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1.  Poxviruses and the Evolution of Host Range and Virulence 
Poxviruses as a group can infect a large number of animals. However, at the level of individual viruses, even closely related poxviruses display highly diverse host ranges and virulence. For example, variola virus, the causative agent of smallpox, is human-specific and highly virulent only to humans, whereas related cowpox viruses naturally infect a broad spectrum of animals and only cause relatively mild disease in humans. The successful replication of poxviruses depends on their effective manipulation of the host antiviral responses, at the cellular-, tissue- and species-specific levels, which constitutes a molecular basis for differences in poxvirus host range and virulence. A number of poxvirus genes have been identified that possess host range function in experimental settings, and many of these host range genes target specific antiviral host pathways. Herein, we review the biology of poxviruses with a focus on host range, zoonotic infections, virulence, genomics and host range genes as well as the current knowledge about the function of poxvirus host range factors and how their interaction with the host innate immune system contributes to poxvirus host range and virulence. We further discuss the evolution of host range and virulence in poxviruses as well as host switches and potential poxvirus threats for human and animal health.
PMCID: PMC3945082  PMID: 24161410
2.  Noninvasive detection of macrophages in atherosclerotic lesions by computed tomography enhanced with PEGylated gold nanoparticles 
Macrophages are becoming increasingly significant in the progression of atherosclerosis (AS). Molecular imaging of macrophages may improve the detection and characterization of AS. In this study, dendrimer-entrapped gold nanoparticles (Au DENPs) with polyethylene glycol (PEG) and fluorescein isothiocyanate (FI) coatings were designed, tested, and applied as contrast agents for the enhanced computed tomography (CT) imaging of macrophages in atherosclerotic lesions. Cell counting kit-8 assay, fluorescence microscopy, silver staining, and transmission electron microscopy revealed that the FI-functionalized Au DENPs are noncytotoxic at high concentrations (3.0 μM) and can be efficiently taken up by murine macrophages in vitro. These nanoparticles were administered to apolipoprotein E knockout mice as AS models, which demonstrated that the macrophage burden in atherosclerotic areas can be tracked noninvasively and dynamically three-dimensionally in live animals using micro-CT. Our findings suggest that the designed PEGylated gold nanoparticles are promising biocompatible nanoprobes for the CT imaging of macrophages in atherosclerotic lesions and will provide new insights into the pathophysiology of AS and other concerned inflammatory diseases.
PMCID: PMC4260660  PMID: 25506213
atherosclerosis; CT; in vivo imaging
3.  Atrophy and Other Potential Factors Affecting Long Term Deep Brain Stimulation Response: A Case Series 
PLoS ONE  2014;9(10):e111561.
To describe three DBS cases which presented with new side effects or loss of benefit from stimulation after long-term follow-up and to discuss the potential contributing factors.
A University of Florida (UF) database (INFORM) search was performed, identifying three patients, two Parkinson's disease (PD) and one Essential Tremor (ET), with an unexpected change in long-term programming thresholds as compared to initial evaluation. Clinical follow-up, programming, imaging studies, and lead measurements were reviewed. The UF Institutional Review Board (IRB) approved this study.
A substantial increase in the 3rd ventricular width (120%), Evans index (6%), ventricular index (5%), and cella media index (17%) was uncovered. A change in thresholds across lead contacts with a decrease in current densities as well as a relative lateral change of lead location was also observed. Hardware-related complications, lead migration, and impedance variability were not identified.
Potential factors contributing to long-term side effects should be examined during a DBS troubleshooting assessment. Clinicians should be aware that in DBS therapy there is delivery of electricity to a changing brain, and atrophy may possibly affect DBS programming settings as part of long-term follow-up.
PMCID: PMC4216112  PMID: 25360599
4.  Polyethylene glycol-modified dendrimer-entrapped gold nanoparticles enhance CT imaging of blood pool in atherosclerotic mice 
Nanoscale Research Letters  2014;9(1):529.
