Biomedical subjects

Qiang Shi

Publications and source records attributed to Qiang Shi.

16 recordsLinked to original sources

PubMed2026

Multicellular ecosystems: Linking cellular diversity to tissue function and disease.

Tissue function emerges from coordinated interactions among diverse cell populations, whereas disruption of these interactions can lead to dysfunction. Recent advances in single-cell and spatial genomics have not only cataloged cellular diversity but also revealed how tissues are organized as dynamic multicellular ecosystems. Moving beyond descriptive cell atlases toward functional, system-level representations represents a major frontier in tissue biology. In this review, we outline conceptual and methodological frameworks for dissecting multicellular coordination, highlight recurrent multicellular ecosystems across physiological and pathological contexts, and explore translational opportunities such as patient stratification, therapeutic reprogramming, and regenerative strategies. Viewing tissues through an ecosystem lens provides a unifying framework that links cellular diversity to emergent tissue function and informs strategies for disease intervention.

Humans↗

PubMed2006

Mixed atomistic and coarse-grained molecular dynamics: simulation of a membrane-bound ion channel.

The recently developed multiscale coarse-graining (MS-CG) method (Izvekov, S.; Voth, G. A. J. Phys. Chem. B 2005, 109, 2469; J. Chem. Phys. 2005, 123, 134105) is used to build a mixed all-atom and coarse-grained (AA-CG) model of the gramicidin A (gA) ion channel embedded in a dimyristoylphosphatidylcholine (DMPC) lipid bilayer and water environment. In this model, the gA peptide was described in full atomistic detail, while the lipid and water molecules were described using coarse-grained representations. The atom-CG and CG-CG interactions in the mixed AA-CG model were determined using the MS-CG method. Molecular dynamics (MD) simulations were performed using the resulting AA-CG model. The results from simulations of the AA-CG model compare very favorably to those from all-atom MD simulations of the entire system. Since the MS-CG method employs a general and systematic approach to obtain effective interactions from the underlying all-atom models, the present approach to rigorously develop mixed AA-CG models has the potential to be extended to many other systems.

Computer Simulation↗

PubMed2006

Further evidence that rat liver microsomal glutathione transferase 1 is not a cellular protein target for S-nitrosylation.

By adopting biotin switch method, we recently reported that liver microsomal glutathione transferase 1 (MGST1) might not be a protein target for S-nitrosylation in rat microsomes or in vivo. However, alternative analytic methods are needed to confirm this observation, as a single biotin switch method in judging specific protein S-nitrosylation in biological samples is increasingly recognized as insufficient, or even unreliable. Besides, only MGST1 localized on endoplasmic reticulum (ER), but not mitochondria which favors protein S-nitrosylation was examined in the previous report. Present study was therefore carried out to address these issues. Primary cultured hepatocytes were used. A physiological existing nitric oxide (NO) donor S-nitrosoglutathione (GSNO) was adopted to trigger protein S-nitrosylation. MGST1 was immunoprecipitated and its S-nitrosothiol content was measured by the NO probe 2,3-diaminonaphthalene. In parallel, S-nitrosylated proteins were immunoprecipitated by a monoclonal anti-S-nitrosocysteine antibody and probed with an anti-MGST1 antibody. In hepatocytes, neither ER nor mitochondria were found to contain S-nitrosylated MGST1 after GSNO treatment, showing that differently distributed MGST1 was consistently un-nitrosylable in the cellular environment. But under broken cell conditions, when samples were incubated directly with GSNO, MGST1 S-nitrosylation was indeed detectable in both the microsomal and mitochondrial proteins, indicating that previous failure in detecting MGST1 S-nitrosylation in microsomes is due to the limitations of biotin switch method. These results clearly, if not definitely, demonstrate that MGST1 is not a ready candidate for S-nitrosylation in the cellular content, despite its susceptibility to S-nitrosylation under broken cell conditions.

2-Naphthylamine↗

PubMed2005

Multi-scale modeling of phase separation in mixed lipid bilayers.

