Biomedical subjects

B Hu

Publications and source records attributed to B Hu.

At least 55 records · Page 3Linked to original sources

PubMed2002

Extracortical descending projections to the rat inferior colliculus.

Feedback controlling is an important element in the sensory processing in the auditory system. It has been long recognized that the inferior colliculus (IC) sends direct ascending projections to the medial geniculate body (MGB), but receives feedback regulation from the auditory cortex. In the present study we probed the shorter extracortical projections to the IC, including the direct descending pathway from the MGB. In the rat, the fluorescence retrograde tracers Fluorogold, True Blue or Rhodamine latex microspheres were injected into the IC, and the auditory thalamus and surrounding regions were examined for fluorescent neurones. We did not find any retrograde labelling in the ventral division of the MGB. However, retrogradely labelled neurones were found in the medial and suprageniculate nuclei of the MGB. We also observed densely packed groups of fluorescent neurones in the peripeduncular nucleus and numerous labelled neurones in the nucleus of the brachium of the IC. The existence of a direct descending pathway to the IC from at least some auditory thalamic nuclei challenges the perception of the colliculo-thalamic relationship as one-way traffic and suggests more direct involvement of the auditory thalamus in the feedback regulation of the incoming acoustic signals.

Animals↗

PubMed2001

Nonlinear modulation of multidimensional lattice waves.

The equations governing weakly nonlinear modulations of N-dimensional lattices are considered using a quasidiscrete multiple-scale approach. It is found that the evolution of a short wave packet for a lattice system with cubic and quartic interatomic potentials is governed by the generalized Davey-Stewartson (GDS) equations, which include mean motion induced by the oscillatory wave packet through cubic interatomic interaction. The GDS equations derived here are more general than those known in the theory of water waves because of the anisotropy inherent in lattices. The generalized Kadomtsev-Petviashvili equations describing the evolution of long-wavelength acoustic modes in two- and three-dimensional lattices are also presented. Then the modulational instability of an N-dimensional Stokes lattice wave is discussed based on the N-dimensional GDS equations obtained. Finally, the one- and two-soliton solutions of two-dimensional GDS equations are provided by means of Hirota's bilinear transformation method.

Journal Article↗

PubMed2001

1H and 13C NMR investigation of the influence of nonligated residue contacts on the heme electronic structure in cyanometmyoglobin complexes reconstituted with centro- and pseudocentrosymmetric hemins.

The 1H and 13C chemical shifts for the heme methyls of low-spin, ferric sperm whale cyanometmyoglobin reconstituted with a variety of centrosymmetric and pseudocentrosymmetric hemins have been recorded and analyzed to shed light on the nature of heme-protein contacts, other than that of the axial His, that modulate the rhombic perturbation to the heme's in-plane electronic asymmetry. The very similar 1H dipolar shifts for heme pocket residues in all complexes yield essentially the same magnetic axes as in wild type, and the resultant dipolar shifts allow the direct determination of the heme methyl proton and 13C contact shifts in all complexes. It is demonstrated that, even when the magnetic axes and anisotropies are known, the intrinsic uncertainties in the orientational parameters lead to a sufficiently large uncertainty in dipolar shift that the methyl proton contact shifts are inherently significantly less reliable indicators of the unpaired electron spin distribution than the methyl 13C contact shifts. The pattern of the noninversion symmetry in 13C contact shifts in the centro- or pseudocentrosymmetric hemes is shown to correlate with the positions of aromatic rings of Phe43(CD1) and His97(FG3) parallel to, and in contact with, the heme. These results indicate that such pi-pi interactions significantly perturb the in-plane asymmetry of the heme pi spin distribution and cannot be ignored in a quantitative interpretation of the heme methyl 13C contact shifts in terms of the axial His orientation in b-type hemoproteins.

Animals↗

PubMed2001

A novel contractile phenotype with cardiac transgenic expression of the human P2X4 receptor.

