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PubMed1999

Pharmaceutical fingerprinting in phase space. 2. Pattern recognition.

The current study introduces an approach for pattern recognition of drug manufacturers according to their HPLC trace impurity data. This method considers signals in phase space and accounts for two different types of noise: additive and perturbative. The pharmaceutical fingerprints are estimated as mean trajectories of HPLC trace impurity data and are used as reference models for recognition of new data by the minimal length classifier. The chromatographic trace organic impurity patterns collected from six different manufacturers of L-tryptophan are analyzed as an example. The prediction ability of the new method tested using three different cross-validation procedures remains about 95% even if the number of available data in the training sets decreases by 5 times. The accuracy of prediction in phase space is superior compared to results calculated using a Window Preprocessing method and artificial neural networks. The difference in performance between new and previous methods becomes more significant under particular conditions that are more adequate for practical application of the method. In addition, the current approach enables simple and comprehensive interpretation of the calculated results.

Artificial Intelligence↗
PubMed2006

A rate equation approach to elucidate the kinetics and robustness of the TGF-beta pathway.

We present a rate equation model for the TGF-beta pathway in endothelial cells together with novel measurements. This pathway plays a prominent role in inter- and intracellular communication and subversion can lead to cancer, fibrosis vascular disorders, and immune diseases. The model successfully describes the kinetics of experimental data and also correctly predicts the behavior in experiments where the system is perturbed. A novel method in this context, simulated tempering, is used to fit the model parameters to the data. It provides an ensemble of high quality solutions, which are analyzed with clustering methods and display a hierarchical structure highlighting distinct parameter subspaces with biological interpretations. This analysis discriminates between different biological mechanisms to achieve a transient signal from a sustained TGF-beta input, where one mechanism is to use a negative feedback to turn the signal off. Further analysis in terms of parameter sensitivity reveals that this negative feedback loop in TGF-beta signaling renders the system global robustness. This sheds light upon the role of the Smad7 protein in this system.

Computer Simulation↗
PubMed1976

Incorporation of 75Se-selenomethionine into human apoproteins. III. Kinetic behavior of isotopically labeled plasma apoprotein in man.

The metabolism of lipoprotein-apoprotein was examined in four subjects with normal lipid metabolism and in one subject with type II hyperlipemia by means of isotopic tracer methodology. Studies were performed after intravenous injection of a radioactive amino acid precursor for apoprotein synthesis (75Se-selenomethionine), in both the basal state and following the acute injection of intravenous heparin. Computer technics were used to evaluate a series of multicompartmental models, and a general model is proposed that yields optimum fitting of experimental data for serum free amino acid precursor, very-low-density lipoprotein-apoprotein (VLD-apoprotein), and low-density lipoprotein-apoprotein (LDL-apoprotein) in man. The analysis demonstrates that approximately half of the transport of 75Se-apoVLDL from the plasma VLDL pool is converted to 75Se-apoLDL. The acute injection of heparin in two normal subjects results in a two-and-a-half-fold increase in this rate of conversion of 75Se-apoVLDL to 75Se-apoLDL. 75Se-apoLDL is metabolized by rapid transport into a recycling extravascular pool and by irreversible catabolism. The fractional rate of recycling is large relative to the fractional rate of catabolism of apoLDL (3.7:1.0), suggesting extravascular recycling as a potential site of regulation of the plasma concentration of apoLDL. In a patient with type II hyperlipemia, the extravascular recycling pathway is reduced and is not corrected with D-thyroxine therapy. However, this therapy did reduce conversion of apoVLDL to apoLDL in this type II patient. The kinetic data support the validity of the compartmental model in simulating both normal and pathologic apoprotein metabolism and that perturbation of physiology seen with heparin injection and D-thyroxine therapy. These data support a quantitative role of apoVLDL as a precursor of apoLDL and identify an important recycling pathway of apoLDL metabolism in addition to that of catabolism.

