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PubMed1993

Covalent modification of DNA by daunorubicin.

Daunorubicin, a clinically useful antitumor agent, induces mammary adenocarcinoma in Sprague-Dawley rats. As part of an investigation of the mechanism of tumor induction by daunorubicin, the formation of daunorubicin-DNA adducts has been investigated by 32P-postlabeling assay. Rat-liver DNA incubated with either 0.05 or 0.1 mM daunorubicin, rat-liver microsomes, and 5 mM reduced nicotinamide adenine dinucleotide phosphate (NADPH) for 1 h contained covalent DNA adducts in addition to the endogenous adduct profile present in control DNA. With 1.5 mM cumene hydroperoxide serving as a cofactor, higher levels of these two adducts and two additional adducts were formed, all of which most likely were daunorubicin-DNA adducts. This latter treatment also resulted in an intensification of three endogenous DNA modifications over levels occurring in control DNA. Covalent DNA alterations in vivo were studied in rats treated with 20 mg/kg daunorubicin for 2 days and 200 mg/kg on the 3rd day. Daunorubicin-DNA adducts as observed in vitro could not be detected in DNA of liver or mammary epithelial cells. The levels of endogenous modifications in drug-treated rats were increased by 200% in mammary DNA and by 50% in hepatic DNA as compared with controls. It was concluded from these experiments that daunorubicin may be metabolically activated to a reactive metabolite that binds covalently to DNA. These daunorubicin-DNA adducts may not play a role in tumor induction because they were not detectable in vivo. However, the increase in levels of endogenous DNA modifications induced by daunorubicin both in vitro and in vivo is consistent with a role of this class of DNA modification in the carcinogenic process.

Animals↗
PubMedDate not supplied

Recent approaches to probe functional groups in ribonuclease P RNA by modification interference.

Modification interference is a powerful method to identify important functional groups in RNA molecules. We review here recent developments of techniques to screen for chemical modifications that interfere with (i) binding of (pre-)tRNA to bacterial RNase P RNA or (ii) pre-tRNA cleavage by this ribozyme. For example, two studies have analyzed positions at which a substitution of sulfur for the pro-Rp oxygen affects tRNA binding [1] or catalysis [2]. The results emphasize the functional key role of a central core element present in all known RNase P RNA subunits. The four sulfur substitutions identified in one study [2] to inhibit the catalytic step also interfered with binding of tRNA to E. coli RNase P RNA [1]. This suggests that losses in binding energy due to the modification at these positions affect the enzyme-substrate and the enzyme-transition state complex. In addition, the two studies have revealed, for the first time, sites of direct metal ion coordination in RNase P RNA. The potentials, limitations and interpretational ambiguities of modification interference experiments as well as factors influencing their outcome are discussed.

Base Sequence↗
PubMed1993

Random chemical modification of the oxygen-linked chloride-binding sites of hemoglobin: those in the central dyad axis may influence the transition between deoxy- and oxy-hemoglobin.

The features of random chemical modification are defined with reference to acetylation of bovine hemoglobin, which has been performed in a random manner so that all of the amino groups that participate in functional chloride binding (i.e., those that are oxygen-linked) could be identified. Random chemical modification, which has objectives different from those of both specific (selective) and extensive chemical modification, has been achieved for bovine hemoglobin with the mild reagent, 14C-methyl acetate phosphate; retention of function was demonstrated by a Hill coefficient of n = 2.2 for the modified hemoglobin. After removal of unmodified Hb chains, the mixture of randomly modified acetylated alpha or beta chains was subjected to tandem treatment with trypsin and chymotrypsin. Peptides were purified by HPLC and identified by amino acid analysis. The amount of radioactivity in the acetylated amino group of a purified peptide was taken as an estimate of the degree of chloride binding. For bovine Hb, two amino groups of the alpha-chain (Val-1 and Lys-99) and three amino groups of the beta-chain (Met-1, Lys-81, and Lys-103) were shown to be oxygen-linked (i.e., to have incorporated significantly more radioactivity in the deoxy conformation compared to the same site in the oxy conformation). Three of these sites were already known chloride-binding sites [i.e., Val-1(alpha), the N-terminus of the alpha-chain, and two sites between the 2 beta-chains of bovine hemoglobin, Met-1(beta) and Lys-81(beta); these findings support the conclusions of the random modification approach. Two other chloride-binding sites, Lys-99(alpha) and Lys-103(beta), align the sides of the central dyad axis connecting the two well-known major chloride-binding sites of bovine Hb. The interrelationship of these five chloride-binding sites was assessed by improved molecular graphics. When viewed through the central dyad axis, the functional chloride-binding sites in the central cavity appear to be symmetrically related and to connect the two major chloride-binding sites. Modifiers or mutants that are directed at these regions in the central dyad axis may favor the deoxy conformation to provide a lower oxygen affinity by preventing the constriction of the central cavity that normally occurs upon oxygenation.