An approach to bridging the phenomenological field theory description of phase separation in binary mixed lipid bilayers with coarse-grained (CG) molecular dynamics (MD) simulation is presented. CG MD simulation is carried out for a 1:1 dipalmitoylphosphatidylcholine/dipalmitoylphosphatidylethanolamine lipid mixture at the liquid-gel phase coexistence condition. The liquid-gel phase separation can be characterized by the bilayer thickness, area per lipid molecule, and orientation parameter of the lipid tails. After a local order parameter is defined using the lipid tail bond orientation parameter, the CG MD data are bridged to a mesoscopic model based on the phenomenological Landau-Ginzberg free-energy functional. All parameters in this mesoscopic model are defined from the information of the phase boundary structure and the distributions of the order parameter in the liquid and gel phases. It is found that the mesoscopic model reproduces the equilibrium properties of the system very well, including collective fluctuations in both phases, spatial correlation functions of the order parameter, and the line tension. The possibility of using a time-dependent Landau-Ginzberg model to mimic the phase-separation dynamics is also investigated, using the relaxation time constant obtained by fitting the time-dependent correlation functions of the order parameter.

Cell Membrane↗

PubMed2005

Vibrational energy relaxation rates via the linearized semiclassical approximation: applications to neat diatomic liquids and atomic-diatomic liquid mixtures.

We report the results obtained from the application of our previously proposed linearized semiclassical method for computing vibrational energy relaxation (VER) rates (J. Phys. Chem. A 2003, 107, 9059, 9070) to neat liquid oxygen, neat liquid nitrogen, and liquid mixtures of oxygen and argon. Our calculations are based on a semiclassical approximation for the quantum-mechanical force-force correlation function, which puts it in terms of the Wigner transforms of the force and the product of the Boltzmann operator and the force. The calculation of the multidimensional Wigner integrals is made feasible by the introduction of a local harmonic approximation. A systematic analysis has been performed of the temperature and mole-fraction dependences of the VER rate constant, as well as the relative contributions of centrifugal and potential forces, and of different types of quantum effects. The results were found to be in very good quantitative agreement with experiment, and they suggest that this semiclassical approximation can capture the quantum enhancement, by many orders of magnitude, of the experimentally observed VER rate constants over the corresponding classical predictions.

Algorithms↗

PubMed2005

A comparison between different semiclassical approximations for optical response functions in nonpolar liquid solutions.

The temporal behavior of optical response functions (ORFs) reflects the quantum dynamics of an electronic superposition state, and as such lacks a well-defined classical limit. In this paper, we consider the importance of accounting for the quantum nature of the dynamics when calculating ORFs of different types. To this end, we calculated the ORFs associated with the linear absorption spectrum and the nonlinear two-pulse photon-echo experiment, via the following approaches: (1) the semiclassical forward-backward approach; (2) an approach based on linearizing the path-integral forward-backward action in terms of the difference between the forward and backward paths; (3) an approach based on ground state nuclear dynamics. The calculations were performed on a model that consists of a two-state chromophore solvated in a nonpolar liquid. The different methods were found to yield very similar results for the absorption spectrum and "diagonal" two-pulse photon echo (i.e., the homodyne-detected signal at time t=t(0) after the second pulse, where t(0) is the time interval between the two pulses). The different approximations yielded somewhat different results in the case of the time-integrated photon-echo signal. The reasons for the similarity between the predictions of different approximations are also discussed.

Journal Article↗

PubMed2005

Microsomal glutathione transferase 1 is not S-nitrosylated in rat liver microsomes or in endotoxin challenged rats.

In vitro activation of purified rat microsomal glutathione transferase 1 (MGST1) by S-nitrosylation has been recently reported. This study was designated to explore its in vivo relevance. Unexpectedly, we failed to detect S-nitrosylated MGST1 in rat liver microsomes treated with S-nitrosoglutathione (GSNO); neither did we observe MGST1 S-nitrosylation in endotoxin challenged rats. However, by using matrix-assisted laser dissociation/ionization time-of-flight mass spectrometry (MALDI-TOF MS), we identified several other proteins which are susceptible to S-nitrosylation in liver microsomes, including retinol dehydrogenase type I (RODH I), aldolase B, cytochrome P4502C11, and peroxiredoxin 1. Our results suggest that MGST1 S-nitrosylation is unlikely to be involved in the protection mechanism against nitrosative stress caused by endotoxin challenge. Further studies on the novel S-nitrosylable microsomal proteins are also warranted.

Animals↗

PubMed2005

Arterial endothelial dysfunction in baboons fed a high-cholesterol, high-fat diet.