Adult↗
PubMed1992

A model of the control of cellular regeneration in the intestinal crypt after perturbation based solely on local stem cell regulation.

The control mechanisms involved in regeneration of murine intestinal crypts after perturbations are presently not well understood. The existence of some feedback signals from the cells on the villus to the cells in the crypt has been suggested. However, some recent experimental data point to the fact that regeneration in the crypt starts very early after perturbation, at a time when the villus cell population has hardly changed. In particular, this early cell proliferative activity is seen specifically at the bottom of the crypt, i.e. in the presumed stem cell zone and furthest from the villus. The objective of this study was to investigate whether a new concept of regulation operating solely at the stem cell level could explain the present mass of accumulated data on the post-irradiation recovery, which is an extensively studied perturbation from the experimental point of view. In order to check its validity, the new concept was formalized as a mathematical simulation model thus enabling comparison with experimental data. The model describes the cellular development from stem cells to the mature villus cells. As a basic feature it is assumed that the self-maintenance and the cell cycle activity of the stem cells are controlled by the number of these cells in an autoregulatory fashion. The essential features of the experimental data (i.e. the recovery with time and the consistency between different types of measurements) can be very well reproduced by simulations using a range of model parameters. Thus, we conclude that stem cell autoregulation is a valid concept which could replace the villus crypt feedback concept in explaining the early changes after irradiation when the damage primarily affects the crypt. The question of the detailed nature of the control process requires further investigation.

Animals↗
PubMed1982

On the Hill plot of NMR data for titration of proteins residues.

The Hill plots of NMR titration data for protein residues disclose more clearly than the usual titration curves the presence of multiple weak perturbations originating from other titratable groups, and should be used whenever the conventional curve fitting is poor. For a quantitative interpretation, we derive here expressions for the Hill equation and the Hill coefficient when the titration of the observed group is perturbed by more than one titratable group. When the generalized Hill equation is fitted to the data, values of the interaction parameters between the observed group and the others are extracted provided that there are no mutual interactions between the latter groups. The method is applied to the titration data of two histidyl residues of L-arginine phosphotransferase (E.C. 2.7.3.3.) in the transition state analogue complex (enzyme-Mg2+-ADP-NO3(-)-L-Arg). From the Hill plots, interactions with three titratable groups are disclosed for both residues, and the fitting with the Hill equation reveals that they experience perturbations from the same three groups. Microscopic pK values are obtained for all the involved groups, indicating large changes (up to 3 pH units) upon protonation of the interacting groups. As compared to the conventional fitting procedure, the use and fitting of Hill plots yields from NMR data more information on the neighbourhood of enzyme residues and on the changes intervening therein through the steps involved in the catalysis.

Arginine Kinase↗
PubMed1999

A neomorphic syntaxin mutation blocks volatile-anesthetic action in Caenorhabditis elegans.

The molecular mechanisms underlying general anesthesia are unknown. For volatile general anesthetics (VAs), indirect evidence for both lipid and protein targets has been found. However, no in vivo data have implicated clearly any particular lipid or protein in the control of sensitivity to clinical concentrations of VAs. Genetics provides one approach toward identifying these mechanisms, but genes strongly regulating sensitivity to clinical concentrations of VAs have not been identified. By screening existing mutants of the nematode Caenorhabditis elegans, we found that a mutation in the neuronal syntaxin gene dominantly conferred resistance to the VAs isoflurane and halothane. By contrast, other mutations in syntaxin and in the syntaxin-binding proteins synaptobrevin and SNAP-25 produced VA hypersensitivity. The syntaxin allelic variation was striking, particularly for isoflurane, where a 33-fold range of sensitivities was seen. Both the resistant and hypersensitive mutations decrease synaptic transmission; thus, the indirect effect of reducing neurotransmission does not explain the VA resistance. As assessed by pharmacological criteria, halothane and isoflurane themselves reduced cholinergic transmission, and the presynaptic anesthetic effect was blocked by the resistant syntaxin mutation. A single gene mutation conferring high-level resistance to VAs is inconsistent with nonspecific membrane-perturbation theories of anesthesia. The genetic and pharmacological data suggest that the resistant syntaxin mutant directly blocks VA binding to or efficacy against presynaptic targets that mediate anesthetic behavioral effects. Syntaxin and syntaxin-binding proteins are candidate anesthetic targets.

