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PubMed1999

Dynamic models for nonstationary signal segmentation.

This paper investigates Hidden Markov Models (HMMs) in which the observations are generated from an autoregressive (AR) model. The overall model performs nonstationary spectral analysis and automatically segments a time series into discrete dynamic regimes. Because learning in HMMs is sensitive to initial conditions, we initialize the HMM model with parameters derived from a cluster analysis of Kalman filter coefficients. An important aspect of the Kalman filter implementation is that the state noise is estimated on-line. This allows for an initial estimation of AR parameters for each of the different dynamic regimes. These estimates are then fine-tuned with the HMM model. The method is demonstrated on a number of synthetic problems and on electroencephalogram data.

Algorithms↗
PubMed1997

Hexamethylmelamine as a single second-line agent in ovarian cancer: follow-up report and review of the literature.

From December 1982 to December 1986, 52 patients with recurrent ovarian cancer were treated with single-agent HMM. Chemotherapy was given for a period of 1 year unless progression of disease or toxicity was noted. Survival was determined from the time of diagnosis to the date of death or September 30, 1992. The regimen was well tolerated with only one case of severe gastrointestinal toxicity. Nine patients were found to be clinically free of disease following completion of HMM treatment; they had initially responded to cisplatin-based therapy (i.e., potentially cisplatin-sensitive) and subsequently recurred. Four were found to have gross disease at the time of reassessment laparotomy. Three of these 9 patients are alive 81-92 months since diagnosis, having maintained disease-free intervals of up to 6 years. The median survival for the 9 patients without evidence of disease at the end of therapy was 75 months versus 9 months for the nonresponders. No patient who had progressive disease on first-line cisplatin-based combination chemotherapy (i.e., primary cisplatin-resistant) responded to second-line single-agent oral hexamethylmelamine. With a follow-up close to 10 years, our data show that hexamethylmelamine, with reasonable toxicity, can provide an extended, disease-free interval to a selected group of patients.

Adult↗
PubMed1998

Electron microscopic observation of monomeric actin attached to a myosin head.

Attachment of G-actin to a myosin head was for the first time visualized by electron microscopy of heavy meromyosin (HMM) molecules decorated using a chemical crosslinker with G-actin, which is made resistant to salt- and myosin-induced polymerization by treatment with m-maleimidobenzoic acid N-hydroxysuccinimide ester (MBS). Rotary-shadowed images of acto-HMM molecules crosslinked using MBS or water-soluble carbodiimide showed that MBS-G-actin binds to the distal half of a myosin head (the region 14-15 nm away from the head-rod junction).

Actins↗
PubMed1993

Interaction between two myosin heads in acto-smooth muscle heavy meromyosin rigor complex.

Muscle contraction occurs as a result of the cyclic interaction between actin and myosin, coupled with the hydrolysis of ATP by the myosin heads. A myosin molecule consists of two globular heads and a rod-shaped tail. It is thought that each myosin head functions as a contractile machinery unit, because each head shows ATPase activity and binds to F-actin. A still unsolved question is whether or not the two heads of a myosin molecule interact with each other during their cyclic interaction with F-actin. Here we report that when chicken gizzard heavy meromyosin (HMM) in its rigor complex with F-actin is reacted with the zero-length cross-linker 1-ethyl-3-[3-(dimethylamino)propyl] carbodiimide (EDC), the two heads of the HMM molecule are cross-linked. This result suggests that the two heads of smooth muscle myosin are in contact with each other when myosin is attached to F-actin. It is thus possible that the two myosin heads interact with each other when cross-bridges are formed.

Animals↗
PubMed1993

Force on single actin filaments in a motility assay measured with an optical trap.

We have used an optical trap to measure or exert a force on single actin filaments via the attachment of polystyrene beads which were coated with NEM-modified HMM. In the simplest experiment, beads were attached to rhodamine phalloidin labelled actin filaments and observed to move on an HMM coated surface in the presence of ATP. Moving beads were steered into the vicinity of the trap using a PZT operated microscope stage. The minimum force needed to stop a moving bead was measured by lowering the trap strength until the bead resumed movement. By aligning the optical trap with the centre of a quadrant detector placed in an image plane of the microscope, it was possible to measure the force exerted on a filament by measuring the displacement of the bead position from the centre of the trap. In each of these experiments, the trap was calibrated by applying a Stokes force to a bead in free solution. The characteristics of the trap were studied, and the displacement of the bead from the centre of the trap was shown to be directly proportional to the applied force over a large part of the total range of the trap. The compliance of the trap could be substantially reduced by the use of feedback control to deflect the laser beam via an acousto-optic modulator. The advantages and limitations of this technique will be discussed.

