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1.  Accumulation of heptaprenyl diphosphate sensitizes Bacillus subtilis to bacitracin: Implications for the mechanism of resistance mediated by the BceAB transporter 
Molecular microbiology  2014;93(1):37-49.
Heptaprenyl diphosphate (C35-PP) is an isoprenoid intermediate in the synthesis of both menaquinone and the sesquarterpenoids. We demonstrate that inactivation of ytpB, encoding a C35-PP utilizing enzyme required for sesquarterpenoid synthesis, leads to an increased sensitivity to bacitracin, an antibiotic that binds undecaprenyl pyrophosphate (C55-PP), a key intermediate in cell wall synthesis. Genetic studies indicate that bacitracin sensitivity is due to accumulation of C35-PP, rather than the absence of sesquarterpenoids. Sensitivity is accentuated in a ytpB menA double mutant, lacking both known C35-PP consuming enzymes, and in a ytpB strain overexpressing the HepST enzyme that synthesizes C35-PP. Conversely, sensitivity in the ytpB background is suppressed by mutation of hepST or by supplementation with 1,4-dihydroxy-2-naphthoate, a co-substrate with C35-PP for MenA. Bacitracin sensitivity results from impairment of the BceAB and BcrC resistance mechanisms by C35-PP: in a bceAB bcrC double mutant disruption of ytpB no longer increases bacitracin sensitivity. These results suggest that C35-PP inhibits both BcrC (a C55-PP phosphatase) and BceAB (an ABC transporter that confers bacitracin resistance). These findings lead to a model in which BceAB protects against bacitracin by transfer of the target, C55-PP, rather than the antibiotic across the membrane.
PMCID: PMC4077933  PMID: 24806199
Bacillus subtilis; bacitracin; undecaprenyl pyrophosphate; antibiotic resistance; peptidoglycan
2.  Investigation of Ground-Level Ozone and High-Pollution Episodes in a Megacity of Eastern China 
PLoS ONE  2015;10(6):e0131878.
Differential Optical Absorption Spectroscopy (DOAS) was used for the long-term observation of ground-level ozone (O3) from March 2010 to March 2013 over Shanghai, China. The 1-hour average concentration of O3 was 27.2 ± 17.0 ppbv. O3 level increased during spring, reached the peak in late spring and early summer, and then decreased in autumn and finally dropped to the bottom in winter. The highest monthly average O3 concentration in June (41.1 ppbv) was nearly three times as high as the lowest level recorded in December (15.2 ppbv). In terms of pollution episodes, 56 hourly samples (on 14 separate days) in 2010 exceeded the 1-hour ozone limit of 200 μg/m3 specified by the Grade II of the Chinese Ambient Air Quality Standards (CAAQS, revised GB 3095-2012). Utilizing the Hybrid Single Particle Lagrangian Integrated Trajectory (HYSPLIT) model, the primary contribution to high ozone days (HODs) was identified as the regional transportation of volatile organic compounds (VOC) and high concentrations of O3 from the chemical industrial zone in the Jinshan district of Shanghai. HODs showed higher concentrations of HONO and NO2 than non-episode conditions, implying that HONO at high concentration during HODs was capable of increasing the O3 concentration. The photolysis rate of HONO was estimated, suggesting that the larger number of OH radicals resulting from high concentrations of HONO have a considerable impact on ozone concentrations.
PMCID: PMC4486460  PMID: 26121146
3.  Fast Shear Compounding Using Robust Two-dimensional Shear Wave Speed Calculation and Multi-directional Filtering 
Ultrasound in medicine & biology  2014;40(6):1343-1355.
A fast shear compounding method was developed in this study using only one shear wave push-detect cycle, such that the shear wave imaging frame rate is preserved and motion artifacts are minimized. The proposed method is composed of the following steps: 1. applying a comb-push to produce multiple differently angled shear waves at different spatial locations simultaneously; 2. decomposing the complex shear wave field into individual shear wave fields with differently oriented shear waves using a multi-directional filter; 3. using a robust two-dimensional (2D) shear wave speed calculation to reconstruct 2D shear elasticity maps from each filter direction; 4. compounding these 2D maps from different directions into a final map. An inclusion phantom study showed that the fast shear compounding method could achieve comparable performance to conventional shear compounding without sacrificing the imaging frame rate. A multi-inclusion phantom experiment showed that the fast shear compounding method could provide a full field-of-view (FOV), 2D, and compounded shear elasticity map with three types of inclusions clearly resolved and stiffness measurements showing excellent agreement to the nominal values.