Aldicarb↗
PubMed1997

Acipimox attenuates hypertriglyceridemia in dyslipidemic noninsulin dependent diabetes mellitus patients without perturbation of insulin sensitivity and glycemic control.

Hyperlipidemia, hypertriglyceridemia in particular, is a common feature in patients with noninsulin dependent diabetes mellitus (NIDDM) and may associate with insulin insensitivity. Acipimox, being widely prescribed for treating hypertriglyceridemia, is also used in NIDDM patients for their dyslipidemia. In the present study, we evaluated the effect of acipimox in Chinese NIDDM patients with hypertriglyceridemia. A total of 16 patients enrolled in a double-blind, randomized, placebo-controlled and two-period crossover study. After an 8 week run-in period, patients were randomly assigned into two groups receiving either acipimox (250 mg, twice daily) or placebo treatment. A total of 12 weeks later, these two groups switched their treatment for an additional 12 weeks. Blood samples were collected at the end of the run-in period and then at 4-week intervals in the whole study for lipid profile. A modified insulin suppression test was performed at the ends of the run-in period, 12-week and 24-week treatment to assess changes in insulin sensitivity. Our results showed that acipimox significantly lowered serum total triglyceride while compared to those by placebo. However, no difference was observed in serum non-esterified fatty acid, low-density lipoprotein cholesterol, total cholesterol (TC), high density lipoprotein-cholesterol (HDL-C) and HDL-C/ TC ratio between the two groups. Furthermore, glycemic indices and insulin sensitivity were similar during the base-line, placebo or acipimox periods. Taken together, our data suggest that acipimox significantly lowered TG without perturbation of insulin sensitivity in hypertriglyceridemic NIDDM patients.

Adult↗
PubMed2000

Neuroendocrine perturbations in fibromyalgia and chronic fatigue syndrome.

A large body of data from a number of different laboratories worldwide has demonstrated a general tendency for reduced adrenocortical responsiveness in CFS. It is still not clear if this is secondary to CNS abnormalities leading to decreased activity of CRH- or AVP-producing hypothalamic neurons. Primary hypofunction of the CRH neurons has been described on the basis of genetic and environmental influences. Other pathways could secondarily influence HPA axis activity, however. For example, serotonergic and noradrenergic input acts to stimulate HPA axis activity. Deficient serotonergic activity in CFS has been suggested by some of the studies as reviewed here. In addition, hypofunction of sympathetic nervous system function has been described and could contribute to abnormalities of central components of the HPA axis. One could interpret the clinical trial of glucocorticoid replacement in patients with CFS as confirmation of adrenal insufficiency if one were convinced of a positive therapeutic effect. If patient symptoms were related to impaired activation of central components of the axis, replacing glucocorticoids would merely exacerbate symptoms caused by enhanced negative feedback. Further study of specific components of the HPA axis should ultimately clarify the reproducible abnormalities associated with a clinical picture of CFS. In contrast to CFS, the results of the different hormonal axes in FMS support the assumption that the distortion of the hormonal pattern observed can be attributed to hyperactivity of CRH neurons. This hyperactivity may be driven and sustained by stress exerted by chronic pain originating in the musculoskeletal system or by an alteration of the CNS mechanism of nociception. The elevated activity of CRH neurons also seems to cause alteration of the set point of other hormonal axes. In addition to its control of the adrenal hormones, CRH stimulates somatostatin secretion at the hypothalamic level, which, in turn, causes inhibition of growth hormone and thyroid-stimulating hormone at the pituitary level. The suppression of gonadal function may also be attributed to elevated CRH because of its ability to inhibit hypothalamic luteinizing hormone-releasing hormone release; however, a remote effect on the ovary by the inhibition of follicle-stimulating hormone-stimulated estrogen production must also be considered. Serotonin (5-HT) precursors such as tryptophan (5-HTP), drugs that release 5-HT, or drugs that act directly on 5-HT receptors stimulate the HPA axis, indicating a stimulatory effect of serotonergic input on HPA axis function. Hyperfunction of the HPA axis could also reflect an elevated serotonergic tonus in the CNS of FMS patients. The authors conclude that the observed pattern of hormonal deviations in patients with FMS is a CNS adjustment to chronic pain and stress, constitutes a specific entity of FMS, and is primarily evoked by activated CRH neurons.

