Biomedical subjects
Publications and source records attributed to C Sun.
[reaction: see text]. A total synthesis of racemic lepadiformine has been achieved via a route that utilizes as key steps a novel stereocontrolled intramolecular spirocyclization of an allylsilane/N-acyliminium ion and the application of our radical-based methodology for production of N-acylimines from o-aminobenzamides.
L-lysine monohydrochloride (LMH) dihydrate was crystallized and the resulting powder was sieved to obtain various size fractions. The influence of other factors, such as crystallinity and crystal shape, was minimized by using the same batch of crystals. Compression of smaller particles at low compaction pressures resulted in tablets of greater porosity. The differences in porosity decreased with increasing compaction pressure. At the same compaction pressure, smaller particles formed tablets of greater tensile strength. However, fragmentation of the larger particles tended to equalize the particle size and reduce its influence. The differences were reduced for particles larger than 710 microm. For crystals of all size fractions, tensile strength increased with increasing compaction pressure. The tensile strength increased more rapidly for smaller crystals. Tensile strength decreased exponentially with increasing porosity for all fractions. The dependence of tensile strength on porosity is explained in term of tablet structure. Yield strength, calculated from 'out-of-die' Heckel analysis, increased with increasing particle size.
The molecular mechanism(s) that regulate apoptosis by caspase inhibition remain poorly understood. The main endogenous inhibitors are members of the IAP family and are exemplified by XIAP, which regulates the initiator caspase-9, and the executioner caspases-3 and -7. We report the crystal structure of the second BIR domain of XIAP (BIR2) in complex with caspase-3, at a resolution of 2.7 A, revealing the structural basis for inhibition. The inhibitor makes limited contacts through its BIR domain to the surface of the enzyme, and most contacts to caspase-3 originate from the N-terminal extension. This lies across the substrate binding cleft, but in reverse orientation compared to substrate binding. The mechanism of inhibition is due to a steric blockade prohibitive of substrate binding, and is distinct from the mechanism utilized by synthetic substrate analog inhibitors.
The purpose of this study is to understand the influence of crystal shape on the tableting performance of L-lysine monohydrochloride (LMH) dihydrate, using the method of data analysis developed by Joiris E et al. 1998. Pharm Res 15:1122-1130. Phase-pure crystals of LMH dihydrate, prism-shaped (S) and plate-shaped (T), were prepared by adjusting the composition of the crystallization solvent. At the same compaction pressure, T always gives stronger tablets than S, (i.e.; the tabletability of T is greater). The porosity of tablets from T crystals is always greater than that of S crystals when compressed at the same pressure, (i.e.; the compressibility of T is lower). The tensile strength of T tablets, at the same porosity, is greater than that of S tablets, (i.e.; the compactibility of T is greater). Therefore, the greater tabletability of T is a result of its better compactibility that overcomes the negative effects by its lower compressibility. The greater compactibility of T is related to favorable orientation of the slip planes in the tablet, corresponding to greater plasticity under load. The yield strengths of T and S crystals are essentially the same (20 MPa). Therefore, the crystal shape influences the tableting performance but does not, in principle, affect the yield strength of LMH dihydrate.
The byssal threads of marine mussels are a fiber-reinforced composite material. Fibers are continuous, separated by matrix, and consist of chimeric collagens that encompass within the same primary protein structure domains corresponding to collagen, polyhistidine, and either elastin or dragline spider silk. The elastic modulus (stiffness) of the proximal portion of byssal threads was measured by cyclic stress-strain analysis at 50% extension. Before measurement, the threads were conditioned by various treatments, particularly agitation in aerated or nitrogen-sparged seawater. Stiffness can be permanently increased by more than two times, e.g., from 25 MPa to a maximum of 65 MPa, by simple agitation in aerated seawater. Much but not all of this stiffening can be prevented by agitation under nitrogen. Reversible strain stiffening would seem to be a useful adaptation to lower residual stresses arising from the deformation of two joined materials, i.e., distal and proximal portions with rather different elastic moduli. The permanent strain stiffening that characterizes proximal byssal threads subjected to oxidative stress is probably due to protein cross-linking. In the short term, this results in a stronger thread but at the expense of dynamic interactions between the molecules in the structure.
