Unveiling Tatun volcanic plumbing structure induced by post-collisional extension of Taiwan mountain belt.

The Tatun Volcanic Group (TVG) is proximal to the metropolis of Taipei City (population of ca. 7 million) and has long been a major concern due to the potential risks from volcanic activity to the population and critical infrastructure. While the TVG has been previously considered a dormant or extinct volcano, recent evidence suggests a much younger age of the last eruption event (~ 6000 years) and possible existence of a magma reservoir beneath the TVG. However, the location, dimension, and detailed geometry of the magma reservoir and plumbing system remains largely unknown. To examine the TVG volcanic plumbing structure in detail, the local P-wave travel time data and the teleseismic waveform data from a new island-wide Formosa Array Project are combined for a 3D tomographic joint inversion. The new model reveals a magma reservoir with a notable P-wave velocity reduction of 19% (ca. ~ 19% melt fraction) at 8-20 km beneath eastern TVG and with possible northward extension to a shallower depth near where active submarine volcanoes that have been detected. Enhanced tomographic images also reveal sporadic magmatic intrusion/underplating in the lower crust of Husehshan Range and northern Taiwan. These findings suggest an active volcanic plumbing system induced by post-collisional extension associated with the collapse of the orogen.

[Expression of platelet-derived growth factor-b and transforming growth factor-beta 1 in the alveolar macrophages of allergic rats].

OBJECTIVE: To investigate the role of alveolar macrophages in airway remodeling in asthma. METHOD: Sixteen Wistar rats were divided into two groups: control group and asthmatic group. The expressions of platelet-derived growth factor-b (PDGF-b) and transforming growth factor-beta. (TGF-beta 1) in the alveolar macrophages of allergic rats were detected by immunohistochemistry and in situ hybridization. RESULTS: The expression of TGF-beta 1 in alveolar macrophages in allergic group was increased in both protein level (P < 0.05) and TGF-beta 1 mRNA(P < 0.01); but the expression of PDGF-b had no difference between the two groups. CONCLUSION: The alveolar macrophages may involve in the airway remodeling of asthma.

[Expression of interleukin-5 and interleukin-10 and their relationship in asthma].

UNLABELLED: To explore the expression of interleukin-5(IL-5) and interleukin-10(IL-10) and their relationship in asthma, we measured the cells in bronchial alveolar lavage fluid(BALF) of guinea pigs, and examined the expression of IL-5 mRNA and IL-10 mRNA of bronchial tissue by reverse transcription polymerase chain reaction(RT-PCR) in control group(Group C, n = 10), asthmatic group(Group A, n = 11) and dexamethasone treatment group(Group B, n = 10). The results showed that the eosinophil(EOS) percentage and the expression of IL-5 mRNA were significantly higher in Group A[(48.64 +/- 17.8)%, (106.91 +/- 20.09)% respectively] than that in Group C[(15.10 +/- 11.48)%, (62.60 +/- 13.84)%] and Group B[(28.4 +/- 10.32)%, (75.30 +/- 10.70)%]. In contrast, the IL-10 mRNA expression in Group A[(47.5 +/- 5.3)%] was obviously lower compared with that in Group C[(101.2 +/- 4.2)%] and Group B[(80.1 +/- 8.3)%]. The correlation between the expression level of IL-5 mRNA and percentage of EOS was positive(r = 0.924, P < 0.01), whereas the IL-5 mRNA was negatively correlated with IL-10 mRNA expression(r = -0.731, P < 0.01). CONCLUSION: IL-5 and EOS might play a role in the pathogenesis of asthma, the inhibition of IL-10 mRNA expression may cause the increase of IL-5 expression in asthma. The beneficial effects of corticosteroid treatment in asthma may partly result from increasing IL-10 mRNA expression and inhibiting IL-5 mRNA expression.

[Effects of retinoic acid on proliferation and differentiation of human lung squamous carcinoma cell line].

Human lung squamous carcinoma cell line(TUL cell) was treated with 5 x 10(-6) mol.L-1 all-trans retinoic acid(ATRA). Cell numbers were estimated by 0.4% trypon blue stain. MTT test was used for determining the percentage of cell growth inhibition(GI). DNA syntheses of cells were evaluated by 3H-thymidine incorporation. Cell ultrastructure was examined by transmission electron microscope(TEM). TUL cells were treated with or without ATRA, and transplanted in cutaneous of Balb/c nude mice. The results showed that: 1. The speed of cell growth in study group was smaller than that in control group. 2. The GI of cell lines TUL was 42.3%. 3. The percentage of 3H-thymidine incorporation of TUL cells was declined significantly. 4. Ultrastructure under TME showed that TUL cells treated with ATRA was suppressed. These results suggest that ATRA has the effects on growth-inhibition and differentiation-induction of TUL cell.

