Biomedical subjects

Hong Qian

Publications and source records attributed to Hong Qian.

At least 19 recordsLinked to original sources

PubMed2007

Relationship between thermodynamic driving force and one-way fluxes in reversible processes.

Chemical reaction systems operating in nonequilibrium open-system states arise in a great number of contexts, including the study of living organisms, in which chemical reactions, in general, are far from equilibrium. Here we introduce a theorem that relates forward and reverse fluxes and free energy for any chemical process operating in a steady state. This relationship, which is a generalization of equilibrium conditions to the case of a chemical process occurring in a nonequilibrium steady state in dilute solution, provides a novel equivalent definition for chemical reaction free energy. In addition, it is shown that previously unrelated theories introduced by Ussing and Hodgkin and Huxley for transport of ions across membranes, Hill for catalytic cycle fluxes, and Crooks for entropy production in microscopically reversible systems, are united in a common framework based on this relationship.

Biological Transport↗

PubMed2007

Phosphorylation energy hypothesis: open chemical systems and their biological functions.

Biochemical systems and processes in living cells generally operate far from equilibrium. This review presents an overview of a statistical thermodynamic treatment for such systems, with examples from several key components in cellular signal transduction. Open-system nonequilibrium steady-state (NESS) models are introduced. The models account quantitatively for the energetics and thermodynamics in phosphorylation-dephosphorylation switches, GTPase timers, and specificity amplification through kinetic proofreading. The chemical energy derived from ATP and GTP hydrolysis establishes the NESS of a cell and makes the cell--a mesoscopic-biochemical reaction system that consists of a collection of thermally driven fluctuating macromolecules--a genetically programmed chemical machine.

Kinetics↗

PubMed2006

Macrophages regulate the angiogenic switch in a mouse model of breast cancer.

The development of a tumor vasculature or access to the host vasculature is a crucial step for the survival and metastasis of malignant tumors. Although therapeutic strategies attempting to inhibit this step during tumor development are being developed, the biological regulation of this process is still largely unknown. Using a transgenic mouse susceptible to mammary cancer, PyMT mice, we have characterized the development of the vasculature in mammary tumors during their progression to malignancy. We show that the onset of the angiogenic switch, identified as the formation of a high-density vessel network, is closely associated with the transition to malignancy. More importantly, both the angiogenic switch and the progression to malignancy are regulated by infiltrated macrophages in the primary mammary tumors. Inhibition of the macrophage infiltration into the tumor delayed the angiogenic switch and malignant transition whereas genetic restoration of the macrophage population specifically in these tumors rescued the vessel phenotype. Furthermore, premature induction of macrophage infiltration into premalignant lesions promoted an early onset of the angiogenic switch independent of tumor progression. Taken together, this study shows that tumor-associated macrophages play a key role in promoting tumor angiogenesis, an essential step in the tumor progression to malignancy.

Animals↗

PubMed2006

Phytogeographical analysis of seed plant genera in China.

BACKGROUND AND AIMS: A central goal of biogeography and ecology is to uncover and understand distributional patterns of organisms. China has long been a focus of attention because of its rich biota, especially with respect to plants. Using 290 floras from across China, this paper quantitatively characterizes the composition of floristic elements at multiple scales (i.e. national, provincial and local), and explores the extent to which climatic and geographical factors associated with each flora can jointly and independently explain the variation in floristic elements in local floras. METHODS: A study was made of 261 local floras, 28 province-level floras and one national-level flora across China. Genera of seed plants in each flora were assigned to 14 floristic elements according to their worldwide geographical distributions. The composition of floristic elements was related to climatic and geographical factors. KEY RESULTS AND CONCLUSIONS: Variations in percentages of cosmopolitan, tropical and temperate genera among local floras tend to be greater at higher latitudes than at lower latitudes. Latitude is strongly correlated with the proportions of 13 of the 14 floristic elements. Correlations of the proportions of floristic elements with longitude are much weaker than those with latitude. Climate represented by the first principal component of a principal component analysis was strongly correlated with the proportions of floristic elements in local floras (|r| = 0.75 +/- 0.18). Geographical coordinates independently explained about four times as much variation in floristic elements as did climate. Further research is necessary to examine the roles of water-energy dynamics, geology, soils, biotic interactions, and historical factors such as land connections between continents in the past and at present in creating observed floristic patterns.

China↗

PubMed2006

Open-system nonequilibrium steady state: statistical thermodynamics, fluctuations, and chemical oscillations.

