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Articles by S Wang
Total Records ( 28 ) for S Wang
  X Mu , Y Chen , S Wang , X Huang , H Pan and M. Li
 

Vascular endothelial growth factor-correlated chemokine 1 (VCC-1), a novel chemokine, is hypothesized to be associated with carcinogenesis. VCC-1 is expressed in hepatocellular carcinoma (HCC) cells, but its function remains unknown. To investigate the molecular effects of VCC-1 on HCC cells, the HCC cell line SMMC7721 was stably transfected with the recombinant plasmid pcDNA3.1/VCC-1. Our data demonstrated that overexpression of VCC-1 in SMMC7721 cells significantly enhanced the cellular proliferation, invasive ability, and tumor growth, when compared with both empty vector control cells and parental cells. These results strongly suggest that VCC-1 plays an important role in SMMC7721 invasion and tumor growth, and indicate that VCC-1 may serve as a potential biomarker for anti-HCC therapies.

  D. M Albert , A Neekhra , S Wang , S. R Darjatmoko , C. M Sorenson , R. R Dubielzig and N. Sheibani
 

Objectives  To study the progressive changes of intense cyclic light–induced retinal degeneration and to determine whether it results in choroidal neovascularization (CNV).

Methods  Albino rats were exposed to 12 hours of 3000-lux cyclic light for 1, 3, or 6 months. Fundus examination, fundus photography, fluorescein and indocyanine green angiography, and optical coherence tomography were performed prior to euthanization. Light-exposed animals were euthanized after 1, 3, or 6 months for histopathological evaluation. Retinas were examined for the presence of 4-hydroxy-2-nonenal– and nitrotyrosine-modified proteins by immunofluorescence staining.

Results  Long-term intense cyclic light exposure resulted in retinal degeneration with loss of the outer segments of photoreceptors and approximately two-thirds of the outer nuclear layer as well as development of subretinal pigment epithelium neovascularization after 1 month. Almost the entire outer nuclear layer was absent with the presence of CNV, which penetrated the Bruch membrane and extended into the outer retina after 3 months. Absence of the outer nuclear layer, multiple foci of CNV, retinal pigment epithelial fibrous metaplasia, and connective tissue bands containing blood vessels extending into the retina were observed after 6 months. All intense light–exposed animals showed an increased presence of 4-hydroxy-2-nonenal and nitrotyrosine staining. Optical coherence tomographic and angiographic studies confirmed retinal thinning and leakiness of the newly formed blood vessels.

Conclusions  Our results suggest that albino rats develop progressive stages of retinal degeneration and CNV after long-term intense cyclic light exposure, allowing the detailed study of the pathogenesis and treatment of age-related macular degeneration.

Clinical Relevance  The ability to study the progressive pathogenesis of age-related macular degeneration and CNV will provide detailed knowledge about the disease and aid in the development of target-specific therapy.

  S Wang , B Nan , N Zhu and J. Zhu
 

In many biological and other scientific applications, predictors are often naturally grouped. For example, in biological applications, assayed genes or proteins are grouped by biological roles or biological pathways. When studying the dependence of survival outcome on these grouped predictors, it is desirable to select variables at both the group level and the within-group level. In this article, we develop a new method to address the group variable selection problem in the Cox proportional hazards model. Our method not only effectively removes unimportant groups, but also maintains the flexibility of selecting variables within the identified groups. We also show that the new method offers the potential for achieving the asymptotic oracle property.

  S Wang , L Qian and R. J. Carroll
 

Efficient estimation of parameters is a major objective in analyzing longitudinal data. We propose two generalized empirical likelihood-based methods that take into consideration within-subject correlations. A nonparametric version of the Wilks theorem for the limiting distributions of the empirical likelihood ratios is derived. It is shown that one of the proposed methods is locally efficient among a class of within-subject variance-covariance matrices. A simulation study is conducted to investigate the finite sample properties of the proposed methods and compares them with the block empirical likelihood method by You et al. (2006) and the normal approximation with a correctly estimated variance-covariance. The results suggest that the proposed methods are generally more efficient than existing methods that ignore the correlation structure, and are better in coverage compared to the normal approximation with correctly specified within-subject correlation. An application illustrating our methods and supporting the simulation study results is presented.

  S Yao , S Wang , Y Zhu , L Luo , G Zhu , S Flies , H Xu , W Ruff , M Broadwater , I. H Choi , K Tamada and L. Chen
 

Programmed death one (PD-1) is an inducible molecule belonging to the immunoglobulin superfamily. It is expressed on activated T and B lymphocytes and plays pivotal roles in the negative regulation of adaptive immune responses. We report here an unexpected finding: that PD-1 could also be induced on splenic dendritic cells (DCs) by various inflammatory stimuli. Adoptive transfer of PD-1–deficient DCs demonstrates their superior capacity to wild-type DCs in innate protection of mice against lethal infection by Listeria monocytogenes. Furthermore, PD-1–deficient mice are also more resistant to the infection than wild-type controls, even in the absence of T and B cells, accompanied by elevated production of DC-derived interleukin-12 and tumor necrosis factor-. Our results reveal a novel role of PD-1 in the negative regulation of DC function during innate immune response.