BACKGROUND: Endothelial dysfunction signals the initiation and progression of atherosclerosis. Elevated LDL-cholesterol concentrations have been suggested to induce endothelial dysfunction, but direct in vivo evidence for the relation is still lacking. OBJECTIVE: We examined the hypothesis that a high-cholesterol, high-fat (HCHF) diet can directly cause endothelial dysfunction in vivo. DESIGN: We measured inflammatory and endothelial dysfunctional markers in circulating blood and directly in endothelial cells, which were collected by femoral artery biopsies, in 10 baboons before and after a 7-wk HCHF dietary challenge. RESULTS: We found that the HCHF diet induced a high inflammatory status, as indicated by increased concentrations of interleukin 6, tumor necrosis factor alpha (TNF-alpha), and monocyte chemoattractant protein 1. Although the concentrations of endothelial dysfunctional markers, such as soluble vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1, were not increased by the HCHF diet, membrane-bound VCAM-1 and membrane-bound E-selectin on endothelial cells were highly increased after 7 wk of the HCHF diet (P < 0.01). In contrast, the concentrations of endothelial nitric oxide synthase in endothelial cells were significantly reduced by the 7-wk HCHF diet (P < 0.01). Furthermore, the dietary challenge attenuated endothelial cell responses to TNF-alpha, lipopolysaccharide, native LDL cholesterol, and oxidized LDL-cholesterol stimulation. CONCLUSIONS: Our results show that an HCHF diet can directly induce inflammation and endothelial dysfunction. Prior in vivo exposure to an HCHF diet attenuates the in vitro responses of endothelial cells to atherogenic risk factors. This preconditioning phenomenon may have significant clinical relevance.

Animals↗

PubMed2005

[Rosiglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice].

OBJECTIVE: To study the effect of rosiglitazone on atherosclerosis and potential mechanism in ApoE-knockout mice. METHODS: Thirty-two 6-week-old ApoE-knockout mice were used as atherosclerosis model in two groups: rosiglitazone group (n = 18) and control group (n = 14). Each group contained equal numbers of male and female mice. All mice were fed with normal chow diet. In addition to normal diet, rosiglitazone group received rosiglitazone 17 mg/kg of body weight/day. Venous bloods were collected for plasma glucose and lipid analysis, and aorta were prepared for morphologic and immunohistochemical analysis after 14 weeks. Aortic root (1 cm) was cut and prepared for paraffin slice. The histomorphometric analysis of atherosclerotic lesion was performed by means of HE; positive percentage of macrophage cell and tumor necrosis factor-alpha were measured by means of immunohistochemistry in cross section. The ratio of lesion/aortic wall surface in the rest aorta was measured by means of Sudan IV staining in longitudinal section. RESULTS: The amount of fatty streak in rosiglitazone group was significantly greater than that of control group; the gross number of lesions and the number of fibrous plaque and atheromatous plaque were similar in two groups. There were no differences in percentage of lesions in cross section in two groups. Rosiglitazone could significantly reduce the extend of atherosclerosis of longitudinal section, decrease the amount of macrophage cell and the level of tumor necrosis factor-alpha in lesions. The plasma glucose was normal and similar in two groups, and total cholesterol, LDL-cholesterol and triglyceride were significantly higher in rosiglitazone group. CONCLUSION: Rosiglitazone suppresses the expression of tumor necrosis factor-alpha, reduces the number of macrophage cell in lesion, and inhibits the development of atherosclerosis.

Animals↗

PubMed2004

A derivation of the mixed quantum-classical Liouville equation from the influence functional formalism.

We show that the mixed quantum-classical Liouville equation is equivalent to linearizing the forward-backward action in the influence functional. Derivations are provided in terms of either the diabatic or adiabatic basis sets. An application of the mixed quantum-classical Liouville equation for calculating the memory kernel of the generalized quantum master equation is also presented. The accuracy and computational feasibility of such an approach is demonstrated in the case of a two-level system nonlinearly coupled to an anharmonic bath.

Journal Article↗

PubMed2004

A semiclassical generalized quantum master equation for an arbitrary system-bath coupling.