Gibbsian equilibrium statistical thermodynamics is the theoretical foundation for isothermal, closed chemical, and biochemical reaction systems. This theory, however, is not applicable to most biochemical reactions in living cells, which exhibit a range of interesting phenomena such as free energy transduction, temporal and spatial complexity, and kinetic proofreading. In this article, a nonequilibrium statistical thermodynamic theory based on stochastic kinetics is introduced, mainly through a series of examples: single-molecule enzyme kinetics, nonlinear chemical oscillation, molecular motor, biochemical switch, and specificity amplification. The case studies illustrate an emerging theory for the isothermal nonequilibrium steady state of open systems.

Enzymes↗

PubMed2006

Reducing intrinsic biochemical noise in cells and its thermodynamic limit.

In living cells, the specificity of biomolecular recognition can be amplified and the noise from non-specific interactions can be reduced at the expense of cellular free energy. This is the seminal idea in the Hopfield-Ninio theory of kinetic proofreading: The specificity is increased via cyclic network kinetics without altering molecular structures and equilibrium affinites. We show a thermodynamic limit of the specificity amplification with a given amount of available free energy. For a normal cell under physiological condition with sustained phosphorylation potential, this gives a factor of 10(10) as the upper bound in specificity amplification. We also study an optimal kinetic network design that is capable of approaching the thermodynamic limit.

Cells↗

PubMed2006

Cytokines regulate postnatal hematopoietic stem cell expansion: opposing roles of thrombopoietin and LNK.

The role of cytokines as regulators of hematopoietic stem cell (HSC) expansion remains elusive. Herein, we identify thrombopoietin (THPO) and the cytokine signaling inhibitor LNK, as opposing physiological regulators of HSC expansion. Lnk(-/-) HSCs continue to expand postnatally, up to 24-fold above normal by 6 mo of age. Within the stem cell compartment, this expansion is highly selective for self-renewing long-term HSCs (LT-HSCs), which show enhanced THPO responsiveness. Lnk(-/-) HSC expansion is dependent on THPO, and 12-wk-old Lnk(-/-)Thpo(-/-) mice have 65-fold fewer LT-HSCs than Lnk(-/-) mice. Expansions of multiple myeloid, but not lymphoid, progenitors in Lnk(-/-) mice also proved THPO-dependent.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Free-energy distribution of binary protein-protein binding suggests cross-species interactome differences.

Major advances in large-scale yeast two-hybrid screening have provided a global view of binary protein-protein interactions across species as dissimilar as human, yeast, and bacteria. Remarkably, these analyses have revealed that all species studied have a degree distribution of protein-protein binding that is approximately scale-free (varies as a power law) even though their evolutionary divergence times differ by billions of years. The universal power law shows only the surface of the rich information harbored by these high-throughput data. We develop a detailed mathematical model of the protein-protein interaction network based on association free energy, the biochemical quantity that determines protein-protein interaction strength. This model reproduces the degree distribution of all of the large-scale yeast two-hybrid data sets available and allows us to extract the distribution of free energy, the likelihood that a pair of proteins of a given species will bind. We find that across-species interactomes have significant differences that reflect the strengths of the protein-protein interaction. Our results identify a global evolutionary shift: more evolved organisms have weaker binary protein-protein binding. This result is consistent with the evolution of increased protein unfoldedness and challenges the dogma that only specific protein-protein interactions can be biologically functional.

Animals↗

PubMed2006

Generalized Haldane equation and fluctuation theorem in the steady-state cycle kinetics of single enzymes.

Enzyme kinetics are cyclic. We study a Markov renewal process model of single-enzyme turnover in nonequilibrium steady state (NESS) with sustained concentrations for substrates and products. We show that the forward and backward cycle times have identical nonexponential distributions: Theta + (t)=Theta_(t). This equation generalizes the Haldane relation in reversible enzyme kinetics. In terms of the probabilities for the forward (p+) and backward (p-) cycles, kBT ln(p+/p-) is shown to be the chemical driving force of the NESS, Delta mu. More interestingly, the moment generating function of the stochastic number of substrate cycle v(t), , follows the fluctuation theorem in the form of Kurchan-Lebowitz-Spohn-type symmetry. When lambda=delta mu/kBT, we obtain the Jarzynski-Hatano-Sasa-type equality identical with 1 for all t, where v Delta mu is the fluctuating chemical work done for sustaining the NESS. This theory suggests possible methods to experimentally determine the nonequilibrium driving force in situ from turnover data via single-molecule enzymology.

Journal Article↗

PubMed2006

Powering a burnt bridges Brownian ratchet: a model for an extracellular motor driven by proteolysis of collagen.