The P2X4 receptor is a newly identified receptor expressed in the heart cell. Its function was elucidated with cardiac transgenic (TG) expression of the receptor by using the myocardium-specific a-myosin heavy chain promoter. The presence of the transgene was determined by polymerase chain reaction by using primers specific to the receptor and the vector linker region, by Southern blotting of the genomic DNA, and by immunoblotting and immunohistochemistry of both isolated cardiac myocytes and intact hearts. In intact heart study, the P2X4 receptor TG mouse exhibited significantly elevated basal cardiac contractility with greater rates of contraction and relaxation, left ventricular developed pressure, and cardiac output compared with nontransgenic (NTG) animals but showed no evidence of hypertrophy or heart failure. The TG heart also showed a greater increase of cardiac contractility in response to the P2X receptor agonist 2-methylthioATP, consistent with overexpression of a functional P2X4 receptor with consequent increase in the receptor-mediated response. In isolated cardiac cell study, the TG heart cell showed a similar level of basal contraction amplitude as the NTG heart cell while exhibiting a threefold greater increase in contractility during stimulation by 2-methylthioATP. Thus, an increased responsiveness of the overexpressed P2X4 receptor to endogenous ATP is responsible for the enhanced basal cardiac performance in the intact TG heart. The sustained enhanced contractile function with no associated heart pathology in the P2X4 receptor TG mouse suggests a novel physiologic role of the P2X4 receptor, that of stimulating the cardiac contractility.

Adenosine Triphosphate↗

PubMed2001

Immunogene therapy of tumors with vaccine based on Xenopus homologous vascular endothelial growth factor as a model antigen.

Overcoming immune tolerance of the growth factors associated with tumor growth should be a useful approach to cancer therapy by active immunity. We used vascular endothelial growth factor (VEGF) as a model antigen to explore the feasibility of the immunogene tumor therapy with a vaccine based on a single xenogeneic homologous gene, targeting the growth factors associated with angiogenesis. To test this concept, we constructed a plasmid DNA encoding Xenopus homologous VEGF (XVEGF-p) and control vectors. We found that immunogene tumor therapy with a vaccine based on XVEGF was effective at both protective and therapeutic antitumor immunity in several tumor models in mice. VEGF-specific autoantibodies in sera of mice immunized with XVEGF-p could be found in Western blotting analysis and ELISA assay. The purified immunoglobulins were effective at the inhibition of VEGF-mediated endothelial cell proliferation in vitro, and at antitumor activity and the inhibition of angiogenesis by adoptive transfer in vivo. The elevation of VEGF in the sera of the tumor-bearing mice could be abrogated with XVEGF-p immunization. The antitumor activity and production of VEGF-specific autoantibodies, significantly elevated IgG1 and IgG2b, could be abrogated by the depletion of CD4(+) T lymphocytes. The observations may provide a vaccine strategy for cancer therapy through the induction of autoimmunity against the growth factors associated with tumor growth in a cross reaction with single xenogeneic homologous gene and may be of importance in the further exploration of the applications of other xenogeneic homologous genes identified in human and other animal genome sequence projects in cancer therapy.

Animals↗

PubMed2001

Effective nonlinear optical properties of metal-dielectric composite media with shape distribution.

The effective linear and nonlinear optical properties have been investigated in granular metal-dielectric composites taking the geometric shape of inclusions into account. Recently derived Maxwell-Garnett-type approximations are generalized to study the spectral function for composites in which the metal inclusions have a uniform distribution of geometric shapes. The numerical results show that the spectral density function becomes a prominent peak around small spectral value s within the non-self-consistent Maxwell-Garnett approximation but a broad continuous spectrum around large s besides the prominent peak around small s within the self-consistent Maxwell-Garnett approximation. Based on the spectral representation, we investigate the optical absorption and third-order nonlinear optical susceptibility. The results indicate that the shape distribution can lead to the separation of the nonlinearity enhancement peak from the absorption peak and thereby make the figure of merit more attractive.

Journal Article↗

PubMed2001

Array-enhanced coherence resonance: nontrivial effects of heterogeneity and spatial independence of noise.