We report a new use of dendrimer-entrapped gold nanoparticles (Au DENPs) modified by polyethylene glycol (PEG) with good biocompatibility for in vitro and in vivo imaging of atherosclerotic mice by computed tomography (CT). In this study, Au DENPs were synthesized using poly(amidoamine) (PAMAM) dendrimers of generation 5 (G5.NH2) modified by PEG monomethyl ether (G5.NH2-mPEG20) as templates. In vitro cytotoxicity and flow cytometry assays show that the formed PEGylated Au DENPs have good biocompatibility and are non-cytotoxic at the Au concentration up to 300 μM. Silver staining and transmission electron microscopy (TEM) further confirm that the Au DENPs are able to be uptaken by macrophages and are located dominantly in the lysosomes of the cells. Importantly, the formed PEGylated Au DENPs are able to be used for CT imaging of murine macrophages in vitro and macrophages in atherosclerotic mice in vivo using apolipoprotein-E-gene-deficient mice as a model. These findings suggest that the formed PEGylated Au DENPs are a promising contrast agent for CT imaging of atherosclerosis.
PMCID: PMC4184899  PMID: 25288918
Atherosclerosis; Macrophages; Gold nanoparticles; Dendrimers; Computed tomography imaging
6.  Inhibition of Rho-Kinase by Fasudil Suppresses Formation and Progression of Experimental Abdominal Aortic Aneurysms 
PLoS ONE  2013;8(11):e80145.
Accumulating evidence suggests that inflammatory cell infiltration is crucial pathogenesis during the initiation and progression of abdominal aortic aneurysm (AAA). Given Rho-kinase (ROCK), an important kinase control the actin cytoskeleton, regulates the inflammatory cell infiltration, thus, we investigate the possibility and mechanism of preventing experimental AAA progression via targeting ROCK in mice porcine pancreatic elastase (PPE) model.
Methods and Results
AAA was created in 10-week-old male C57BL/6 mice by transient intraluminal porcine pancreatic elastase infusion into the infrarenal aorta. The mRNA level of RhoA, RhoC, ROCK1 and ROCK2 were elevated in aneurismal aorta. Next, PPE infusion mice were orally administrated with vehicle or ROCK inhibitor (Fasudil at dose of 200 mg/kg/day) during the period of day 1 prior to PPE infusion to day 14 after PPE infusion. PPE infusion mice treated with Fasudil produced significantly smaller aneurysms as compare to PPE infusion mice treated with vehicle. AAAs developed in all vehicle-treated groups within 14 days, whereas AAAs developed in six mice (66%, 6/9) treated with Fasudil within 14 days. Furthermore, our semi-quantitative histological analysis revealed that blood vessels and macrophages were significantly reduced in Fasudil treated mice during the AAA progression. Finally, when mice with existing AAAs were treated with Fasudil, the enlargement was nearly completely suppressed.
Fasudil inhibits experimental AAA progression and stabilize existing aneurysms, through mechanisms likely related to impaired mural macrophage infiltration and angiogenesis. These findings suggest that ROCK inhibitor may hold substantial translational value for AAA diseases.
PMCID: PMC3828185  PMID: 24244631
7.  Aberrantly hypermethylated Homeobox A2 derepresses metalloproteinase-9 through TBP and promotes invasion in Nasopharyngeal carcinoma 
Oncotarget  2013;4(11):2154-2165.
Nasopharyngeal carcinoma (NPC) is notorious for its high invasiveness and metastatic ability. In this study, we identified a differential hypermethylated transcription repressor, Homeobox A2 (HOXA2), which may render NPC cells invasive and metastatic. Aberrant hypermethylation of HOXA2 led to low RNA expression in NPC tumors and cells. Addition of methylation inhibitor 5'Aza restored HOXA2 RNA expression in NPC cells. Methylated HOXA2 promoter reduces the binding affinity of the transcriptional co-activator p300, causing transcriptional repression of HOXA2. In NPC cells, re-expression of ectopic HOXA2 was correlated with decreased invasive ability and reduced metalloproteinase MMP-9 RNA and protein expression. Promoter, ChIP and DNA-pull down assays indicated that HOXA2 competes with the transcription activator, TATA-box binding protein (TBP) for a recognition sequence near the MMP-9 transcription start site, and suppresses MMP-9 transcription. Thus, HOXA2 acts as a suppressor or TBP-antagonist to inhibit MMP-9 expression; while methylation-mediated inactivation of HOXA2 in NPC derepresses MMP-9 production and increases invasion of NPC cells. In NPC plasma samples, increased plasma EBV copy number was correlated with increased in cell-free HOXA2 hypermethylation and elevated MMP-9 levels. Plasma EBV DNA and methylated cell-free HOXA2 can be used as biomarkers for monitoring NPC treatment.
