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PubMed1978

Modification of HLA antigens in patients with malignancies following hormone therapy.

In 23 out of 39 patients with various malignancies, treated with hormones (Prednison, Agostiben, Agovirin, separately, or combined; Prednison plus another hormone) modification of HLA antigens was established. Out of 51 patients with hitherto untreated malignancies HLA modification was demonstrated in 12 cases. This variation is statistically significant (P 0.0006), and suggests hormonal therapy to be one of the causes of HLA modification in malignant tumors. The serological pattern of HLA modification varied: in five patients lymphocyte polyreactivity; in 10, loss of HLA antigens; in six, weakening of HLA antigens and in two, transformation of HLA--A2 IN HLA--A28. The modification was transient in character. It occurred most frequently following administration of Prednison, or Prednison combined with some other hormone, and was unrelated to drug dosage.

Breast Neoplasms↗
PubMed1985

Changes in the post-translational modification of lysosomal enzymes during development of Dictyostelium.

The form of post-translational modification present on two lysosomal enzymes--acid phosphatase and alpha-mannosidase--changes as part of the developmental program of Dictyostelium discoideum. Prior to 8 h of development, all enzyme molecules are of a single modification type (early form enzyme). Starting at 8 h of development, enzyme molecules with a second type of modification (late-form enzymes) begin to appear in the cell. We separated the early and late forms of these enzymes from each other by chromatography on DEAE-cellulose. We found that the change in protein modification affects the enzymes' in vitro properties. The early and late forms of both of these enzymes differ in thermostability and susceptibility to proteolytic inactivation. We also found that the late form of alpha-mannosidase is preferentially secreted. We suggest that by synthesizing molecules with a second form of modification, the cell confers new characteristics to its lysosomal enzymes.

Acid Phosphatase↗
PubMed1979

Evidence by chemical modification for the involvement of one or more tryptophanyl residues of bovine antithrombin in the binding of high-affinity heparin.

Tryptophanyl residues of bovine antithrombin were modified with N-bromosuccinimide at near-neutral pH. The reaction was found to be specific for tryptophan at low levels of modification, i.e. when only up to 1--1.3 mol tryptophan/mol protein were oxidized. Further modification led to extensive side reactions. Modification of an average of about one tryptophanyl residue per protein molecule did not affect antithrombin activity measured in the absence of heparin, but decreased the activity assayed in the presence of heparin to about half the value given by unmodified antithrombin. Addition of an excess of high-affinity heparin to a similarly modified antithrombin sample resulted in much smaller circular dichroism, ultraviolet absorption and fluorescence changes than those observed with the intact protein. Modification experiments in the presence of excess high-affinity heparin gave a definitely lower extent of modification than when heparin was excluded. These studies thus reinforce the conclusion from previous spectroscopic analyses that one or more tryptophanyl residues of antithrombin are involved in the binding of high-affinity heparin, presumably by being located at or close to the heparin binding site.

Animals↗
PubMed1989

Studies on the active site of rat glutathione S-transferase isoenzyme 4-4. Chemical modification by tetrachloro-1,4-benzoquinone and its glutathione conjugate.

The active site of glutathione S-transferase isoenzyme 4-4, purified from rat liver, was studied by chemical modification. Tetrachloro-1,4-benzoquinone, a compound previously shown to inactivate glutathione S-transferases very efficiently by covalent binding in or close to the active site, completely prevented the alkylation of the enzyme by iodoacetamide, indicating that the reaction had taken place with cysteine residues. Both from radioactive labeling and spectral quantification experiments, evidence was obtained for the covalent binding of three benzoquinone molecules per subunit, i.e. equivalent to the number of cysteine residues present. This threefold binding was achieved with a fourfold molar excess of the benzoquinone, illustrating the high reactivity of this compound. Comparison of the number of amino acid residues modified by tetrachloro-1,4-benzoquinone with the decrease of catalytic activity revealed an almost complete inhibition after modification of one cysteine residue. Chemical modification studies with diethylpyrocarbonate indicated that all four histidine residues of the subunit are ethoxyformylated in an at least partially sequential manner. Modification of the second histidine residue resulted in complete loss of catalytic activity. Preincubation of the transferase with the glutathione conjugate of tetrachloro-1,4-benzoquinone resulted in 78% protection against this modification. However, glutathione itself hardly protected against the reaction with diethylpyrocarbonate. The intrinsic fluorescence properties of the enzyme were affected by covalent binding of tetrachloro-1,4-benzoquinone. The concentration dependency of the fluorescence quenching is strongly correlated with the inactivation of the enzyme, indicating that covalent binding of the benzoquinone occurs in the vicinity of at least one tryptophan residue. Finally, the binding of bilirubin, as measured by means of circular dichroism, was inhibited by preincubation of the enzyme with tetrachloro-1,4-benzoquinone in a manner which strongly correlated with the loss of enzymatic activity, the protection against inactivation by diethylpyrocarbonate, and the fluorescence quenching. All processes showed a 70-80% decrease after incubation of the enzyme with an equimolar amount of the benzoquinone. Thus, evidence is presented for the presence of a cysteine, a histidine and a tryptophan residue in, or in the vicinity of, the active site of the glutathione S-transferase 4 subunit.