Fatigue Syndrome, Chronic↗
PubMed2002

Encapsulation-induced aggregation and loss in activity of gamma-chymotrypsin and their prevention.

Development of alternative procedures to the commonly employed water-in-oil-in-water technique to encapsulate proteins in polymers is needed due to protein stability issues. Herein the model protein gamma-chymotrypsin has been encapsulated in poly(D,L-lactic-co-glycolic)acid (PLGA) microspheres using the solid-in-oil-in-water (s/o/w) encapsulation technique. The model protein was chosen because it has a measurable biological activity and its unfolding is irreversible. The latter make the protein an excellent sensor for unfolding events in the encapsulation procedure. While lyophilization did not cause any irreversible aggregation or loss in activity, encapsulation of the lyophilized enzyme by the s/o/w technique proved detrimental to its integrity. Specifically, 34% of the encapsulated protein was aggregated and the specific activity of enzyme released within 24 h was reduced to ca. 50% of that prior to encapsulation. FTIR spectra demonstrated substantial encapsulation-induced perturbations of the secondary structure of gamma-chymotrypsin. To achieve stabilization of gamma-chymotrypsin during encapsulation, excipients were employed during the initial lyophilization process. When gamma-chymotrypsin was co-lyophilized with poly(ethylene glycol) (PEG) the formation of non-covalent aggregates inside the microspheres decreased significantly to 8%. FTIR data showed that PEG prevented encapsulation-induced structural perturbations. In contrast, the amount of aggregates remained high (34%) when gamma-chymotrypsin was co-lyophilized with trehalose. No additional non-soluble aggregates were formed during 1 week of in vitro release. Furthermore, the amount of non-soluble aggregates in the microspheres after encapsulation correlated with the amount of non-released protein. Therefore in vitro release did not cause aggregation. Similar results were found with respect to the retention of the specific enzyme activity where PEG afforded excellent stability.

Chymotrypsin↗
PubMed1976

Spectral studies of the tryptophan exposure in the enzyme rhodanese.

Tryptophan exposure in the enzyme rhodanese (thiosulfate:cyanide sulfur-transferase, EC 2.8.1.1.) has been studied by the methods of solvent perturbation difference spectroscopy, fluorescence spectroscopy and fluorescence quenching. The data from all these techniques are consistent with two classes of tryptophan:surface and buried. The surface residues appear to be relatively shielded and in an anionic environment. The buried residues have spectral characteristics suggesting they are in a very apolar environment and have less than the expected contact with the peptide backbone. The solvent perturbation difference spectra indicate further that additional tyrosine as well as tryptophan residues are buried as rhodanese is converted from the free enzyme to the sulfur-substituted enzyme: forms which are obligatory intermediates in the catalytic cycle.

Animals↗
PubMed1996

The mechanical or metabolic function of secondary osteonal bone in the monkey Macaca fascicularis.