PMCID: PMC3875777  PMID: 24243817
HOXA2; DNA methylation; NPC; MMP9
8.  Reconstruction and Analysis of Transcription Factor–miRNA Co-Regulatory Feed-Forward Loops in Human Cancers Using Filter-Wrapper Feature Selection 
PLoS ONE  2013;8(10):e78197.
As one of the most common types of co-regulatory motifs, feed-forward loops (FFLs) control many cell functions and play an important role in human cancers. Therefore, it is crucial to reconstruct and analyze cancer-related FFLs that are controlled by transcription factor (TF) and microRNA (miRNA) simultaneously, in order to find out how miRNAs and TFs cooperate with each other in cancer cells and how they contribute to carcinogenesis. Current FFL studies rely on predicted regulation information and therefore suffer the false positive issue in prediction results. More critically, FFLs generated by existing approaches cannot represent the dynamic and conditional regulation relationship under different experimental conditions.
Methodology/Principal Findings
In this study, we proposed a novel filter-wrapper feature selection method to accurately identify co-regulatory mechanism by incorporating prior information from predicted regulatory interactions with parallel miRNA/mRNA expression datasets. By applying this method, we reconstructed 208 and 110 TF-miRNA co-regulatory FFLs from human pan-cancer and prostate datasets, respectively. Further analysis of these cancer-related FFLs showed that the top-ranking TF STAT3 and miRNA hsa-let-7e are key regulators implicated in human cancers, which have regulated targets significantly enriched in cellular process regulations and signaling pathways that are involved in carcinogenesis.
In this study, we introduced an efficient computational approach to reconstruct co-regulatory FFLs by accurately identifying gene co-regulatory interactions. The strength of the proposed feature selection method lies in the fact it can precisely filter out false positives in predicted regulatory interactions by quantitatively modeling the complex co-regulation of target genes mediated by TFs and miRNAs simultaneously. Moreover, the proposed feature selection method can be generally applied to other gene regulation studies using parallel expression data with respect to different biological contexts.
PMCID: PMC3812136  PMID: 24205155
9.  Are C-Reactive Protein Associated Genetic Variants Associated with Serum Levels and Retinal Markers of Microvascular Pathology in Asian Populations from Singapore? 
PLoS ONE  2013;8(7):e67650.
C-reactive protein (CRP) levels are associated with cardiovascular disease and systemic inflammation. We assessed whether CRP-associated loci were associated with serum CRP and retinal markers of microvascular disease, in Asian populations.
Genome-wide association analysis (GWAS) for serum CRP was performed in East-Asian Chinese (N = 2,434) and Malays (N = 2,542) and South-Asian Indians (N = 2,538) from Singapore. Leveraging on GWAS data, we assessed, in silico, association levels among the Singaporean datasets for 22 recently identified CRP-associated loci. At loci where directional inconsistencies were observed, quantification of inter-ethnic linkage disequilibrium (LD) difference was determined. Next, we assessed association for a variant at CRP and retinal vessel traits [central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE)] in a total of 24,132 subjects of East-Asian, South-Asian and European ancestry.