  A Eusebio , A Pogosyan , S Wang , B Averbeck , L. D Gaynor , S Cantiniaux , T Witjas , P Limousin , J. P Azulay and P. Brown
 

Neuronal activity within and across the cortex and basal ganglia is pathologically synchronized, particularly at ~ 20 Hz in patients with Parkinson's disease. Defining how activities in spatially distributed brain regions overtly synchronize in narrow frequency bands is critical for understanding disease processes like Parkinson's disease. To address this, we studied cortical responses to electrical stimulation of the subthalamic nucleus (STN) at various frequencies between 5 and 30 Hz in two cohorts of eight patients with Parkinson's disease from two different surgical centres. We found that evoked activity consisted of a series of diminishing waves with a peak latency of 21 ms for the first wave in the series. The cortical evoked potentials (cEPs) averaged in each group were well fitted by a damped oscillator function (r ≥0.9, P < 0.00001). Fits suggested that the natural frequency of the subthalamo-cortical circuit was around 20 Hz. When the system was forced at this frequency by stimulation of the STN at 20 Hz, the undamped amplitude of the modelled cortical response increased relative to that with 5 Hz stimulation in both groups (P ≤ 0.005), consistent with resonance. Restoration of dopaminergic input by treatment with levodopa increased the damping of oscillatory activity (as measured by the modelled damping factor) in both patient groups (P ≤0.001). The increased damping would tend to limit resonance, as confirmed in simulations. Our results show that the basal ganglia–cortical network involving the STN has a tendency to resonate at ~ 20 Hz in Parkinsonian patients. This resonance phenomenon may underlie the propagation and amplification of activities synchronized around this frequency. Crucially, dopamine acts to increase damping and thereby limit resonance in this basal ganglia–cortical network.

  T Zhou , S Wang , H Ren , X. R Qi , S Luchetti , W Kamphuis , J. N Zhou , G Wang and D. F. Swaab
 

The recently discovered dendritic cell nuclear protein-1 is the product of a novel candidate gene for major depression. The A allele encodes full-length dendritic cell nuclear protein-1, while the T allele encodes a premature termination of translation at codon number 117 on chromosome 5. In the present study we investigate whether the two forms of dendritic cell nuclear protein-1 might act on corticotropin-releasing hormone, which plays a crucial role in the stress response and in the pathogenesis of depression. The messenger RNA expression of dendritic cell nuclear protein-1 appeared to be increased in the laser micro-dissected paraventricular nucleus of patients with depression compared with control subjects. Dendritic cell nuclear protein-1 was also found to be co-localized with corticotropin-releasing hormone in paraventricular nucleus neurons. Moreover, full-length dendritic cell nucleus protein-1 bound to and transactivated the promoter of corticotropin-releasing hormone in human embryonic kidney 293 cells. We propose that full-length dendritic cell nucleus protein-1 may play a role in the pathogenesis of depressive disorders by enhancing corticotropin-releasing hormone expression in the hypothalamic paraventricular nucleus.

  Z Han , Z Hong , C Chen , Q Gao , D Luo , Y Fang , Y Cao , T Zhu , X Jiang , Q Ma , W Li , L Han , D Wang , G Xu , S Wang , L Meng , J Zhou and D. Ma
 

Tumor cells acquire the ability to proliferate uncontrollably, resist apoptosis, sustain angiogenesis and evade immune surveillance. Signal transducer and activator of transcription (STAT) 3 regulates all of these processes in a surprisingly large number of human cancers. Consequently, the STAT3 protein is emerging as an ideal target for cancer therapy. This paper reports the generation of an oncolytic adenovirus (M4), which selectively blocks STAT3 signaling in tumor cells as a novel therapeutic strategy. M4 selectively replicated in tumor cells and expressed high levels of antisense STAT3 complementary DNA during the late phase of the viral infection in a replication-dependent manner. The viral progeny yield of M4 in tumor cells was much higher than that of the parent adenoviral mutants, Ad5/dE1A. M4 effectively silenced STAT3 and its target genes in tumor cells while sparing normal cells and exhibited potent antitumoral efficacy in vitro and in vivo. Systemic administration of M4 significantly inhibited tumor growth in an orthotopic gastric carcinoma mouse model, eliminated abdominal cavity metastases and prolonged survival time. In summary, M4 has low toxicity and great potential as a therapeutic agent for different types of cancers.