Animals↗
PubMed1981

Brain actin synthesized in vitro undergoes two different and sequential posttranslational modifications.

The have studied the posttranslational processing of actin molecules synthesized in a cell-free system. The results of these experiments indicate that during the in vitro synthesis of the actins from rat brain the primary translational products undergo two different and sequential posttranslational modifications. These modifications are accompanied by slight changes in the isoelectric points of the proteins and can be detected by isoelectric focusing analysis. The same posttranslational modifications can be detected during the in vitro synthesis of chick embryo skeletal muscle actin. The evidence presented suggest that the first posttranslational modification may correspond to the methylation of a histidine residue, and the second modification most likely corresponds to the acetylation of the NH(2)-terminal amino acid residues of actin molecules.

Acetyl Coenzyme A↗
PubMed1990

Regional distribution of alpha-[3H]amino-3-hydroxy-5-methylisoxazole-4-propionic acid binding sites in rat brain: effect of chemical modification of SH- groups in tissue sections.

Previous studies have shown that chemical modifications of sulfhydryl (SH-) groups with mercurial compounds in rat brain membrane preparations increase the binding of alpha-[3H]amino-3-hydroxy-5-methylisoxazole-4-propionic acid [(3H]AMPA), a ligand for the quisqualate/AMPA type of glutamate receptors. In the present study we investigated the regional distribution of SH- group modification by quantitative analysis of autoradiographic images of [3H]AMPA binding in tissue sections. We also compared the effect of SH- group modification to that of the chaotropic ion thiocyanate (SCN-) which has been generally utilized to study [3H]AMPA binding sites. Low levels of binding sites were observed in the absence of potassium thiocyanate (KSCN), with binding predominantly found in telencephalic structures. The presence of KSCN induced a relatively uniform and large (four- to fivefold) increase in binding throughout the different brain structures. Pretreatment of the tissue sections with the SH- group reagent p-chloromercuriphenylsulfonic acid produced a 0.5- to 1.5-fold increase in [3H]AMPA binding. The enhanced binding displayed a regional variation with the largest increase in binding observed in the outer layer of the parietal cortex whereas the lowest increase occurred in the striatum. These results indicate that SH- group modification of tissue sections produces an increase in [3H]AMPA binding similar to that observed in detergent-treated membrane preparations. Moreover they reveal that [3H]AMPA binding sites in different brain regions vary in their susceptibility to modification by SH- reagents, suggesting the existence in brain of a heterogeneous distribution of quisqualate/AMPA receptor subtypes.

4-Chloromercuribenzenesulfonate↗
PubMed2005

Effect of dietary modification on urinary stone risk factors.

