Biomedical subjects

C K Hu

Publications and source records attributed to C K Hu.

At least 19 recordsLinked to original sources

PubMed2006

Loss of heterozygosity of M6P/IGF2R gene is an early event in the development of prostate cancer.

BACKGROUND: The genetic events leading to initiation and/or progression of prostate cancer are not well characterized. The gene coding for the mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) has recently been identified as a tumor suppressor in several types of cancer. The purpose of the present study is to determine whether the M6P/IGF2R gene is inactivated in human prostate cancer, and if so, whether this is an early or late transformational event. METHODS: In total, 43 patients with prostate cancer treated by radical prostatectomy, with archival material available for analysis, were assessed for loss of heterozygosity (LOH) in the M6P/IGF2R gene using six different gene-specific nucleotide polymorphisms. Regions of tumor, normal prostate and premalignant high-grade prostate intraepithelial neoplasia (PIN) were identified and cells were excised by laser capture microdissection (LCM). DNA segments were amplified using polymerase chain reaction (PCR). RESULTS: The M6P/IGF2R gene was polymorphic in 83.7% (36/43) of patients, and 41.7% (15/36) of these informative patients had LOH in the tumor tissue. In 11/15 patients with LOH in malignant tissue, high-grade PIN could be identified, and 63.6% (7/11) also had LOH in this premalignant tissue. CONCLUSIONS: This study is the first to find that the M6P/IGF2R gene is inactivated in prostate cancer. LOH in premalignant tissue as well suggests that mutation in the M6P/IGF2R gene is an early event in the development of prostate cancer, supporting the conclusion that it functions as a tumor suppressor gene in this disease.

Aged↗

PubMed2001

Proteinlike behavior of a spin system near the transition between a ferromagnet and a spin glass.

A simple spin system is studied as an analog for proteins. We investigate how the introduction of randomness and frustration into the system affects the designability and stability of ground-state configurations. We observe that the spin system exhibits proteinlike behavior in the vicinity of the transition between a ferromagnet and a spin glass. Our results illuminate some guiding principles in protein evolution.

Biophysical Phenomena↗

PubMed2001

Exact phase diagram for an asymmetric avalanche process.

The Bethe ansatz method and an iterative procedure based on detailed balance are used to obtain exact results for an asymmetric avalanche process on a ring. The average velocity of particle flow, v, is derived as a function of the toppling probabilities and the density of particles, rho. As rho increases, the system shows a transition from intermittent to continuous flow, and v diverges at a critical point rho(c) with exponent alpha. The exact phase diagram of the transition is obtained and alpha is found to depend on the toppling rules.

Journal Article↗

PubMed2001

Universal scaling functions for bond percolation on planar-random and square lattices with multiple percolating clusters.

Percolation models with multiple percolating clusters have attracted much attention in recent years. Here we use Monte Carlo simulations to study bond percolation on L1xL2 planar random lattices, duals of random lattices, and square lattices with free and periodic boundary conditions, in vertical and horizontal directions, respectively, and with various aspect ratios L(1)/L(2). We calculate the probability for the appearance of n percolating clusters, W(n); the percolating probabilities P; the average fraction of lattice bonds (sites) in the percolating clusters, (n) ( (n)), and the probability distribution function for the fraction c of lattice bonds (sites), in percolating clusters of subgraphs with n percolating clusters, f(n)(c(b)) [f(n)(c(s))]. Using a small number of nonuniversal metric factors, we find that W(n), P, (n) ( (n)), and f(n)(c(b)) [f(n)(c(s))] for random lattices, duals of random lattices, and square lattices have the same universal finite-size scaling functions. We also find that nonuniversal metric factors are independent of boundary conditions and aspect ratios.

Journal Article↗

PubMed2001

Exact universal amplitude ratios for two-dimensional Ising models and a quantum spin chain.

Let f(N) and xi(-1)(N) represent, respectively, the free energy per spin and the inverse spin-spin correlation length of the critical Ising model on a N x infinity lattice, with f(N)-->f(infinity) as N-->infinity. We obtain analytic expressions for a(k) and b(k) in the expansions N( f(N)-f(infinity)) = SUM (k = 1)(infinity)a(k)/N(2k-1) and xi(-1)(N) = SUM (k = 1)(infinity)b(k)/N(2k-1) for square, honeycomb, and plane-triangular lattices, and find that b(k)/a(k) = (2(2k)-1)/(2(2k-1)-1) for all of these lattices, i.e., the amplitude ratio b(k)/a(k) is universal. We also obtain similar results for a critical quantum spin chain and find that such results could be understood from a perturbated conformal field theory.