Acetylation↗
PubMed1987

Effect of calcium and F-actin on the rate of SH2 modification in skeletal myosin.

The rate constant of modification of a specific thiol group, SH2, with N-ethylmaleimide (NEM) has been used to estimate the conformational change in the local area containing SH2 (SH2 region) of skeletal myosin as a structural probe. The rate of Mg2+-ATP-induced SH2 modification of subfragment-1 (S-1) isozymes was regulated by Ca2+ in the pCa range below 6.4 and was not regulated in the pCa range above 6.4. No substantial difference between S-1 containing alkali light chain, A1, (S-1(A1] and S-1 containing alkali light chain, A2, (S-1(A2] was observed in the Ca2+-dependent rate of SH2 modification. Due to the presence of this Ca2+ regulation in myosin (absence in S-1 isozymes) in the pCa range above 6.4, absence of 5,5'-dithiobis-(2-nitrobenzoic acid) (DTNB) light chain in S-1 isozymes, and high affinity of Ca2+ for DTNB light chain, this Ca2+ regulation in the pCa range above 6.4 is possibly related to the Ca2+ binding to DTNB light chain. F-Actin, which is entirely free from tropomyosin and troponin, enhanced the rate of Mg2+-ATP-induced SH2 modification of S-1 isozymes equally and of myosin, and reduced the Ca2+ sensitivity with an increase in F-actin concentration.

Actins↗
PubMed1995

Glutathione adducts, not carbamylated lysines, are the major modification of lens alpha-crystallins from renal failure patients.

alpha-Crystallins from the water-soluble and the water-insoluble, guanidine-soluble portions of lenses from four renal failure patients and two normal donors of similar age were isolated and enzymatically digested into peptides. Molecular weights of the peptides, determined by fast atom bombardment mass spectrometry, indicated modifications specifically associated with renal failure. The only modifications observed in the alpha-crystallins from renal failure patients, but not in the normal old lenses, were glutathione adducts to Cys 131 and Cys 142. These adducts were present in the lenses of all four renal failure patients, but not in the two normal old lenses. The four lenses from the renal failure patients were searched for evidence of carbamylation at lysyl or cysteinyl residues: carbamylation was not detected. Because the same mass spectrometric methods had previously demonstrated sufficient sensitivity and specificity to detect as little as 5% modification in the examination of in vitro carbamylated bovine lenses, these results indicated that carbamylation is not a major modification of the lens alpha-crystallins of renal failure patients.

Aged↗
PubMed1991

Parametric determinants in pre-stimulus modification of acoustic startle: interaction with ketamine.

Prepulse inhibition of the acoustic startle response is a form of reflex modification known to be sensitive to drugs and to subtle procedural manipulations. The present study examined the importance of prepulse length and prepulse-pulse interval in the expression of prepulse inhibition and its modification by the noncompetitive N-methyl-D-aspartate antagonist, ketamine. In contrast to a previous report, ketamine disrupted prepulse inhibition at doses of 5.6 and 10 mg/kg when its short time course was taken into consideration. In a second experiment, the amount of prepulse inhibition was found to be directly related to prepulse length, with prepulse inhibition produced by shorter prepulse durations slightly more sensitive to disruption by ketamine. A third experiment examined prepulse-pulse time intervals (30-2000 ms). While prepulse inhibition produced by prepulses occurring 60-500 ms before the startle stimulus was disrupted by 10 mg/kg of ketamine, prepulses preceding the startle stimulus by only 30 ms produced either no effect or slight prepulse facilitation under control conditions, and significant prepulse facilitation when ketamine was administered. A fourth experiment examined the time course of prestimulus modification by continuous lead stimuli, ranging in onset from 15 to 75 ms before the startle stimulus. Prepulse facilitation, when observed, tended to occur in earlier portions of the session and was enhanced by ketamine. These results suggest that prestimulus modification of the startle reflex has important parametric and experiential determinants that may influence the effects of drugs. Some of these temporal determinants may have relevance to sensorimotor function in schizophrenia.

