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PubMed1985

Heavy meromyosin and subfragment-1 from squid mantle myosin, and Ca-sensitivity of their Mg-ATPases.

Heavy meromyosin (HMM) and subfragment-1 (S1) were obtained from squid mantle myosin by tryptic digestion and chymotryptic digestion, respectively. Squid HMM(T) and S1(CT) preparations contained stoichiometric amounts of the two types of light chain subunit; regulatory light chain, LC-2, and essential light chain, LC-1. No difference was detected in the chymotryptic digestibilities of squid mantle myosin in Ca-medium and in EDTA-medium. This is in contrast to the digestibility of scallop adductor myosin. The Mg-ATPase activity of HMM(T) alone and that of acto-HMM(T) were both sensitive to calcium ions. In contrast, the activity of S1(CT) alone and that of acto-S1(CT) were both insensitive to calcium ions. The affinity of HMM(T) for actin was not affected by calcium ions, but the amount of HMM(T) bound to actin was increased by calcium ions from 20% to 60% of the total amount of HMM(T). On the other hand, the actin affinity of S1(CT) and the amount of S1(CT) bound to actin were both unaffected by calcium ions. The role of calcium ions in the regulation of contraction in molluscan muscles is discussed.

Actins↗
PubMed2004

Introduction of plant and fungal genes into pea (Pisum sativum L.) hairy roots reduces their ability to produce pisatin and affects their response to a fungal pathogen.

Pisatin is an isoflavonoid phytoalexin synthesized by pea (Pisum sativum L.). Previous studies have identified two enzymes apparently involved in the synthesis of this phytoalexin, isoflavone reductase (IFR), which catalyzes an intermediate step in pisatin biosynthesis, and (+)6a-hydroxymaackiain 3-O-methyltransferase (HMM), an enzyme catalyzing the terminal step. To further evaluate the involvement of these enzymes in pisatin biosynthesis, sense- and antisense-oriented cDNAs of Ifr and Hmm fused to the 35s CaMV promoter, and Agrobacterium rhizogenes, were used to produce transgenic pea hairy root cultures. PDA, a gene encoding pisatin demethylating activity (pda) in the pea-pathogenic fungus Nectria haematococca, also was used in an attempt to reduce pisatin levels. Although hairy root tissue with either sense or antisense Ifr cDNA produced less pisatin, the greatest reduction occurred with sense or antisense Hmm cDNA. The reduced pisatin production in these lines was associated with reduced amounts of Hmm transcripts, HMM protein, and HMM enzyme activity. Hairy roots containing the PDA gene also produced less pisatin. To evaluate the role of pisatin in disease resistance, the virulence of N. haematococca on the transgenic roots that produced the lowest levels of pisatin was tested. Hairy roots expressing antisense Hmm were more susceptible than the control hairy roots to isolates of N. haematococca that are either virulent or nonvirulent on wild-type pea plants. This appears to be the first case of producing transgenic plant tissue with a reduced ability to produce a phytoalexin and demonstrating that such tissue is less resistant to fungal infection: these results support the hypothesis that phytoalexin production is a disease resistance mechanism.

Cloning, Molecular↗
PubMed1999

Glucose effectiveness and insulin sensitivity from the minimal models: consequences of undermodeling assessed by Monte Carlo simulation.

The unlabeled (cold) minimal model (MM) and the labeled (hot) minimal model (HMM) are a powerful tool to investigate in vivo metabolism from a standard intravenous glucose tolerance test (IVGTT) or hot IVGTT (HIVGTT). They allow to estimate metabolic indexes of the glucose-insulin system, namely glucose effectiveness (GE) and insulin sensitivity (IS) (of uptake and production those of MM, and of uptake only those of HMM). Here, the consequences of the single-compartment glucose kinetics approximation used in the MM's are investigated via Monte Carlo simulation, using a physiologic reference model (RM) of the system. RM allows to generate noisy synthetic plasma concentrations of glucose, tracer glucose, and insulin during IVGTT and HIVGTT, which are then analyzed with MM and HMM. The MM and HMM GE and IS are then compared with the RM ones. Results of 400 runs show that: 1) correlation of MM GE with the RM index is weak; 2) MM IS is well correlated with the RM index, but severely underestimates it; 3) HMM clearance rate is correlated with RM clearance; and 4) HMM IS is well correlated and only slightly overestimates the RM index. These results demonstrate that GE of MM is most affected by the single-compartment approximation and the indexes of HMM are more robust than those of MM.