Actin Cytoskeleton↗
PubMed1993

Gross structural features of myosin head during sliding movement of actin as studied by quick-freeze deep-etch electron microscopy.

With quick-freeze deep-etch electron microscopy coupled with mica-flake technique, I showed previously that myosin subfragment-1 (S1) attached to F-actin in the presence of ATP is short and rounded, in contrast to its elongated and tilted appearance under rigor condition [J. Biochem. 106, 751-770 (1989)]. I further indicated that each head of heavy meromyosin (HMM) changes its configuration in a likely manner as above by the addition of various nucleotides, i.e. heads were pear-shaped in the absence of nucleotide, in a ball-on-a-stick appearance when complexed with ADP and strongly kinked to the particular direction in the presence of ATP or ADP.Vi [J. Muscle Res. Cell Motility 12, 313 (1991)]. Such morphological data not only corroborates the independent biophysical evidences suggesting gross conformational changes of myosin head upon binding ATP or ADP.Vi, but also provide strong evidence for the distinct polarity in the structure of each myosin head. Negatively stained image of chemically cross-linked acto-S1 also included cross-bridges sharply kinked to the same direction, confirming the above observation. Attempts were made to examine if such conformational change of myosin cross-bridge occurs during actomyosin superprecipitation. Samples were quick-frozen during rapid turbidity-increasing phase where actin filaments actively slide past myosin heads. The resultant image included actin-attached myosin heads all in a kinked configuration with the same polarity as observed for HMM. Several heads associated with a single actin filament were bent to the same direction suggesting that myosin heads might be in a kinked configuration with distinct polarity during contraction.

Actins↗
PubMed1998

Measurement of ATPase activities of myosin at the level of tracks and single molecules.

In order to determine the degree of mechanochemical coupling in actomyosin in vitro motility assays, it is desirable to measure the sliding velocity and the associated ATP turnover simultaneously at the single filament level. Actin sliding over tracks of immobilised heavy meromyosin (HMM) has been initiated by flash photolysis of caged ATP. Flash photolysis has also been used to displace fluorescent Cy3-EDA-nucleotides from HMM tracks to monitor the ATPase activity. These assays are now being combined using total internal reflectance fluorescence (TIRF) microscopy with a dual-view detection system for Cy3/Cy5 labels on ATP and actin respectively. In other experiments, we are exploring the use of the single molecule kinetic technique developed by Funatsu et al. (Nature 374, 555-559, 1995) to scale down ATPase assays of Dictyostelium myosin fragments and to elucidate the mechanism of regulation of the molluscan (scallop) myosin ATPase. Although fluctuations occur from the binding and release of Cy3-EDA-nucleotides during turnover and might provide a measure of the ATPase activity, other sources of fluctuations also need to be considered.

Adenosine Triphosphatases↗
PubMed1994

Myosin filament ATPase is enhanced by intramolecularly cross-linked actin.

Reaction of rabbit skeletal muscle F-actin with the lysine-directed photolabile cross-linker, N-5-azido-2-nitrobenzoyloxy succinimide was limited to Lysine-328 and Lysine-326, with Lysine-328 being labelled to a greater extent. Photolysis of the modified actin enhanced the actin-activated MgATPase activity of filamentous scallop myosin 3-4-fold more than unmodified actin, without affecting calcium sensitivity. Unphotolysed modified actin behaved as untreated actin, indicating that photolysis was essential for the effect. The actin-activated ATPase of filamentous rabbit myosin was similarly increased by photolysed N-5-azido-2-nitrobenzoyloxy succinimide-modified actin. After photolysis in either the monomeric (G-) or filamentous (F-) form, N-5-azido-2-nitrobenzoyloxy succinimide-modified actin moved as a monomeric (42 kDa) species on SDS gels, and depolymerized and polymerized readily, demonstrating that any cross-linking event produced by photolysis must be intramolecular. In contrast to the substantial increase in actin-activated ATPase activity observed when photolysed ANB-NOS-modified actin was added to filamentous myosin, the enhancement was not observed with the soluble HMM and S-1 fragments of myosin. Photolysed modified actin showed only poor movement on a rabbit HMM-coated surface in vitro motility assays. These results can be explained if the internally cross-linked G-actin subunits which comprise only a fraction of the actin population, either weaken the actin-actin contacts or have an increased affinity for myosin.

