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PubMed2002

Kinetic analysis of the general modifier mechanism of Botts and Morales involving a suicide substrate.

Suicide substrates are widely used in enzymology for studying enzyme mechanisms and designing potential drugs. The presence of a reversible modifier decreases or increases the rate of substrate-induced inactivation, with evident physiological and experimental consequences. To date, only the action of a competitive or uncompetitive inhibitor of an enzyme system involving suicide substrate has been reported. In this paper, we analyse the kinetics of enzyme-catalysed reactions which evolve in accordance with the general modifier mechanisms of Botts and Morales in which enzyme inactivation is induced by suicide substrate. Rapid equilibrium of all of the reversible reaction steps involved is assumed and the time course equations for the residual enzyme activity, the inactive enzyme forms and the reaction product are derived. Partition ratios giving the relative weight of the product and inactive enzyme concentrations, and the relative contribution to the product formation of each of the unmodified and modified catalytic routes, are studied. New indices pointing to the conditions under which the modifier acts as inhibitor or as activator are suggested. The goodness of the analytical solutions is tested by comparison with the simulated curves obtained by numerical integration. An experimental design and kinetic data analysis to evaluate the kinetic parameters from the time progress curves of the product are proposed. From these results, those corresponding to several reaction mechanisms involving both a suicide substrate and a modifier, and which can be regarded as particular cases of the general case analysed here, can be directly and easily derived.

Animals↗
PubMed2001

Two point mutations increase targeted transduction and stabilize vector association of a modified retroviral envelope protein.

The current strategy of targeting retroviral vector transduction by inserting a peptide ligand into the envelope protein has met with several obstacles. These modified proteins redirected vector binding to a new cognate receptor on a specific cell type but gave little or no gene transfer because they did not fuse the vector and target cell membranes. They dissociated readily from vectors and often required coassembly of wild-type envelope protein. Here we report a novel strategy to overcome the fusion and stability defects of modified retroviral envelope proteins. We inserted a prototypic ligand, the receptor binding domain of amphotropic murine leukemia virus, into an ecotropic murine leukemia virus envelope protein mutant containing glutamine 227-to-arginine plus aspartate 243-to-tyrosine substitutions. This modified protein increased transduction redirected to human cells expressing the amphotropic receptor to a level within 10-fold that of wild-type amphotropic virus, an increase of as great as 2000-fold over transduction by modified protein lacking the mutations. In addition to suppressing the fusion defect, these mutations unexpectedly stabilized the association of the modified protein with vector particles. Insertion of clinically relevant ligands into this envelope mutant should improve the efficiency and reliability of retroviral transduction of specific cell types for gene therapy applications.

Cells, Cultured↗
PubMed1983

Modified nucleosides in body fluids of tumor-bearing patients.

The catabolism of nucleic acids, particularly tRNA, produces a variety of modified nucleosides which are not reutilized by mammalian cells. Investigation of these compounds in body fluids, mainly urine, has recently provided evidence of altered metabolic situations in tumor-bearing patients. The factors involved in the alterations of modified nucleosides formation are connected with altered tRNA-modifying enzymes and/or altered turnover of subpopulations of tRNA. A common pattern in tumor cells or tissues is the presence of isoaccepting tRNA species containing aberrant nucleoside modifications. Several modified nucleosides have been detected and quantitated by HPLC analysis of the urine of normal subjects and cancer patients. Results obtained, in the authors' laboratory, among others, indicate a possible correlation between urinary excretion of these compounds and the course of the disease, with implications for the follow-up of therapeutic treatment. Particular reference should be made to psi, which appears to be a suitable marker for monitoring these subjects. The data from the authors' laboratory also show that the analysis of modified nucleosides in blood may be considered a useful tool in the search for proper markers associated with the cancer status. In this respect psi is suggested as a biochemical indicator for cancer patients.

Chromatography, High Pressure Liquid↗
PubMed1995

Identification of two opaque2 modifier loci in quality protein maize.

