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PubMed1983

Actin filament localization and distribution in the young adult mouse cornea: a correlative immunofluorescent and cytochemical study.

The localization and distribution of actin filaments was determined in the corneal epithelium and endothelium of the young adult Swiss Webster mouse by correlative indirect immunofluorescence using rabbit anti-skeletal muscle actin antiserum and by in situ labelling with heavy meromyosin subfragment-1 (HMM-S1). A diffuse fluorescent staining was observed in the cytoplasm of epithelial and endothelial cells and in stromal keratocytes. In addition, a highly fluorescent punctate cytoplasmic staining was seen only in the corneal epithelium. Ultrastructurally, HMM-S1 decorated actin filament bundles were generally distributed within the cytoplasm of glycerinated superficial, wing and basal epithelial cells and within pedicle-like processes on the posterior surface of superficial and wing cells. Actin filament bundles also were seen in close association with intermediate filament bundles in the epithelium. HMM-S1 labelled filaments were observed in the endothelial cytoplasm anteriorly near Descemet's membrane, posteriorly near the anterior chamber and adjacent to lateral cell borders. Actin filaments in epithelial and endothelial cells appeared to insert into the plasma membrane.

Actins↗
PubMed1985

A new function of kininogens as thiol-proteinase inhibitors: inhibition of papain and cathepsins B, H and L by bovine, rat and human plasma kininogens.

The amidolytic activities of papain and rat liver cathepsins B, H and L were strongly inhibited by high (HMM) and low (LMM) molecular mass kininogens from bovine, human and rat plasmas, and their Ki values were estimated to be in the order of 10(-10) - 10(-11)M for papain and 10(-8) - 10(-9)M for cathepsins. The derivatives of bovine kininogens, HMM kinin-free protein, HMM kinin- and fragment 1 X 2-free protein, and LMM kinin-free protein also showed strong inhibitory activity toward these thiol-proteinases. These results suggest that a reactive site which interacts with thiol-proteinases is contained in the heavy chain portion in kininogens.

Animals↗
PubMed1988

Hydroxyprolyl3-bradykinin in high molecular mass kininogen. Presence in human and monkey kininogens, but not in kininogens from bovine, rat, rabbit, guinea pig and mouse plasmas.

The contents of hydroxyprolyl3-bradykinin in high molecular mass (HMM) kininogens from human and animal plasmas were examined by reversed-phase HPLC following their proteolytic scission by bovine plasma kallikrein. The relative contents of hydroxyprolyl3-bradykinin in kinins from HMM kininogens from pooled plasmas of human and monkey origin were 33 and 73%, respectively. On the other hand, hydroxyprolyl3-bradykinin could not be detected in HMM kininogen preparations from bovine, rat, guinea pig, rabbit and mouse plasmas. Hydroxyproline in hydroxyprolyl3-bradykinin was assigned as trans-4-hydroxyproline by comparison of the retention times on reversed-phase HPLC with isomers of hydroxyproline after derivatization with 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole chloride.

Amino Acid Sequence↗
PubMed1984

Pancreatic beta cell vacuolation in rats after oral administration of hexamethylmelamine.

The effects of hexamethylmelamine (HMM) on morphology and function of the endocrine pancreas were investigated following the induction of a diabetic-like syndrome in a reproduction study in rats. Doses of 0, 20, 40, or 80 mg/kg/day were administered once daily, by gavage, to groups of 10 male and 10 female Sprague-Dawley rats for up to 77 days. Signs of toxicity were observed at all treatment levels and were of such severity at 80 mg/kg/day that this group was terminated after 8 days of treatment. Measurement of serum glucose levels revealed a dose- and time-related hyperglycemia in rats from the 20- and 40-mg/kg/day groups with levels exceeding 700 mg/dl in some rats after 77 days of treatment. Reversal of the hyperglycemia after discontinuing treatment with HMM occurred in some rats receiving 20 mg/kg/day, whereas the effects of higher doses were still present following a 2-month recovery period. Microscopically, there were hydropic degeneration of renal tubular epithelium and vacuolation of pancreatic beta cells. Ultrastructurally, vesiculation of the Golgi-smooth membrane reticular complex and a marked reduction in the number of insulin granules were observed. It appeared that HMM exerted a disruptive effect on the production of insulin at or prior to the level of the Golgi complex. The severity and time course of morphologic changes and hyperglycemia were dependent on dose and duration of treatment.