Serum CRP was associated with SNPs in/near APOE, CRP, HNF1A and LEPR (p-values ≤4.7×10−8) after meta-analysis of Singaporean populations. Using a candidate-SNP approach, we further replicated SNPs at 4 additional loci that had been recently identified to be associated with serum CRP (IL6R, GCKR, IL6 and IL1F10) (p-values ≤0.009), in the Singaporean datasets. SNPs from these 8 loci explained 4.05% of variance in serum CRP. Two SNPs (rs2847281 and rs6901250) were detected to be significant (p-value ≤0.036) but with opposite effect directions in the Singaporean populations as compared to original European studies. At these loci we did not detect significant inter-population LD differences. We further did not observe a significant association between CRP variant and CRVE or CRAE levels after meta-analysis of all Singaporean and European datasets (p-value >0.058).
Common variants associated with serum CRP, first detected in primarily European studies, are also associated with CRP levels in East-Asian and South-Asian populations. We did not find a causal link between CRP and retinal measures of microvascular disease.
PMCID: PMC3699653  PMID: 23844046
10.  Role of Vascular Endothelial Growth Factor in the Breakdown of the Blood-Aqueous Barrier After Retinal Laser Photocoagulation in Pigmented Rabbits 
Retinal laser photocoagulation is used to treat a variety of retinal diseases. Breakdown of the blood-aqueous barrier has been noted after retinal laser photocoagulation. The effect of vascular endothelial growth factor (VEGF) on the function of the blood-aqueous barrier after retinal laser photocoagulation remains undetermined. The current study was designed to evaluate the relationship between intraocular levels of VEGF and breakdown of the blood-aqueous barrier after retinal laser photocoagulation in rabbits.
Pigmented rabbits were treated with retinal laser photocoagulation in one eye; the other served as control. Laser flare photometry was carried out on post-treatment days 1, 3, 7, and 14. Animals were sacrificed at the time period just mentioned postlaser, the eyes were removed, and samples of vitreous and aqueous humor were collected. Intraocular VEGF levels were measured by using an immunoassay. An intravitreal injection of VEGF was administered, and the aqueous flare intensity and VEGF levels in the aqueous and vitreous humor were measured at the time periods just mentioned.
A significant increase in the aqueous flare intensity after retinal laser photocoagulation was noticed on postoperative day 1, with the values returning to baseline levels on day 14. The VEGF levels in the vitreous of the lasered eyes were significantly increased on day 1 compared with the nonlasered control eyes. The VEGF levels in the aqueous humor of the lasered eyes were also significantly increased on day 1 compared with the control eyes. An intravitreal injection of VEGF induced a significant increase in the aqueous flare intensity and VEGF levels in the aqueous and vitreous humor.
The current results suggested that retinal laser photocoagulation can produce a breakdown of the blood-aqueous barrier. VEGF may play a role in the blood-aqueous barrier dysfunction after retinal laser photocoagulation.
PMCID: PMC3272238  PMID: 22011077
11.  Optimization of the Preparation of Fish Protein Anti-Obesity Hydrolysates Using Response Surface Methodology 
The enzymatic condition for producing the anti-obesity hydrolysates from fish water-soluble protein was optimized with the aid of response surface methodology, which also derived a statistical model for experimental validation. Compared with neutral protease, papain and protamex, the porcine pancreas lipase inhibitory rate of hydrolysates from fish water-soluble protein was higher with alkaline protease. Results showed that the model terms were significant, the terms of lack of fit were not significant, and the optimal conditions for the hydrolysis by alkaline protease were initial pH 11, temperature 39 °C, enzyme dosage 122 U/mL and 10 h of hydrolysis time. Under these conditions, the porcine pancreas lipase and the α-amylase inhibitory rate could reach 53.04% ± 1.32% and 20.03 ± 0.89%, while predicted value were 54.63% ± 1.75%, 21.22% ± 0.70%, respectively. In addition, Lineweaver-Burk plots showed noncompetitive inhibition. The Ki value calculated was 84.13 mg/mL. These results demonstrated that fish water-soluble protein could be used for obtaining anti-obesity hydrolysates.
PMCID: PMC3588035  PMID: 23377020
anti-obesity; fish protein; kinetics; porcine pancreas lipase; α-amylase; response surface methodology (RSM)
12.  Emerging Opportunities for Serotypes of Botulinum Neurotoxins  
Toxins  2012;4(11):1196-1222.