[Abnormal expression of the FHIT gene in human primary gastrointestinal cancers].

OBJECTIVE: To evaluate the relationship between FHIT gene and gastrointestinal cancers. METHODS: Matched normal and cancerous tissues from 26 patients with primary gastric carcinoma and 30 patients with colorectal carcinoma were analysed by nested polymerase chain reaction(RT-PCR) and direct sequencing of the products. RESULTS: Seven of 26(26.9%) gastric cancer tissues and eight of 30(26.7%) colorectal cancer tissues expressed aberrant FHIT transcripts, but no aberrant FHIT transcript was observed in all the matched normal tissues. Sequence analysis of the aberrant transcripts of 2 gastric cancer tissues(G8T, G25T) and 2 colorectal cancer tissues(C5T, C26T) confirmed the absence of 1 to 3 exons of FHIT gene. CONCLUSIONS: The expression of aberrant FHIT transcripts is common and tumor-specific in gastrointestinal cancers and abnormalities of FHIT gene may be associated with gastrointestinal tumorigenesis.

Measurement of molecular diffusion in solution by multiphoton fluorescence photobleaching recovery.

Multiphoton fluorescence photobleaching recovery (MP-FPR) is a technique for measuring the three-dimensional (3D) mobility of fluorescent molecules with 3D spatial resolution of a few microns. A brief, intense flash of mode-locked laser light pulses excites fluorescent molecules via multiphoton excitation in an ellipsoidal focal volume and photobleaches a fraction. Because multiphoton excitation of fluorophores is intrinsically confined to the high-intensity focal volume of the illuminating beam, the bleached region is restricted to a known, three-dimensionally defined volume. Fluorescence in this focal volume is measured with multiphoton excitation, using the attenuated laser beam to measure fluorescence recovery as fresh unbleached dye diffuses in. The time course of the fluorescence recovery signal after photobleaching can be analyzed to determine the diffusion coefficient of the fluorescent species. The mathematical formulas used to fit MP-FPR recovery curves and the techniques needed to properly utilize them to acquire the diffusion coefficients of fluorescently labeled molecules within cells are presented here. MP-FPR is demonstrated on calcein in RBL-2H3 cells, using an anomalous subdiffusion model, as well as in aqueous solutions of wild-type green fluorescent protein, yielding a diffusion coefficient of 8.7 x 10(-7) cm(2)s(-1) in excellent agreement with the results of other techniques.

[A prospective study on etiologic bacteria in 200 patients with pneumonia].

The etiologic agents in 200 patients with pneumonia were studied by the bacterial culture of sputums obtained from the protected single catheter brush or quantitative expectoration at one morning or three-morning expectoration. Two hundred patients were divided into 3 groups. Group 1 was Nosocomial pneumonia (NP patients). Group 2-1 and Group 2-2 were community acquired pneumonia (CAP patients). All cases in Group 1 and Group 2-2 suffered from significant underlying diseases while Group 2-1 did not. Gram-negative bacilli(GNB) were isolated from the specimens in Group 1 (87%) and Group 2-2 (75%), respectively. Pseudomonas (30.8%) and klebsiella (20.5%) were the predominant bacteria (in Group 1 and pseudomonas bacteria) in Group 1 and pseudomonas (27.3%), acinetobacter (23%) and kledsiella (18%) were the major etiologic agents in Group 2-2. The commonest pathogens in Group 2-1 were gram-positive cocci (75%), in which streptococcus (38%) and staphylococcus aureus (25%) were the dominant agents. Compared with Group 2, Group 1 suffered from more mixed bacteria and the agents presented severer drug-resistant. The prognosis was worse in Group 2-2 than in Group 2-1. The results showed that the GNB pneumonia was more common in the cases who had underlying disease, no matter whether the pneumonia was NP or CAP. These patients had more trouble on their antibiotic therapy. Thus it is important that doctors should use vigorous antibiotics timely while treating these patients' underying diseases.

In vitro muscarinic activity of spiromuscarones and related analogs.