Genetic modifiers of opaque2 convert the soft, starchy endosperm of opaque2 maize mutants to a hard, vitreous phenotype, while maintaining the enhanced lysine content of the grain. Genetic analysis of F2 segregating seeds from crosses of opaque2 by modified opaque2 genotypes indicated that the modifiers are complex traits that act codominantly. We developed two different segregating F2 populations and mapped the modifier loci by restriction fragment length polymorphism (RFLP) analysis. A relationship was found between formation of vitreous endosperm and the locus encoding the gamma-zein storage protein, which maps near the centromere of chromosome 7. Endosperm modification was consistently associated with the presence of two rather than one gamma-zein gene at this locus. A second modifier locus was mapped near the telomere of chromosome 7L.

Alleles↗
PubMed1985

The assessment of analogical thinking modifiability among regular, special education, disadvantaged, and mentally retarded children.

The objectives of the current study were (a) to develop a measure of children's analogical thinking modifiability (CATM) based on the Feuerstein, Rand, and Hoffman (1979) theory of dynamic assessment of cognitive modifiability, (b) to compare the performance of groups assumed to be differentially modified by intervention, (c) to compare CATM performance with performance on a conventional test, and (d) to study qualitative changes after a learning process. Subjects were disadvantaged, regular, and special education kindergarten children (N = 140), and mentally retarded children (N = 20). The CATM was administered together with the Ravens Colored Progressive Matrices (RCPM) in a balanced order. Disadvantaged and regular children achieved higher gain scores than other groups in both none-or-all and partial credit methods (p less than .01). The MR and the special education groups showed small gains according to the none-or-all credit method; however, according to the partial credit method, the MR group showed high gains and the special education group a performance decrease. Performance scores on the CATM were higher than on the RCPM, especially in comparison to the B8-B12 items--differences reach a peak of 61% and 67% for the disadvantaged and regular groups, respectively. Qualitative analysis indicated that form mistakes were most resistant to change, whereas color mistakes were most easy to modify. Results were explained within Feuerstein's theoretical framework of cognitive modifiability. Impaired cognitive functions as well as analytic versus synthetic processes were suggested to explain group differences.

Adolescent↗
PubMed1991

Reduction of fresh gas flow requirements by a circle-modified bain breathing circuit.

We modified a Bain circuit by placing the circuit into the Y piece of a standard carbon dioxide absorber circle, connecting the fresh gas hose on the anesthetic machine to the Bain's fresh gas inlet, and occluding the circle's fresh gas inlet. This circle-modified Bain breathing circuit was studied to evaluate whether it reduces fresh gas flow requirements. The Bain and modified Bain steady states were analyzed by mechanical and computer modeling. The mechanical model consisted of an artificial lung ventilated to steady state. Carbon dioxide was measured with capnography. Computer modeling was by compartmental analysis calculated with spread-sheet software. Steady-state solutions were obtained by numeric analysis. The circle-modified Bain greatly reduced retention of carbon dioxide. For example, with 1-liter tidal volumes, 10-liter minute volumes (10 breaths per minute), and a 2.1 L/min fresh gas flow, the steady-state end-tidal carbon dioxide values of the Bain and modified Bain were 9.3 and 4.6%, respectively, in the physical model (carbon dioxide inflow of 230 ml/min). Results from the mechanical model helped validate the computer model.

Anesthesia, Closed-Circuit↗
PubMed1989

Gating in iodate-modified single cardiac Na+ channels.

Elementary Na+ currents were recorded at 19 degrees C during 220-msec lasting step depolarizations in cell-attached and inside-out patches from cultured neonatal rat cardiocytes in order to study the modifying influence of iodate, bromate and glutaraldehyde on single cardiac Na+ channels. Iodate (10 mmol/liter) removed Na+ inactivation and caused repetitive, burst-like channel activity after treating the cytoplasmic channel surface. In contrast to normal Na+ channels under control conditions, iodate-modified Na+ channels attain two conducting states, a short-lasting one with a voltage-independent lifetime close to 1 msec and, likewise tested between -50 and +10 mV, a long-lasting one being apparently exponentially dependent on voltage. Channel modification by bromate (10 mmol/liter) and glutaraldehyde (0.5 mmol/liter) also included the occurrence of two open states. Also, burst duration depended apparently exponentially on voltage and increased when shifting the membrane in the positive direction, but there was no evidence for two bursting states. Chemically modified Na+ channels retain an apparently normal unitary conductance (12.8 +/- 0.5 pS). Of the two substates observed, one of them is remarkable in that it is mostly attained from full-state openings and is very short living in nature; the voltage-independent lifetime was close to 2 msec. Despite removal of inactivation, open probability progressively declined during membrane depolarization. The underlying deactivation process is strongly voltage sensitive but, in contrast to slow Na+ inactivation, responds to a voltage shift in the positive direction with a retardation in kinetics. Chemically modified Na+ channels exhibit a characteristic bursting state much shorter than in DPI-modified Na+ channels, a difference not consistent with the hypothesis of common kinetic properties in noninactivating Na+ channels.