We demonstrate the effect of coherence resonance in a heterogeneous array of coupled Fitz Hugh-Nagumo neurons. It is shown that coupling of such elements leads to a significantly stronger coherence compared to that of a single element. We report nontrivial effects of parameter heterogeneity and spatial independence of noise on array-enhanced coherence resonance; especially, we find that (i) the coherence increases as spatial correlation of the noise decreases, and (ii) inhomogeneity in the parameters of the array enhances the coherence. Our results have the implication that generic heterogeneity and background noise can play a constructive role to enhance the time precision of firing in neural systems.

Journal Article↗

PubMed2001

The paralemmin protein family: identification of paralemmin-2, an isoform differentially spliced to AKAP2/AKAP-KL, and of palmdelphin, a more distant cytosolic relative.

Paralemmin is a protein implicated in plasma membrane dynamics. Here we describe the identification of two new paralemmin-related proteins. A partial paralemmin homolog, palmdelphin, is predominantly cytosolic, unlike paralemmin which is lipid-anchored to the plasma membrane through a C-terminal CaaX motif. We have mapped the mouse palmdelphin gene to distal chromosome 3 between Amy2 and Abcd3, in a region homologous to human chromosome 1p22-p21 where the human palmdelphin gene is located. We have also identified a second paralemmin isoform, paralemmin-2. It is expressed from a gene on human chromosome 9q31-q33 which ends only 33 kb upstream of the gene encoding the protein kinase A-binding protein,AKAP2/AKAP-KL. The closely adjacent paralemmin-2 and AKAP2 genes are functionally linked in a very unusual manner. Chimeric mRNAs are expressed, apparently by RNA readthrough and differential splicing, that encode natural fusion proteins in which either the N-terminal coiled-coil region or nearly the complete sequence of paralemmin-2 except its C-terminal CaaX motif is fused to AKAP2/AKAP-KL. The N-terminal coiled-coil region is conserved in paralemmin-1, paralemmin-2/AKAP2, palmdelphin and a fourth, uncharacterized gene, suggesting that it is a modular functional domain.

A Kinase Anchor Proteins↗

PubMed2001

Characteristics of a piecewise smooth area-preserving map.

We are reporting a study carried out in a system concatenated by two area-preserving maps. The system can be viewed as a model of an electronic relaxation oscillator with over-voltage protection. We found that a border-collision bifurcation may interrupt a period-doubling bifurcation cascade, and that some special features, such as "quasicoexisting periodic orbits crossing border" as well as the transition between "quasitransience" and chaotic orbits, accompany the process. These features belong to the so-called "quasidissipative" properties. Here "quasitransience" denotes the behavior of iterations outside elliptic islands. They are "attracted" to the islands. As soon as it reaches the islands, the iteration follows the conservative regulations exactly. This induces a kind of escaping from strange sets. The scaling behavior of the escaping rate is obtained numerically.

Journal Article↗

PubMed2001

Rim1 and rabphilin-3 bind Rab3-GTP by composite determinants partially related through N-terminal alpha -helix motifs.

Rim1 is a protein of the presynaptic active zone, the area of the plasma membrane specialized for neurotransmitter exocytosis, and interacts with Rab3, a small GTPase implicated in neurotransmitter vesicle dynamics. Here, we have studied the molecular determinants of Rim1 that are responsible for Rab3 binding, employing surface plasmon resonance and recombinant, bacterially expressed Rab3 and Rim1 proteins. A site that binds GTP- but not GDP-saturated Rab3 was localized to a short alpha-helical sequence near the Rim1 N terminus (amino acids 19-55). Rab3 isoforms A, C, and D were bound with similar affinities (K(d) = 1-2 microm). Low affinity binding of Rab6A-GTP was also observed (K(d) = 16 microm), whereas Rab1B, -5, -7, -8, or -11A did not bind. Adjacent sequences up to amino acid 387, encompassing differentially spliced sequences, the zinc finger module, and the SGAWFF motif of Rim1, did not significantly contribute to the strength or the specificity of Rab3 binding, whereas a point mutation within the helix (R33G) abolished binding. This Rab3 binding site of Rim1 is reminiscent of the N-terminal alpha-helix that is part of the Rab3-binding region of rabphilin-3, and indeed we observed low affinity, specific binding of Rab3A (K(d) on the order of magnitude of 10-100 microm) to this region of rabphilin-3 alone (amino acids 40-88), whereas additional sequences up to amino acid 178 are needed for high affinity Rab3A binding to rabphilin-3 (K(d) = 10-20 nm). In contrast, an N-terminal alpha-helix motif in aczonin, with sequence similarity to the Rab3-binding site of Rim1, did not bind Rab3A, -C, or -D or several other Rab proteins. These results were qualitatively confirmed in pull-down experiments with native, prenylated Rab3 from brain lysate in Triton X-100. Munc13 bound to the zinc finger domain of Rim1 but not to the rabphilin-3 or aczonin zinc fingers. Pull-down experiments from brain lysate in the presence of cholate as detergent detected binding to downstream Rim1 sequences, between amino acids 56 and 387, of syntaxin and of Rab3. The latter, however, was inhibited rather than stimulated by GTP.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Breather induced modification of the speed of sound.