Administration, Oral↗
PubMed1991

Erythrocyte-bound low-density lipoprotein immune complexes lead to cholesteryl ester accumulation in human monocyte-derived macrophages.

We have recently shown that incubation of macrophages with insoluble immune complexes (IC) containing low-density lipoproteins (LDL) leads to intracellular accumulation of esterified cholesterol (CE). This accumulation is associated with morphological transformation of the macrophages into "foam cells." In order to better characterize the conditions that lead to the uptake of LDL-IC and CE accumulation on macrophages, we studied the effects of soluble, insoluble, and red blood cell (RBC)-bound LDL-IC on macrophage lipid and lipoprotein metabolism. Using both apoB or IgG [anti-LDL] as the labeled moieties, we observed that the uptake of LDL-IC by human monocyte-derived macrophages (HMM) was markedly enhanced when the IC were adsorbed to RBC. Competition studies with unlabeled heat-aggregated IgG, native LDL, and acetylated LDL demonstrated that LDL-IC were ingested via the Fc receptor of HMM. The uptake of RBC-bound LDL-IC led to a marked intracellular accumulation of cholesteryl esters in HMM (78.4 +/- 1.7 vs 5.5 +/- 0.6 micrograms/mg cell protein; P less than 0.01) which apparently resulted from delayed degradation of the ingested LDL. Thus, it appears that the metabolism of LDL is altered when it is ingested as part of an antigen-antibody complex. These findings suggest that the formation of LDL-IC and their adsorption to red cells may play a significant role in the onset or in the evolution of human atherosclerosis.

Antigen-Antibody Complex↗
PubMed1987

Hexamethylmelamine in ovarian cancer after failure of cisplatin-based multiple-agent chemotherapy.

A prospective study was initiated in 1979 to investigate the effect of hexamethylmelamine (HMM) as a second-line chemotherapeutic agent in the treatment of advanced adenocarcinoma of the ovary after failure of cisplatin-based multiple-agent chemotherapy. Of 20 evaluable patients, there were 5 patients (25%) who had objective responses (4 complete and 1 partial). Four additional patients have remained without evidence of disease. Six of these 9 patients are still alive, disease free. There were significant differences (P less than 0.001) in both the progression-free interval and survival time for these 9 patients, 13.3 and 15.1 months, respectively, as compared to the 15 nonresponders, 0.8 and 5.8 months, respectively. There was no significant difference in survival between the 4 patients with stable disease and the 11 patients with progressive disease. Performance status less than 2 (P less than 0.05) and absence of clinically measurable disease at the time of entry into the study (P less than 0.05) were found to be significant variables with regard to determining outcome. Only 2 of 24 patients suffered severe enough side effects from the HMM to warrant its discontinuation. This study demonstrates that HMM at doses of 6-8 mg/kg/day for 21 out of every 28 days can induce a complete response and provide an extended disease-free interval and prolonged survival with tolerable side effects in a significant number of patients with ovarian cancer who have previously failed cisplatin-based multiple-agent chemotherapy.

Adenocarcinoma↗
PubMed1990

Hexamethylmelamine as a single second-line agent in ovarian cancer.

