and the risk of atherosclerosis, and because exogenous antioxidants appear to retard atherosclerosis without influencing the plasma cholesterol level, antioxidants may prove to be of use in the prevention of atherosclerosis. There are strong indications for a role of the immune system in atherogenesis. Modified lipoproteins are highly immunogenic and stimulate immunocompetent cells to secrete vasoactive factors and cytokines. From animal studies it appears that pro- and antioxidative conditions can modulate these processes. It is concluded that additional research on the relation between lipoprotein modification and the immune system, and on the possible beneficial effects of antioxidants in atherogenesis is warranted, not only to elucidate further the mechanism of atherosclerosis, but also to develop new approaches to the prevention of atherosclerosis.

Animals↗
PubMed1993

The effect of chemical modification of basic amino acid residues on the activation and amidolytic activity of Hageman factor (factor XII).

Modification of arginyl residues of Hageman factor by phenylglyoxal hydrate inhibits activation of this clotting factor in a plasma-free system, that is, in the absence of the other constituents of the contact activation system. Activation is also inhibited by alteration of the other two basic amino acid residues present, lysine and histidine. Chemical modification of histidine and arginine residues does not inhibit the amidolytic activity of activated Hageman factor. In contrast, modification of amino group(s) in N-terminal and lysine residues inhibits activated Hageman factor. Thus, basic amino acid residues essential to the activation or activity of Hageman factor appear to be variably accessible to chemical modification.

Amides↗
PubMed1993

[Prostaglandin H synthase. Chemical modification of histidine residues in various forms of the enzyme by diethylpyrocarbonate].

Prostaglandin H synthase (PGHS) as apo- and holoenzyme and the enzyme inactivated during the conversion of arachidonic acid into prostaglandin H2 has been modified by diethyl pyrocarbonate (DEPC). DEPC (40 mol/l mol protein) rapidly, but quantitatively differently interacted with the three forms of the enzyme (pH 6.0, 25 degrees C). The exhausted reaction with DEPC corresponded to modification of seven histidine residues in apo-PGHS and four residues in holo-PGHS. All of the 18 histidine residues were available for modification in the enzyme inactivated during the catalysis. The modification of apo-PGHS was accompanied by a concerted loss of the combined cyclooxygenase plus peroxidase and peroxidase activities. The velocities of the tryptic cleavage of the three forms of the enzyme into the 33 and 38 kDa polypeptides were essentially different, but the modification of each enzyme form did not affect the velocity of its cleavage. Two of the three histidine residues essential for the interaction with the heme within the 38 kDa fragment might be His-309 and His-388. Based on the comparison of availability for the reaction with DEPC of all the 18 histidine residues in the enzyme molecule inactivated by the interaction with arachidonic acid and on the abnormally high velocity of the tryptic cleavage of this form of PGHS, a hypothesis has been put forward about the fast and dramatic changes in the protein structure in the course of catalysis.

Catalysis↗
PubMed1993

Relative effects of weight loss and dietary fat modification on serum lipid levels in the dietary treatment of obesity.

The independent effects of weight loss and dietary fat modification on serum lipids were investigated in two groups of healthy moderately obese men and women. In one group (sequential group, n = 19), a weight-stable low-fat, low-saturated-fat diet (Low-Sat) was given for 7 weeks (= dietary modification), followed by a 4.2 MJ/day deficit Low-Sat diet for 13 weeks (i.e., weight loss alone). Another group (simultaneous group, n = 22) received a 4.2 MJ/day deficit Low-Sat diet for 13 weeks (i.e., weight loss+dietary fat modification). Each group was subject to an initial weight-stable high-fat, high-saturated fat diet for 3 weeks and a final weight stable Low-Sat diet for 3 weeks. Both groups lost similar amounts of body weight, about 13 kg, and had similar overall changes in total cholesterol, low density lipoprotein (LDL), cholesterol, high density lipoprotein (HDL) cholesterol, the HDL/LDL ratio, and triglycerides. Analysis of the separate effects of the Low-Sat diet without energy restriction and of weight loss in the sequential group showed that weight loss per se was responsible for about 50% of the total reduction in total cholesterol, and for about 60% and 70% of the fall in LDL cholesterol and triglycerides, respectively. Fat modification without weight loss reduced HDL cholesterol by 11.1% and the HDL/LDL ratio by 7.7%, while weight loss per se led to increases in HDL cholesterol of 12.5% and in the HDL/LDL ratio of 24.0%. We conclude that the effects of reduction in fat and saturated fat intake and weight loss are additive.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Isolation and characterization of a temperature-sensitive mutant of Salmonella typhimurium defective in prolipoprotein modification.