Secondary osteonal bone is believed by many to serve a mechanical function, altering the properties and/or orientation of bone in response to fluctuating mechanical demands or in the prevention and/or repair of fatigue microdamage. Based on this belief, secondary osteons should be concentrated mainly in regions experiencing high peak-strain conditions. Others contend that secondary osteonal bone functions primarily in meeting the body's calcium needs, and should be expected to form principally in low peak-strain regions so as to avoid compromising the mechanical strength of the bone. These two hypotheses were tested by examining the distribution of secondary osteonal bone in both relatively high- and low-strain regions of the macaque face. Previous strain-gauge studies have demonstrated a steep strain gradient in the macaque face, with relatively high peak strains in the anterior portion of the zygomatic arch and in the mandibular corpus. Relatively low peak strains have been found in the posterior portion of the zygomatic arch and supraorbital bar. Results presented here show that in the mature macaques, there is no consistent relation between newly forming secondary osteons (i.e. those labelled with fluorescent dyes) and peak strain levels. From these data it is concluded that, in the non-perturbed adult, either mechanical and metabolic factors contribute equally to the observed pattern or that metabolically driven remodelling is initiated without regard to strain levels. In immature macaques, however, the relation between peak strain levels and secondary osteon density is positive, with a significantly higher density of labelled osteons in the high strain regions. From these data it is concluded that, in immature individuals, mechanical factors are predominantly responsible for the initiation of secondary osteonal remodelling.

Age Factors↗
PubMed1989

Binding of novel macrolide structures to macrolides-lincosamides-streptogramin B-resistant ribosomes inhibits protein synthesis and bacterial growth.

Dimethylation of adenine 2058 in 23S rRNA renders bacteria resistant to macrolides, lincosamides, and streptogramin B (MLS resistance), because the antibiotic binding site on the altered 50S ribosomal subunit is no longer accessible. We now report that certain 6-O-methyl-11,12-cyclic carbamate derivatives of erythromycin are able to bind to dimethylated MLS-resistant 50S ribosomal subunits, thus inhibiting protein synthesis and cell growth. One of these novel structures, an 11-deoxy-11-(carboxyamino)-6-O-methylerythromycin A 11,12-(cyclic ester) derivative, structure 1a, was studied in detail. It inhibited in vitro protein synthesis in extracts prepared from both susceptible and MLS-resistant Bacillus subtilis with 50% inhibitory concentrations of 0.4 and 20 microM, respectively. The derivative bound specifically to a single site on the 50S subunit of MLS-resistant ribosomes prepared from B. subtilis and Staphylococcus aureus, and no binding to 30S subunits was observed. The association rate constant of derivative 1a with sensitive and resistant ribosomes was 100- and 500-fold slower, respectively, than that of the parent compound, erythromycin, with sensitive ribosomes. The dissociation rate constant of 1a from sensitive and resistant ribosomes was 50- to 100-fold slower than the rate of erythromycin dissociation from sensitive ribosomes. Furthermore, 1a binding to sensitive 50S subunits led to induction of ermC and ermD, while binding to resistant 50S subunits did not, showing that perturbation of sensitive and resistant 50S subunit function by 1a differs. These data demonstrated that 1a is unique in its interaction with MLS-resistant ribosomes and that this interaction causes a novel allosteric perturbation of ribosome function.

Anti-Bacterial Agents↗
PubMed1999

The G464S amino acid substitution in Candida albicans sterol 14alpha-demethylase causes fluconazole resistance in the clinic through reduced affinity.

Fluconazole selectively inhibits fungal sterol 14alpha-demethylase, a cytochrome P450 enzyme found in plants, animals, fungi, and Mycobacteria. The mutation G464S, observed in the heme-binding domain of sterol 14alpha-demethylase in clinical strains of fluconazole-resistant Candida albicans, is shown here to cause resistance through substantially reducing the inhibitory effect of fluconazole and is associated with perturbation of the heme environment as indicated by spectral data. The protein exhibits 42% of the maximal enzymatic rate of the wild-type protein allowing continued production of the end product of fungal sterol biosynthesis, ergosterol, in resistant strains. This mutation may cause these phenotypes through altering the heme location, thus changing the ability of residues above the heme to bind the drug effectively. This perturbation would also account for the observation of reduced sterol demethylase catalytic activity by changing the location of the 14alpha-methyl group in relation to oxygen-bound heme during the catalytic cycle.