Fifty-two patients with advanced ovarian cancer were treated with single-agent hexamethylmelamine (HMM), 260 mg/m2 po per day for 14 days followed by 14 days off drug. All patients had been previously treated with chemotherapy. Of these patients, 92% (48/52) received cisplatin and cyclophosphamide +/- doxorubicin prior to hexamethylmelamine. Two additional patients received other cisplatin-based regimens. Fifteen percent (8/52) were found to have no evidence of disease (NED) at the completion of treatment with HMM. Five of these patients are alive at 12 to 65 months (median follow-up of 32 months); one patient died at 41 months of an intercurrent illness with no clinical evidence of recurrence; two patients died of recurrent tumor at 21 and 31 months. The median survival of the series of 52 patients is 11 months: 9 months for patients who did not respond versus 41 months for patients with NED post-HMM (P less than 0.05). The regimen was well tolerated: moderate gastrointestinal toxicity was reported by 8 patients; only one patient reported severe gastrointestinal toxicity. Moderate neurologic toxicity (primarily sensory) was reported by 5 patients, 3 patients experienced white counts less than 2000 or platelet counts less than 100,000, and no patient sustained severe hematologic toxicity. This moderate-dose intermittent regimen was associated with moderate toxicity and was well accepted by patients. The overall response is comparable to or higher than that reported for more toxic chemotherapy regimes. Based on these data and those recently reported by other authors, hexamethylmelamine should be considered in the treatment of recurrent ovarian cancer.

Adult↗
PubMed1986

Sexual orientation and visuo-spatial ability.

On the basis of a literature review it was concluded that sex differences in cognitive ability and the etiology of male homosexuality may have a common biological base, leading to the prediction that in terms of cognitive ability homosexual males (HmM) would resemble heterosexual females (HtF) rather than heterosexual males (HtM). This prediction was investigated using visuo-spatial tasks on which males are known to perform better than females. In Experiment 1 HtM performed better on a water level task than HmM and HtF whose performances did not differ significantly. A different version of the water level task and the Vincent Mechanical Diagrams Test were used in Experiment 2; on both tasks the HtM performed better than the HmM and the HtF whose performance did not differ significantly. The results are interpreted as support for a common biological determinant of cognitive ability and male sexual orientation.

Adult↗
PubMed1991

A comparison of hexamethylmelamine (altretamine), cyclophosphamide, doxorubicin, and cisplatin (H-CAP) vs. cyclophosphamide, doxorubicin, and cisplatin (CAP) in advanced ovarian cancer.

We retrospectively compared the results of treatment with hexamethylmelamine (HMM), cyclophosphamide, doxorubicin, and cisplatin (H-CAP) to treatment results using cyclophosphamide, doxorubicin, and cisplatin (CAP) in patients with advanced ovarian cancer. The treatments were identical in dosage and schedule with the exception of the addition of HMM to one regimen. Fifty-five patients treated with H-CAP between August 1977 and March 1980 were compared with a subsequent group of 22 patients who received CAP between October 1984 and October 1987. Following 6 months of therapy, patients were restaged either with second-look laparotomy or with clinical restaging. Fifty-three of 55 patients (96%) and 14/21 (67%) patients had objective responses to H-CAP and CAP respectively (p = 0.001). The pathologic complete response rate as determined by second-look laparotomy was higher in the patients who received H-CAP (35% vs. 19%). The median survival of patients receiving H-CAP is 47 months compared to 21 months for the CAP patients. In limited residual disease patients (maximum tumor diameter less than or equal to 3 cm), the median survival also favored the H-CAP treatment (101 months vs. 21 months, p = 0.002). The median time to progression was greater in patients receiving H-CAP vs. those receiving CAP (67 months vs. 16 months, p = 0.045). Treatment-related toxicity was similar for the two regimens. These findings suggest that the addition of HMM to CAP chemotherapy prolongs the median survival for patients with limited residual disease advanced ovarian cancer.

Altretamine↗
PubMed2003

Silanized surfaces for in vitro studies of actomyosin function and nanotechnology applications.

We have previously shown that selective heavy meromyosin (HMM) adsorption to predefined regions of nanostructured polymer resist surfaces may be used to produce a nanostructured in vitro motility assay. However, actomyosin function was of lower quality than on conventional nitrocellulose films. We have therefore studied actomyosin function on differently derivatized glass surfaces with the aim to find a substitute for the polymer resists. We have found that surfaces derivatized with trimethylchlorosilane (TMCS) were superior to all other surfaces tested, including nitrocellulose. High-quality actin filament motility was observed up to 6 days after incubation with HMM and the fraction of motile actin filaments and the velocity of smooth sliding were generally higher on TMCS than on nitrocellulose. The actomyosin function on TMCS-derivatized glass and nitrocellulose is considered in relation to roughness and hydrophobicity of these surfaces. The results suggest that TMCS is an ideal substitute for polymer resists in the nanostructured in vitro motility assay. Furthermore, TMCS derivatized glass also seems to offer several advantages over nitrocellulose for HMM adsorption in the ordinary in vitro motility assay.