Animals↗
PubMed1993

Evaluating the fate of genetically modified microorganisms in the environment: are they inherently less fit?

Genetically modified microorganisms hold great promise for environmental applications. Nonetheless, some may have unintended adverse effects. Of particular concern for risk assessment is the simple fact that microorganisms are self-replicating entities, so that it may be impossible to control an adverse effect simply by discontinuing further releases of the organism. It has been suggested, however, that genetically modified microorganisms will be poor competitors and therefore unable to persist in the wild due to energetic inefficiency, disruption of genomic coadaptation, or domestication. Many studies support the hypothesis that genetically modified microorganisms are less fit than their progenitors, but there are a few noteworthy counter-examples in which genetic modifications unexpectedly enhance competitive fitness. Furthermore, subsequent evolution may eliminate the maladaptive effects of some genes, increasing the likelihood that a modified organism or its engineered genes will persist. Evaluating the likelihood that a genetically modified microorganism or its engineered genes will persist is a complex ecological and evolutionary problem. Therefore, an efficient regulatory framework would require such evaluations only when there are plausible scenarios for significant adverse environmental effects.

Bacteria↗
PubMed2006

Effects of CTLA4-Ig gene-modified dendritic cells on the corneal allografts.

In order to investigate the effects of mouse CTLA4Ig gene-modified dendritic cells (DCs) on the survival of the corneal allografts in rats, the plasmid PG\CTLA4Ig was transfected into DCs of F344 rats mediated by Lipofectamine 2000. The expression of CTLA4Ig was detected by immunofluorescent microscopy. The effects of donor DCs on the proliferation of T cells in Lewis rats (recipients) were tested by by CCK8. Corneal transplantation was performed from F344 rats to Lewis rats. The DCs modified with CTLA4Ig gene were injected into the Lewis rats on the day 0 and 3 after transplantation. The movement of the DCs after modification in vivo was observed by immunofluorescent microscopy, and the survival of corneal allografts was evaluated by Holland criterion. The results showed that the CTLA4Ig-modified DCs could restrain the proliferation of allogenetic T cells. The CTLA4Ig-modified DCs prolonged survival of corneal allografts. (P < 0.01). It was suggested that the injection of CTLA4Ig gene-modified DCs could obviously inhabit the allograft rejection and prolong the survival of corneal allografts.

Abatacept↗
PubMed2005

Treatment of spinal cord injury with co-grafts of genetically modified Schwann cells and fetal spinal cord cell suspension in the rat.

Fetal spinal cord cells, Schwann cells and neurotrophins all have the capacity to promote repair of injured spinal cord in animal models. To explore the possibility of using these approaches to treat clinical patients, we have examined whether a combination of these protocols produces functional and anatomical improvement. The spinal cords of adult rats (n=16) were injured with a modified New York University (NYU) device (10 gram.5cm). One week after injury, the injured cords were injected with Dulbecco-modified Eagles Medium (DMEM, control group), or fetal spinal cord cell suspension (FSCS) plus nerve growth factor (NGF) gene-modified Schwann cells (SC) and brain-derived neurotrophic factor (BDNF) gene-modified SC (treatment group). The rats were subjected to BBB (Basso, Beattie, Bresnahan, Exp. Neurol. 139:244, 1996) behavioral tests. Anterograde tracing of corticospinal tract was performed before sacrifice 3 months after the treatment. The results showed that the combination treatment elicited a robust growth of corticospinal axons within and beyond the injury site. A dramatic functional recovery in the treatment group was observed compared with the control group. We conclude that the combination of FSCS with genetically modified Schwann cells over-expressing NGF and BDNF was an effective protocol for the treatment of severe spinal cord injury.