Biased diffusion of collagenase on collagen fibrils may represent the first observed adenosine triphosphate-independent extracellular molecular motor. The magnitude of force generated by the enzyme remains unclear. We propose a propulsion mechanism based on a burnt bridges Brownian ratchet model with a varying degree of coupling of the free energy from collagen proteolysis to the enzyme motion. When constrained by experimental observations, our model predicts 0.1 pN stall force for individual collagenase molecules. A dimer, surprisingly, can generate a force in the range of 5 pN, suggesting that the motor can be of biological significance.

Collagen↗

PubMed2006

Rapid hypoxia preconditioning protects cortical neurons from glutamate toxicity through delta-opioid receptor.

BACKGROUND AND PURPOSE: Hypoxia preconditioning (HPC), rapid or delayed, has been reported to induce neuroprotection against subsequent severe stress. Because delta-opioid receptor (DOR) plays an important role in delayed HPC-induced neuroprotection against severe hypoxic injury, we asked whether DOR is also involved in the rapid HPC-induced neuroprotection. METHODS: Cultured rat cortical neurons at culture days 8 to 9 were exposed to a short-term hypoxia (1% O2 for 30 minutes) to induce HPC followed by 30-minute normoxia before exposing to glutamate toxicity (100 micromol/L; 4 hours). Neuronal viability was assessed by lactate dehydrogenase leakage and morphological assessment. Protein and mRNA levels of DOR were detected by receptor binding and RT-PCR, respectively. Naltrindole was used to block DOR. Developmental changes in NMDA receptor expression was measured by Western blots. RESULTS: HPC significantly reduced the glutamate-induced neuronal injury. Receptor binding showed that HPC increased DADLE (a DOR ligand) binding density in the cultured cortical neurons by >90% over control level (P<0.05), although RT-PCR did not detect any appreciable change in DOR mRNA. DOR inhibition with naltrindole had no effect on neuronal injury and completely abolished the HPC-induced neuroprotection. In contrast to HPC-induced increase in DADLE binding density, prolonged hypoxia caused severe neuronal injury with a significant decrease in DADLE binding density and DOR mRNA level. CONCLUSIONS: DOR is involved in neuroprotection induced by rapid HPC in cortical neurons.

Animals↗

PubMed2006

Chromatin looping and the probability of transcription.

Recent studies of several multigene clusters have shown that gene activation by a remote enhancer is associated with chromatin loop formation. It is not fully understood how a chromatin loop forms in a nucleus or how it is involved in gene regulation. In this article, we propose that the major feature that determines loop formation is the flexibility of chromatin, and that this flexibility is modulated by histone acetylation (and other modifications). Thus, histone modifications will modulate distribution of the preferential looping site in chromatin, which, in turn, determines the probability of interaction between a remote enhancer and the cognate genes. This model can explain gene expression changes in the Hoxd gene cluster and the beta-globin locus.

Acetylation↗

PubMed2006

ErbB3-dependent motility and intravasation in breast cancer metastasis.

A better understanding of how epidermal growth factor receptor family members (ErbBs) contribute to metastasis is important for evaluating ErbB-directed therapies. Activation of ErbB3/ErbB2 heterodimers can affect both proliferation and motility. We find that increasing ErbB3-dependent signaling in orthotopic injection models of breast cancer can enhance intravasation and lung metastasis with no effect on primary tumor growth or microvessel density. Enhanced metastatic ability due to increased expression of ErbB2 or ErbB3 correlated with stronger chemotaxis and invasion responses to heregulin beta1. Suppression of ErbB3 expression reduced both intravasation and metastasis. A human breast cancer tumor tissue microarray showed a significant association between ErbB3 and ErbB2 expression and metastasis independent of tumor size. These results indicate that ErbB3-dependent signaling through ErbB3/ErbB2 heterodimers can contribute to metastasis through enhancing tumor cell invasion and intravasation in vivo and that ErbB-directed therapies may be useful for the inhibition of invasion independent of effects on tumor growth.

Animals↗

PubMed2006

Grand canonical Markov model: a stochastic theory for open nonequilibrium biochemical networks.

In this paper we present the results of a stochastic model of reversible biochemical reaction networks that are being driven through an open boundary, such that the system is interacting with its surrounding environment with explicit material exchange. The stochastic model is based on the master equation approach and is intimately related to the grand canonical ensemble of statistical mechanics. We show that it is possible to analytically calculate the joint probability function of the random variables describing the number of molecules in each state of the system for general linear networks. Definitions of reaction chemical potentials and conductances follow from inherent properties of this model, providing a description of energy dissipation in the system. We are also able to suggest novel methods for experimentally determining reaction fluxes and biochemical affinities at nonequilibrium steady state as well as the overall network connectivity.