Amino Acid Sequence↗
PubMed1989

The effects of perinatal diazepam exposure on stress-induced activation of the mesotelencephalic dopamine system.

The effects of perinatal diazepam exposure of rats on stress-induced metabolic activation of the mesotelencephalic dopamine (DA) system were examined. Footshock stress parameters were selected such that DA turnover was increased in the prefrontal cortex and certain mesolimbic dopaminergic regions; a stress-induced activation of striatum was not observed. Perinatal treatment with the anxiolytic benzodiazepine diazepam (days E8 through the first week after gestation) did not alter basal dopamine turnover in the prefrontal cortex or striatum, or in any of the mesolimbic sites examined except for the nucleus accumbens and ventral tegmental area (in which turnover was decreased). However, perinatal exposure to diazepam significantly reduced the magnitude of the stress-elicited increase in prefrontal cortical dopamine turnover, and conversely resulted in a stress-induced enhancement of turnover in the striatum. These data suggest that although perinatal exposure to diazepam may alter basal dopaminergic function in some regions, certain enduring changes in dopamine function in other mesotelencephalic DA sites are revealed only under conditions that result in perturbation of central dopamine neurons, such as environmental stress. These data also suggest that perinatal benzodiazepine exposure may be reflected in the adult in a decreased ability to cope with stress.

Animals↗
PubMed1998

Infrared studies of protein-induced perturbation of lipids in lipoproteins and membranes.

The paper reviews the main recent publications concerning infrared (IR) spectroscopy as applied to the study of lipid-protein interactions in model and cell membranes, lipoproteins, and related systems (e.g. lung surfactant). The review focuses mainly on transmission IR. Based on the available data, a number of general conclusions are presented on the perturbations caused by proteins on either the hydrocarbon chains, the polar headgroups or the interface region. Lipid-protein interactions in native cell membranes do not reveal significant differences from what is observed in semisynthetic model systems.

Animals↗
PubMed2005

Role of ion pairing in anionic additive effects on the separation of cationic drugs in reversed-phase liquid chromatography.

Mobile phase additives can significantly affect the separation of cationic drugs in reversed-phase liquid chromatography (RPLC). Although there are many applications for anionic additives in RPLC separations, the retention mechanism of basic drugs in the presence of inorganic and highly hydrophilic anionic species in the mobile phase is not at all well understood. Two major retention mechanisms by which anionic additives can influence the retention of cations are: (1) ion pair formation in the mobile phase with subsequent retention of the neutral ion pair; (2) pre-sorption of anionic additives on the stationary phase followed by "dynamic ion-exchange" or "electrostatic interaction" with the analytes. Because the use of ion pair chromatography in the separation of proteins, peptides, and basic drugs is rapidly increasing, understanding the retention mechanism involved is becoming more important, especially for the smaller commonly used hydrophilic anionic additives (e.g., formate HCOO, chloride Cl-, trifluoroacetate CF3COO-, perchlorate ClO4-, and hexafluorophosphate PF6-). In this work, we compared various anionic additives in light of their effects on the retention of basic drugs. As did many others we found that the addition of anionic additives (Cl-, CF3COO-, ClO4-, PF6-) profoundly influences the retention of basic drugs. In order to explain the data and differentiate the mechanisms by which the anionic additives perturb the chromatography, we used ion pair formation constants independently measured by capillary electrophoresis (CE) under the mobile phase conditions (pH, solvent composition) identical to those used in chromatography. Agreement between the predicted and experimental chromatographic data under various conditions was evaluated. Under specific circumstances (e.g., pH, stationary phase, and nature of anionic additive), we conclude that the ion pair mechanism is more important than the dynamic ion-exchange and at other conditions it remains a significant contribution.