Actomyosin↗
PubMed2003

Sequence alignments and pair hidden Markov models using evolutionary history.

This work presents a novel pairwise statistical alignment method based on an explicit evolutionary model of insertions and deletions (indels). Indel events of any length are possible according to a geometric distribution. The geometric distribution parameter, the indel rate, and the evolutionary time are all maximum likelihood estimated from the sequences being aligned. Probability calculations are done using a pair hidden Markov model (HMM) with transition probabilities calculated from the indel parameters. Equations for the transition probabilities make the pair HMM closely approximate the specified indel model. The method provides an optimal alignment, its likelihood, the likelihood of all possible alignments, and the reliability of individual alignment regions. Human alpha and beta-hemoglobin sequences are aligned, as an illustration of the potential utility of this pair HMM approach.

Algorithms↗
PubMed2005

What limits the velocity of fast-skeletal muscle contraction in mammals?

In rat skeletal muscle the unloaded shortening velocity (Vo) is defined by the myosin isoform expressed in the muscle fibre. In 2001 we suggested that ADP release from actomyosin in solution (controlled by k(-AD)) was of the right size to limit Vo. However, to compare mechanical and solution kinetic data required a series of corrections to compensate for the differences in experimental conditions (0.5 M KCl, 22 degrees C for kinetic assays of myosin, 200 mM ionic strength, 12 degrees C to measure Vo). Here, a method was developed to prepare heavy meromyosin (HMM) from pure myosin isoforms isolated from single muscle fibres and to study k(-AD) (determined from the affinity of the acto-myosin complex for ADP, KAD) and the rate of ATP-induced acto-HMM dissociation (controlled by K1k+2) under the same experimental condition used to measure Vo). In fast-muscle myosin isolated from a wide range of mammalian muscles, k(-AD) was found to be too fast to limit Vo, whereas K1k+2 was of the right magnitude for ATP-induced dissociation of the cross-bridge to limit shortening velocity. The result was unexpected and prompted further experiments using the stopped-flow approach on myosin subfragment-1 (S1) and HMM obtained from bulk preparations of rabbit and rat muscle. These confirmed that the rate of cross-bridge dissociation by ATP limits the velocity of contraction for fast myosin II isoforms at 12 degrees C, while k(-AD) limits the velocity of slow myosin II isoforms. Extrapolating our data to 37 degrees C suggests that at physiological temperature the rate of ADP dissociation may limit Vo for both isoforms.

Adenosine Diphosphate↗
PubMed2006

Catalytic specificity of pea O-methyltransferases suggests gene duplication for (+)-pisatin biosynthesis.

S-adenosyl-l-methionine: 2-hydroxyisoflavanone 4'-O-methyltransferase (HI4'OMT) methylates 2,7, 4'-trihydroxyisoflavanone to produce formononetin, an essential intermediate in the synthesis of isoflavonoids with methoxy or methylenedioxy groups at carbon 4' (isoflavone numbering). HI4'OMT is highly similar (83% amino acid identity) to (+)-6a-hydroxymaackiain 3-O-methyltransferase (HMM), which catalyzes the last step of (+)-pisatin biosynthesis in pea. Pea contains two linked copies of HMM with 96% amino acid identity. In this report, the catalytic activities of the licorice HI4'OMT protein and of extracts of Escherichia coli containing the pea HMM1 or HMM2 protein are compared on 2,7,4'-trihydroxyisoflavanone and enantiomers of 6a-hydroxymaackiain. All these enzymes produced radiolabelled 2,7-dihydroxy-4'-methoxyisoflavanone or (+)-pisatin from 2,7,4'-trihydroxyisoflavanone or (+)-6a-hydroxymaakiain when incubated with [methyl-(14)C]-S-adenosyl-l-methionine. No product was detected when (-)-6a-hydroxymaackiain was used as the substrate. HI4'OMT and HMM1 showed efficiencies (relative V(max)/K(m)) for the methylation of 2,7,4'-trihydroxyisoflavanone 20 and 4 times higher than for the methylation of (+)-6a-hydroxymaackiain, respectively. In contrast, HMM2 had a higher V(max) and lower K(m) on (+)-6a-hydroxymaackiain, and had a 67-fold higher efficiency for the methylation of (+)-6a-hydroxymaackiain than that for 2,7,4'-trihydroxyisoflavanone. Among the 15 sites at which HMM1 and HMM2 have different amino acid residues, 11 of the residues in HMM1 are the same as found in HI4'OMTs from three plant species. Modeling of the HMM proteins identified three or four putative active site residues responsible for their different substrate preferences. It is proposed that HMM1 is the pea HI4'OMT and that HMM2 evolved by the duplication of a gene encoding a general biosynthetic enzyme (HI4'OMT).