  S Wang , J Tang , M Wang , L Yuan and Z. Zhang
 

Recently, two genome-wide association studies identified a significant association between the prostate stem cell antigen (PSCA) rs2294008 (C>T) polymorphism and risk of diffuse-type of gastric cancer in Asians and bladder cancer in Caucasians, respectively. PSCA has been reported highly expressed in bladder cancer and been considered as a useful marker for diagnosis and progression of bladder cancer. To determine whether rs2294008 polymorphism is associated with risk of bladder cancer in Chinese populations, we conducted a hospital-based case–control study of 581 cases and 580 controls. Sixteen normal bladder tissues adjacent to tumors were used to evaluate the functionality of this polymorphism. We genotyped the rs2294008 polymorphism and assessed its association with risk of bladder cancer and messenger RNA (mRNA) expression in normal bladder tissues. A significant increased risk of bladder cancer was found for rs2294008 CT/TT genotypes (adjusted odds ratio, 1.38; 95% confidence interval, 1.09–1.75) compared with the CC genotype. Furthermore, analysis of PSCA mRNA expression identified a clear correlation of rs2294008 with expression levels of PSCA mRNA. These results indicated that the rs2294008 polymorphism of PSCA gene may play a role in bladder cancer carcinogenesis and it could be served as a biomarker for genetic susceptibility to bladder cancer in Chinese populations.

  Q Li , Y Guo , Q Ou , C Cui , W. J Wu , W Tan , X Zhu , L. B Lanceta , S. K Sanganalmath , B Dawn , K Shinmura , G. D Rokosh , S Wang and R. Bolli
 

Background— Although inducible nitric oxide synthase (iNOS) is known to impart powerful protection against myocardial infarction, the mechanism for this salubrious action remains unclear.

Methods and Results— Adenovirus-mediated iNOS gene transfer in mice resulted 48 to 72 hours later in increased expression not only of iNOS protein but also of heme oxygenase (HO)-1 mRNA and protein; HO-2 protein expression did not change. iNOS gene transfer markedly reduced infarct size in wild-type mice, but this effect was completely abrogated in HO-1–/– mice. At 48 hours after iNOS gene transfer, nuclear factor-B was markedly activated. In transgenic mice with cardiomyocyte-restricted expression of a dominant negative mutant of IB (IBS32A,S36A), both basal HO-1 levels and upregulation of HO-1 by iNOS gene transfer were suppressed. Chromatin immunoprecipitation analysis of mouse hearts provided direct evidence that nuclear factor-B subunits p50 and p65 were recruited to the HO-1 gene promoter (–468 to –459 bp) 48 hours after iNOS gene transfer.

Conclusions— This study demonstrates for the first time the existence of a close functional coupling between cardiac iNOS and cardiac HO-1: iNOS upregulates HO-1 by augmenting nuclear factor-B binding to the region of the HO-1 gene promoter from –468 to –459 bp, and HO-1 then mediates the cardioprotective effects of iNOS. These results also reveal an important role of nuclear factor-B in both basal and iNOS-induced expression of cardiac HO-1. Collectively, the present findings significantly expand our understanding of the regulation of cardiac HO-1 and of the mechanism whereby iNOS exerts its cardioprotective actions.

  M Juhaszova , D. B Zorov , Y Yaniv , H. B Nuss , S Wang and S. J. Sollott
 

Limitation of infarct size by ischemic/pharmacological pre- and postconditioning involves activation of a complex set of cell-signaling pathways. Multiple lines of evidence implicate the mitochondrial permeability transition pore (mPTP) as a key end effector of ischemic/pharmacological pre- and postconditioning. Increasing the ROS threshold for mPTP induction enhances the resistance of cardiomyocytes to oxidant stress and results in infarct size reduction. Here, we survey and synthesize the present knowledge about the role of glycogen synthase kinase (GSK)-3β in cardioprotection, including pre- and postconditioning. Activation of a wide spectrum of cardioprotective signaling pathways is associated with phosphorylation and inhibition of a discrete pool of GSK-3β relevant to mitochondrial signaling. Therefore, GSK-3β has emerged as the integration point of many of these pathways and plays a central role in transferring protective signals downstream to target(s) that act at or in proximity to the mPTP. Bcl-2 family proteins and mPTP-regulatory elements, such as adenine nucleotide translocator and cyclophilin D (possibly voltage-dependent anion channel), may be the functional downstream target(s) of GSK-3β. Gaining a better understanding of these interactions to control and prevent mPTP induction when appropriate will enable us to decrease the negative impact of the reperfusion-induced ROS burst on the fate of mitochondria and perhaps allow us to limit propagation of damage throughout and between cells and consequently, to better limit infarct size.

  S Wang , M Zhang , B Liang , J Xu , Z Xie , C Liu , B Viollet , D Yan and M. H. Zou
 

Rational: AMP-activated protein kinase (AMPK) is an energy sensor and ubiquitously expressed in vascular cells. Recent studies suggest that AMPK activation improves endothelial function by counteracting oxidative stress in endothelial cells. How AMPK suppresses oxidative stress remains to be established.

Objective: The aim of this study is to examine the effects of AMPK in regulating NAD(P)H oxidase, oxidative stress, and endothelial function.