The modification of the speed of sound induced by the presence of breathers in a quasi-one-dimensional magnetic chain is examined in the framework of the sine-Gordon model. Within the "pseudoharmonic" phonon approximation it was found that the spin-phonon interaction could have a significant influence on the phonon frequencies, and it consequently leads to the modification of the speed of sound which, in the case of breathers, shows quite different magnetic field and temperature behavior when compared to the case of the linear excitations and solitons. An interesting possibility of an indirect experimental examination of the breathers arises from these predictions.

Journal Article↗

PubMed2001

Cobalt induces heme oxygenase-1 expression by a hypoxia-inducible factor-independent mechanism in Chinese hamster ovary cells: regulation by Nrf2 and MafG transcription factors.

We have shown previously that activation of the heme oxygenase-1 (ho-1) gene by hypoxia in aortic smooth muscle cells is mediated by hypoxia-inducible factor-1 (HIF-1). In mutant (Ka13) Chinese hamster ovary cells lacking HIF activity, accumulation of ho-1 mRNA in response to hypoxia and the hypoxia-mimetic CoCl(2) was similar to that observed in wild type (K1) cells. These results support the existence of HIF-dependent and HIF-independent mechanisms for ho-1 gene activation by hypoxia and CoCl(2). In Ka13 cells, CoCl(2) stimulated expression of a luciferase reporter gene under the control of a 15-kilobase pair mouse ho-1 promoter (pHO15luc). Mutation analyses identified the cobalt-responsive sequences as the stress-response elements (StREs). In electrophoretic mobility shift assays, two specific StRE-protein complexes were observed using extracts from Ka13 cells. In response to cobalt, the level of the slower migrating complex X increased, whereas that of complex Y decreased, in a time-dependent manner. Members of the AP-1 superfamily of basic-leucine zipper factors bind to the StRE. Antibody supershift electrophoretic mobility shift assays did not detect Jun, Fos, or ATF/CREB proteins but identified Nrf2 and the small Maf protein, MafG, as components of complex X. Furthermore, dominant-negative mutants of Nrf2 and small Maf, but not of other bZIP factors, attenuated cobalt-mediated gene activation. Additional experiments demonstrated that induction by cobalt does not result from increased expression of MafG or regulated nuclear translocation of Nrf2 but is dependent on cellular oxidative stress. Unlike cobalt, hypoxia did not stimulate pHO15luc expression and did not increase StRE binding activity, indicating distinct mechanisms for ho-1 gene activation by cobalt and hypoxia in Chinese hamster ovary cells.

Animals↗

PubMed2001

(4-Piperidin-1-yl)phenyl amides: potent and selective human beta(3) agonists.

In search of potent and selective human beta(3) agonists as potential drugs for the treatment of human obesity and type II diabetes, a series of (4-piperidin-1-yl)phenyl amides was prepared and evaluated for their biological activity on the human beta(3)-adrenergic receptor. The leucine derivative 26e and the reverse amide 33b were found to be the two most potent and selective compounds in this study. With EC(50) values of 0.008 and 0.009 microM, respectively, at the beta(3) receptor, nearly completely abolished intrinsic activity at either the beta(1) or beta(2) receptor, and significant thermogenesis effects on human beta(3)-adrenergic receptor transgenic mice, 26e and33b are among the most potent and selective human beta(3) agonists known to date.