Anions↗
PubMed1995

Effect of cysteine to serine mutations on the properties of the [4Fe-4S] center in Escherichia coli fumarate reductase.

Site-directed mutants of Escherichia coli fumarate reductase in which FrdB Cys148, Cys151, Cys154, and Cys158 are replaced individually by Ser have been constructed and overexpressed in a strain of E. coli lacking a wild-type copy of fumarate reductase and succinate dehydrogenase. The consequences of these mutations on bacterial growth, enzymatic activity, and the EPR properties of the constituent iron-sulfur clusters have been investigated. The Cys154Ser and Cys158Ser FrdB mutations result in enzymes with negligible activity that have largely dissociated from the cytoplasmic membrane and consequently are incapable of supporting cell growth under conditions requiring a functional fumarate reductase. EPR studies indicate that these effects are associated with loss of both the [3Fe-4S] and [4Fe-4S] clusters. In contrast the Cys148Ser and Cys151Ser FrdB mutations result in functional membrane bound enzymes that are able to support growth under anaerobic and aerobic conditions. EPR studies of these mutants indicate that all three of the constituent Fe-S clusters are assembled, and the redox and spectroscopic properties of the [2Fe-2S] and [3Fe-4S] clusters are unchanged compared to the wild-type enzyme. In both mutants the [4Fe-4S] cluster is assembled with one non-cysteinyl ligand, and the available data suggest serinate coordination. The physicochemical consequences are perturbation of the intercluster spin interaction between the S = 1/2 [4Fe-4S]+ and S = 2 [3Fe-FS]0 clusters and a 60-mV decrease in redox potential for the [4Fe-FS]2+,+ cluster in the FrdB Cys148Ser mutant, and a S = 1/2 to S = 3/2 spin state conversion for the [4Fe-4S]+ cluster and a 72-mV decrease in redox potential for the [4Fe-4S]2+,+ cluster in the FrdB Cys151Ser mutant. Taken together with the previous FrdB Cys to Ser mutagenesis results [Werth, M. T., Cecchini, G., Manodori, A., Ackrell, B. A. C., Schröder, I., Gunsalus, R. P., & Johnson, M. K. (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 8965-8969; Manodori, A., Cecchini, G., Schröder, I., Gunsalus, R. P., Werth, M. T., & Johnson, M. K. (1992) Biochemistry 31, 2703-2712], the results provide strong support for the proposal that all three clusters are located in the FrdB subunit with Cys57, Cys62, Cys65, and Cys77 ligating the [2Fe-2S] cluster, Cys148, Cys151, Cys154, and Cys214 ligating the [4Fe-4S] cluster, and Cys158, Cys204, and Cys210 ligating the [3Fe-4S] cluster. The role of the low potential [4Fe-4S] cluster in mediating electron transfer from menaquinol to the FAD active site is discussed in light of these mutagenesis results.

Amino Acid Sequence↗
PubMed1997

A wavelet-based multiresolution regularized least squares reconstruction approach for optical tomography.

In this paper, we present a wavelet-based multigrid approach to solve the perturbation equation encountered in optical tomography. With this scheme, the unknown image, the data, as well as the weight matrix are all represented by wavelet expansions, thus yielding a multiresolution representation of the original perturbation equation in the wavelet domain. This transformed equation is then solved using a multigrid scheme, by which an increasing portion of wavelet coefficients of the unknown image are solved in successive approximations. One can also quickly identify regions of interest (ROI's) from a coarse level reconstruction and restrict the reconstruction in the following fine resolutions to those regions. At each resolution level a regularized least squares solution is obtained using the conjugate gradient descent method. This approach has been applied to continuous wave data calculated based on the diffusion approximation of several two-dimensional (2-D) test media. Compared to a previously reported one grid algorithm, the multigrid method requires substantially shorter computation time under the same reconstruction quality criterion.

Algorithms↗