Methods and Results: The markers of oxidative stress, NAD(P)H oxidase subunit expression (gp91phox, p47phox, p67phox, NOX1 to -4), NAD(P)H oxidase–mediated superoxide production, 26S proteasome activity, IB degradation, and nuclear translocation of nuclear factor (NF)-B (p50 and p65) were examined in cultured human umbilical vein endothelial cells and mouse aortas isolated from AMPK2 deficient mice. Compared to the wild type, acetylcholine-induced endothelium-dependent relaxation was significantly impaired in parallel with increased production of oxidants in AMPK2–/– mice. Further, pretreatment of aorta with either superoxide dismutase (SOD) or tempol or apocynin significantly improved acetylcholine-induced endothelium-dependent relaxation in AMPK2–/– mice. Analysis of aortic endothelial cells from AMPK2–/– mice and human umbilical vein endothelial cells expressing dominant negative AMPK or AMPK2-specific siRNA revealed that loss of AMPK activity increased NAD(P)H oxidase subunit expression (gp91phox, p47phox, p67phox, NOX1 and -4), NAD(P)H oxidase–mediated superoxide production, 26S proteasome activity, IB degradation, and nuclear translocation of NF-B (p50 and p65), whereas AMPK activation by AICAR or overexpression of constitutively active AMPK had the opposite effect. Consistently, we found that genetic deletion of AMPK2 in low-density lipoprotein receptor knockout (LDLr–/–) strain markedly increased 26S proteasome activity, IB degradation, NF-B transactivation, NAD(P)H oxidase subunit overexpression, oxidative stress, and endothelial dysfunction, all of which were largely suppressed by chronic administration of MG132, a potent cell permeable proteasome inhibitor.

Conclusions: We conclude that AMPK2 functions as a physiological suppressor of NAD(P)H oxidase and ROS production in endothelial cells. In this way, AMPK maintains the nonatherogenic and noninflammatory phenotype of endothelial cells.

  S Wang , H Zhang , X Dai , R Sealock and J. E. Faber
  Rationale:

Collaterals are arteriole-to-arteriole anastomoses that connect adjacent arterial trees. They lessen ischemic tissue injury by serving as endogenous bypass vessels when the trunk of 1 tree becomes narrowed by vascular disease. The number and diameter ("extent") of native (preexisting) collaterals, plus their amount of lumen enlargement (growth/remodeling) in occlusive disease, show remarkably wide variation among inbred mouse strains (eg, C57BL/6 and BALB/c), resulting in large differences in tissue injury in models of occlusive disease. Evidence suggests similar large differences exist among healthy humans.

Objective:

To identify candidate loci responsible for genetic-dependent collateral variation.

Methods and Results:

Cerebral collateral number and diameter were determined in 221 C57BL/6xBALB/c F2 progeny, followed by linkage analysis to identify quantitative trait loci (QTL) for collateral number and diameter. Four QTL were obtained for collateral number, including epistasis between 2 loci. A QTL that was identical to the strongest QTL for collateral number on chromosome 7 (logarithm of the odds [LOD]=29, effect size=37%) was also mapped for collateral diameter (LOD=17, effect size=30%). Chromosome substitution strain analysis confirmed this locus. We also obtained a unique QTL on chromosome 11 for collateral remodeling after middle cerebral artery occlusion. Association mapping within the chromosome 7 QTL interval using collateral traits measured for 15 inbred strains delineated 172-kbp (P=0.00002) and 290-kbp (P=0.0004) regions on chromosome 7 containing 2 and 7 candidate genes, respectively.

Conclusions:

We conclude that collateral extent and remodeling are unique, highly heritable complex traits, with 1 QTL predominantly affecting native collateral number and diameter.

  N Mathur , S Sood , S Wang , R. J van Oort , S Sarma , N Li , D. G Skapura , J. H Bayle , M Valderrabano and X. H.T. Wehrens
 

Background— Mutations in the cardiac ryanodine receptor gene (RyR2) have been recently identified in victims of sudden infant death syndrome. The aim of this study was to determine whether a gain-of-function mutation in RyR2 increases the propensity to cardiac arrhythmias and sudden death in young mice.

Methods and Results— Incidence of sudden death was monitored prospectively in heterozygous knock-in mice with mutation R176Q in RyR2 (R176Q/+). Young R176Q/+ mice exhibited a higher incidence of sudden death compared with wild-type littermates. Optical mapping of membrane potentials and intracellular calcium in 1- to 7-day-old R176Q/+ and wild-type mice revealed an increased incidence of ventricular ectopy and spontaneous calcium releases in neonatal R176Q/+ mice. Surface ECGs in 3- to 10-day-old mice showed that R176Q/+ mice developed more ventricular arrhythmias after provocation with epinephrine and caffeine. Intracardiac pacing studies in 12- to 18-day-old mice revealed the presence of an arrhythmogenic substrate in R176Q/+ compared with wild-type mice. Reverse transcription–polymerase chain reaction and Western blotting showed that expression levels of other calcium handling proteins were unaltered, suggesting that calcium leak through mutant RyR2 underlies arrhythmogenesis and sudden death in young R176Q/+ mice.