Algorithms↗

PubMed2006

Contribution of alpha6 integrins to hematopoietic stem and progenitor cell homing to bone marrow and collaboration with alpha4 integrins.

The laminin receptor integrin alpha6 chain is ubiquitously expressed in human and mouse hematopoietic stem and progenitor cells. We have studied its role for homing of stem and progenitor cells to mouse hematopoietic tissues in vivo. A function-blocking anti-integrin alpha6 antibody significantly reduced progenitor cell homing to bone marrow (BM) of lethally irradiated mice, with a corresponding retention of progenitors in blood. Remarkably, the anti-integrin alpha6 antibody profoundly inhibited BM homing of long-term multilineage engrafting stem cells, studied by competitive repopulation assay and analysis of donor-derived lymphocytes and myeloid cells in blood 16 weeks after transplantation. A similar profound inhibition of long-term stem cell homing was obtained by using a function-blocking antibody against alpha4 integrin, studied in parallel. Furthermore, the anti-integrin alpha6 and alpha4 antibodies synergistically inhibited homing of short-term repopulating stem cells. Intravenous injection of anti-integrin alpha6 antibodies, in contrast to antibodies against alpha4 integrin, did not mobilize progenitors or enhance cytokine-induced mobilization by G-CSF. Our results provide the first evidence for a distinct functional role of integrin alpha6 receptor during hematopoietic stem and progenitor cell homing and collaboration of alpha6 integrin with alpha4 integrin receptors during homing of short-term stem cells.

Animals↗

PubMed2006

Differential tissue and subcellular expressionof ERM proteins in normal and malignant tissues: cytoplasmic ezrin expression has prognostic signficance for head and neck squamous cell carcinoma.

BACKGROUND: Members of the ezrin-radixin-moesin (ERM) protein family regulate cellular shape, motility, and proliferation and potentially influence ability to metastasize. We investigated the correlation between ERM subcellular localization and survival in patients with squamous cell carcinoma (SCC) METHODS: Tissue microarrays (TMAs) were constructed from paraffin-embedded tissue. TMA sections were evaluated for ERM protein expression immunohistochemically. The results were compared across clinical and histopathologic variables RESULTS: ERM staining results for 47 patients showed that cytoplasmic ERM expression was prevalent in tumors (>92%). Whereas ezrin and moesin also localized to the membrane, only willin was found in the nucleus of tumors. Multivariable Cox regression analysis demonstrated that strong cytoplasmic ezrin expression was independently associated with poorer survival (p = .04, hazard ratio 1.82) CONCLUSIONS: Both level of expression and subcellular localization of ERM proteins may be important indicators of clinical outcome in SCC. This pilot study justifies the need for an expanded validation study of ERM proteins and clinical outcome.

Adult↗

PubMed2006

A stochastic model of oscillatory blood testosterone levels.

A continuous-time, discrete-state stochastic model of testosterone secretion in men is considered. Blood levels of testosterone in men fluctuate periodically with a period of 2-3 h. The deterministic model, on which the stochastic model considered here is based, is well studied and has been shown to have a globally stable fixed point. Thus, no sustained oscillations are possible in the deterministic case. However, the stochastic model does observe periodic, pulsatile behavior. This demonstrates how oscillations can occur due to a switching behavior dependent on the random degradation of testosterone molecules in the system. The Gillespie algorithm is used to simulate the hormone secretion model. Important parameters of the model are discussed and results from the model are compared to experimental observations.

Biological Clocks↗

PubMed2006

Distributions of exotic plants in eastern Asia and North America.

Although some plant traits have been linked to invasion success, the possible effects of regional factors, such as diversity, habitat suitability, and human activity are not well understood. Each of these mechanisms predicts a different pattern of distribution at the regional scale. Thus, where climate and soils are similar, predictions based on regional hypotheses for invasion success can be tested by comparisons of distributions in the source and receiving regions. Here, we analyse the native and alien geographic ranges of all 1567 plant species that have been introduced between eastern Asia and North America or have been introduced to both regions from elsewhere. The results reveal correlations between the spread of exotics and both the native species richness and transportation networks of recipient regions. This suggests that both species interactions and human-aided dispersal influence exotic distributions, although further work on the relative importance of these processes is needed.

Asia↗