Journal Article↗

PubMed2001

Surface critical behavior of random systems: ordinary transition.

We calculate the surface critical exponents of the ordinary transition occurring in semi-infinite, quenched dilute Ising-like systems. This is done by applying the field theoretic approach directly in d=3 dimensions up to the two-loop approximation as well as in 4-epsilon dimensions. At d=4-epsilon we extend, up to the next-to-leading order, the previous first-order results of the square root of epsilon expansion by Ohno and Okabe [Phys. Rev. B 46, 5917 (1992)]. In both cases numerical estimates for surface exponents are computed using Padé approximants extrapolating the perturbation theory expansions. The obtained results indicate that the critical behavior of semi-infinite systems with quenched bulk disorder is characterized by the new set of surface critical exponents.

Journal Article↗

PubMed2001

New mechanism of x-ray radiation from a relativistic charged particle in a dielectric random medium.

Based on the diffusional scattering of pseudophotons, we propose a new mechanism of x-ray radiation from a relativistic charged particle moving in a system consisting of microspheres distributed randomly in a dielectric material. The mechanism leads to a stronger dependence of radiation intensity on the particle energy, gamma = E/mc(2), than that predicted by the transition radiation, and explains recent experimental data from a detector which contains randomly distributed superconducting granules.

Journal Article↗

PubMed2001

Multifractal characterization of stochastic resonance.

We use a multifractal formalism to study the effect of stochastic resonance in a noisy bistable system driven by various input signals. To characterize the response of a stochastic bistable system we introduce a new measure based on the calculation of a singularity spectrum for a return time sequence. We use wavelet transform modulus maxima method for the singularity spectrum computations. It is shown that the degree of multifractality defined as a width of singularity spectrum can be successfully used as a measure of complexity both in the case of periodic and aperiodic (stochastic or chaotic) input signals. We show that in the case of periodic driving force, singularity spectrum can change its structure qualitatively becoming monofractal in the regime of stochastic synchronization. This fact allows us to consider the degree of multifractality as a new measure of stochastic synchronization also. Moreover, our calculations have shown that the effect of stochastic resonance can be catched by this measure even from a very short return time sequence. We use also the proposed approach to characterize the noise-enhanced dynamics of a coupled stochastic neurons model.

Journal Article↗

PubMed2001

Synthesis, biological activity, and solution structures of a cyclic dodecapeptide from the EGF-2 domain of blood coagulation factor VII.

The cyclic dodecapeptide, disulfide-cyclo-[H-Cys-Val-Asn-Glu-Asn-Gly-Gly-Cys(Acm)-Glu-Gln-Tyr-Cys-OH], which corresponds to the 91-102 sequence of the second epidermal growth factor domain of human blood coagulation factor VII, was synthesized using solid-phase procedures. It was shown to be an inhibitor at the key step in the induction of coagulation by the extrinsic pathway, i.e. the factor VII/tissue factor-catalyzed activation of coagulation factor X. The solution structure of this peptide was investigated by NMR spectroscopy and was computer-modeled via molecular mechanics. Structures were calculated based on 112 distance and nine dihedral angle constraints. The resulting backbone structures were classified into two structural subsets: one which exhibited a twisted '8'-shaped folding and another describing an open, circular 'O' outline. The local backbone structures of segments Asn3-Glu4-Asn5, Gly7-Cys8 and Gln10-Tyr11 were well preserved among the two subsets. Apart from the unrestrained N- and C-termini, Gly6 and Glu9 sites exhibited marked local disorder between the two subsets, suggesting localized flexible hinges likely to govern tertiary structure interconversion between the two subsets. Two transient hydrogen bonds were identified from pH chemical shift titrations by matching the pKa values of NH and carboxylate groups, which supported the occurrence of the '8' structure, and agreed with temperature coefficients of peptidyl NH resonances. Structure-function relationships of the peptide were discussed in terms of the likely physiological function of the disulfide-bonded loop in factor VII which the peptide represents.

Amides↗

PubMed2000

Inversion symmetry and exact critical exponents of dissipating waves in the sandpile model.

By an inversion symmetry, we show that in the Abelian sandpile model the probability distribution of dissipating waves of topplings that touch the boundary of the system shows a power-law relationship with critical exponent 5/8 and the probability distribution of those dissipating waves that are also last in an avalanche has an exponent of 1. Our extensive numerical simulations not only support these predictions, but also show that inversion symmetry is useful for the analysis of the two-wave probability distributions.