Conclusions— Our findings demonstrate that a gain-of-function mutation in RyR2 confers an increased risk of cardiac arrhythmias and sudden death in young mice and that young R176Q/+ mice may be used as a model for elucidating the complex interplay between genetic and environmental risk factors associated with sudden infant death syndrome.

  S Wang , C Schmaderer , E Kiss , C Schmidt , M Bonrouhi , S Porubsky , N Gretz , L Schaefer , C. J Kirschning , Z. V Popovic and H. J. Grone
  Shijun Wang, Christoph Schmaderer, Eva Kiss, Claudia Schmidt, Mahnaz Bonrouhi, Stefan Porubsky, Norbert Gretz, Liliana Schaefer, Carsten J. Kirschning, Zoran V. Popovic, and Hermann-Josef Grone

Toll-like receptors (TLRs) recognize specific molecular patterns derived from microbial components (exogenous ligands) or stressed cells (endogenous ligands). Stimulation of these receptors leads to a pronounced inflammatory response in a variety of acute animal models. Chronic allograft dysfunction (CAD) was regarded as a candidate disease to test whether TLRs influence chronic fibrosing inflammation. Potential endogenous renal TLR ligands, specifically for TLR2 and TLR4, have now been detected by a significant upregulation of glucose regulated protein (GRP)-94, fibrinogen, heat shock protein (HSP)-60, HSP-70, biglycan (Bgn) and high-mobility group box chromosomal protein 1 (HMGB1) in the acute and chronic transplant setting. In a genetic approach to define the contribution of TLR2 and TLR4, and their adaptor proteins MyD88 and TRIF [Toll/interleukin (IL)-1 receptor domain-containing adaptor-protein inducing interferon β], to CAD, kidney transplantation of TLR wild-type grafts to recipients who were deficient in TLR2, TLR4, TLR2/4, MyD88 and TRIF was performed. TLR and adaptor protein deficiencies significantly improved the excretory function of chronic kidney grafts by between 65% and 290%, and histopathologic signs of chronic allograft damage were significantly ameliorated. T cells, dendritic cells (DCs) and foremost macrophages were reduced in grafts by up to 4.5-fold. The intragraft concentrations of IL-6, IL-10, monocyte chemotactic protein-1 (MCP-1) and IL-12p70 were significantly lower. TLR-, MyD88- and TRIF-deficient recipients showed a significant reduction in fibrosis. -smooth muscle actin (-SMA)-positive cells were decreased by up to ninefold, and collagen I and III were reduced by up to twofold. These findings highlight the functional relevance of TLRs and their two major signaling pathways in graft-infiltrating mononuclear cells in the pathophysiology of CAD. A TLR signaling blockade may be a therapeutic option for the prevention of CAD.

  D. H Parks , M Porter , S Churcher , S Wang , C Blouin , J Whalley , S Brooks and R. G. Beiko
 

The increasing availability of genetic sequence data associated with explicit geographic and ecological information is offering new opportunities to study the processes that shape biodiversity. The generation and testing of hypotheses using these data sets requires effective tools for mathematical and visual analysis that can integrate digital maps, ecological data, and large genetic, genomic, or metagenomic data sets. GenGIS is a free and open-source software package that supports the integration of digital map data with genetic sequences and environmental information from multiple sample sites. Essential bioinformatic and statistical tools are integrated into the software, allowing the user a wide range of analysis options for their sequence data. Data visualizations are combined with the cartographic display to yield a clear view of the relationship between geography and genomic diversity, with a particular focus on the hierarchical clustering of sites based on their similarity or phylogenetic proximity. Here we outline the features of GenGIS and demonstrate its application to georeferenced microbial metagenomic, HIV-1, and human mitochondrial DNA data sets.

  S Wang , Z Zhang , X Lin , D. S Xu , Y Feng and K. Ding
 

Ophiopogon japonicus is a traditional Chinese medicine used to treat cardiovascular disease. Recent studies have confirmed its beneficial properties, but not the mechanism of action. Herein, we investigate the anti-ischemic properties of a water-soluble β-d-fructan (MDG-1) from Ophiopogon japonicus, and assess the cytoprotective and proangiogenic effects of MDG-1. MDG-1 protects cardiomyocyte and microvascular endothelial cells (HMEC-1) against oxygen glucose deprivation (OGD)-induced cell death, as well as protect myocardial cells from ischemia-induced death occurring after coronary artery ligation in rats. Meanwhile, MDG-1 stimulates the differentiation of HMEC-1 cells into capillary-like structures in vitro and functions as a chemoattractant in migration assays, and promotes neovascularization in ischemic myocardium. In addition, MDG-1 upregulates sphingosine kinase 1 and sphingosine-1-phosphate (S1P) receptor 1 expression. Both MDG-1 and S1P induce basic fibroblast growth factor (bFGF) expression in HMEC-1 cells. Further study revealed that both MDG-1 and S1P induce Akt and ERK phosphorylation in a dose- and time-dependent manner, an effect that is attenuated by pre-treatment with either the Akt inhibitor wortmannin or the ERK inhibitor PD98059, and MDG-1 can also induce eNOS phosphorylation and increases in production of NO. These data indicate that MDG-1 presented remarkable anti-ischemic activity and protects cardiomyocyte and HMEC-1 cells from ischemia-induced cell damage by inducing S1P1 and bFGF cytoprotective and proangiogenic effects via the S1P/bFGF/Akt/ERK/eNOS signaling pathway.