Germination rate and root elongation, as a rapid phytotoxicity test method, possess several advantages, such as sensitivity, simplicity, low cost and suitability for unstable chemicals or samples. These advantages made them suitable for developing a large-scale phytotoxicity database and especially applicable for developing quantitative structure-activity relationship (QSAR) to study mechanisms of phytotoxicity. In this paper, the comparative inhibition of germination rate and root elongation of Cucumis sativus by selected halogen-substituted phenols and anilines were determined. The suitability of germination rate and root elongation as phytotoxicity endpoints was evaluated. Excellent reproducibility and stability of germination rate and root elongation in the control test, relatively greater sensitivity and similar dose-response relations for all tested compounds were observed. These results together with those of a 2-day test were used to demonstrate the suitability of this phytotoxicity test method. A QSAR was developed for the phytotoxicity mode of action of the tested compounds to C sativus seeds. Models that combined the logarithm of 1-octanol/water partition coefficient (log Kow) and the energy of the lowest unoccupied molecular orbital (Elumo) were developed for both germination rate inhibition and root elongation inhibition. The results of these studies indicate that phytotoxicity of substituted phenols and anilines to C. sativus seeds could be explained by a polar narcosis mechanism. This paper will promote the application of germination rate and root elongation method and the development of large-scale phytotoxicity database, which will provide the fundamental data for QSAR and ecological risk assessment of organic pollutants.
The aim of this study is to acquire the relationship between the aggregation behavior of collagen in aqueous solution and its property of stabilizing liposomes in vitro. Firstly, we used an intramolecular charge transfer compound 3-methoxy-4'-N,N-dimethylamino flavone derivative (DMMF) as a fluorescence probe to detect collagen association in aqueous solution. Results showed that, when collagen concentration was increased to 0.5 mg/ml or above, the fluorescence intensity of DMMF at 465 nm increased dramatically. This indicated that collagen could associate in aqueous solution. The subsequent fluorescence polarization study on the same collagen solutions also proved that the aggregation behavior existed in the aqueous solution of collagen. Secondly. to evaluate the in vitro stability of small unilamellar vesicles (SUV), made from soybean phosphatidylcholine (PC) and coated with collagen, 5(6)-carboxyfluorescein was used as a fluorescence probe to determine the change of their permeability. We found that the coating with a collagen/PC weight ratio of 2:1, significantly decreased the permeability of liposomal membranes. The likely weight ratio of collagen and PC was mainly dependent on the critical aggregation concentration of collagen in aqueous solution. In addition, the fluorescence polarization method was also used to study the influence of a coating with collagen at the above ratio on the fluidity of liposomal membranes, employing DMMF as a fluorescence probe. The fluidity of liposomal membranes coated with collagen showed no obvious change, indicating that SUV coated with collagen at an appropriate ratio, could significantly improve the in vitro stability of liposomal membranes without disturbing their fluidity. It is thus clear that collagen self-association behavior is closely correlated to its coating liposomes to improve their stability.
The stems of Hedychium villosum yielded the new diterpenoid 1, named villosin, along with coronarin E and beta-sitosterol. Their structures were elucidated by spectroscopic methods including mono- and bi-dimensional NMR.
The aggregation and location of morin in CTMAB micellar solution was studied by light scattering spectra, electronic absorption spectra and pulsed FT NMR techniques. The difference in the light scattering property of morin with and without CTMAB proved that a large particle of the morin-CTMAB associate formed. Morin has a self-assembly tendency, but the assembly number is not high. With the increase of morin concentration, morin changed from a monomer to dimer. The hyperchromic and bathochromic effect of morin, with the increase in pH value or
PURPOSE: To understand the influence of polymorphic structure on the tableting properties of sulfamerazine. METHODS: Bulk powders of sulfamerazine polymorph I and of two batches. II(A) and II(B) of different particle size, of polymorph II were crystallized. The powders were compressed to form tablets whose porosity and tensile strength were measured. The relationships between tensile strength, porosity and compaction pressure were analyzed by the method developed by Joiris. E., et al. Pharm. Res. 15:1122-1130 (1998). RESULTS: The sensitivity of tensile strength to compaction pressure, known as the tabletability, follows the order. I >> II(A) > II(B) and the porosity at the same compaction pressure, which measures the compressibility, follows the order, I << II(A) < II(B). Therefore. the superior tabletability of I over II(A) or II(B) is attributed to its greater compressibility. Molecular simulation reveals slip planes in crystals of I but not in II. Slip planes provide I crystals greater plasticity and therefore greater compressibility and tabletability. Larger crystal size of II(B) than of II(A) leads to fewer contact points between crystals in the tablets and results in a slightly lower tabletability. CONCLUSIONS: Slip planes confer greater plasticity to crystals of I than II and therefore greater tabletability.