The Nakajima-Zwanzig generalized quantum master equation (GQME) provides a general, and formally exact, prescription for simulating the reduced dynamics of a quantum system coupled to a, possibly anharmonic, quantum bath. In this equation, a memory kernel superoperator accounts for the influence of the bath on the dynamics of the system. In a previous paper [Q. Shi and E. Geva, J. Chem. Phys. 119, 12045 (2003)] we proposed a new approach to calculating the memory kernel, in the case of arbitrary system-bath coupling. Within this approach, the memory kernel is obtained by solving a set of two integral equations, which requires a new type of two-time system-dependent bath correlation functions as input. In the present paper, we consider the application of the linearized semiclassical (LSC) approximation for calculating those correlation functions, and subsequently the memory kernel. The new approach is tested on a benchmark spin-boson model. Application of the LSC approximation for calculating the relatively short-lived memory kernel, followed by a numerically exact solution of the GQME, is found to provide an accurate description of the relaxation dynamics. The success of the proposed LSC-GQME methodology is contrasted with the failure of both the direct application of the LSC approximation and the weak coupling treatment to provide an accurate description of the dynamics, for the same model, except at very short times. The feasibility of the new methodology to anharmonic systems is also demonstrated in the case of a two level system coupled to a chain of Lennard-Jones atoms.

Journal Article↗

PubMed2004

The effects of betamethasone (BM) on endothelial nitric oxide synthase (eNOS) expression in adult baboon femoral arterial endothelial cells.

Glucocorticoids have significant effects on endothelium mediated vascular function throughout life. The baboon model has been used extensively to study cellular responses to glucocorticoids at several stages of the lifespan. Endothelial nitric oxide synthase (eNOS) is a major regulator of endothelium dependent arterial vasodilation. We have previously demonstrated that synthetic glucocorticoids down regulate eNOS in the baboon placenta. We have now conducted studies to determine whether glucocorticoids would alter eNOS expression in adult systemic vascular endothelial cells in this important animal model. We explored this potential mechanism in endothelial cells from femoral arteries of adult baboons at necropsy and cultured to the fourth passage. Endothelial cells were treated with 10-100nM betamethasone for 24h at 37 degrees C. Vascular endothelial growth factor (VEGF) was used as a positive control and medium as negative controls. The role of glucocorticoid receptor mediation in betamethasone-induced eNOS changes was investigated with the glucocorticoid receptor antagonist mifepristone. RNA (real-time quantitative RT-PCR) and protein (ELISA) were extracted and measured for eNOS. Expression and subcellular distribution of glucocorticoid receptor were detected with fluorescence labeled antibody microscopy. eNOS mRNA and protein in baboon endothelial cells were downregulated 25% by betamethasone treatment. This effect was attenuated by pre-incubation with mifepristone (P < 0.01). VEGF upregulated eNOS transcription and translation (P < 0.001), medium did not alter eNOS expression. We observed that mifepristone and VEGF increased glucocorticoid receptor cytoplasmic accumulation by fluorescence microscopy. We conclude that betamethasone can downregulate eNOS in cultured baboon endothelial cells via the glucocorticoid receptor pathway.

Animals↗

PubMed2004

Passage-dependent changes in baboon endothelial cells--relevance to in vitro aging.

In vitro cell culture system is a useful model for aging-related changes in a wide spectrum of biomedical research. In this study, we explored the passage and donor age-dependent changes in baboon macrovascular endothelial cells that are relevant to both in vitro cell culture aging models and experiments using cell culture techniques. We collected baboon femoral arterial samples from nine baboons ranging in age from 6 months to 30 years (equivalent to humans approximately 18 months to 90 years of age). We then cultured baboon femoral artery endothelial cells (BFAECs) in standard DMEM medium with 20% fetal calf serum with 1:3 split for subculture. Endothelial functions were documented by morphology, Dil-LDL uptake and expression of eNOS, MCP-1, vWF, VCAM-1, ICAM-1, and E-Selectin with or without cytokine stimulation. Most of the cells became nonmitotic after 30 population doublings, or 10 passages, when they became flattened, enlarged, and senescent. While it took approximately 3 days to reach confluence from three-dilution seeding at early passages (<6), confluence was not achieved even after 7 days of culture for cells after the 9th or 10th passage. There was a linear decline in eNOS expression with passage. However, this decline was significantly less in endothelial cells from a young baboon (6 months) than those from an old baboon (30 years). While basal expression of adhesion molecules was not changed with passaging, responses to cytokine stimulation appeared to be increased in later passaged cells. Our study has provided evidence for passage-related changes in key endothelial functions. The donor age-related differences in this in vitro aging process suggests that in vitro endothelial culture can serve as a biomarker for in vivo aging. Nonhuman primates can provide a model for investigating such aging-related biological characteristics.

Aging↗

PubMed2004

Comparative analysis of vascular endothelial cell activation by TNF-alpha and LPS in humans and baboons.