  S Wang , L Zhang and M. Matz
 

Mining for microsatellites (also called simple sequence repeats [SSRs]) in public sequence databases of a common Indo-Pacific coral Acropora millepora identified 191 SSRs from 10 258 expressed sequence tag (EST) and 618 SSRs from 14 625 whole-genome shotgun (WGS) sequences. In contrast to other animals, trinucleotide repeats, rather than dinucleotide repeats, are dominant in the WGS-SSRs, and AAT is the most frequent trinucleotide motif in EST-SSRs. We successfully developed 40 polymorphic markers from EST-SSRs and WGS-SSRs. Both EST- and WGS-SSRs show high levels of polymorphism within corals from the same reef patch. Interestingly, markers WGS079 and WGS227 revealed SSR duplications in a few individuals, suggesting recent duplication events. Genotypic linkage disequilibrium was identified in 5 pairs of SSR markers, which will be invaluable for high-resolution studies of genetic admixture in natural populations of A. millepora. Transferability analysis showed that 25 of these markers can be successfully amplified in one of the most ubiquitous Indo-Pacific corals Acropora hyacinthus. The marker collection reported here is the largest ever developed for any reef-building coral. It holds great potential for addressing coral reef connectivity across the Indo-Pacific with an unprecedented precision, especially taking into account the cross-species transferability of a substantial number of markers.

  D. L Nehrenberg , S Wang , R. M Hannon , T Garland and D. Pomp
 

Exercise improves many aspects of human health, yet many people remain inactive even when exercise is prescribed. We previously created a backcross (BC) between mice selectively bred for high levels of voluntary wheel running (VWR) and fixed for "mini muscle" (MM), a recessive mutation causing ~50% reduction in triceps surae mass. We previously showed that BC mice having the MM trait ran faster and further than mice without MM and that MM maps to chromosome 11. Here, we genotyped the BC with genome-wide single nucleotide polymorphisms to identify quantitative trait loci (QTL) controlling voluntary exercise and tissue and body mass traits and to determine whether these QTL interact with the MM locus or with sex. We detected 3 VWR QTL, representing the first voluntary exercise QTL mapped using this high running selection line, and 5 tissue mass QTL. Several interactions between trait QTL and the MM locus as well as sex were also identified. These results begin to explain the genetic architecture of VWR and further support MM as a locus having major effects, including its main effects on the muscle phenotype, its pleiotropic effects on wheel running and tissue mass traits, and through its interactions with other QTL and with sex.

  H. B Hartman , S. J Gardell , C. J Petucci , S Wang , J. A Krueger and M. J. Evans
 

The role of farnesoid X receptor (FXR) in the development of atherosclerosis has been unclear. Here, LDL receptor (LDLR–/–) or apolipoprotein E (apoE–/–) female or male mice were fed a Western diet and treated with a potent synthetic FXR agonist, WAY-362450. Activation of FXR blocked diet-induced hypertriglyceridemia and elevations of non-HDL cholesterol and produced a near complete inhibition of aortic lesion formation. WAY-362450 also induced small heterodimer partner (SHP) expression and repressed cholesterol 7-hydroxylase (CYP7A1) and sterol 12 -hydroxylase (CYP8B1) expression. To determine if SHP was essential for these protective activities, LDLR–/–SHP–/– and apoE–/–SHP–/– mice were similarly treated with WAY-362450. Surprisingly, a notable sex difference was observed in these mice. In male LDLR–/–SHP–/– or apoE–/–SHP–/– mice, WAY-362450 still repressed CYP7A1 and CYP8B1 expression by 10-fold and still strongly reduced non-HDL cholesterol levels and aortic lesion area. In contrast, in the female LDLR–/–SHP–/– or apoE–/–SHP–/– mice, WAY-362450 only slightly repressed CYP7A1 and CYP8B1 expression and did not reduce non-HDL cholesterol or aortic lesion size. WAY-362450 inhibition of hypertriglyceridemia remained intact in LDLR–/– or apoE–/– mice lacking SHP of both sexes. These results suggest that activation of FXR protects against atherosclerosis in the mouse, and this protective effect correlates with repression of bile acid synthetic genes, with mechanistic differences between male and female mice.