BACKGROUND: This study was undertaken to ascertain the effect of dietary modification on urinary stone risks, and to determine whether the response depends on the prevailing urinary calcium. METHODS: A retrospective data analysis was conducted from our stone registry involving 951 patients with calcareous stones undergoing ambulatory evaluation, whereby 24-hour urine samples were collected during random diet and after dietary modification composed of restriction of calcium, oxalate, sodium, and meat products. Samples were analyzed for stone risk factors. Urinary calcium was also obtained after overnight fast and following a 1 g-calcium load. Changes produced by dietary modification from the random diet were evaluated in 356 patients with moderate-severe hypercalciuria (>6.88 mmol/day, group I), 243 patients with mild hypercalciuria (5.00-6.88 mmol/day, group II), and 352 with normocalciuria (<5.00 mmol/day, group III). RESULTS: Urinary calcium postcalcium load and the percentage of patients with absorptive hypercalciuria type I were highest in group I, intermediate in group II, and lowest in group III. During dietary modification, urinary calcium declined by 29% in group I, 19% in group II, and 10% in group III. Urinary oxalate did not change. Urinary saturation of calcium oxalate declined by only 12% in group I, 6% in group II, and nonsignificantly in group III, owing to various physicochemical changes in urinary biochemistry, which attenuated the effect of the decline in urinary calcium. Urinary saturation of brushite declined in all 3 groups due to the fall in urinary calcium, phosphorus, and pH. This reduction was more marked in the hypercalciuric groups than in the normocalciuric group. Urinary saturation of monosodium urate also decreased from a decline in urinary sodium and uric acid. CONCLUSION: Secondary rise in urinary oxalate occurring from calcium restriction can be avoided by concurrent dietary oxalate restriction. Dietary modification (restriction of dietary calcium, oxalate, sodium, and meat products) is more useful in reducing urinary saturation of calcium oxalate among patients with hypercalciuria than among those with normocalciuria.

Adult↗
PubMed2005

Barriers to coronary heart disease risk modification in women without prior history of coronary heart disease.

PURPOSE: To explore the extent to which women perceive barriers to coronary heart disease (CHD) risk modification and to determine if access to a nurse practitioner (NP) decreases perceived barriers to CHD risk modification. DATA SOURCES: Surveys completed by 120 women between the ages of 35 and 60 years, with no known history of CHD. The barriers scale was used to examine women's perceived barriers to CHD risk modification. CONCLUSIONS: Women with access to an NP had less perceived barriers to CHD risk modification. IMPLICATIONS FOR PRACTICE: NPs are ideally suited to decrease the mortality and morbidity associated with CHD through education strategies and attention to individual barriers women face when attempting to incorporate CHD risk factor modification into their lifestyles.

Adult↗
PubMed1994

Aggregation of collagen exposed to UVA in the presence of riboflavin: a plausible role of tyrosine modification.

Riboflavin-sensitized photodynamic modification of collagen led to significant formation of cross-linked molecules. Sodium azide or 1,4-diazabicyclo(2,2,2)octane, which are known to be singlet oxygen quenchers, and catalase could not inhibit the modification. Surprisingly, the collagen modification was accelerated in the presence of superoxide dismutase. The aggregation was accompanied by the loss of tyrosine and histidine residues in the collagen. An inhibitory effect of dissolved oxygen on the modification of collagen was observed. Similarly, the loss of tyrosine residues in the irradiated collagen was inhibited in the presence of dissolved oxygen. Dityrosine formation was also observed with the loss of tyrosine. These results indicate that photodynamic modification of tyrosine probably contributes to the riboflavin-sensitized cross-linking of collagen through the formation of dityrosine.

Animals↗
PubMed1995

Improvement of transdermal delivery of tetragastrin by lipophilic modification with fatty acids.

The in-vitro permeability of chemically modified tetragastrin with fatty acids through the rat skin was studied. The permeability of these compounds through intact skin and stripped skin of rat was determined with a Franz-type diffusion cell. The permeation of tetragastrin across the intact skin was improved by chemical modification with acetic acid and butyric acid. However, tetragastrin and caproyl-tetragastrin did not permeate across the intact skin up to the end of experiment. The permeation of tetragastrin across the stripped skin was improved by chemical modification, the skin flux of these acyl derivatives being in the order:acetyl > butyroyl > caproyl. The stability of tetragastrin in skin homogenate was also significantly improved by chemical modification with fatty acids. These results suggest that chemical modifications of tetragastrin with fatty acids increases its lipophilicity, which makes it permeable across the stratum corneum. Moreover, the chemical modification reduced the degradation of tetragastrin in the viable skin, resulting an increase in permeation of tetragastrin across the skin.