Background: Two decades ago, botulinum neurotoxin (BoNT) type A was introduced to the commercial market. Subsequently, the toxin was approved by the FDA to address several neurological syndromes, involving muscle, nerve, and gland hyperactivity. These syndromes have typically been associated with abnormalities in cholinergic transmission. Despite the multiplicity of botulinal serotypes (designated as types A through G), therapeutic preparations are currently only available for BoNT types A and B. However, other BoNT serotypes are under study for possible clinical use and new clinical indications; Objective: To review the current research on botulinum neurotoxin serotypes A-G, and to analyze potential applications within basic science and clinical settings; Conclusions: The increasing understanding of botulinal neurotoxin pathophysiology, including the neurotoxin’s effects on specific neuronal populations, will help us in tailoring treatments for specific diagnoses, symptoms and patients. Scientists and clinicians should be aware of the full range of available data involving neurotoxin subtypes A-G.
PMCID: PMC3509704  PMID: 23202312
Botulinum toxin serotypes; neurotoxins subtypes; neuro-pharmacology toxins
13.  Randomized fMRI Trial of the Central Effects of Acute Acupuncture on Glucose Levels and Core Body Temperature in “Overweight” Males 
Medical Acupuncture  2011;23(3):165-173.
This study focuses on how acupoints ST 36 (Zu San Li) and SP 9 (Yin Ling Quan) and their sham acupoints act acutely on the limbic system via dopamine to affect satiety, glucose (GLU) blood levels, and core body temperature (CBT).
This controlled clinical trial compared real acupuncture (ACU) versus minimal sham acupuncture (min SHAM) effects on metabolic physiology using functional magnetic resonance imaging (fMRI).
The study took place at the West China Hospital in Chengdu, Sichuan Province, China.
The study subjects were 19 right-handed healthy, “overweight,” nondieting adult Chinese males ages 21–45 (10 for ACU treatment and 9 for min SHAM) who had abstained from eating 12 hours prior to the fMRI experiment.
Values for GLU and CBT indicated no significant differences (P>0.05) in both inter- and intragroup comparisons resulting from variable individual responses to treatment. Hunger survey feedback was significant (P<0.05) between the ACU and min SHAM groups. Soreness, or De Qi, was the only significant (P<0.05) intergroup sensation.
Acupuncture stimulation activated neurophysiological pathways involving dopamine, basal metabolic rate, heart rate, and satiety regulation. This project will be of great importance in helping scientists understand how acupuncture can be studied as a safe inexpensive treatment modality for weight control.
PMCID: PMC3579202
Acupuncture; Dopamine; Glucose; Core Body Temperature; Satiety; De Qi; Overweight; fMRI
14.  Dendrimer-entrapped gold nanoparticles as potential CT contrast agents for blood pool imaging 
Nanoscale Research Letters  2012;7(1):190.
The purpose of this study was to evaluate dendrimer-entrapped gold nanoparticles [Au DENPs] as a molecular imaging [MI] probe for computed tomography [CT]. Au DENPs were prepared by complexing AuCl4- ions with amine-terminated generation 5 poly(amidoamine) [G5.NH2] dendrimers. Resulting particles were sized using transmission electron microscopy. Serial dilutions (0.001 to 0.1 M) of either Au DENPs or iohexol were scanned by CT in vitro. Based on these results, Au DENPs were injected into mice, either subcutaneously (10 μL, 0.007 to 0.02 M) or intravenously (300 μL, 0.2 M), after which the mice were imaged by micro-CT or a standard mammography unit. Au DENPs prepared using G5.NH2 dendrimers as templates are quite uniform and have a size range of 2 to 4 nm. At Au concentrations above 0.01 M, the CT value of Au DENPs was higher than that of iohexol. A 10-μL subcutaneous dose of Au DENPs with [Au] ≥ 0.009 M could be detected by micro-CT. The vascular system could be imaged 5 and 20 min after injection of Au DENPs into the tail vein, and the urinary system could be imaged after 60 min. At comparable time points, the vascular system could not be imaged using iohexol, and the urinary system was imaged only indistinctly. Findings from this study suggested that Au DENPs prepared using G5.NH2 dendrimers as templates have good X-ray attenuation and a substantial circulation time. As their abundant surface amine groups have the ability to bind to a range of biological molecules, Au DENPs have the potential to be a useful MI probe for CT.