Adrenergic beta-Agonists↗

PubMed2001

New oxadiazolidinedione derivatives as potent and selective human beta3 agonists.

As part of our investigation into the development of potent and selective human beta3 agonists, a series of thiazolidinedione analogues was prepared and evaluated for their biological activity on the human beta3-adrenergic receptor. The oxadiazolidinedione derivative 17 was found to be the most potent and selective compound in this study, with an EC50 value of 0.02 microM at the beta3 receptor, 259-fold selectivity over the beta1 receptor, and 745-fold selectivity over the beta2 receptor.

Adrenergic beta-3 Receptor Agonists↗

PubMed2001

Cellular automaton traffic flow model between the Fukui-Ishibashi and Nagel-Schreckenberg models.

We propose and study a one-dimensional traffic flow cellular automaton model of high-speed vehicles with the Fukui-Ishibashi-type acceleration for all cars, and the Nagel-Schreckenberg-type (NS) stochastic delay only for cars following the trail of the car ahead. The main difference in the delay scenario between our model and the NS model is that a car with spacing ahead longer than the velocity limit M may not be delayed in our model. By using a car-oriented mean-field theory, we analytically derive fundamental diagrams of the average speed as a function of the car density. Our theoretical results are in excellent agreement with numerical simulations.

Journal Article↗

PubMed2001

2,4-Thiazolidinediones as potent and selective human beta3 agonists.

Methylsulfonamide substituted 2,4-thiazolidinedione 22c is a potent (EC50=0.01 microM, IA=1.19) and selective (more than 110-fold over beta1 and beta2 agonist activity) beta3 agonist. This compound has also been proven to be active and selective in an in vivo mode.

Adrenergic beta-3 Receptor Agonists↗

PubMed2001

Identification of activating transcription factor 4 (ATF4) as an Nrf2-interacting protein. Implication for heme oxygenase-1 gene regulation.

Nrf2 regulates expression of genes encoding enzymes with antioxidant (e.g. heme oxygenase-1 (HO-1)) or xenobiotic detoxification (e.g. NAD(P)H:quinone oxidoreductase, glutathione S-transferase) functions via the stress- or antioxidant-response elements (StRE/ARE). Nrf2 heterodimerizes with small Maf proteins, but the role of such dimers in gene induction is controversial, and other partners may exist. By using the yeast two-hybrid assay, we identified activating transcription factor (ATF) 4 as a potential Nrf2-interacting protein. Association between Nrf2 and ATF4 in mammalian cells was confirmed by co-immunoprecipitation and mammalian two-hybrid assays. Furthermore, Nrf2.ATF4 dimers bound to an StRE sequence from the ho-1 gene. CdCl(2), a potent inducer of HO-1, increased expression of ATF4 in mouse hepatoma cells, and detectable induction of ATF4 protein preceded that of HO-1 (30 min versus 2 h). A dominant-negative mutant of ATF4 inhibited basal and CdCl(2)-stimulated expression of a StRE-dependent/luciferase fusion construct (pE1-luc) in hepatoma cells but only basal expression in mammary epithelial MCF-7 cells. A dominant mutant of Nrf2 was equally inhibitory in both cell types in the presence or absence of CdCl(2). These results indicate that ATF4 regulates basal and CdCl(2)-induced expression of the ho-1 gene in a cell-specific manner and possibly in a complex with Nrf2.

Activating Transcription Factor 3↗

PubMed2001

Collective directional transport in coupled nonlinear oscillators without external bias.

Directed collective motion in a circular array of unidirectionally coupled oscillators with symmetric potential is obtained numerically in the absence of external bias. This striking feature is interpreted as the effect of the spontaneous breaking of temporal symmetry of the coupling. It is revealed that a proper match of various control parameters is important in generating an optimal coherent global transport. Noise-sustained directed transport is also observed, and the related stochastic resonance in an autonomous system is identified.

Journal Article↗