Administration, Cutaneous↗
PubMed1991

Effects of sulphydryl modification on skinned rat skeletal muscle fibres using 5,5'-dithiobis(2-nitrobenzoic acid).

1. The sulphydryl groups of skinned skeletal muscle fibres have been reacted with 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB) in order to determine whether the effects of modifications to the contractile proteins are reflected in changes in the physiological properties of the contractile apparatus and Ca(2+)-regulatory system. 2. Results obtained from fast-twitch and slow-twitch rat fibres which were treated with DTNB (10 mM, pH 8.6, 5 degrees C) for various periods of time under relaxing conditions showed that a major effect of the modification was to reduce the level of maximally Ca(2+)-activated force and fibre stiffness. Force and fibre stiffness were found to decline in proportion. Treatment with DTNB under these conditions did not cause a rise in force or fibre stiffness in relaxed fibres of either type. 3. The effects induced by DTNB under relaxing conditions were substantially reversed by exposure to the reducing agent dithiothreitol (DTT) (10 mM, pH 7.1, 23 degrees C). Force abolished by 30-35 s treatment with DTNB recovered after subsequent DTT treatment to 67 +/- 3% (mean +/- S.E.M., n = 4) in fast-twitch fibres and to 91 +/- 2% (n = 7) in slow-twitch fibres. These results were significantly different (t test, P less than 0.001) indicating that the level of force recovery depended upon the fibre type. 4. DTNB was found to affect not only the maximal Ca(2+)-activated force, but also the force-pCa (pCa = -log10[Ca2+]) relationships of the fibres in a complex, fibre-type specific way. DTT treatment partially reversed these DTNB effects. 5. The skinned fibre preparations reacted differently with DTNB under rigor conditions than under relaxing conditions, indicating that rigor modifies the reactivity of the functional sulphydryl groups to the thiol-targeted agents. 6. When superprecipitation assays (an in vitro analogue of fibre contraction) were carried out with recombined myofibrillar proteins which had been previously reacted with DTNB it was found that modification of myosin, but not modification of thin filament proteins, led to changes in the superprecipitation reaction. 7. Both the skinned fibre results and the superprecipitation results indicate that the effects of DTNB upon the fibre characteristics are primarily due to modifications of the sulphydryl groups of myosin. Therefore, these results show that myosin is not only involved in determining the ability of the contractile apparatus to develop force but also in determining the Ca(2+)-regulatory characteristics of the muscle fibre.

Animals↗
PubMed1997

Acceptability for temporal modification of consecutive segments in isolated words.

Perceptual sensitivity to temporal modification in two consecutive speech segments was measured in word contexts to explore the following two questions: (1) whether there is an interaction between multiple segmental durations, and (2) what aspect of the stimulus context determines the perceptually salient temporal markers? Experiment 1 obtained acceptability ratings for words with temporal modifications. The results showed that the compensatory change in duration of a vowel (V) and its adjacent consonant (C) is not perceptually so salient as expected for the simultaneous modifications in the two segments. This finding suggests the presence of a time perception range wider than a single segment (V or C). The results of experiment 1 also showed that rating scores for compensatory modification between V and C do not depend on the temporal order of modified pairs (VC or CV), but rather on the loudness difference between V and C; the acceptability decreased when the loudness difference between V and C became high. This suggests that perceptually salient markers locate around major jumps in loudness. The second finding, the dependence on the loudness jump, was replicated in experiment 2, which utilized a detection task for temporal modifications on nonspeech stimuli modeling the time-loudness features of the speech stimuli. Experiment 3 further investigated the influence of the temporal order of V and C by utilizing the detection task for the speech stimuli instead of the acceptability ratings.

Humans↗
PubMed1998

Acceptability for temporal modification of single vowel segments in isolated words.