PURPOSE: To examine the effects of salt form, i.e., different anions with a common cation (L-lysinium), on compaction properties and to identify the factors that determine the tensile strength of tablets. METHODS: L-Lysine salts with the following anions were compressed at various pressures: acetate, monochloride, dichloride, L-aspartate, L-glutamate (dihydrate), and L-lysine (zwitterionic monohydrate). The yield strength of each salt was evaluated from the "out-of-die" Heckel plot. RESULTS: At low compaction pressures, the tensile strength of the compacts increases linearly with increasing compaction pressure. Simultaneously. the compact tensile strength decreases exponentially with increasing yield strength of the salt. However, at high compaction pressures, the compact tensile strength is determined by the interparticulate bonding strength and not by the yield strength. The compact tensile strength, extrapolated to zero porosity, increases linearly with increasing melting temperature of the salts. CONCLUSIONS: The counterion affects the tableting properties of L-lysine salts. The tensile strength is controlled by both the yield strength and the interparticulate interaction strength with the former predominant at low compaction pressures and the latter predominant at high compaction pressures. The melting temperature of each L-lysine salt is a good indicator of the tensile strength of its compacts at zero porosity.
Myotonia congenita is a non-dystrophic muscle disorder affecting the excitability of the skeletal muscle membrane. It can be inherited either as an autosomal dominant (Thomsen's myotonia) or an autosomal recessive (Becker's myotonia) trait. Both types are characterised by myotonia (muscle stiffness) and muscular hypertrophy, and are caused by mutations in the muscle chloride channel gene, CLCN1. At least 50 different CLCN1 mutations have been described worldwide, but in many studies only about half of the patients showed mutations in CLCN1. Limitations in the mutation detection methods and genetic heterogeneity might be explanations. In the current study, we sequenced the entire CLCN1 gene in 15 Northern Norwegian and three Northern Swedish MC families. Our data show a high prevalence of myotonia congenita in Northern Norway similar to Northern Finland, but with a much higher degree of mutation heterogeneity. In total, eight different mutations and three polymorphisms (T87T, D718D, and P727L) were detected. Three mutations (F287S, A331T, and 2284+5C>T) were novel while the others (IVS1+3A>T, 979G>A, F413C, A531V, and R894X) have been reported previously. The mutations F413C, A531V, and R894X predominated in our patient material. Compound heterozygosity for A531V/R894X was the predominant genotype. In two probands, three mutations cosegregated with myotonia. No CLCN1 mutations were identified in two families. Our data support the presence of genetic heterogeneity and additional modifying factors in myotonia congenita.
A new preresonance light scattering (PRLS) assay of nucleic acids is presented. At pH 7.30, the weak PRLS of morin-cetyltrimethylammonium bromide (CTMAB) can be greatly enhanced by the addition of nucleic acids, owing to the interaction between the nucleic acid and morin-CTMAB. After the addition of morin and CTMAB to DNA, the zeta potential of DNA decreases and changes from negative to positive, which is due to the formation of an associate, the aggregation of morin on nucleic acids and the electric neutralization between DNA and the cationic surfactant CTMAB. Mechanism studies showed that the enhanced PRLS comes from the aggregation of morin in the presence of nucleic acids and CTMAB. The enhanced intensity of PRLS is in proportion to the concentration of nucleic acids in the range 7.5 x 10(-9)-1.0 x 10(-5) g ml(-1) for calf thymus DNA, 7.5 x 10(-9)-1.0 x 10(-6) g ml(-1) for salmon sperm DNA and 1.0 x 10(-8)-1.0 x 10(-6) g ml(-1) for yeast RNA. The detection limits are 3.4, 6.2 and 4.1 ng ml(-1) for calf thymus DNA, salmon sperm DNA and yeast RNA, respectively. Synthetic samples were analyzed satisfactorily.