A temperature-sensitive (ts) mutant of Salmonella typhimurium that accumulated unmodified murein prolipoprotein at 42 degrees C but not at 30 degrees C was identified. In vivo and in vitro studies of the biosynthesis of Braun's lipoprotein revealed that this mutant (SE5221) was defective in the glyceryl modification of prolipoprotein. The ts mutation was mapped to 60.6 min of the S. typhimurium chromosome and was linked to argA and cysH. A clone with a 1.4-kilobase S. typhimurium DNA insert that complemented the ts mutation and restored the prolipoprotein modification activity both in vivo and in vitro was isolated. DNA sequencing of the complementing region revealed an open reading frame encoding a protein with 291 amino acids lacking NH2-terminal signal sequence. This open reading frame is immediately 5' to the thyA gene and is allelic to umpA of Escherichia coli. Wild-type strains harboring the cloned gene exhibited elevated levels of prolipoprotein modification activity. At the non-permissive temperature, the mutation affected both growth and viability, and the mutant cells exhibited anomalous cell morphology. The ts phenotype was suppressed by the introduction of a lpp::Tn10 mutation. These results suggest that the cloned gene encodes prolipoprotein glyceryl transferase (lgt), and in the wild-type background, this prolipoprotein modification enzyme is essential for the growth and viability of S. typhimurium.

Alleles↗
PubMed1995

A massive new posttranslational modification occurs on axonemal tubulin at the final step of spermatogenesis in Drosophila.

Using two antibodies raised against Paramecium axonemal tubulin, a monoclonal antibody, AXO 49 (Callen et al., Biol. Cell 81, 95-119 (1994)), and a polyclonal antibody, PAT (Cohen et al., Biol. Cell 44, 35-44 (1982)), which have been shown elsewhere to detect a new posttranslational modification of tubulin presumably corresponding to polyglycylation, we have analyzed the occurrence of this modification during spermatogenesis in Drosophila. Results obtained by immunofluorescence on cysts isolated by laceration of testes showed that the antibodies reacted on axonemal microtubules of several species within the genus. Observation of different stages of differentiation of D. obscura sperm cells indicated, first, that the epitopes reactive with both antibodies appeared at late stages, and secondly, that they were detected simultaneously along all axonemes within a cyst. Immunofluorescence on semithin sections and electron microscopic immunocytochemistry on ultrathin sections confirmed that the appearance of the epitope recognized by the monoclonal antibody occurred at the time of the individualization process of spermatids in D. melanogaster. These results indicate that the posttranslational modification occurs as a very late event, after complete assembly of axonemal microtubules, and that the axonemal tubulin becomes modified when axonemal microtubules become coupled with the membrane, suggesting that the modification may in some way be induced by the microtubule-membrane interaction.

Animals↗
PubMed1995

Modification of the Miya hook in vaginal colpopexy.

OBJECTIVE: To evaluate a modification of the Miya hook in performing vaginal sacrospinous ligament fixation. STUDY DESIGN: The modification was performed in over 50 patients. It involves placing the needle through the ligament unloaded; then the hook is back-threaded with the appropriate suture. The hook is then withdrawn, bringing the suture with it. RESULTS: There were no complications as a result of this modification. The technique was faster, used fewer instruments and obviated fraying of the suture. It could also be adapted when retrieving the suture when the classic technique proved difficult. CONCLUSION: The ease of this modification should promote the use of this instrument in performing vaginal sacrospinous ligament fixation.

Equipment Design↗
PubMed1995

[Cooperative interactions of oligodeoxyribonucleotides upon binding with DNA by chemical modification].

Quantitative characteristics of the modification of deoxyribooligonucleotide TTGCCTTGAATGG-GAAGAGGGTCATT (P) with 4-(N-2-chloroethyl-N-methylamino)benzyl phosphamide derivative of oligonucleotide pTTCCCA (X) were studied. The modification was performed in the presence of derivatives of the oligonucleotides (Phn-L)pTTCAAGGCp(L-Phn) (E1) and (Phn-L)pTGACCCTCp(L-Phn) (E2), where Phn is the residue of N-(2-hydroxyethyl)phenazinium, and L is ethylene diamine spacer. In PXE1, PXE2, and PXE1E2 complexes, E1, E2, and reagent X are bound with target P in tandem, with E1 near the 3'-end and E2 near the 5'-end of the reagent X. From the dependences of the maximum in time modification degree of target P and the shorter targets containing the complementary binding site for the reagent X on its concentration, the association constants of the complexes PX, PE1, and PE2 were determined as Kx = (4.2 +/- 0.6) x 10(4) M-1, Ke1 = (1.25 +/- 0.44) x 10(7) M-1, and Ke2 = (2.56 +/- 1.22) x 10(6) M-1, respectively. The cooperativity coefficients of joint binding the X, E1, and E2 with the target giving rise to the complexes PXE1, PXE2, and PXE1E2 were estimated as alpha 1 = 15.7 +/- 2.1, alpha 2 = 8.7 +/- 1.2, and alpha 12 = 136.5 +/- 2.6, respectively. The data obtained suggest that E2 is not only the effector of modification but it is also an inhibitor due to the formation of the complex PE2* with Ke2* = (1.97 +/- 1.27) x 10(7) M-1 not capable of adding the reagent X.

Base Sequence↗