Few perceptual studies of the temporal aspects of speech have investigated the influence of changes in segmental durations in terms of acceptability. Aiming to contribute to the assessment of rules for assigning segmental durations in speech synthesis, the current study measured the perceptual acceptability of changes in the segmental duration of vowels as a function of the segment attributes or context, such as base duration, temporal position in a word, vowel quality, and voicing of the following segment. Seven listeners estimated the acceptability of word stimuli in which one of the vowels was subjected to a temporal modification from -50 ms (for shortening) to +50 ms (for lengthening) in 5-ms steps. The temporal modification was applied to vowel segments in 70 word contexts; their durations ranged from 35-145 ms, the mora position in the word was first or third, the vowel quality was /a/ or /i/, and the following segment was a voiced or an unvoiced consonant. The experimental results showed that the listeners' acceptable range of durational modification was narrower for vowels in the first moraic position in the word than for those in the third moraic position. The acceptable range was also narrower for the vowel /a/ than for the vowel /i/, and similarly narrower for vowels followed by unvoiced consonants than for those followed by voiced consonants. The vowel that fell into the least vulnerable class (the third /i/, followed by a voiced consonant) required 140% of the modification of that which fell into the most vulnerable class (the first /a/, followed by an unvoiced consonant) to yield the same acceptability decrement. In contrast, the effect of the original vowel duration on the acceptability of temporal modifications was not significant despite its wide variation (35-145 ms).

Humans↗
PubMed2003

Reversal and stabilization of synaptic modifications in a developing visual system.

Persistent synaptic modifications are essential for experience-dependent refinement of developing circuits. However, in the developing Xenopus retinotectal system, activity-induced synaptic modifications were quickly reversed either by subsequent spontaneous activity in the tectum or by exposure to random visual inputs. This reversal depended on the burst spiking and activation of the N-methyl-D-aspartate subtype of glutamate receptors. Stabilization of synaptic modifications can be achieved by an appropriately spaced pattern of induction stimuli. These findings underscore the vulnerable nature of activity-induced synaptic modifications in vivo and suggest a temporal constraint on the pattern of visual inputs for effective induction of stable synaptic modifications.

2-Amino-5-phosphonovalerate↗
PubMed2005

Inducible covalent posttranslational modification of histone H3.

The physiological state of a eukaryotic cell is determined by endogenous and exogenous signals, and often the endpoint of the pathways that transmit these signals is DNA. DNA is organized into chromatin, a nucleoprotein complex, which not only facilitates the packaging of DNA within the nucleus but also serves as an important factor in the regulation of gene function. The nucleosome is the basic unit of chromatin and generally consists of approximately two turns of DNA wrapped around an octamer of core histone proteins. Each histone also contains an accessible N-terminal tail that extends outside the chromatin complex and is subject to posttranslational modifications that are crucial in the regulation of gene expression. Two distinct categories of histone posttranslational modification have been observed: (i) inducible or stimulation-dependent and (ii) mitosis-dependent. Stimulation by mitogens or stress leads to rapid transient posttranslational modifications of histones, in particular histone H3, which are mechanistically and temporarily distinct from modifications associated with mitosis. This Review focuses mainly on the inducible phosphorylation of histone H3 brought about by different stimuli, such as epidermal growth factor, 12-O-tetradecanoylphorbol-13-acetate, arsenite, or ultraviolet radiation. We examine the most recent, and at times controversial, research data concerning the identity of the histone H3 kinases responsible for this phosphorylation. In addition, the interdependence of phosphorylation and acetylation will be discussed in light of data showing patterns of inducible modification at specific genes.

Acetylation↗
PubMed1975

Comparative studies on microbial and chemical modifications of trichothecene mycotoxins.