Animals↗
PubMed2000

Translaryngeal tracheostomy: two modified techniques versus the basic technique--early experience in 75 critically ill adults.

OBJECTIVES: Elective tracheostomy is an established procedure in the management of ICU patients on long-term ventilation. In addition, percutaneous tracheostomy techniques are increasingly being used. In 1997, Fantoni's translaryngeal technique (TLT), another minimally invasive procedure, was introduced. While clinical studies of TLT showed that the technique is safe and can be performed rapidly, technical difficulties which sometimes led to prolonged operating times were also noted. Our study compared the basic TLT technique to a modified TLT approach and to TLT performed with the manufacturer's new, improved "Straight Cannula" set. Twenty-five patients were enrolled in each group, and the advantages and disadvantages of the respective techniques were evaluated. SETTING: Surgical ICU of a university hospital. PATIENTS: Seventy-five adult, surgical intensive care patients. MEASUREMENTS AND RESULTS: Average operating times with the modified TLT techniques were significantly shorter, 4 and 5 min respectively, as compared to 11 min for the basic TLT technique. Initially, use of the new, improved TLT set resulted in a complete passage of the tracheal cannula in two patients; uneventful Griggs's tracheostomy was performed instead. Regardless of the technique used, no other perioperative complications were noted and the perioperative gas exchange remained unaffected by the tracheostomy procedure. CONCLUSIONS: The modified TLT procedures are safer and more readily performed than the basic technique. Difficulty in the retrograde passage of the guide wire was seen only occasionally with the modified techniques. Based on our data we conclude that the modified techniques are superior to the basic technique and represent significant progress in TLT.

Adult↗
PubMed2002

Modified extravesical ureteral reimplantation and routine stenting in kidney transplantation.

In the past, extravesical ureteroneocystostomy has been technically modified several times, with varying results. In this study, we evaluate our experience with modified extravesical re-implantation and routine stenting. From January 1988 to September 2001, 411 consecutive renal transplantations (220 LRD/LUD, 191 CAD) were performed at our institutions. Of 220 kidneys utilized for living related transplantation, 39 were retrieved laparoscopically and 181 were retrieved by open nephrectomy. The ureteroneocystostomy performed was a modified Lich-Gregoir re-implantation with routine stenting, using the upper transplant ureter. A double ureter was encountered in 11 patients and was managed with a conjoint ureteral ostium-to-mucosa anastomosis, using two stents. In two patients with graft ureteropelvic junction (UPJ) stenosis, a double ipsilateral drainage was performed, applying modified extravesical reimplantation with concomitant ureteroneocystostomy. There were no ureteral leaks. Five (1.22%) patients developed temporary ureterovesical junction (UVJ) obstruction/edema following stent removal, which necessitated re-stenting for 4-6 weeks. Two patients (0.49%) developed delayed stenosis and were successfully treated with retrograde balloon dilatation.(One at the UPJ of a pediatric kidney, and one at UVJ). All patients with functioning grafts in this series are currently stent-free. We conclude that the modified extravesical reimplantation with routine stenting is an effective and safe technique in renal transplantation, associated with almost no complications.

Cystostomy↗
PubMed2006

Disease modifying genes in cystic fibrosis: therapeutic option or one-way road?

Cystic fibrosis (CF) is the most common genetic disease among Caucasians and is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CF affects multiple organs but lung disease is the major determinant for morbidity and mortality. Many studies have focussed on the correlation between CFTR genotype and severity of disease. Since patients with identical CFTR mutations often show considerable variability in disease progression, genes other than CFTR are thought to have the potential to modify the course of lung disease in CF patients. Therefore, identification of CF-modifying genes has become the goal of several studies over the last 15 years. Pharmaceutical approaches for CF lung disease have been developed regardless of the underlying genetic defect and in general target symptoms such as airway obstruction and treatment of bacterial infection. Analysing the pathophysiological processes of modifiers may lead to the discovery of pathways involved in CF pathophysiology and possibly to the design of new therapeutics. The purpose of this review is not only to list potential CFTR modifier genes, but also to discuss new therapeutic strategies that could be derived from knowledge of these CF modifiers.