Journal Article↗

PubMed1999

Exact phase diagrams for an Ising model on a two-layer Bethe lattice.

Using an iteration technique, we obtain exact expressions for the free energy and the magnetization of an Ising model on a two-layer Bethe lattice with intralayer coupling constants J1 and J2 for the first and the second layer, respectively, and interlayer coupling constant J3 between the two layers; the Ising spins also couple with external magnetic fields, which are different in the two layers. We obtain exact phase diagrams for the system and find that when /J3/-->0, DeltaT(c) identical with[T(c)(J3)-T(c)(0)]/T(c)(0) approximately [J3]/J(1)/(1/psi), where T(c)(J3) is the phase-transition temperature for the system with interlayer coupling constant J3 and the shift exponent psi is 1 for J(1)=J(2) and is 0.5 for J1 not equal to J2. Such results are consistent with predictions of a scaling theory. We also derive equations for DeltaT(c) when /J3/ approaches infinity.

Journal Article↗

PubMed1999

Cluster analysis and finite-size scaling for Ising spin systems.

Based on the connection between the Ising model and a correlated percolation model, we calculate the distribution function for the fraction (c) of lattice sites in percolating clusters in subgraphs with n percolating clusters, f(n)(c), and the distribution function for magnetization (m) in subgraphs with n percolating clusters, p(n)(m). We find that f(n)(c) and p(n)(m) have very good finite-size scaling behavior and that they have universal finite-size scaling functions for the model on square, plane triangular, and honeycomb lattices when aspect ratios of these lattices have the proportions 1:square root[3]/2:square root[3]. The complex structure of the magnetization distribution function p(m) for the system with large aspect ratio could be understood from the independent orientations of two or more percolation clusters in such a system.

Journal Article↗

PubMed1999

Synchronization and coherence in thermodynamic coupled map lattices with intermediate-range coupling.

In spatially extended systems, intermediate-range interactions arise naturally in some physical contexts. To study them, we investigate a model of coupled map lattices (CML's) with intermediate-range coupling, and derive analytic conditions for its synchronization. We find that in these CML's, if the range of coupling is fixed, the law of large numbers applies for the mean field. The total normalized power in nonzero components of the power spectrum of the mean field goes to zero in the thermodynamic limit. We also show that in the same limit the relevant parameter for synchronization and coherence is the fraction of sites coupled, and not their number.

Journal Article↗

PubMed1999

Multistability and symmetry breaking in the two-dimensional flow around a square cylinder.

We use numerical methods to study two-dimensional flow passing a square cylinder at low Reynolds numbers, and observe period-1 and -3 vortices behind the cylinder at the same Reynolds number Re. When Re increases from a small number to a critical value Re(c) approximately equal to 320, the system could change from bistability, which maintains the spatial symmetry, to tristability, which breaks the spatial symmetry. Our results suggest many interesting problems for further studies.

Journal Article↗

PubMed1999

Geometry, thermodynamics, and finite-size corrections in the critical Potts model.

We establish an intriguing connection between geometry and thermodynamics in the critical q-state Potts model on two-dimensional lattices, using the q-state bond-correlated percolation model (QBCPM) representation. We find that the number of clusters of the QBCPM has an energy-like singularity for q not equal to 1, which is reached and supported by exact results, numerical simulation, and scaling arguments. We also establish that the finite-size correction to the number of bonds, , has no constant term and explains the divergence of related quantities as q-->4, the multicritical point. Similar analyses are applicable to a variety of other systems.

Journal Article↗

PubMed1997

Ligand preferences of kringle 2 and homologous domains of human plasminogen: canvassing weak, intermediate, and high-affinity binding sites by 1H-NMR.