  T Chiba , C. Y Han , T Vaisar , K Shimokado , A Kargi , M. H Chen , S Wang , T. O McDonald , K. D O'Brien and J. W Heinecke
 

Adipose tissue secretes proteins like serum amyloid A (SAA), which plays important roles in local and systemic inflammation. Circulating SAA levels increase in obese humans, but the roles of adipose-derived SAA and hyperlipidemia in this process are unclear. We took advantage of the difference in the inducible isoforms of SAA secreted by adipose tissue (SAA3) and liver (SAA1 and 2) of mice to evaluate whether adipose tissue contributes to the circulating pool of SAA in obesity and hyperlipidemia. Genetically obese (ob/ob) mice, but not hyperlipidemic mice deficient in apolipoprotein E (Apoe–/–), had significantly higher circulating levels of SAA than their littermate controls. SAA1/2 mRNA expression in the liver and SAA3 mRNA expression in intra-abdominal fat were significantly higher in obese than thin mice, but they were not affected by hyperlipidemia in Apoe–/– mice. However, only SAA1/2 and the constitutive form of SAA (SAA4) could be detected in the circulation by mass spectrometric analysis of HDL, the major carrier of circulating SAA. In contrast, SAA3 could be detected in medium from cultured adipocytes. Our findings indicate that the expression of SAA3 in adipose tissue is upregulated by obesity, but it does not contribute to the circulating pool of SAA in mice.

  S Wang , T. M Lincoln and J. E. Murphy Ullrich
 

Diabetes is a major predictor of in-stent restenosis, which is associated with fibroproliferative remodeling of the vascular wall due to increased transforming growth factor-β (TGF-β) action. It is well established that thrombospondin1 (TSP1) is a major regulator of TGF-β activation in renal and cardiac complications of diabetes. However, the role of the TSP1-TGF-β pathway in macrovascular diabetic complications, including restenosis, has not been addressed. In mesangial cells, high glucose concentrations depress protein kinase G (PKG) activity, but not PKG-I protein, thereby downregulating transcriptional repression of TSP1. Previously, we showed that high glucose downregulates PKG-I protein expression by vascular smooth muscle cells (VSMCs) through altered NADPH oxidase signaling. In the present study, we investigated whether high glucose regulation of PKG protein and activity in VSMCs similarly regulates TSP1 expression and downstream TGF-β activity. These studies showed that high glucose stimulates both TSP1 expression and TGF-β bioactivity in primary murine aortic smooth muscle cells (VSMCs). TSP1 is responsible for the increased TGF-β bioactivity under high glucose conditions, because treatment with anti-TSP1 antibody, small interfering RNA-TSP1, or an inhibitory peptide blocked glucose-mediated increases in TGF-β activity and extracellular matrix protein (fibronectin) expression. Overexpression of constitutively active PKG, but not the PKG-I protein, inhibited glucose-induced TSP1 expression and TGF-β bioactivity, suggesting that PKG protein expression is insufficient to regulate TSP1 expression. Together, these data establish that glucose-mediated downregulation of PKG levels stimulates TSP1 expression and enhances TGF-β activity and matrix protein expression, which can contribute to vascular remodeling in diabetes.

  Y Xue , S Wang and X. Feng
 

Site-specific recognition and DNA-binding activity of p53 are crucial for its tumour suppressor function. Previous reports have shown that metal ions can affect the specific recognition and DNA-binding activity of p53DBD. Here we firstly report that magnesium ion can bind to the protein and influence its DNA-binding activity. To elucidate the nature and the effect of metal ions in the reaction chemistry, we utilized endogenous tryptophan fluorescence to quantitate the interaction between p53DBD and metal ions. The Ka value for the binding of Mg2+ to the protein is 1.88 x 103 M–1. Analysis of the CD data clearly suggested that the binding of magnesium ion induced a subtle conformational change rather than a radical modification of the overall protein architecture. Based on the results of electrophoretic mobility shift assays and fluorescence experiments, we concluded that the binding of Mg2+ significantly stimulated the binding of the protein to DNA in a sequence-independent manner, which differed from that of zinc ions in a sequence-specific manner. Based on these results and the fact that Mg2+ exists at relatively high concentration in the cell, we propose that Mg2+ is one of potential factors to affect or regulate the transactivation of p53.

  Y Xue , S Wang and X. Feng
 

The tumour suppressor protein p53 is a sequence-specific transcription factor that coordinates one molecule of zinc in the core domain. In our recent study, magnesium can also bind to the p53DBD and enhance its DNA-binding activity. In this study, a systematic analysis of the conformation and stability changes induced by these two metal ions was reported. The spectra of protein intrinsic fluorescence were used to measure the equilibrium unfolding of the p53DBD protein. The stability against chemical denaturation increased in the order apo < Mg2+ < Zn2+. The thermal stability monitored by DSC scans showed that the binding of metal ions to p53DBD increased the thermal stability of the protein. To explore additional information of structural changes after the binding of metal ions, we used the fluorescent probes to evaluate the hydrophobic surface exposure. The results established that metal ions binding increased hydrophobic exposure on the surface of p53DBD. Analysis of acrylamide quenching experiments revealed that the binding of metal ions to p53DBD induced a structural modification of the protein and this change provided significant protection against acrylamide quenching. Overall, the present results indicated that p53DBD underwent a conformational change upon the binding of metal ions, which was characterized by an increased stability of the protein.