Actins↗
PubMed1984

Immunocytochemical demonstration of caldesmon and actin in thyroid glands of rats.

The distribution of caldesmon (a calmodulin-binding, F-actin interacting protein; Sobue et al. 1982) and actin was studied in the rat thyroid gland by means of light-microscopic immunocytochemistry, and the fine-structural distribution of actin filaments was examined by use of heavy meromyosin (HMM). Caldesmon and actin were demonstrated in the apical cytoplasm of almost all the follicle epithelial cells in normal as well as TSH-treated animals. Immunoreactivities for both caldesmon and actin showed almost the same pattern in localization. The smooth muscle cells of the blood vessels were also positive for caldesmon and actin. By electron microscopy, numerous actin filaments decorated by HMM and running perpendicularly or randomly to the apical surface were recognized in the apical cytoplasm of the follicle epithelial cell. These results suggest that caldesmon and actin, in conjugation with calmodulin, play a role in the regulation of cellular activity such as exocytosis and endocytosis in the apical portion of the follicle epithelial cell.

Actins↗
PubMed1975

Intracytoplasmic filaments in pulmonary lymphatic endothelial cells. Fine structure and reaction after heavy meromyosin incubation.

The cytochemistry and ultrastructure of intracytoplasmic filaments of pulmonary lymphatic endothelial cells of neonatal rabbits were studied by comparison with myofilaments of the peribronchial and pulmonary vascular smooth muscle cells. Two types of endothelial filaments were observed: thin filaments (diameter: 50 A) which lie close to the abluminal cell membrane; and thick filaments (diameter: 90 A) which are dispersed throughout the cell cytoplasm. Following heavy meromyosin (HMM) treatment, characteristic arrowhead complexes formed in the thin lymphatic endothelial filaments as well as in the actin filaments of the smooth muscle cells. There was no detectable reaction of HMM with the thick filaments. After incubation with EDTA, the thin filaments were labile, and the thick filaments became the major filamentous component in the endothelial cells. In smooth muscle cells, the actin myofilaments were also labile while the 100 A filaments were stable. These observations support the hypothesis that the actin-like thin endothelial lymphatic filaments form part of a contractile system, while the thick filaments constitute a plastic cell skeleton. The significance of the contractile system in lymphatic endothelial cells might lie in a mechanism for the active regulation of the endothelial intercellular junction and gaps and hence the permeability of the lymphatic endothelial cell lining.

Actins↗
PubMed1983

Distribution, metabolism, and irreversible binding of hexamethylmelamine in mice bearing ovarian carcinoma.

The covalent binding of hexamethylmelamine (HMM) and its metabolites was studied in liver, tumor, blood, kidney, spleen, lung, brain, heart, and small intestine after a single IP injection of 2,4,6-14C-hexamethylmelamine (50 mg/kg) to C57Bl/6J female mice bearing 20-day-old M5076/73A ovarian cancer. Covalent binding to tissue macromolecules was measured 2, 10, and 40 h after injection of the drug. At 2 h liver and small intestine showed the highest levels of irreversibly bound metabolites, the lowest being found in brain and heart. Except in the small intestine, where a decrease was observed between 2 and 10 h, the level of covalent binding was constant up to 40 h. HMM metabolism was also studied. Tissue distribution of pentamethylmelamine (PMM), 2,2,4,6-tetramethylmelamine (TMM), and 2,4,6-trimethylmelamine (TriMM) was determined at the three times considered. At 2 h the drug was already extensively metabolized, TriMM being the major metabolite among those determined.

Altretamine↗
PubMed1988

Cystatins from bovine brain: purification, some properties, and action on substance P degrading activity.

Two cystatins were purified from tissue extract of bovine brain by alkaline treatment, acetone fractionation, gel chromatography on Sephadex G-75, and affinity chromatography on S-carboxymethyl-papain-Sepharose. One of the inhibitors had a relatively high molecular mass, 25 kDa (HMM-cystatin) with pI 4.7, and the other, 11 kDa (LMM-cystatin) with pI 5.23. Both inhibitors showed considerable stability at pH 2 and 80 degrees C. The cystatins inhibited papain, ficin, and cathepsins B and H, but not trypsin, chymotrypsin, thermolysin, nagarse, and cathepsin D. Ki values for the complexes of papain and the inhibitors were estimated to be 2.8 x 10(-10) M for HMM-cystatin and 1.3 x 10(-9) M for LMM-cystatin. Both purified cystatins prevented degradation of substance P by soluble fraction and lysosomal extract obtained from synaptosomes, but did not suppress the cleavage of the peptide by synaptosomal plasma membranes.