Amino Acid Sequence↗
PubMed2004

Proteasome activity and the post-translational control of sucrose synthase stability in maize leaves.

The serine-170 (S170) calcium-dependent protein kinase phosphorylation site of maize (Zea mays L.) sucrose synthase (SUS) (EC 2.4.1.13) has been implicated in the post-translational regulation of SUS protein stability. To clarify the proteolytic process and the role of phosphorylation, SUS degradation and proteasome activities were studied in the maize leaf elongation zone. Size-exclusion chromatography resolved two peaks of proteasome-like proteolytic activity. The large molecular mass ( approximately 1350 kDa) peak required Mg(2+) and ATP for maximal activity and was inhibited by the proteasome inhibitors MG132 and NLVS. Anion-exchange chromatography resolved a similar proteolytic activity that was activated by ATP, characteristics that are consistent with those of a 26S-proteasome. Appropriately, immunoblotting revealed the presence of a 26S-proteasome subunit and highly ubiquitinated proteins within the active fractions eluted from both columns. The smaller molecular mass ( approximately 600 kDa) peak represented only 40% of the total proteasome-like activity and is likely a maize 20S-proteasome as it was activated in vitro by low levels of sodium dodecyl sulfate (SDS). S170 phosphorylated SUS (pS170-SUS) was detected as both high molecular mass (HMM) forms and proteolytic fragments that co-eluted with 26S-proteasome activities on both size-exclusion and anion-exchange columns. Conditions that maintained maximal 26S-proteasome activity reduced the amounts of pS170-SUS recovered. In vitro, the 26S-proteasome degraded SUS and proteasome-specific inhibitors reduced SUS proteolysis. HMM-SUS conjugates were produced in vitro and immunoprecipitations suggested that some SUS might be ubiquitinated in vivo. The results suggest that S170 phosphorylation promotes the formation of HMM, ubiquitin-SUS conjugates that can be targeted for 26S-proteasome-dependent degradation.

Cysteine Endopeptidases↗
PubMed2005

Sodium silicate as alternative to liming-reduced aluminium toxicity for Atlantic salmon (Salmo salar L.) in unstable mixing zones.

When acid aluminium (Al) rich water is limed, unstable mixing zones are formed until equilibrium is reached. In such mixing zones transient high molecular mass positively charged Al-species (HMM Al(i)) being extremely gill reactive are produced, causing toxic effects in fish. The transient HMM Al(i)-species are formed due to hydrolysis and polymerization of low molecular positively charged Al-species (LMM Al(i)), e.g. initiated by liming and the subsequent increase in pH. To counteract the toxicity of transient Al polymers in such mixing zones, sodium silicate, forming non-toxic hydroxyaluminosilicate (HAS) complexes, can be used as alternative to liming. In the present work the effect of sodium silicate on polymerization of LMM Al(i) in unstable mixing zones and subsequent gill reactivity and mortality of fish was compared to results obtained from liming. Diluted sodium silicate (<1.5 g l(-1)) and lime slurry (Ca(OH)(2)), respectively, were continually added to acidified Al-rich water in six different channel-tank systems, to obtain mixing zones with pH 5.9, 6.0 and 6.4, respectively. Utilising in situ size and charge fractionation techniques and following the exposure of Atlantic presmolt (Salmo salar L.) kept in cages at defined stations along the channel-tank systems, changes of Al-species in the mixing zones, the gill reactivity of Al-species and thus Al toxicity could be followed downstream the confluences (time of reaction after mixing: 1-100 min). By increasing the pH of the acid water to 6.0 or 6.4 by sodium silicate, the detoxification of Al was faster than using lime. Using sodium silicate, the transformation of LMM Al(i), the formation of HMM Al(i), the Al deposition in fish gills and fish mortality were lower than using lime. The formation of neutral LMM Al-species (Al(o)) was, however, higher and the formation of colloidal Al-species (Al(c)) lower in the presence of silicate compared to lime. Furthermore, the Al deposition in fish gills and fish mortality decreased by increasing concentration of sodium silicate dosed. Thus, sodium silicate is a good alternative to liming, and under certain circumstances when aging of water may represent a problem (e.g. aquaculture) sodium silicate should be the preferred agent.