Acoustic Stimulation↗
PubMed2004

Quantification of left ventricular modification in weightlessness conditions from the spatio-temporal analysis of 2D echocardiographic images.

Two-dimensional echocardiography (2DE) performed during flights with a parabolic trajectory to simulate weightlessness provides a unique means to study left ventricular (LV) modifications to prevent post-flight orthostatic intolerance in astronauts. However, conventional analysis of 2DE is based on manual tracings and depends on experience. Accordingly, the aim was objectively to quantify, from 2DE images, the LV modifications related to different gravity levels, by applying a semi-automated level-set border detection technique. The algorithm validation was performed by the comparison of manual tracing results, obtained by two independent observers with 20 images, with the semi-automated measurements. To quantify LV modifications, three consecutive cardiac cycles were analysed for each gravity phase (1 Gz, 1.8 Gz, 0 Gz). The level-set procedure was applied frame-by-frame to detect the LV endocardial contours and obtain LV area against time curves, from which end-diastolic (EDA) and end-systolic (ESA) areas were computed and averaged to compensate for respiratory variations. Linear regression (y = 0.91x + 1.47, r = 0.99, SEE:0.80cm2) and Bland-Altman analysis (bias = -0.58 cm2, 95% limits of agreement= +/- 2.14cm2) showed excellent correlation between the semi-automatic and manually traced values. Inter-observer variability was 5.4%, and the inter-technique variability was 4.1%. Modifications in LV dimensions during the parabola were found: compared with 1 Gz values, EDA and ESA were significantly reduced at 1.8 Gz by 8.8 +/- 5.5% and 12.1 +/- 10.1%, respectively, whereas, during 0 Gz, EDA and ESA increased by 13.3 +/- 7.3% and 11.6 +/- 5.1%, respectively, owing to abrupt changes in venous return. The proposed method resulted in fast and reliable estimations of LV dimensions, whose changes caused by different gravity conditions were objectively quantified.

Adult↗
PubMed2001

Study on modification of the Misgav Ladach method for cesarean section.

172 cases of pregnant women scheduled for delivery by cesarean section were randomly assigned to 59 cases in modification group with modified Misgav Ladach technique, 57 cases in Misgav Ladach group with Misgav Ladach technique and 56 cases in Pfannenstiel group with Pfannenstiel technique from May to Dec. 1999. The modified points included: transversely incising the fascia 2 to 3 cm, then dividing it bluntly; without opening and dissociating the visceral peritoneum; two layers suturing of low transverse uterine incision; closing the skin by continuous suturing. Results showed the average delivery time in the modification group was (3.6 +/- 2.6) min and (5.7 +/- 2.9) min in the Misgav Ladach group (P < 0.05). Median operating time was (28.3 +/- 5.4) min in modification group compared with (27.5 +/- 6.5) min in the Misgav Ladach group (P > 0.05). Average blood loss was (128 +/- 35) ml in modification group compared with (212 +/- 147) ml in the Pfannenstiel group (P < 0.05). It was concluded that the modified Misgav Ladach technique not only preserved all advantages of Misgav Ladach method, but also had additional advantages, such as faster in delivering the fetus, less damage, easier mastering for obstetricians.

Adult↗
PubMed2005

Bulk and surface modifications of polylactide.