Blood Glucose↗
PubMed1988

Liver involvement at diagnosis of primary myelofibrosis: a clinicopathological study of twenty-two cases.

Liver biopsies were carried out at diagnosis in 22 patients with primary myelofibrosis. Pathological changes were semiquantitatively evaluated and correlated with either liver function tests, peripheral blood features, bone marrow biopsy changes or patient survival. Hepatic myeloid metaplasia (HMM), primarily consisting of the presence of morphologically abnormal megakaryocytes, was found in all cases. Other remarkable pathological changes included increased reticulin network, sinusoidal widening not related to the intensity of HMM, and iron overload in the absence of previous blood transfusions. High serum alkaline phosphatase was the most frequent biochemical abnormality, and reflected rather the presence of sinusoidal widening than the degree of HMM. The number of immature myeloid cells was the only peripheral blood parameter positively correlated with the degree of HMM. No relationship could be established between bone marrow changes and the degree of HMM. Finally, patients with mild HMM survived longer than those showing marked HMM.

Adolescent↗
PubMed1989

Interaction of tropomyosin with F-actin-heavy meromyosin complex.

The effect of phosphorylated and dephosphorylated heavy meromyosins (HMMs) saturated with Ca2+ or Mg2+ on the binding of tropomyosin to F-actin and on the conformational changes of tropomyosin on actin was investigated. The experimental data were analysed on the basis of th emodel of cooperative binding of tropomyosin to F-actin with overlapping binding sites. In general, attachment of both HMMs to F-actin increased around 100-fold the tropomyosin-binding affinity but concomittantly reduced the cooperatively of binding. In the presence of Ca2+ and in the absence of ATP the binding of tropomyosin to F-actin in a "doubly contiguous" manner was three-fold stronger for F-actin saturated with dephosphorylated HMM as compared to phosphorylated HMM. Under the same rigor conditions but in the absence of Ca2+ the reverse was true but the difference was about 1.5-fold. The binding stoichiometry of tropomyosin to actin was 7:1 in the presence of dephosphorylated HMM saturated with Ca2+ or phosphorylated-saturated with Mg2+ and tended to be about 6:1 for both after the exchange of the cation bound to myosin heads. Bound HMM was also found to influence the fluorescence polarization of 1,5-IAEDANS-labelled tropomyosin complexed with F-actin in muscle ghost fibres. In the presence of Ca2+, the amount of randomly arranged tropomyosin fluorophores decreased when dephosphorylated HMM was bound to ghost fibres, in contrast to an observed increase in the case of bound phosphorylated HMM. Thus HMM induced conformational changes of tropomyosin in the actin-tropomyosin complex that was reflected in an alteration of the geometrical arrangement between tropomyosin and actin.(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗
PubMed1990

Lys-65 and Glu-168 are the residues for carbodiimide-catalyzed cross-linking between the two heads of rigor smooth muscle heavy meromyosin.

We have previously demonstrated that the two heads of chicken gizzard heavy meromyosin (HMM) in a rigor complex with rabbit skeletal F-actin could be cross-linked by the water-soluble carbodiimide 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide. Here, we report the location of the cross-linked sites in the amino acid sequence of the HMM heavy chain. One of the cross-linked residues was identified as Glu-168 by sequencing the CN1.CN6 cross-linked peptide containing residues 1-77 (CN1) and 164-203 (CN6). This site is located close to the ATP-binding site of HMM. Since the other site was further into the amino acid sequence of CN1, another cross-linked peptide corresponding to residues 53-66 and 145-182 was isolated from the 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide-treated acto-tryptic gizzard HMM digested further by other proteolytic enzymes. The amino acid sequence of this peptide and its cyanogen bromide fragment indicated that the cross-linking occurred between Glu-168 and Lys-65. Our results suggests that these two amino acid side chains are in contact with each other in the acto-gizzard HMM rigor complex and participate in the electrostatic interaction between the two HMM heads bound to F-actin. Based on the head-to-head contact, we propose a three-dimensional model for the attachment of gizzard HMM heads to F-actin.