  Y Wang , D Liang , S Wang , Z Qiu , X Chu , S Chen , L Li , X Nie , R Zhang , Z Wang and D. Zhu
 

It has been previously reported by us that hypoxia activates lung 15-lipoxygenase (15-LO), which catalyzes arachidonic acid to 15-hydroxyeicosatetraenoic acid (15-HETE), leading to the constriction of pulmonary artery (PA). Rho-associated serine/threonine kinase (ROK), a downstream effector of small GTPase RhoA that may be modulated by G-protein and tyrosine kinase, plays an important role in smooth muscle contraction. However, whether the 15-HETE induced PA vasoconstriction involves the Rho/ROK pathway remains to be demonstrated. Therefore, we studied the contribution of ROK as well as G-protein and tyrosine kinase to the 15-HETE induced pulmonary vasoconstriction using PA ring technique, RNA interference technology, RP-HPLC, western blot and RT-PCR combined with the blockers. The hypoxia-induced expression of ROK is regulated by 15-HETE in rat PA smooth muscle cells (PASMCs), leading to vasoconstriction. The up-regulation of ROK expression caused by 15-HETE appears to be mediated by the G-protein and tyrosine kinase pathways. The translocation of ROK2 from the nucleus to the cytoplasm during hypoxia exposure relies on the mechanism for 15-HETE production. These results suggest that 15-HETE may mediate the up-regulation of ROK expression through G-protein and tyrosine kinase pathways under hypoxic condition, leading to PA vasoconstriction.

  J. F Salazar Gonzalez , M. G Salazar , B. F Keele , G. H Learn , E. E Giorgi , H Li , J. M Decker , S Wang , J Baalwa , M. H Kraus , N. F Parrish , K. S Shaw , M. B Guffey , K. J Bar , K. L Davis , C Ochsenbauer Jambor , J. C Kappes , M. S Saag , M. S Cohen , J Mulenga , C. A Derdeyn , S Allen , E Hunter , M Markowitz , P Hraber , A. S Perelson , T Bhattacharya , B. F Haynes , B. T Korber , B. H Hahn and G. M. Shaw
 

Identification of full-length transmitted HIV-1 genomes could be instrumental in HIV-1 pathogenesis, microbicide, and vaccine research by enabling the direct analysis of those viruses actually responsible for productive clinical infection. We show in 12 acutely infected subjects (9 clade B and 3 clade C) that complete HIV-1 genomes of transmitted/founder viruses can be inferred by single genome amplification and sequencing of plasma virion RNA. This allowed for the molecular cloning and biological analysis of transmitted/founder viruses and a comprehensive genome-wide assessment of the genetic imprint left on the evolving virus quasispecies by a composite of host selection pressures. Transmitted viruses encoded intact canonical genes (gag-pol-vif-vpr-tat-rev-vpu-env-nef) and replicated efficiently in primary human CD4+ T lymphocytes but much less so in monocyte-derived macrophages. Transmitted viruses were CD4 and CCR5 tropic and demonstrated concealment of coreceptor binding surfaces of the envelope bridging sheet and variable loop 3. 2 mo after infection, transmitted/founder viruses in three subjects were nearly completely replaced by viruses differing at two to five highly selected genomic loci; by 12–20 mo, viruses exhibited concentrated mutations at 17–34 discrete locations. These findings reveal viral properties associated with mucosal HIV-1 transmission and a limited set of rapidly evolving adaptive mutations driven primarily, but not exclusively, by early cytotoxic T cell responses.

  X Huang , X Bai , Y Cao , J Wu , M Huang , D Tang , S Tao , T Zhu , Y Liu , Y Yang , X Zhou , Y Zhao , M Wu , J Wei , D Wang , G Xu , S Wang , D Ma and J. Zhou
 

Angiogenesis is increasingly recognized as an important prognosticator associated with the progression of lymphoma and as an attractive target for novel modalities. We report a previously unrecognized mechanism by which lymphoma endothelium facilitates the growth and dissemination of lymphoma by interacting with circulated T cells and suppresses the activation of CD4+ T cells. Global gene expression profiles of microdissected endothelium from lymphoma and reactive lymph nodes revealed that T cell immunoglobulin and mucin domain–containing molecule 3 (Tim-3) was preferentially expressed in lymphoma-derived endothelial cells (ECs). Clinically, the level of Tim-3 in B cell lymphoma endothelium was closely correlated to both dissemination and poor prognosis. In vitro, Tim-3+ ECs modulated T cell response to lymphoma surrogate antigens by suppressing activation of CD4+ T lymphocytes through the activation of the interleukin-6–STAT3 pathway, inhibiting Th1 polarization, and providing protective immunity. In a lymphoma mouse model, Tim-3–expressing ECs promoted the onset, growth, and dissemination of lymphoma by inhibiting activation of CD4+ T cells and Th1 polarization. Our findings strongly argue that the lymphoma endothelium is not only a vessel system but also a functional barrier facilitating the establishment of lymphoma immune tolerance. These findings highlight a novel molecular mechanism that is a potential target for enhancing the efficacy of tumor immunotherapy and controlling metastatic diseases.

 
 
 
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