The cholinergic hypothesis of Alzheimer's disease suggests that cholinergic agonists may have therapeutic potential for treating the attendant memory deficits of the disease. As part of a program aimed at preparing metabolically stable, nonquaternary analogs of muscarone, 1-oxa-2,8-dimethyl-8-azaspiro[4.5]decan-3-one, 2a, and related analogs have been synthesized and their in vitro muscarinic activity evaluated. The synthetic strategy in the formation of the 1-spiro[4.5]decan-3-one ring system of 2a involved cyclization of the diol 4 in the presence of Nafion-Hg. The spiromuscarone 2a was found to displace [3H]Oxo-M binding with a Ki value of 7 nM. Affinities of the oxime and hydrazone analogs of 2a were lower than 2a. The compounds in these series were partial muscarinic agonists as demonstrated by stimulation of phosphatidyl inositol hydrolysis assay, with 2a showing the highest intrinsic intrinsic activity (60% as compared with carbachol). The results from this study indicate that an exo double bond at the C-3 position is essential for the receptor binding.

Flavones. 3. Synthesis, biological activities, and conformational analysis of isoflavone derivatives and related compounds.

A series of 2-alkylisoflavone derivatives 1 was prepared with the intent to study the importance of the phenyl group (at the 3-position) of the isoflavone in imparting antihypertensive activity and the substitution effects at the 2-position of isoflavone. With the exception of the 2-isopropyl analog, the antihypertensive activity of these compounds appears to have a slow onset and long duration. None of the analogs appears better than the corresponding flavone (3) and 3-phenylflavone (2) analogs. An unsuccessful attempt to correlate the relationship between antihypertensive activity and the calculated torsional angle of C2-C3-C1'-C2' is discussed. Antiinflammatory activities of these compounds along with 7-(oxypropylamine)flavones were also evaluated and found to be not very potent. The antiinflammatory activity appears to be sensitive to steric effects of the alkyl group on the nitrogen and of substituents at the 2-position of the isoflavones, while the hydroxyl group of the propanolamine side chain is not essential.

The mobility of a fluorescent ubiquinone in model lipid membranes. Relevance to mitochondrial electron transport.

The diffusion and location of a functional, fluorescent ubiquinone molecule, NBDHA-Q, were determined as a function of temperature using microscopic observation, fluorescence recovery after photobleaching and fluorescence spectroscopy in protein-free, pure-lipid dimyristoylphosphatidylcholine and dimyristoylphosphatidylcholine/cholesterol multibilayers. The data reveal that in a liquid-crystalline membrane (1) ubiquinone is highly mobile, (2) ubiquinone uniformly diffuses laterally with the same diffusion coefficient (3.10(-8) cm2/s at 25 degrees C) as the phospholipids in which it resides, (3) the diffusion coefficients of ubiquinone and phospholipid both decrease at the exothermic phase transition of the phospholipid, (4) cholesterol affects the diffusion coefficients of ubiquinone and phospholipids to the same degree, (5) cholesterol induces a lateral phase separation progressively excluding ubiquinone from cholesterol-containing domains. These data suggest that ubiquinone does not reside at the membrane surface or in the mid-plane for any appreciable length of time. Rather, the data indicate that ubiquinone is highly mobile laterally and transversely, spending the majority of its time in the acyl chain region of the membrane, where its lateral and transverse diffusion is limited by the lateral diffusion and the transverse microviscosity gradient of the phospholipids and where its lateral location can be affected by the presence of cholesterol. In addition, based upon a comparison of the diffusion coefficients for ubiquinone, phospholipids and mitochondrial redox complexes, we hypothesize that no significant portion of the ubiquinone pool remains bound to redox complexes for any significant length of time relative to that for electron transport as resolvable by fluorescence recovery after photobleaching.

Flavodilol: a new antihypertensive agent.

Flavodilol, a new antihypertensive drug, was evaluated in a variety of test systems for better understanding of its biologic properties and the nature of its mechanism of action. Oral administration of the drug to spontaneously hypertensive rats (SHR) lowered arterial blood pressure (ABP) in a dose-related manner, and doses greater than 35 mg/kg increased duration but not magnitude of the response. In contrast, oral administration of flavodilol to normotensive rats did not significantly alter ABP at 35 mg/kg, although larger doses of 75 or 150 mg/kg significantly lowered ABP. In rats with DOCA/salt hypertension, flavodilol effectively lowered ABP to a degree similar to that observed in SHR. At antihypertensive doses, flavodilol did not alter blood pressure responses to a 90 degrees head-up tilt in SHR and did not influence cardiac output in conscious SHR. In addition, flavodilol did not appear to manifest its antihypertensive activity through an interaction with beta-adrenoceptors, dopamine (DA) receptors or prostaglandin synthetase. Daily oral administration of flavodilol to SHR for 4 days resulted in augmented vasopressor responses to exogenously administered epinephrine (EPI) or norepinephrine (NE) and attenuated responses to exogenously administered tyramine. In addition, flavodilol treatment attenuated in a dose-related manner ABP and heart rate (HR) responses of pithed SHR to electrical stimulation of sympathetic nerves. We conclude that flavodilol is an effective antihypertensive drug which decreases the release of NE from postganglionic sympathetic nerves, resulting in attenuation of peripheral noradrenergic function.