The interaction of various small aliphatic and aromatic ionic ligands with the human plasminogen (HPg) recombinant kringle 2 (r-K2) domain has been investigated by 1H-NMR spectroscopy at 500 MHz. The results are compared against ligand-binding properties of the homologous, lysine-binding HPg kringle 1 (K1), kringle 4 (K4), and kringle 5 (K5). The investigated ligands include the omega-aminocarboxylic acids 4-aminobutyric acid (4-ABA), 5-aminopentanoic acid (5-APA), 6-aminohexanoic acid (6-AHA), 7-aminoheptanoic acid (7-AHA), lysine and arginine derivatives with free and blocked alpha-amino and/or carboxylate groups, and a number of cyclic analogs, zwitterions of similar size such as trans-(aminomethyl)cyclohexanecarboxylic acid (AMCHA) and p-benzylaminesulfonic acid (BASA), and the nonzwitterions benzylamine and benzamidine. Equilibrium association constant (Ka) values were determined from 1H-NMR ligand titration profiles. Among the aliphatic linear ligands, 5-APA (Ka approximately 3.4 mM-1) shows the strongest interaction with r-K2 followed by 6-AHA (Ka approximately 2.3 mM-1), 7-AHA (Ka approximately 0.45 mM-1), and 4-ABA (Ka approximately 0.22 mM-1). In contrast, r-K1, K4, and K5 exhibit a preference for 6-AHA (Ka approximately 74.2, 21.0, and 10.6 mM-1, respectively), a ligand approximately 1.14 A longer than 5-APA. Mutations R220G and E221D increase the affinity of r-K2 for these ligands but leave the selectivity profile essentially unaffected: 5-APA > 6-AHA > 7-AHA > 4-ABA (Ka approximately 6.5, 3.9, 1.8, and 0.74 mM-1, respectively). We find that, while r-K2 definitely interacts with Nalpha-acetyl-L-lysine and L-lysine (Ka approximately 0.96 and 0.68 mM-1, respectively), the affinity for analogs carrying a blocked carboxylate group is relatively weak (Ka approximately 0.1 mM-1). We also investigated the interaction of r-K2 with L-arginine (Ka approximately 0.31 mM-1) and its derivatives Nalpha-acetyl-L-arginine (Ka approximately 0.55 mM-1), Nalpha-acetyl-L-arginine methyl ester (Ka approximately 0.07 mM-1), and L-arginine methyl ester (Ka approximately 0.03 mM-1). Zwitterionic gamma-guanidinobutyric acid, containing one less methylene group than arginine, exhibits a Ka of approximately 0.28 mM-1. The affinity of r-K2 for lysine and arginine derivatives suggests that K2 could play a role in intermolecular as well as intramolecular interactions of HPg. As is the case for the HPg K1, K4, and K5, among the tested ligands, AMCHA is the one which interacts most firmly with r-K2 (Ka approximately 7.3 mM-1) while the aromatic ligands BASA, benzylamine, and benzamidine exhibit Ka values of approximately 4.0, approximately 0.04, and approximately 0.03 mM-1, respectively. The relative stability of these interactions indicates a strict requirement for both cationic and anionic polar groups in the ligand, whereas the presence of a lipophilic aromatic group seems to be of lesser consequence. Ligand-induced shifts of r-K2 (1)H-NMR signals and two-dimensional nuclear Overhauser effect (NOESY) experiments in the presence of 6-AHA reveal direct involvement of residues Tyr36, Trp62, Phe64, and Trp72 (kringle residue numbering convention) in ligand binding. Starting from the X-ray crystallographic structure of HPg K4 and the intermolecular 1H-NMR NOE data, two models of the K2 lysine binding site complexed to 6-AHA have been derived which differ mainly in the extent of electrostatic pairing between the K2 Arg56 and Glu57 side chains. Competition between these two conformations in equilibrium may account for the relatively lesser affinity of the K2 domain for zwitterionic lysine-type ligands.

Amino Acid Sequence↗

PubMed1996

Complexation of the tissue plasminogen activator protease with benzamidine-type inhibitors: interference by the kringle 2 module.