Actins↗
PubMed1986

Control of stimulus-secretion coupling in adrenal medullary chromaffin cells by microfilament-specific macromolecules.

We have incorporated the myosin fragment heavy meromyosin (HMM), which is known to interact mechanochemically and enzymatically with actin filaments, into intact chromaffin cells of the bovine adrenal medulla, in order to study the possible involvement of actin and myosin in stimulus-secretion coupling. HMM was found to stimulate secretion of catecholamines, to cause depolarization of the plasma membrane, and to enhance 22Na+ uptake. HMM-stimulated catecholamine secretion was dependent on the presence of extracellular Na+. The Na+ uptake caused by HMM was inhibited by 10 microM amiloride. Acetylcholine-stimulated catecholamine secretion and 22Na+ uptake were both enhanced by HMM incorporation. A Na+/H+ antiporter, activated by the interaction of HMM with the cells' microfilaments, seems to be involved in HMM action and could possibly also be a component of stimulus-secretion coupling in chromaffin cells, induced by regular agonists.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMedDate not supplied

Tumor pharmacokinetics of hexamethylmelamine in CDF1 mice bearing P388 leukemia.

The pharmacokinetics and metabolism of hexamethylmelamine (HMM) have been studied in CDF1, mice bearing P388 leukemia. The results obtained for this tumor, which is naturally resistant to HMM, were compared with data on HMM sensitive RC tumor and plasma. The pharmacokinetic parameters, estimated by an original algorithm (FADHA), indicated that HMM Cmax and AUC were very high in RC and P388 tumors as compared to plasma values, but could not be directly correlated with HMM activity. Hydroxymethylpentamethylmelamine (HMPMM), a potentially anticancer metabolite of HMM, was easily detected in P388 leukemia while very poorly detected in RC tissue. This finding led us to make the hypothesis that HMM activity could correlate with HMPMM ability to interact irreversibly with DNA and proteins in tumors.

Altretamine↗
PubMed1987

Phosphorylation of the 20,000-dalton light chain of smooth muscle myosin by the calcium-activated, phospholipid-dependent protein kinase. Phosphorylation sites and effects of phosphorylation.

Smooth muscle heavy meromyosin (HMM) is phosphorylated by the Ca2+-activated phospholipid-dependent protein kinase, i.e. protein kinase C, at three sites on each 20,000-dalton light chain. Phosphorylation of three sites also is observed with isolated 20,000-dalton light chain and HMM subfragment 1. The phosphorylation sites are serine 1, serine 2, and threonine 9. Threonine is phosphorylated most rapidly followed by either serine 1 or 2. Phosphorylation of the third site occurs only on prolonged incubation. Phosphorylation is a random process. HMM phosphorylated at two sites per light chain by protein kinase C can be dephosphorylated, as shown using two phosphatase preparations. Increasing levels of phosphorylation of HMM by protein kinase C causes a progressive inhibition of the subsequent rate of phosphorylation of serine 19 by myosin light chain kinase and causes a progressive inhibition of actin-activated ATPase activity of HMM, prephosphorylated by myosin light chain kinase. Inhibition of ATPase activity is due to a decreased affinity of HMM for actin rather than a change in Vmax. Previous results with HMM and protein kinase C (Nishikawa, M., Sellers, J. R., Adelstein, R. S., and Hidaka, H. (1984) J. Biol. Chem. 259, 8808-8814) examined effects induced by phosphorylation of the threonine residues. Our results confirm these and consider also the influence of higher levels of phosphorylation by protein kinase C.

Amino Acid Sequence↗
PubMed1981

Immunochemically detected structural difference in the heavy chains of chicken breast muscle myosin isozymes.