Flavodilol: a new antihypertensive agent that preferentially depletes peripheral biogenic amines.

Flavodilol, ((+/-)-7-[2-hydroxy-3-(propylamine)-propoxy]flavone maleate), a new orally effective antihypertensive agent, extensively depleted catecholamines and serotonin in heart tissue of normotensive and spontaneously hypertensive rats (SHR). Dose-response studies demonstrated that greater than or equal to 75% depletion of cardiac norepinephrine (NE) was accompanied by marked blood pressure decline in SHR. In contrast, whole brain biogenic amine levels were decreased only by 15-20% after acute or chronic treatment with antihypertensive doses (35-75 mg/kg). Adrenal epinephrine (EPI) stores were unaffected by acute treatment, although chronic treatment for 18 days with an antihypertensive dose of 75 mg/kg flavodilol decreased EPI by 70%. Acute treatment also decreased serotonin content of spleen by 70-80%. In dogs, a cumulative oral dose of 40 mg/kg decreased catecholamines by greater than or equal to 50% in aorta and heart muscle. Although hypothalamic catecholamine stores appeared to be more susceptible to depletion by flavodilol than catecholamines in other brain regions, these changes did not appear functionally related to blood pressure decreases since analogs of flavodilol without antihypertensive properties produced equivalent or greater depletion of hypothalamic catecholamine stores. In vitro flavodilol promoted spontaneous and potassium-evoked release of dopamine from isolated striatal nerve endings (0.3 microM) and blocked uptake of NE by hypothalamus and hippocampal nerve endings (1 microM), suggesting that biogenic amine depletion in vivo may be caused by an interference with storage and release mechanisms. Despite structural features reminiscent of beta-adrenergic antagonists, flavodilol had low affinity for beta-receptors. Neither was there any inhibition of tyrosine hydroxylase. These findings suggest that the antihypertensive activity of flavodilol results, at least in part, from depletion of sympathetic stores of NE in heart and vascular tissues that moderate adrenergic transmission, thereby decreasing heart rate (HR) and prevailing vascular tone.

Flavones. 2. Synthesis and structure-activity relationship of flavodilol and its analogues, a novel class of antihypertensive agents with catecholamine depleting properties.

(3-Phenyl-7-flavonoxy)propanolamines have been shown to exhibit antihypertensive activity in spontaneously hypertensive rats. Although they are structurally similar to classical beta-adrenergic blocking compounds, their activity is not due to inhibition of beta-adrenoceptors. In the present study, a series of simple flavonoxypropanolamines was prepared to further explore the structural requirements for the antihypertensive effect of these compounds. A structure-activity relationship of these derivatives indicates that the position of the oxypropanolamine side chain, the hydroxy group of the side chain, steric bulkiness and length of N substituents, degree of the N-substitution, phenyl group at the 2-position of the chromone nucleus, and substituents of the phenyl group or B ring of the flavone play significant roles in imparting pharmacological effects. In addition, there is a good correlation between the antihypertensive activity and depletion of myocardial norepinephrine. Of these analogues tested, the most effective one was flavodilol. Only the 8-substituted analogue 6 was found to be a beta-antagonist. Flavodilol was chosen for in-depth pharmacological, toxicological, and clinical evaluation.

Flavones. 1. Synthesis and antihypertensive activity of (3-phenylflavonoxy)propanolamines without beta-adrenoceptor antagonism.

The synthesis of a series of (3-phenylflavonoxy)propanolamines is described. These compounds were evaluated for potential antihypertensive activity in spontaneously hypertensive rats, as well as for in vivo and in vitro evidence of beta-adrenoceptor antagonism. Some of the compounds of this series exhibited effective antihypertensive properties but did not antagonize beta-adrenergic receptors. These active compounds represent a unique series of effective antihypertensive agents that, despite possessing structural characteristics typical of beta-blockers, does not have beta-adrenergic receptor blocking activity.

Calcium-mediated fusion to produce ultra large osmotically active mitochondrial inner membranes of controlled protein density.

We have developed a new membrane fusion method which produces ultra large, spherical mitochondrial inner membranes attached to microscope slides. The fused inner membranes measured up to 200 microns in diameter. The technique fuses native inner membranes as well as inner membranes in which the protein density has been varied by enriching with exogenous phospholipid. The fusion process is accomplished through the use of calcium, low pH and elevated temperature. Characterization of the fused membranes was carried out using phase, fluorescence, and freeze-fracture electron microscopy. These ultra large, fused inner membranes were found to model the inner membranes from which they were formed. The fused inner membranes were found to be osmotically active and are large enough for measuring the lateral diffusion of membrane components by fluorescence recovery after photobleaching and are large enough for microelectrode impalement.