Animals↗
PubMed1978

Metal binding to myosin and to myosin DTNB-light chain.

The effects of various divalent cations, Ca2+, Mg2+ and Mn2+ on the intrinsic fluorescence of heavy meromyosin (HMM) and myosin 5,5'-dithio-bis-(2-nitrobenzoate) DTNB-light chain of rabbit striated muscle, are compared. At pH 6.4, th fluorescence change induced by the metal ions is present only in the isolated light chain and disappears in HMM, thus indicating an interaction between the heavy and light chains with respect to the binding of the metal ions. Whereas Mg2+ binds more strongly than Ca2+ to myosin, this order is reversed in the case of the DTNB-light chain.

Animals↗
PubMedDate not supplied

Modeling of the actomyosin ATPase activity. Origin of the initial phosphate burst and implications of the phosphate release kinetics.

In the rapid "quench" kinetics of myosin, the "initial phosphate burst" is the excess inorganic phosphate that is produced during the early time-course of ATP hydrolysis by myosin subfragment-1 (S-1) or HMM. In general, the existence of a Pi burst implies a rapid (i.e., generally an order of magnitude faster than the steady-state hydrolysis rate) lysis of the phospho-anhydride bond within the ATP molecule, followed by one or more slower steps that are rate limiting for the process. Thus, the presence of a Pi burst can provide an important clue to the mechanism of the reaction. However, in the case of actomyosin, this clue has long been the subject of controversy and misunderstanding. To measure the (initial) Pi burst, myosin S-1 (or HMM) is rapidly mixed with ATP and then the mixture is acid quenched after a specific time period. The medium produced contains free Pi generated from hydrolysis of the ATP. The quantitative measure of the phosphate generated in this way has always been significantly greater than that expected by steady-state "release" of Pi alone, and it is that very difference between this measured Pi after the quench and that amount of Pi expected to be released by steady-state considerations in that same time period that has been referred to as the "initial Pi burst." Recent investigations of the kinetics of Pi release have used an entirely new method that directly measures the release of Pi from the enzyme-product complex. These studies have made reference to the properties of the "initial Pi burst" in the presence of actin, as well as to a new kinetic entity: the "burst of Pi release," and have been often vague concerning the true nature of the initial Pi burst, as well as the properties of Pi release as predicted by the current models of the actin activation of the myosin ATPase activity. The purpose of the current article is to correct this oversight, to discuss the "burst" in some detail, and to display the kinetics predicted by the current models for the actin activation of myosin. Furthermore, predictions for the kinetics of the new "burst of Pi release" are discussed in terms of its ability to discriminate between the two current competing models for actin activation of the myosin ATPase activity.

Actins↗
PubMed2006

Bacterial growth and community composition in fractions of dissolved organic carbon of different molar mass from interstitial water.

The ability of different molar-mass fractions of interstitial dissolved organic carbon (DOC) from a small stream to stimulate bacterial growth was determined. Growth was the greatest in the low-molar mass (<1 kDa) (LMM) fraction and the least in the high-molar mass (>10 kDa) (HMM) one. The LMM fraction consistently had a higher ratio of carbon to organic nitrogen than other fractions. The fluorescence in situ hybridization analysis revealed that bacterial populations in interstitial water were dominated by beta-Proteobacteria. gamma-Proteobacteria together with the Cytophaga-Flavobacteria cluster dominated in LMM DOC (66.3%) while the proportions of bacterial groups in HMM and medium-molar mass (MMM) fractions were more equal. The fact that gamma-Proteobacteria strongly dominates in LMM DOC fraction refutes the idea that LMM DOC is readily utilized by all heterotrophic bacteria.

Betaproteobacteria↗
PubMed2003

Impact of CYP2D6*10 on mexiletine pharmacokinetics in healthy adult volunteers.