Antisera against the isozymes of heavy meromyosin from chicken breast muscle myosin were prepared by immunizing rabbits. Both antisera against heavy meromyosin containing g1 light chain (HMM(g1) and that containing g3 light chain (HMM(g3)) reacted with both heavy meromyosin isozymes and myosin, but not with whole light chain mixture. This indicates that only antibodies against the heavy chain of heavy meromysin were elicited. The antisera were applied successively to two columns, one coupled with subfragment-2 and the other with heterologous subfragment-1 isozymes. When the antiserum against HMM(g3) was absorbed with subfragment-1 containing g1 (S-1(g1)), it did not react with HMM(g1), but reacted with HMM(g3). On the other hand, when the antiserum against HMM(g1) was absorbed with subfragment-1 containing g3 (S-1(g3)), it lost its ability to react with both heavy meromyosin isozymes. This indicates the presence of a specific antibody against the heavy chain of HMM(g3). The head portion of myosin containing g3 may hold an unique antigenic determinant which is not present in the head of a myosin containing g1.

Animals↗
PubMed2024

Networks of human milk microbiota are associated with host genomics, childhood asthma, and allergic sensitization.

The human milk microbiota (HMM) is thought to influence the long-term health of offspring. However, its role in asthma and atopy and the impact of host genomics on HMM composition remain unclear. Through the CHILD Cohort Study, we followed 885 pregnant mothers and their offspring from birth to 5 years and determined that HMM was associated with maternal genomics and prevalence of childhood asthma and allergic sensitization (atopy) among human milk-fed infants. Network analysis identified modules of correlated microbes in human milk that were associated with subsequent asthma and atopy in preschool-aged children. Moreover, reduced alpha-diversity and increased Lawsonella abundance in HMM were associated with increased prevalence of childhood atopy. Genome-wide association studies (GWASs) identified maternal genetic loci (e.g., ADAMTS8, NPR1, and COTL1) associated with HMM implicated with asthma and atopy, notably Lawsonella and alpha-diversity. Thus, our study elucidates the role of host genomics on the HMM and its potential impact on childhood asthma and atopy.

Humans↗
PubMed1979

Crystalloids of actin-like filaments in the Sertoli cell of the swine testis.

Normal swine testes, congenital cryptorchid swine testes, and normal human tests were exposed to HMM (heavy meromyosin) after either glycerination or saponin treatment in order to determine whether the fine filaments composing the crystalloids in the Sertoli cells of the cryptorchid swine testes bind HMM to form arrowhead complexes. Short bundles of microfilaments observed in the basal part of the Sertoli cells in both normal and cryptorchid testes also bind HMM. Similar bundles of HMM-bound filaments are observed in the vicinity of spermatocytes. The periodicity of the arrowhead complexes is about 35 nm, and all arrowheads on a given filament point in the same direction. In addition, the polarity of the HMM-bound filaments in a given crystalloid or bundle is uni-directional. A mechanism for the formation of the swine crystalloids has been strongly support this hypothesis. Fine filaments of Charcot-Boettcher's crystalloid in human Sertoli cells did not bind HMM. Therefore the fine filaments of the human crystalloid are not actin-like in nature.

Actins↗
PubMed1993

Hexamethylmelamine/altretamine as second-line therapy for epithelial ovarian carcinoma.

The purpose of this report was to review second-line hexamethylmelamine (HMM) chemotherapy of epithelial ovarian cancer to determine if HMM was active in cisplatin-resistant disease. Forty-four women with measurable disease received 100-300 mg/day HMM for 14 days, courses repeated every 4 weeks. There were 6 complete and 3 partial responses for an objective response rate of 20%. Among responding patients disease-free survival was 55% and overall survival was 88% at 3 years. Five of the 6 patients with a complete response remained disease-free at 10-117 months. Only 7/35 (20%) nonresponding patients were alive with mean follow-up of 16 months, and all had persistent cancer. Five women manifesting disease progression during cisplatin or carboplatin were subsequently treated with HMM, and none responded. Seventeen patients developing progressive cancer while receiving HMM were subsequently treated with cisplatin or carboplatin and objective responses occurred in 5 (29%). HMM was an active drug against epithelial ovarian cancer previously treated with cisplatin, but further study is needed to determine its activity against cisplatin-resistant ovarian cancer.