OBJECTIVES: Patients undergoing cardiopulmonary bypass frequently manifest generalized systemic inflammation and occasionally manifest serious multiorgan failure. Inflammatory responses of bypass are triggered by contact of blood with artificial surfaces of the bypass circuits, surgical trauma, and ischemia-reperfusion injury. We studied the effects of specific inhibition of the alternative complement cascade by using an anti-factor D monoclonal antibody (166-32) in extracorporeal circulation of human whole blood used as a simulated model of cardiopulmonary bypass. METHODS: Five healthy blood donors were used in the study. Monoclonal antibody 166-32 was added to freshly collected, heparinized human blood recirculated in a pediatric cardiopulmonary bypass circuit at a final concentration of 18 microg/mL. An irrelevant monoclonal antibody was used as a negative control with the same donor blood in a parallel bypass circuit on the same day. Blood samples were collected at different time points during recirculation for measurement of activation of complement, neutrophils, and platelets by immunofluorocytometric methods and enzyme-linked immunosorbent assays. RESULTS: Monoclonal antibody 166-32 inhibited the alternative complement activation and the production of Bb, C3a, sC5b-9, and C5a. Upregulation of CD11b on neutrophils and CD62P on platelets was also significantly inhibited by monoclonal antibody 166-32. This is consistent with the inhibition of the release of neutrophil-specific myeloperoxidase and elastase and platelet thrombospondin. The production of proinflammatory cytokine interleukin 8 was also suppressed by the antibody. CONCLUSIONS: The alternative complement cascade is predominantly activated during extracorporeal circulation. Anti-factor D monoclonal antibody 166-32 is effective in inhibiting the activation of complement, neutrophils, and platelets. Inhibition of the alternative complement pathway by targeting factor D could be useful in reducing systemic inflammation in patients undergoing cardiopulmonary bypass.
The Heckel equation is one of the most useful equations for describing the compaction properties of pharmaceutical powders. Important material properties (e.g., yield strength) of powders can be derived using Heckel analysis. Two types of Heckel analysis are in common use. One is the "out-of-die," or "zero-pressure" method, the other is the "in-die" or "at-pressure" method. Because particles undergo elastic deformation under pressure, which tends to lower the porosity of the powder bed, the "out-of-die" method describes powder consolidation and compaction more accurately than the "in-die" method. However, "in-die" Heckel analysis has been widely used because of the speed and ease of data collection. Using L-lysine monohydrochloride dihydrate as a model compound, this work analyzes quantitatively the effects of elastic deformation on the calculation of porosity of a tablet, and therefore on the Heckel analysis. The effects of a small change in porosity, epsilon, on Heckel analysis are presented mathematically. It is found that a decrease in porosity of 0.001, when the porosity is lower than 0.05, causes a significant increase in the value of -ln epsilon. Therefore, data at epsilon < 0.05 should be interpreted with caution when using Heckel analysis. Elastic deformation causes positive deviations in the Heckel plot, and therefore leads to a yield strength that is lower than the true value. The lower the elastic modulus of the powder, the greater is the deviation from the true value. Therefore, the "in-die" method gives values of yield strength that are significantly lower than the true values for most pharmaceutical powders.
We have developed a high-density EST map of the rat, consisting of >11,000 ESTs. These ESTs were placed on a radiation hybrid framework map of genetic markers spanning all 20 rat autosomes, plus the X chromosome. The framework maps have a total size of approximately 12,400 cR, giving an average correspondence of 240 kb/cR. The frameworks are all LOD 3 chromosomal maps consisting of 775 radiation-hybrid-mapped genetic markers and ESTs. To date, we have generated radiation-hybrid-mapping data for >14,000 novel ESTs identified by our Rat Gene Discovery and Mapping Project (http://ratEST.uiowa.edu), from which we have placed >11,000 on our framework maps. To minimize mapping errors, ESTs were mapped in duplicate and consensus RH vectors produced for use in the placement procedure. This EST map was then used to construct high-density comparative maps between rat and human and rat and mouse. These maps will be a useful resource for positional cloning of genes for rat models of human diseases and in the creation and verification of a tiling set of map order for the upcoming rat-genome sequencing.
Comparative inhibition effect of selected nitrogen-containing aromatics on germination rate of Cucumis sativus was investigated, and quantitative structure-activity relationships were developed and mechanistically interpreted. Energy of lowest unoccupied orbital was found to successfully model the toxicity of the test chemicals. It was discovered that inhibition of nitrogen-containing aromatics to germination of Cucumis sativus was caused mainly by their in vivo redox reaction.
The ubiquitin fusion of apidaecin was expressed in Lactococcus lactis, using a novel nisin-inducible expression system. After induction, a specific band could be detected in the extracts of the host strain by Tricine-SDS-PAGE and Western blotting. Production of the fusion was up to 7.2% of the total soluble protein of the host strain. While the fusion was cut by ubiquitin specific protease-UBP1, the product had distinct antibacterial activity.