This article reviews various methods of modifying the bulk and surface properties of poly(lactic acid) (PLA) so that the polymer may be used as a drug carrier in a drug delivery system (DDS) and as a cell scaffold in tissue engineering. Copolymerization of lactide with other lactone-type monomers or monomers with functional groups such as malic acid, copolymerization of lactide with macromolecular monomer such as poly(ethylene glycol) (PEG) or dextran, as well as blending polylactide and natural derivatives and other methods of bulk modification are discussed. Surface modifications of PLA-type copolymers, such as surface coating, chemical modification, and plasma treatment are described. Cell culture technology proves the efficiency of bulk and surface modification and the potential application of PLA in tissue engineering.

Absorbable Implants↗
PubMed2001

Medial prefrontal lesions attenuate conditioned reflex facilitation but do not affect prepulse modification of the eyeblink reflex in rabbits.

Conditioned reflex facilitation occurs when the amplitude of the eyeblink (EB) unconditioned reflex (UR) is increased as a result of prior pavlovian conditioning. Prepulse modification of the EB reflex is produced by preceding the unconditioned stimulus (US) by a brief low-level neutral stimulus. This study examined both conditioned EB facilitation and prepulse modification in rabbits with either medial prefrontal (mPFC) lesions or sham lesions. Conditioned reflex facilitation was assessed by comparing EB UR amplitude prior to and after pavlovian EB conditioning. Animals that received CS/US paired presentations showed evidence of conditioned reflex facilitation, but animals with unpaired training did not. However, this increase in EB UR magnitude in the paired groups was smaller in animals with mPFC lesions, compared to those with sham lesions. In two subsequent experiments different groups of sham and lesion animals received an intense burst of white noise preceded by tones with different interstimulus interval durations to assess prepulse modification. Unlike conditioned facilitation, prepulse modification was unaffected by mPFC lesions.

Acoustic Stimulation↗
PubMed2003

Identification of novel histone post-translational modifications by peptide mass fingerprinting.

The extent and pattern of histone post-translational modifications is a key determinant dictating the structure of chromatin. We employed mass spectrometry to map the post-translational modifications present on mammalian core histones. Using accurate peptide mass fingerprinting on proteolytic digests of purified histones, we identified more than 20 novel sites of histone modification. One newly identified site of methylation, histone H4 lysine 59, maps to the surface of the nucleosome in close proximity to the site of the only identified histone core modification, histone H3 lysine 79. Consistent with the role of histone H3 lysine 79 methylation in the formation of silent chromatin structure, histone H4 lysine 59 is essential for transcriptional silencing at the yeast silent mating loci and telomeres.

Alanine↗
PubMed2000

Nucleoli undergo structural and molecular modifications during hibernation.

The nucleolus is a very dynamic structure able rapidly to adapt its activity to the cellular metabolic state. An interesting physiological model characterized by drastic modifications of cellular metabolism is represented by hibernating animals. In the present study we investigated the hepatocyte nuclei of euthermic and hibernating edible dormice (Glis glis) with the aim of revealing, by means of ultrastructural and immunocytochemical analyses, possible modifications of nucleolar components during hibernation. Our observations demonstrate that, in deep hibernation, nucleoli undergo structural and molecular modifications: (a) they show numerous nucleoplasmic invaginations and clumps of dense fibrillar component extend from the nucleolar surface; (b) they are frequently in contact with coiled bodies and fibro-granular material, two nuclear bodies usually occurring in the nucleoplasm; (c) the dense fibrillar component contains significant amounts of small nuclear ribonucleoproteins, splicing factors usually distributed in the nucleoplasm. Taken together, these results suggest that during hibernation complex relationships are established between the nucleolus and nucleoplasm, probably related to functional activities peculiar to this physiological phase. However, since no evident nucleolar modification was found in early hibernating dormice, it seems likely that the particular structural and molecular arrangement of nucleoli establishes progressively during hibernation, becoming evident only in the deepest phase, and then disappears upon arousal.

Animals↗
PubMed2006

Influence of a new surface modification of intraocular lenses with fluoroalkylsilan on the adherence of endophthalmitis-causing bacteria in vitro.