As an Old World nonhuman primate, baboons have been extensively used for research on dyslipidemia and atherogenesis. With increasing knowledge about the endothelium's role in the initiation and progression of atherosclerosis, the value of the baboon model can be increased by developing it for research on the role of dysfunctional endothelium in atherogenesis. Toward that goal, we have established and validated methods of isolating and culturing baboon femoral artery endothelial cells (BFAECs) and compared baboon endothelial cellular characteristics with those of humans. Our results indicated that baboon and human endothelial cells share similar growth and culture behaviors. As was the case for human endothelial cells, BFAECs responded to tumor necrosis factor (TNF)-alpha stimulation with increased expression of adhesion molecules (maximum increase for intracellular adhesion molecule (ICAM): 1.76 +/- 0.26-fold; vascular cell adhesion molecule (VCAM): 1.65 +/- 0.25-fold; E-selectin: 2.86 +/- 0.57-fold). However, BFAECs were hyporesponsive to lipopolysaccharide (LPS) (range, 0.25-20 microg/mL) in adhesion molecule expression, whereas 1 microg/mL LPS induced 2.14- to 3.71-fold increases in human endothelial cells. The differential responses to LPS were not related to TLR-2 and toll-like receptor (TLR)-4 expression on the cell surface. And baboon microvascular endothelial cells had similar features as BFAECs. We observed constitutive expression of interleukin (IL)-6, IL-8, granulocyte macrophage colony-stimulating factor (GM-CSF), and monocyte chemoattractant protein (MCP)-1 in both human and baboon endothelial cells, and these cytokines were further induced by TNF-alpha and LPS. We also demonstrated that the responses to TNF-alpha or LPS varied among baboons maintained under the same dietary and environmental conditions, suggesting that response may be controlled by genetic factors.

Animals↗

PubMed2004

Arterial wall-determined risk factors to vascular diseases: a nonhuman primate model.

Many decades of research have led to considerable in-depth understanding of circulating factors that may lead to coronary atherosclerosis. However, not every individual with serious known risk factors such as hypercholesterolemia or cigarette smoking develops atherosclerosis. Differential susceptibility of the arterial wall to circulating atherogenic risk factors, which may be largely controlled by genetic variants, may provide this missing link. Endothelial cells, the lining of the arterial wall, are responsible for the integrity and responses to the circulating environment. Dysfunctional endothelial cells and the subsequent proliferation of vascular smooth muscle cells are the prelude of atherosclerosis and acute coronary syndrome. Yet, there have been no detailed studies exploring the interaction between circulating environmental and arterial wall endogenous risk factors in living human subjects. This deficiency is largely the result of restricted access. Genetic factors almost certainly play a key role in directing how the arterial wall responds to circulating "environmental" factors. This endogenous-exogenous (i.e. the arterial wall-circulating) blood balance is the reflection of nature-nurture or gene-environment interaction. Understanding the interaction fully will require direct access to the arteries, and nonhuman primates can provide an excellent model for such investigations. In the current review, we discuss the importance of arterial wall factors in vascular diseases and present a baboon model for practical studies of arterial wall factors and their interaction with circulating factors. Direct biopsy access to baboon arteries will provide a unique opportunity to explore arterial wall susceptibilities and to evaluate the direct effects of diet or pharmaceutical agents on vascular diseases. The use of baboons from large pedigreed families in these studies will enable the identification of genes that interact with these environmental factors in determining individual risk of atherosclerosis.

Animals↗

PubMed2003

[Cardiovascular effect of positive pressure breathing using G-suits with different bladder coverage].

OBJECTIVE: To compare cardiovascular function of subjects exposed to positive pressure breathing (PPB) while wearing G-suits with different bladder coverage. METHOD: 6 male healthy subjects (18-20 years) wearing three kinds of G-suit with bladder coverage of 45%, 65% and 90% respectively, were exposed to PPB with counterpressures of 30, 50 or 70 mmHg for up to 3 min continuously. G-suit bladder pressure value was three times as high as that of PPB counterpressure. Cardiovascular function was observed every minute. The interval between PPBs was 10 min. The equipment consists of G-suit, jerkin, helmet and mask. RESULT: All subjects completed the experiment successfully. Mean arterial pressure (MAP) elevated significantly, while stroke volume had no striking change, as compared with control group when wearing G-suit with 65% or 90% bladder coverage G-suit. During PPB for 3 min, cardiovascular function didn't change significantly. The mean value of MAP was proportional to the level of PPB. CONCLUSION: The greater G-suit bladder coverage, the less cardiovascular function effect when PPB was conducted simultaneously.

Adolescent↗