Adult↗
PubMed1994

Analysing ion channels with hidden Markov models.

Ion channel current amplitudes (mu) and open probabilities (Po) have been analysed so far by defining a 50% threshold to distinguish between open and closed states of the channels. With this standard method (SM) it is very difficult or even impossible to analyse channels of different size in one membrane patch correctly. A stochastical model, named the hidden Markov model (HMM), separates between observation noise and the stochastic process of opening and closing of ion channels. The HMM allows the independent analysis of mu, Po, and mean dwell times (tau) of different channels in one membrane patch, without defining threshold levels. Using this method errors in the analysis are not summarized like in the SM because all different analysing procedures (e.g. filtering, setting of threshold, fitting processes) are done in one step. Two different K+ channels in excised basolateral membranes of the cortical collecting duct of rat (CCD) were analysed by the SM and the HMM. The mu value of the intermediate-conductance K+ channel (i-K+) was 3.9 +/- 0.1 pA (SM) and 3.8 +/- 0.2 pA (HMM) for 11 observations. The Po value of this channel was 10.2 +/- 4.2% (SM) and 10.1 +/- 4.0% (HMM). The mean tau values were 5.4 +/- 0.6 ms for the open state and 9.6 +/- 2.2 ms and 145 +/- 21 ms for the closed states (SM) and 7.8 +/- 1.1 ms, 7.7 +/- 0.9 ms and 148 +/- 24 ms (HMM), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Algorithms↗
PubMedDate not supplied

Stereoselective metabolism of mexiletine in Chagasic women with ventricular arrhythmias.

Following a week of racemic mexiletine HCl at 200 mg tid (2x100 mg capsules), stereoselective aliphatic hydroxylation was studied in eight Chagasic women with chronic ventricular arrhythmias (52-67 yrs) with no history of renal or hepatic diseases. Blood samples were collected at dose interval up to 24 h of drug administration. Plasma concentrations of R(-) and S(+) mexiletine (MEX) and its metabolite hydroxymethylmexiletine (HMM) were determined by HPLC after derivatization with chiral reagent. The differences between R(-) and S(+) enantiomers were compared by paired t-test. Results are mean (95% CI). The following differences (p < 0.05) between R(-) and S(+) enantiomers, respectively, were found: MEX AUCss(0-8) 2.34 (1.84-2.85) vs 2.55 (1.97-3.13) microg.ml(-1) x h(-1); MEX CL/f 11.27 (7.77-14.77) vs 10.46 (7.18-13.74)ml.min(-1).Kg(-1); HMM Cmax 38.26 (24.3-52.22) vs 16.73 (10.1-23.29)ng.ml(-1); HMM Tmax 4.71 (2.67-6.76) vs 3.29 (1.24-5.33) h and HMM AUCss(0-8) 253.50 (165.39-341.61) vs 103.70 (69.51-137.90)ng.ml(-1).h(-1). The AUCss(0-8) ratio R(-)/S(+) for MEX was 0.93 (0.87-0.98) while for HMM was 2.50 (2.16-2.85). Distribution of MEX and HMM enantiomers were not significantly different. In this study we demonstrate that kinetic disposition of mexiletine exhibits stereoselectivity in vivo and that aliphatic hydroxylation is favored for R(-) mexiletine in Chagasic women with ventricular arrhythmias.

Anti-Arrhythmia Agents↗
PubMed1976

Tension development in skinned glycerinated rabbit psoas fiber segments irrigated with soluble myosin fragments.