Well-resolved high-field 1H NMR signals between -0.1 and -0.7 ppm afford convenient probes to monitor the conformational state of the tissue plasminogen activator (tPA) protease, modulated by covalent inhibitor binding or activation cleavage [Hu, C.-K., Kohnert, U., Wilhelm, O., Fischer, S., & Llinas, M. (1994) Biochemistry 33, 11760-11766]. We have investigated recombinant BM 06.022 (a domain-deletion variant mutant from Escherichia coli comprising the kringle 2 and protease modules) and protease constructs of tPA in both single-chain (sc) and two-chain (tc) forms. The two proteins were studied when confronted with the noncovalent (i.e., reversible) active site inhibitors benzamidine and a series of bisbenzamidine derivatives: 2,5-bis(4-amidinobenzylidene)cyclopentanone, 2,6-bis(4-amidinobenzylidene)cyclohexanone, 2,7-bis(4-amidinobenzylidene)cycloheptanone, and 2,8-bis(4-amidino- benzylidene)cyclooctanone. At pH* 4.6, the 1H NMR spectrum is sensitive to complexation of the protease module with the various effectors. The amplitude of the inhibitor-shifted resonances is more pronounced for the tc-protease than for the sc-protease, suggesting that access of inhibitors to the protease catalytic site is facilitated upon conversion to the tc form. The effects detected by the NMR spectrum suggest a biphasic process, involving stronger (primary) and weaker (secondary) bindings to a single protease active site. Binding to the protease module in tc-BM 06.022 essentially generates the same spectral characteristics as detected upon binding to the isolated tc-protease construct. In contrast, a negligible perturbation by the inhibitors is observed on the (sc) BM 06.022. Hence, in the intact BM 06.022 the kringle 2 is structurally coupled to the protease module thus interfering with inhibitor molecules from accessing the protease active site. These domain-domain interactions relax upon conversion to the catalytically active tc form, thus decoupling the kringle 2 from the protease module in BM 06.022 while simultaneously exposing the active site to become accessible to effectors or substrates.

Amino Acid Chloromethyl Ketones↗

PubMed1996

Recombinant gene expression and 1H NMR characteristics of the kringle (2 + 3) supermodule: spectroscopic/functional individuality of plasminogen kringle domains.

The plasminogen kringle 2 (K2HPg) and kringle 3 (K3HPg) modules occur in tandem within the polypeptide segment that affords the heavy chain of plasmin. The K2HPg and K3HPg are unique among the plasminogen kringle domains in that they also are linked to each other via the Cys169-Cys297 (Cys4 of K2HPg to Cys43 of K3HPg, kringle numbering convention) disulfide bridge, thus generating a K2HPg-K3HPg "supermodule". The kringle (2 + 3) sequence of human plasminogen (r-EE[K2HPgK3HPg]DS) was expressed in Escherichia coli, using an expression vector containing the phage T5 promoter/operator N250PSN250P29 and the codons for an N-terminal hexahistidine tag to ensure the isolation of the recombinant protein by affinity chromatography on Ni(2+)-nitrilotriacetic acid/agarose under denaturing and reducing conditions. Kringle (2 + 3) was refolded in the presence of glutathione redox buffer. By taking advantage of the lysine affinity of kringle 2, the protein was purified by affinity chromatography on lysine-Bio-Gel. Recombinant kringle (2 + 3) was identified by amino acid composition, N-terminal sequence and mass determination. The 1H NMR spectrum shows that the intact r-K2HPgK3HPg is properly folded. By reference to spectra of the individual kringles, r-K2HPg and r-K3HPg, resonances of the K2HPg and K3HPg components in the spectrum of the intact r-K2HPgK3HPg can be readily distinguished. The strictly conserved Leu46 residue (kringle residue number convention) yields delta-methyl signals that are characteristic for K2HPg and K3HPg, exhibiting chemical shifts of -0.87 and -0.94 ppm, respectively, which are distinct from those of K1HPg, K4HPg, and K5HPg, (-1.04 to -1.05 ppm). Thus, the high-field Leu46 signals from K2HPg and K3HPg are well resolved from those of other kringles and can be identified unambiguously in spectra of the K1HPgK2HPgK3HPg elastolytic fragment of plasminogen as well as in spectra of Glu-plasminogen. Overall, r-K2HPgK3HPg exhibits broader resonance line widths than does the K1HPg component, consistent with a lesser mobility of the K2HPgK3HPg segment within the K1HPgK2HPgK3HPg fragment, a reflection of the extra structural constraint imposed by the disulfide bridge linking K2HPg to K3HPg. The ligand 6-aminohexanoic acid (6-AHA), which is known to interact with r-K2HPg but not with r-K3HPg, selectively perturbs K2 aromatic signals in the intact r-K2HPgK3HPg spectrum while leaving K3 resonances largely unaffected. Association constant (K(a)) values for 6-AHA determined from 1H NMR ligand titration experiments yield K(a) approximately 2.2 +/- 0.3 mM(-1) for the intact r-K2HPgK3HPg, comparable to K(a) approximately 2.3 +/- 0.2 mM(-1) determined for the isolated r-K2HPg, which demonstrates that the interactions of 6-AHA with the K2HPg ligand-binding site are not significantly affected by the neighboring K3HPg domain within the intact r-K2HPgK3HPg supermodule.

Amino Acid Sequence↗