PMCID: PMC3323415  PMID: 22429280
15.  Establishment of a canine model of cardiac memory using endocardial pacing via internal jugular vein 
Development of experimental animal models has played an important role in understanding the mechanisms of cardiac memory. The purpose of this study was to evaluate a new canine model of cardiac memory using endocardial ventricular pacing via internal jugular vein.
Twelve Beagle dogs underwent placement of a permanent ventricular pacemaker mimicking the use of pacemakers in humans and induction of cardiac memory by endocardial ventricular pacing.
Cardiac memory was achieved in 11 of 12 attempts overall. Procedural mortality due to cardiac tamponade (n = 1) occurred in the first attempt. The T-wave memory persisted for 96 ± 17 minutes and 31 ± 6 days in the short-term and long-term cardiac memory groups, respectively. There were no significant differences in the heart rate, blood pressure and echocardiographic parameters in the animals between before and after ventricular pacing in the short-term and long-term cardiac memory groups. No significant pathologic changes with the light microscopy were found in the present study in all dogs.
The model does require surgery but is not as invasive as an open-chest model. This canine model can serve as a useful tool for studying mechanisms of cardiac memory.
PMCID: PMC2906410  PMID: 20569432
16.  Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1 
The Journal of Experimental Medicine  2009;206(6):1327-1337.
Macrophages (Mφ) are prominent components of solid tumors and exhibit distinct phenotypes in different microenvironments. We have recently found that tumors can alter the normal developmental process of Mφ to trigger transient activation of monocytes in peritumoral stroma. We showed that a fraction of monocytes/Mφ in peritumoral stroma, but not in cancer nests, expresses surface PD-L1 (also termed B7-H1) molecules in tumors from patients with hepatocellular carcinoma (HCC). Monocytes activated by tumors strongly express PD-L1 proteins with kinetics similar to their activation status, and significant correlations were found between the levels of PD-L1+ and HLA-DRhigh on tumor-infiltrating monocytes. Autocrine tumor necrosis factor α and interleukin 10 released from activated monocytes stimulated monocyte expression of PD-L1. The PD-L1+ monocytes effectively suppressed tumor-specific T cell immunity and contributed to the growth of human tumors in vivo; the effect could be reversed by blocking PD-L1 on those monocytes. Moreover, we found that PD-L1 expression on tumor-infiltrating monocytes increased with disease progression, and the intensity of the protein was associated with high mortality and reduced survival in the HCC patients. Thus, expression of PD-L1 on activated monocytes/Mφ may represent a novel mechanism that links the proinflammatory response to immune tolerance in the tumor milieu.
PMCID: PMC2715058  PMID: 19451266
17.  Cross-Layer Adaptive Feedback Scheduling of Wireless Control Systems 
Sensors (Basel, Switzerland)  2008;8(7):4265-4281.
There is a trend towards using wireless technologies in networked control systems. However, the adverse properties of the radio channels make it difficult to design and implement control systems in wireless environments. To attack the uncertainty in available communication resources in wireless control systems closed over WLAN, a cross-layer adaptive feedback scheduling (CLAFS) scheme is developed, which takes advantage of the co-design of control and wireless communications. By exploiting cross-layer design, CLAFS adjusts the sampling periods of control systems at the application layer based on information about deadline miss ratio and transmission rate from the physical layer. Within the framework of feedback scheduling, the control performance is maximized through controlling the deadline miss ratio. Key design parameters of the feedback scheduler are adapted to dynamic changes in the channel condition. An event-driven invocation mechanism for the feedback scheduler is also developed. Simulation results show that the proposed approach is efficient in dealing with channel capacity variations and noise interference, thus providing an enabling technology for control over WLAN.
PMCID: PMC3697173
wireless control systems; feedback scheduling; cross-layer; event-triggered

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