INTRODUCTION: Dynasilan is a fluoroalkylsilan that is able to interact with surface active centres on intraocular lenses (IOL), offering a new way for surface modification of different IOL materials. The purpose of this in vitro study was to investigate the influence of this new surface modification on the adherence of two typical endophthalmitis causing bacteria (Staphylococcus epidermidis, Propionibacterium acnes). MATERIALS AND METHODS: In a pilot experiment, the effect of Dynasilan coating on the adherence of S. epidermidis was tested on glass slides. Forty-two Dynasilan-modified and 42 unmodified IOL (14 PMMA, 14 silicone and 14 hydrogel) were incubated at 37 degrees C in brain heart infusion broth (10(8) CFU/ml) with either S. epidermidis for 24 h or with P. acnes for 1 h. Subsequently, the adherent bacteria were resuspended using ultrasonification at 35 kHz for 3x45 s. After dilution series and incubation at 37 degrees C on Petri dishes for 24 h and 3 days, respectively, the colonies were counted. RESULTS: In the pilot experiment, a markedly lower number of adherent S. epidermidis was observed on Dynasilan-modified glass slides. Of all IOL materials incubated with S. epidermidis, those modified with Dynasilan showed a lower mean number of adherent bacteria (mean 1.37x10(7); SD 2.37x10(7)) than those untreated (2.43x10(7); SD 3.04x10(7)). IOLs incubated with P. acnes showed a significantly lower mean number of adherent bacteria of 2.51x10(4) (SD 2.71x10(4)) on Dynasilan-modified IOLs versus 6.27x10(4) (SD 7.70x10(4)) on untreated IOLs. CONCLUSION: The presented in vitro results indicate that Dynasilan surface modification is able to reduce the adherence of S. epidermidis and P. acnes on all IOL materials tested. Further studies regarding the stability of this modification and its biocompatibility must be performed.

Bacterial Adhesion↗
PubMed2004

Modification of landing conditions at contact via flight.

Weight-bearing tasks performed by humans consist of a series of phases with multiple objectives. Analysis of the relationship between control and dynamics during successive phases of the tasks is essential for improving performance without sustaining injury. Experimental evidence regarding foot landings suggests that the distribution of momentum among segments at contact influences stability during interaction with the landing surface. In this study, we hypothesized that modification of control in one subsystem, in our case shoulder torque, during the flight phase of an aerial task would enable the performer to maintain behavior of other subsystems (e.g.lower extremity kinematics) and initiate contact with momentum conditions consistent with successful task performance. To test this hypothesis, an experimentally validated multilink dynamic model that incorporated modifications in shoulder torque was used to simulate the flight phase dynamics of overrotated landings. The simulation results indicate that modification in shoulder torque during the flight phase enables gymnasts to maintain lower extremity kinematics and initiate contact with trunk angular velocities consistent with those observed during successful landings. These results suggest that modifications in the control logic of one subsystem may be sufficient for achieving both global and local task objectives of landing.

Biomechanical Phenomena↗
PubMed2004

Post-translational modifications of tau protein in Alzheimer's disease.

Microtubule-associated protein tau undergoes several post-translational modifications and aggregates into paired helical filaments (PHFs) in Alzheimer's disease (AD) and other tauopathies. These modifications of tau include hyperphosphorylation, glycosylation, ubiquitination, glycation, polyamination, nitration, and proteolysis. Hyperphosphorylation and glycosylation are crucial to the molecular pathogenesis of neurofibrillary degeneration of AD. The others appear to represent failed mechanisms for neurons to remove damaged, misfolded, and aggregated proteins. This review summarizes the abnormal post-translational modifications of tau and discusses the pathophysiological relevance of hyperphosphorylation and glycosylation of tau. Total tau and phosphorylated tau levels in cerebrospinal fluid as a diagnostic biomarkers are also reviewed. Analyses of the current advances in tau modifications suggest that intervention addressing these abnormalities may offer promising therapeutic opportunities to prevent and treat neurofibrillary degeneration of AD and other tauopathies.

Alzheimer Disease↗
PubMed2005

O-GlcNAc modification of nucleocytoplasmic proteins and diabetes.