Cystic Fibrosis↗
PubMed2003

Validation of a modified mirrored chamber sensitive to anxiolytics and anxiogenics in mice.

RATIONALE: Anxiety is a common disorder in humans that exists in many forms, and animal models of human anxiety are typically employed for the discovery of anxiolytic drugs with human therapeutic potential. OBJECTIVES: Ideally, animal models of anxiety are validated for the detection of both anxiogenic and anxiolytic effects, but most animal models can effectively only measure anxiolytic-like effects. As control animals typically spend small amounts of time in the aversive portion of an apparatus, decreases in time spent in this portion are difficult to detect. METHODS: We have modified an existing test of murine anxiety, the mirrored chamber, and have validated this test using several anxiolytic and anxiogenic drugs. In addition, nine mouse strains were compared on the elevated plus maze and modified mirrored chamber. RESULTS: Increasing doses of ethanol, diazepam, and pentobarbital produced an anxiolytic-like profile while pentylenetetrazol (PTZ), D-amphetamine, and methyl-6, 7-dimethoxyl-4-ethyl-beta-carboline-3-carboxylate (DMCM) appeared anxiogenic. This modified test also dissociated drug effects on anxiety from those on activity for d-amphetamine and diazepam. The inbred mouse strains tested produced a similar range of scores for time spent on the open arms of the elevated plus maze and voluntary reentry time in the mirrored chamber, with an overall genetic correlation of 0.68. CONCLUSIONS: Since control animals reliably reentered the more aversive portion of the apparatus for 25% of the total time available, the modified mirrored chamber may be able to detect anxiogenic states produced by various stressors and drug withdrawal. Further, the strain differences detected suggest that the modified mirrored chamber will be a valuable tool in the discovery of the genetic bases of anxiety states and disorders.

Animals↗
PubMed2001

Chemical modifiers for direct determination of cobalt in coal combustion residues by ultrasonic slurry-sampling-ETAAS.

Five modifiers were tested for the direct determination of cobalt in coal fly ash and slag by ultrasonic slurry-sampling electrothermal atomic absorption spectrometry (USS-ETAAS). The furnace temperature programs and the appropriate amount for each modifier were optimized to get the highest signal and the best separation between the atomic and background signals. Nitric acid (0.5% v/v) was the most adequate chemical modifier for cobalt determination, selecting 1,450 degrees C and 2,100 degrees C as pyrolysis and atomization temperatures, respectively. This modifier also acts as liquid medium for the slurry simplifying the procedure. The remaining modifiers enhanced the background signal, totally overlapped with cobalt peak. The method optimized gave a limit of detection of 0.36 microg g(-1), a characteristic mass of 13 +/- 1 pg and an overall-method precision which is highly satisfactory (<7%, RSD). The method was validated by analyzing two certified coal fly ash materials, and satisfactory recoveries were obtained (83-90%) and no statistical differences were observed between the experimental and the certified cobalt concentrations. Additionally, certified sediment, soil and urban particulate matter were assayed; again good results were obtained. The developed methodology was used to determine cobalt in several coal combustion residues from five Spanish power plants.

Calibration↗
PubMed2001

Lead determination in slurries of biological materials by ETAAS using a W-Rh permanent modifier.

A tungsten-rhodium coating on the integrated platform of a transversely heated graphite atomiser (THGA) was used as a permanent chemical modifier for the determination of lead in biological materials by slurry sampling in electrothermal atomic absorption spectrometry (ETAAS). Slurries were sonicated during 20 s before being delivered to the previously W-Rh treated platform. The number of particles of biological materials introduced into the atomiser for delivering 20 microL slurry aliquot ranged from 5,100 to 39,000. The permanent W-Rh modifier remained stable during approximately 300 analytical measurements when 20 microL of slurries containing up to 1.5% m/v were delivered into the atomiser. In addition, the permanent modifier increases the tube lifetime by approximately 100% when compared to untreated integrated platforms. Also, there is less decrease of sensitivity during the atomiser lifetime when compared with the conventional modifiers, resulting in a decreased need of re-calibration during routine analysis and consequently increasing the sample throughput. The atomiser lifetime was limited to the THGA wall durability, because the W-Rh treated platform was intact after more than 650 analytical firings in a medium containing up to 1.5% m/v slurry of biological material. The detection limit based on integrated absorbance was 20 ng g(-1) Pb for 1.50% m/v slurries. Results from the determination of lead in slurries of biological materials using the W-Rh permanent modifier were in agreement with those obtained with digested solutions using Pd + Mg(NO3)2.