Aluminum↗
PubMed2003

Actomyosin motility on nanostructured surfaces.

We have here, for the first time, used nanofabrication techniques to reproduce aspects of the ordered actomyosin arrangement in a muscle cell. The adsorption of functional heavy meromyosin (HMM) to five different resist polymers was first assessed. One group of resists (MRL-6000.1XP and ZEP-520) consistently exhibited high quality motility of actin filaments after incubation with HMM. A second group (PMMA-200, PMMA-950, and MRI-9030) generally gave low quality of motility with only few smoothly moving filaments. Based on these findings electron beam lithography was applied to a bi-layer resist system with PMMA-950 on top of MRL-6000.1XP. Grooves (100-200nm wide) in the PMMA layer were created to expose the MRL-6000.1XP surface for adsorption of HMM and guidance of actin filament motility. This guidance was quite efficient allowing no U-turns of the filaments and approximately 20 times higher density of moving filaments in the grooves than on the surrounding PMMA.

Actin Cytoskeleton↗
PubMed2003

Activation of Nrf2 and accumulation of ubiquitinated A170 by arsenic in osteoblasts.

Sub-lethal levels of arsenic induce upregulation of stress proteins. We here report for the first time that inorganic arsenic activates the transcription factor Nrf2, which controls the expression of oxidative stress-induced proteins. Treatment of cultured MC3T3-E1 osteoblasts with arsenite or arsenate induced increase of Nrf2, followed by transcriptional activation of target genes encoding HO-1, Prx I, and A170. We found that arsenate (200-800 micro M) only slightly increased the normal 60kDa A170 protein but markedly increased higher molecular mass forms of A170 (HMM-A170) that appeared as smeared bands. Arsenate also markedly increased ubiquitin-conjugated cellular proteins, suggesting that HMM-A170 was one of the poly-ubiquitinated proteins. Arsenite (50-100 micro M) also induced accumulation of HMM-A170 and ubiquitin-conjugated proteins. These results provide the first direct evidence that toxic arsenics impair the normal function of A170. Our findings provide a potential diagnostic tool for monitoring biotoxicity in cells and tissues in response to arsenic compounds.

Adaptor Proteins, Signal Transducing↗
PubMed1989

Characteristics of the myosin and tropomyosin binding regions of the smooth muscle caldesmon.

Limited digestion of caldesmon by alpha-chymotrypsin generates mainly 110, 80, 60, 38, and 28 kDa fragments. Affinity chromatography of these fragments on columns immobilized with myosin, HMM, or tropomyosin showed that the bound fraction from these columns was similar and it contained 110, 80, 60 and 28 kDa fragments. These fragments did not bind to myosin filaments, acto-HMM, actin or tropomyosin-actin in the solution, and they had no effect on the actin-activated ATPase of HMM. In contrast, the flow-through fraction from these affinity columns inhibited the actin-activated ATPase. Binding studies revealed that the 38 kDa fragment and its break down products bound to actin and tropomyosin-actin, and they were released partially from actin by calmodulin with a concomitant increase in the ATPase activity. These results indicate that, unlike the actin binding domain, the myosin and tropomyosin binding domains require the caldesmon molecule to be intact in order to exert their effects on the protein-protein interaction.

Actins↗