Nuclear and cytosolic proteins are glycosylated on serine or threonine residues by O-linked beta-N-acetylglucosamine (O-GlcNAc). O-GlcNAc modification is one of various posttranslational modifications and seems to be involved in the modulation of transcription and signal transduction. Accumulating data suggest a role for O-GlcNAc-modified proteins in diabetes, acting as a glucose sensor. It has been suggested that the hexosamine biosynthetic pathway is involved in the mechanism causing insulin resistance and diabetic complications. Excess glucose entering into the hexosamine biosynthetic pathway might cause elevated O-GlcNAc modification of various proteins. In this article, we review the current data regarding the relationship between O-GlcNAc modification and diabetes.

Acetylglucosamine↗
PubMed2005

Plasticity of histone modifications across the invertebrate to vertebrate transition: histone H3 lysine 4 trimethylation in heterochromatin.

Histone posttranslational modifications mediate establishment of structurally and functionally distinct chromatin compartments of eukaryotic nuclei. The association of different histone modifications with euchromatic and heterochromatic compartments is relatively conserved in highly divergent model organisms such as Drosophila and mammals. However, some differences between these model systems have been uncovered while limited data are available from organisms nearer the invertebrate-vertebrate transition. We identified a chromatin compartment in both diploid and endocycling cells of the urochordate, Oikopleura dioica, enriched in heterochromatic histone modifications and DNA methylation. Surprisingly, this compartment also contained high levels of histone H3 trimethylated at lysine 4 (H3 Me(3)K4), a modification thus far associated with actively transcribed sequences. Although in Drosophila and mouse cells, H3 Me(3)K4 was prevalently associated with euchromatin, we also detected it in their pericentromeric heterochromatin. We further showed that H3 Me(3)K4 abundance was not necessarily proportional to local levels of transcriptional activity in either euchromatin or heterochromatin. Our data indicate greater plasticity across evolution in the association of histone lysine methylation with functionally distinct chromatin domains than previously thought and suggest that H3 Me(3)K4 participates in additional processes beyond marking transcriptionally active chromatin.

Animals↗
PubMed2006

Effects of magnesium sulfate administration during hypoxia on Ca(2+) influx and IP(3) receptor modification in cerebral cortical neuronal nuclei of newborn piglets.

Magnesium is a non-competitive antagonist of the NMDA receptor. Hypoxic insults to the brain are associated with a significant increase in the intranuclear Ca(2+) due to altered nuclear membrane Ca(2+) influx mechanisms including hypoxia-induced modifications of nuclear membrane IP(3) receptors. In this study we have examined the effects of magnesium sulfate administration to newborn piglets subjected to normoxia and severe hypoxia. The animals were randomly divided into normoxic (n=4), hypoxic (n=4) and magnesium sulfate treated hypoxic (n=4) groups. Hypoxia was confirmed biochemically by measuring ATP and phosphocreatine (PCr) levels in the brain tissue. Intranuclear Ca(2+) influx was assessed by measuring (45)Ca(2+) uptake. Results show a significant (P<0.05) decrease in ATP and PCr levels in hypoxic group in comparison with normoxia. On the other hand magnesium-treated hypoxic group showed a significantly (P<0.05) higher ATP and PCr in comparison with the hypoxic group. Intranuclear Ca(2+) was significantly (P<0.05) higher in the hypoxic group in comparison with both normoxic and magnesium-treated hypoxic groups. In addition results show that magnesium prevented hypoxia-induced modification of the IP(3) receptor. Magnesium treatment significantly reduced the hypoxia-induced increase in the number of receptors (reduced B(max) --P<0.05-treated hypoxia vs. hypoxia and normoxia), and reversed the receptor affinity (reduced dissociation coefficient-K(d)--P<0.05-treated hypoxia vs. normoxia). The results demonstrate that the administration of magnesium sulfate prior to hypoxia prevents the hypoxia-induced increase in intranuclear Ca(2+) and IP(3) receptor modifications. We conclude that Mg(2+ )administration prevents hypoxia-induced modification of neuronal nuclear membrane function that leads to intranuclear Ca(2+)-dependent transcription of apoptotic proteins leading to hypoxic neuronal programmed cell death.

Adenosine Triphosphate↗