Animals↗
PubMed2004

Superior cervical ganglionectomy differentially modifies median eminence and anterior and mediobasal hypothalamic GABA content in male rats: effects of hyperprolactinemia.

This work was undertaken to analyze the changes in GABA concentrations in the anterior and mediobasal hypothalamus and in the median eminence after acute or chronic superior cervical ganglionectomy (SCGx), and whether high prolactin levels interfere with the effects of SCGx on GABA content. Acute but not chronic SCGx increased GABA content in all the areas studied, as compared to controls. The presence of a pituitary graft abolished the effects of acute SCGx in the median eminence and anterior hypothalamus, as compared to controls, but potentiated its effects in the mediobasal hypothalamus. Chronic SCGx increased GABA content in the mediobasal and anterior hypothalami, as compared to pituitary grafted controls. Acute SCGx decreased plasma prolactin and GH levels, but chronic surgery did not modify these hormone plasma levels. Acute SCGx increased plasma ACTH levels, whereas chronic SCGx did not modify them. Pituitary grafting increased circulating values of prolactin, ACTH and GH, as compared to controls. Acute SCGx did not modify plasma prolactin levels in grafted animals, although it increased plasma GH levels and decreased those of ACTH in this experimental group. Chronic SCGx further increased both plasma prolactin and GH levels, without modifying plasma ACTH levels. These results suggest that SCGx differentially modifies GABA content within the hypothalamus and median eminence. Induction of hyperprolactinemia in the neonatal age interferes with SCGx effects on both GABA content within the hypothalamus and median eminence and the secretory patterns of the pituitary hormones studied.

Animals↗
PubMed1997

Two types of modified cardiac Na+ channels after cytosolic interventions at the alpha-subunit capable of removing Na+ inactivation.

Failure of inactivation is the typical response of voltage-gated Na+ channels to the cytosolic presence of proteolytic enzymes, protein reagents such as N-bromoacetamide (NBA) or iodate, and antibodies directed against the linker between domains III and IV of the alpha-subunit. The present patch clamp experiments with cardiac Na+ channels aimed to test the hypothesis that these interventions may provoke the occurrence of non-inactivating Na+ channels with distinct kinetic properties. A site-directed polyclonal antibody (anti-SLP2, target sequence 1481-1496 of the cardiac Na+ channel alpha-subunit) eliminated fast Na+ inactivation to induce burst activity which was accompanied by the occurrence of two open states. A deactivation process terminated channel activity during membrane depolarization proceeding with time constants of close to 40 ms (at -40 mV). NBA-modified and iodatemodified Na+ channels were kinetically indistinguishable from the anti-SLP2-modified type since they likewise deactivate and, thus, attain an only moderate Po of close to 20%. This is fundamentally different from the behaviour of enzymatically-modified Na+ channels: after cytosolic proteolysis with alpha-chymotrypsin, trypsin or pronase, mean Po during membrane depolarization amounted to approximately 40% because deactivation operated extremely slowly and less efficiently (time constants 100-200 ms at -40 mV, as a minimum) or was virtually non-operating. Invitro cleavage of the synthetic linker sequence 1481-1496 confirmed that this part of the alpha-subunit provides a substrate for these peptidases or reactants for NBA but cannot be chemically modified by iodate. This iodate resistance indicates that iodate-modified Na+ channels are based on a structural alteration of still another region which is also involved in Na+ inactivation, besides the linker between domains III and IV of the alpha-subunit. Endogenous peptidases such as calpain did not affect Na+ inactivation. This stresses the stochastic nature of a kinetic peculiarity of cardiac Na+ channels, mode-switching to a non-inactivating mode.

Acetamides↗