Single glycerinated rabbit psoas muscle fibers were skinned by splitting them lengthwise. The fiber segments thus obtained were more easily accessible to solutes in the surrounding medium than the intact fibers. Using such segments, active tension could be fully abolished by adding N-ethylmaleimide under conditions which lead to inhibition of actin activation of the ATPase activity of myosin. Such muscles could, however, develop tension after irrigation with myosin or with the water-soluble active myosin fragments heavy meromyosin (HMM) or its subfragment 1 (HMM-S1). The induced tensions increased with increasing protein concentration in the irrigating solution. At any given protein concentration, the tension generated by myosin was larger than that produced by HMM which was, in turn, greater than that induced by HMM-S1 e.g. at 15 mg/ml protein the tensions produced by these three myosin moieties were 44.0, 14.0 and 2.8 g/cm2, respectively. The tension was found to be intimately associated with ATP splitting; thus, HMM and HMM-S1 which have been treated with reagents abolishing actin-activated ATPase failed to induce tension development. A contractile force may thus be generated through the interaction with actin of the water-soluble, enzymatically active, myosin subfragments involving the splitting of ATP.

Actins↗
PubMed1988

Developmental consequences of the lack of myosin heavy chain in Dictyostelium discoideum.

Two different Dictyostelium discoideum cell lines that lack myosin heavy chain protein (MHC A) have been previously described. One cell line (mhcA) was created by antisense RNA inactivation of the endogenous mRNA and the other (HMM) by insertional mutagenesis of the endogenous myosin gene. The two cell lines show similar developmental defects; they are delayed in aggregation and become arrested at the mound stage. However, when cells that lack myosin heavy chain are mixed with wild-type cells, some of the mutant cells are capable of completing development to form mature spores. The pattern of expression of a number of developmentally regulated genes has been examined in both mutant cell lines. Although morphogenesis becomes aberrant before aggregation is completed, all of the markers that we have examined are expressed normally. These include genes expressed prior to aggregation as well as prespore genes expressed later in development. It appears that the signals necessary for cell-type differentiation are generated in the aborted structures formed by cells lacking MHC A. The mhcA cells have negligible amounts of MHC A protein while the HMM cells express normal amounts of a fragment of the myosin heavy chain protein similar to heavy meromyosin (HMM). The expression of myosin light chain was examined in these two cell lines. HMM cells accumulate normal amounts of the 18,000-D light chain, while the amount of light chain in mhcA cells is dramatically reduced. It is likely that the light chains assemble normally with the HMM fragment in HMM cells, while in cells lacking myosin heavy chain (mhcA) the light chains are unstable.

Cell Adhesion↗
PubMed1984

Failure of hexamethylmelamine as salvage therapy in ovarian epithelial adenocarcinoma resistant to combination chemotherapy.

Favorable responses to hexamethylmelamine (HMM) have been documented in untreated as well as in alkylating agent-resistant ovarian epithelial adenocarcinoma (OvCa). Platinum-based combination therapy for OvCa has been used since 1976. Eighteen patients with OvCa were treated with HMM as salvage therapy between February 1979 and October 1981. All patients had histologically confirmed OvCa. Eleven tumors were grade III/III and seven tumors were grade II/III. Sixteen patients had received cisplatin-based combination therapy, whereas two had received doxorubicin/cyclophosphamide because of other medical conditions. HMM was used alone in 16 patients and in combination with other drugs in two patients. The initial dose of HMM was 300 mg/m2/day X 14 days when used alone and 130 mg/m2/day X 14 days when used in combination with other drugs. Six patients were treated at a reduced initial dose because of prior marrow toxicity. Adverse effects were tolerable, with 14 patients experiencing hematologic toxicity (5 mild, 5 moderate, 3 severe, 1 life threatening) and 15 patients experiencing GI toxicity (5 mild, 7 moderate, 3 severe). Only 2 patients experienced no toxicity. No objective tumor responses were observed. Four patients had progression of tumor within 4 weeks of starting therapy and 14 patients had stable disease with a mean progression-free interval of 21 weeks. Although HMM is an active drug in untreated and alkylating agent-resistant OvCa, experience suggests that HMM at the dose and schedule tested has insignificant activity in patients who have failed cisplatin-based combination therapy.

Adenocarcinoma↗