Relationship between lateral diffusion, collision frequency, and electron transfer of mitochondrial inner membrane oxidation-reduction components.

Fluorescence recovery after photobleaching was used to determine the diffusion coefficients of the oxidation-reduction (redox) components ubiquinone, complex III (cytochromes b-c1), cytochrome c, and complex IV (cytochrome oxidase) of the mitochondrial inner membrane. All redox components diffuse in two dimensions as common-pool electron carriers. Cytochrome c diffuses in two and three dimensions concomitantly, and its diffusion rate, unlike that of all other redox components, is modulated along with its activity by ionic strength. The diffusion coefficients established in this study reveal that the theoretical diffusion-controlled collision frequencies of all redox components are greater than their experimental maximum (uncoupled) turnover numbers. Since electron transport is slower than the theoretical limit set by the lateral diffusion of the redox components, ordered chains, assemblies, or aggregates of redox components are not necessary to account for electron transport. Rather, mitochondrial electron transport is diffusion coupled, consistent with a "random-collision model" for electron transport.

Lateral diffusion of cytochrome P-450 in phospholipid bilayers.

The lateral diffusion coefficient (D) of cytochrome P-450 (P-450) has been measured in lipid multibilayers with the method of fluorescence recovery after photobleaching. In the liquid-crystal phase of egg phosphatidylcholine (EPC) and dimyristoylphosphatidylcholine (DMPC), the diffusion of P-450 is fast with D about 2 X 10(-8) cm2/s. In DMPC multibilayers, P-450 diffusion dropped by a factor of 20 near the liquid crystal to gel phase transition region, and D is about 5 X 10(-10) cm2/s in the gel phase. A value of 50 mol % of cholesterol reduced the diffusion of P-450 in the liquid-crystal phase only slightly but enhanced the diffusion of P-450 in the gel phase significantly. In EPC membranes, P-450 diffusion underwent a stepwise drop as the cholesterol contents increased from 20 to 30 mol %. With the assumption of a lateral diffusion mediated electron transfer between P-450 and NADPH-P-450 reductase and with D = 2.5 X 10(-8) cm2/s for both enzymes, the reduction rate for P-450 in liposomes was calculated and compared with the reported experimental value.

Lateral diffusion of gramicidin C in phospholipid multibilayers. Effects of cholesterol and high gramicidin concentration.

We have measured the lateral diffusion coefficient (D), of active dansyl-labeled gramicidin C (DGC), using the technique of fluorescence photobleaching recovery, under conditions in which the cylindrical dimer channel of DGC predominates. In pure, hydrated, dimyristoylphosphatidylcholine (DMPC) multibilayers (MBL), D decreases from 6 X 10(-8) cm2/s at 40 degrees C to 3 X 10(-8) cm2/s at 25 degrees C, and drops 100-fold at 23 degrees C, the phase transition temperature (Tm) of DMPC. Above Tm, addition of cholesterol decreases D; a threefold stepwise drop occurs between 10 and 20 mol %. Below Tm, increasing cholesterol increases D; a 10-fold increase occurs between 10 and 20 mol % at 21 degrees C, between 20 and 25 mol % at 15 degrees C, and between 25 and 30 mol % at 5 degrees C. In egg phosphatidylcholine (EPC) MBL, D decreases linearly from 5 X 10(-8) cm2/s at 35 degrees C to 2 X 10(-8) cm2/s at 5 degrees C; addition of equimolar cholesterol reduces D by a factor of 2. Thus this transmembrane polypeptide at low membrane concentrations diffuses quite like a lipid molecule. Its diffusivity in lipid mixtures appears to reflect predicted changes of lateral composition. Increasing gramicidin C (GC) in DMPC/GC MBL broadened the phase transition, and the diffusion coefficient of the lipid probe N-4-nitrobenzo-2-diazole phosphatidylethanolamine (NBD-PE) at 30 degrees C decreases from 8 X 10(-8) cm2/s below 5 mol % GC to 2 X 10(-8) cm2/s at 14 mol % GC; D for DGC similarly decreases from 4 X 10(-8) cm2/s at 2 mol % GC to 1.4 X 10(-8) cm2/s at 14 mol % GC. Hence, above Tm, high concentrations of this polypeptide restrict the lateral mobility of membrane components.