OBJECTIVE: In vitro studies with human liver microsomes have suggested that the oxidative conversion of mexiletine (MX) to its metabolites is catalyzed by CYP2D6 and is significantly impaired in microsomes with the CYP2D6*10/*10 genotype. Therefore, we examined the influence of the CYP2D6*10 allele on MX pharmacokinetics in Japanese subjects. METHODS: Subjects with CYP2D6*1/*1 (group *1/*1; n=5), CYP2D6*10/*10 (group *10/*10; n=6) and CYP2D6*5/*10 (group *5/*10; n=4) genotypes received a single 200-mg dose of MX. Plasma and urinary levels of MX and its metabolites ( p-hydroxymexiletine (PHM), hydroxymethylmexiletine (HMM) and N-hydroxymexiletine (NHM)) were determined by means of high-performance liquid chromatography. RESULTS: Mean area under the concentration-time curve (AUC) and t(1/2) of MX were significantly ( P<0.05) higher in the CYP2D6*10/*5 group (AUC 11.23+/-3.05 micro g.h/ml; t(1/2) 15.5+/-3.2 h) than in the CYP2D6*1/*1 (AUC 5.53+/-1.01 micro g.h/ml; t(1/2) 8.1+/-1.6 h) and CYP2D6*10/*10 (AUC 7.32+/-2.36 micro g.h/ml; t(1/2) 10.8+/-2.8 h) groups, but there was no significant difference between the CYP2D6*1/*1 and CYP2D6*10/*10 groups. The maximum plasma concentration of MX was not significantly different among the three groups. The values of urinary excretion of PHM and HMM in the CYP2D6*1/*1 group were significantly ( P<0.05) higher than those in the CYP2D6*10/*10 and CYP2D6*5/*10 groups, but there was no significant difference in that of NHM among the three groups. Clearance of MX in the CYP2D6*5/*10 subjects was comparable to that in the poor metabolizers described previously. CONCLUSION: The present findings demonstrated that carriers of the CYP2D6*10 allele showed a decreased clearance of MX. Subjects with CYP2D6*5/ *10 showed significantly ( P<0.05) increased plasma levels of MX, and homozygotes for CYP2D6*10 also showed an increase, although to a lesser extent. Thus, the CYP2D6*10 allele plays an important role in MX pharmacokinetics.

Administration, Oral↗
PubMed2006

Phonocardiographic signal analysis method using a modified hidden Markov model.

Auscultation is an important diagnostic indicator for cardiovascular analysis. Heart sound classification and analysis play an important role in the auscultative diagnosis. This study uses a combination of Mel-frequency cepstral coefficient (MFCC) and hidden Markov model (HMM) to efficiently extract the features for pre-processed heart sound cycles for the purpose of classification. A system was developed for the interpretation of heart sounds acquired by phonocardiography using pattern recognition. The task of feature extraction was performed using three methods: time-domain feature, short-time Fourier transforms (STFT) and MFCC. The performances of these feature extraction methods were then compared. The results demonstrated that the proposed method using MFCC yielded improved interpretative information. Following the feature extraction, an automatic classification process was performed using HMM. Satisfactory classification results (sensitivity > or =0.952; specificity > or =0.953) were achieved for normal subjects and those with various murmur characteristics. These results were based on 1398 datasets obtained from 41 recruited subjects and downloaded from a public domain. Constituents characteristics of heart sounds were also evaluated using the proposed system. The findings herein suggest that the described system may have the potential to be used to assist doctors for a more objective diagnosis.

Data Interpretation, Statistical↗
PubMed2006

Performance enhancement for audio-visual speaker identification using dynamic facial muscle model.

Science of human identification using physiological characteristics or biometry has been of great concern in security systems. However, robust multimodal identification systems based on audio-visual information has not been thoroughly investigated yet. Therefore, the aim of this work to propose a model-based feature extraction method which employs physiological characteristics of facial muscles producing lip movements. This approach adopts the intrinsic properties of muscles such as viscosity, elasticity, and mass which are extracted from the dynamic lip model. These parameters are exclusively dependent on the neuro-muscular properties of speaker; consequently, imitation of valid speakers could be reduced to a large extent. These parameters are applied to a hidden Markov model (HMM) audio-visual identification system. In this work, a combination of audio and video features has been employed by adopting a multistream pseudo-synchronized HMM training method. Noise robust audio features such as Mel-frequency cepstral coefficients (MFCC), spectral subtraction (SS), and relative spectra perceptual linear prediction (J-RASTA-PLP) have been used to evaluate the performance of the multimodal system once efficient audio feature extraction methods have been utilized. The superior performance of the proposed system is demonstrated on a large multispeaker database of continuously spoken digits, along with a sentence that is phonetically rich. To evaluate the robustness of algorithms, some experiments were performed on genetically identical twins. Furthermore, changes in speaker voice were simulated with drug inhalation tests. In 3 dB signal to noise ratio (SNR), the dynamic muscle model improved the identification rate of the audio-visual system from 91 to 98%. Results on identical twins revealed that there was an apparent improvement on the performance for the dynamic muscle model-based system, in which the identification rate of the audio-visual system was enhanced from 87 to 96%.

Adult↗