The microbial modification of several trichothecene mycotoxins by trichothecene-producing strains of Fusarium nivale and F. solani was studied. These results were compared with the corresponding chemical modifications. The growing mycelia of Fusarium spp. did not convert 4beta-acetoxy-3alpha,7alpha, 15-trihydroxy-12, 13-epoxytrichothec-9-en-8-one (fusarenon) into 3alpha,4beta, 7alpha,15-tetrahydroxy-12,13-epoxy-trichothec-9-en-8-one (nivalenol), whereas 3alpha,4beta,7alpha,15-tetracetoxy-12,13-epoxytrichothec-9-en-8-one (tetraacetylnivalenol) was deacetylated to yield 3alpha-hydroxy-4beta,7alpha,15-triacetoxy-12,13-epoxytrichothec-9-en-8-one (4,7,15-triae-tylnivalenol), which was resistant to further deacetylation. T-2 toxin was transformed intoHT-2 toxin, and 8alpha-(3-methylbutyryloxy)-3alpha,4beta,-15-triacetoxy-12,13-epoxytrichothec-9-en-8-one (T-2 acetate) was transformed into HT-2 toxin via T-2 toxin. Chemical modification with ammonium hydroxide converted tetraacetylnivalenol into fusarenon via 4,7,15-triacetylnivalenol. 3alpha-7alpha,15-Triacetoxy-12,13-epoxytrichothec-9-en-8-one (triacetyldeoxynivalenol) gave deacetylation products lacking the C-7 or c-15 acetyl group in addition to 7alpha,15- diacetoxy-3alpha-hydroxy-12, 13-epoxytrichothec-9-en-8-one (7,15-diacetyldeoxynivalenol). These results demonstrate the regio-selectivity in microbial modification of trichothecenes. Based on the results and available knowledge concerning the transformation of trichothecenes, mechanisms for biological modifications of these mycotoxins are postulated.

Chemical Phenomena↗
PubMed1998

Modification of Ras in eukaryotic cells by Pseudomonas aeruginosa exoenzyme S.

Genetic and functional data suggest that Pseudomonas aeruginosa exoenzyme S (ExoS), an ADP-ribosyltransferase, is translocated into eukaryotic cells by a bacterial type III secretory mechanism activated by contact between bacteria and host cells. Although purified ExoS is not toxic to eukaryotic cells, ExoS-producing bacteria cause reduced proliferation and viability, possibly mediated by bacterially translocated ExoS. To investigate the activity of translocated ExoS, we examined in vivo modification of Ras, a preferred in vitro substrate. The ExoS-producing strain P. aeruginosa 388 and an isogenic mutant strain, 388DeltaexoS, which fails to produce ExoS, were cocultured with HT29 colon carcinoma cells. Ras was found to be ADP-ribosylated during coculture with 388 but not with 388DeltaexoS, and Ras modification by 388 corresponded with reduction in HT29 cell DNA synthesis. Active translocation by bacteria was found to be required, since exogenous ExoS, alone or in the presence of 388DeltaexoS, was unable to modify intracellular Ras. Other ExoS-producing strains caused modification of Ras, indicating that this is not a strain-specific event. ADP-ribosylation of Rap1, an additional Ras family substrate for ExoS in vitro, was not detectable in vivo under conditions sufficient for Ras modification, suggesting possible ExoS substrate preference among Ras-related proteins. These results confirm that intracellular Ras is modified by bacterially translocated ExoS and that the inhibition of target cell proliferation correlates with the efficiency of Ras modification.

ADP Ribose Transferases↗
PubMed2001

Enteropathogenic Escherichia coli (EPEC) Tir receptor molecule does not undergo full modification when introduced into host cells by EPEC-independent mechanisms.

Enteropathogenic Escherichia coli (EPEC), like many other gram-negative pathogens, encodes a type III secretion apparatus dedicated to the release of virulence-associated proteins. One such protein, Tir, is translocated into host cells, where it is modified by the addition of phosphate groups, resulting in a number of species with distinct molecular mass. One phosphorylation event, on tyrosine residue 474 of Tir, does not contribute to shifts in molecular mass but is essential for its actin-nucleating function. The role of the nonphosphotyrosine related modifications is unknown. In this paper, we demonstrate, using three different approaches, that Tir does not encode sufficient information to facilitate its complete modification when introduced into host cells in EPEC-independent mechanisms. Each system revealed that Tir is a substrate for a host kinase whose action results in its partial modification to a form similar to one evident in EPEC-infected host cells. Further Tir modification could not be induced by infecting cells with EPEC, suggesting that Tir must be coexpressed with other EPEC factors to enable its full modification within host cells. One approach used Yersinia spp. to deliver Tir into host cells, and this system revealed that Tir secretion and translocation can occur in the absence of the Tir chaperone molecule, CesT (formerly known as OrfU). CesT was found to be an efficiency factor which was not required, unlike in EPEC, for Tir stability, indicating that it may function to guide Tir to the translocation apparatus or maintain it in a secretion-competent form.

Bacterial Proteins↗