PMCID: PMC4011964  PMID: 24613636
shear compounding; shear wave elastography; 2D shear wave speed; directional filter; comb-push; acoustic radiation force
4.  PRAS40 plays a pivotal role in protecting against stroke by linking the Akt and mTOR pathways 
Neurobiology of disease  2014;66:43-52.
The proline-rich Akt substrate of 40 kDa (PRAS40) protein is not only a substrate of the protein kinase Akt but also a component of the mTOR complex 1 (mTORC1), thus it links the Akt and the mTOR pathways. We investigated the potential protective role of PRAS40 in cerebral ischemia and its underlying mechanisms by using rats with lentiviral over-expression of PRAS40 and mice with PRAS40 gene knockout (PRAS40 KO). Our results show that gene transfer of PRAS40 reduced infarction size in rats by promoting phosphorylation of Akt, FKHR (FOXO1), PRAS40, and mTOR. In contrast, PRAS40 KO increased infarction size. Although the PRAS40 KO under normal condition did not alter baseline levels of phosphorylated proteins in the Akt and mTOR pathways, PRAS40 KO that underwent stroke exhibited reduced protein levels of p-S6K and p-S6 in the mTOR pathway but not p-Akt, or p-PTEN in the Akt pathway. Furthermore, co-immunoprecipitation suggests that there were less interactive effects between Akt and mTOR in the PRAS40 KO. In conclusion, PRAS40 appears to reduce brain injury by converting cell signaling from Akt to mTOR.
PMCID: PMC4448971  PMID: 24583056
Focal cerebral ischemia; Akt; Stroke; mTOR; PRAS40; PTEN
5.  Effects of waterlogging on carbon assimilate partitioning in the Zoigê alpine wetlands revealed by 13CO2 pulse labeling 
Scientific Reports  2015;5:9411.
Waterlogging has been suggested to affect carbon (C) turnover in wetlands, but how it affects C allocation and stocks remains unclear in alpine wetlands. Using in situ 13CO2 pulse labelling, we investigated C allocation in both waterlogged and non-waterlogged sites in the Zoigê wetlands on the Tibetan Plateau in August 2011. More than 50% of total 13C fixed by photosynthesis was lost via shoot respiration. Shoots recovered about 19% of total 13C fixed by photosynthesis at both sites. Only about 26% of total fixed 13C was translocated into the belowground pools. Soil organic C pool accounted for 19% and roots recovered about 5–7% of total fixed 13C at both sites. Waterlogging significantly reduced soil respiration and very little 13C was lost via soil respiration in the alpine wetlands compared to that in grasslands. We conclude that waterlogging did not significantly alter C allocations among the C pools except the 13CO2 efflux derived from soil respiration and that shoots made similar contributions to C sequestration as the belowground parts in the Zoigê alpine wetlands. Therefore, changes in waterlogging due to climate change will not affect C assimilate partitioning but soil C efflux.
PMCID: PMC4369740  PMID: 25797457
6.  Improved Shear Wave Motion Detection Using Pulse-Inversion Harmonic Imaging with a Phased Array Transducer 
IEEE transactions on medical imaging  2013;10.1109/TMI.2013.2280903.
Ultrasound tissue harmonic imaging is widely used to improve ultrasound B-mode imaging quality thanks to its effectiveness in suppressing imaging artifacts associated with ultrasound reverberation, phase aberration, and clutter noise. In ultrasound shear wave elastography (SWE), because the shear wave motion signal is extracted from the ultrasound signal, these noise sources can significantly deteriorate the shear wave motion tracking process and consequently result in noisy and biased shear wave motion detection. This situation is exacerbated in in vivo SWE applications such as heart, liver, and kidney. This paper, therefore, investigated the possibility of implementing harmonic imaging, specifically pulse-inversion harmonic imaging, in shear wave tracking, with the hypothesis that harmonic imaging can improve shear wave motion detection based on the same principles that apply to general harmonic B-mode imaging. We first designed an experiment with a gelatin phantom covered by an excised piece of pork belly and show that harmonic imaging can significantly improve shear wave motion detection by producing less underestimated shear wave motion and more consistent shear wave speed measurements than fundamental imaging. Then, a transthoracic heart experiment on a freshly sacrificed pig showed that harmonic imaging could robustly track the shear wave motion and give consistent shear wave speed measurements while fundamental imaging could not. Finally, an in vivo transthoracic study of seven healthy volunteers showed that the proposed harmonic imaging tracking sequence could provide consistent estimates of the left ventricular myocardium stiffness in end-diastole with a general success rate of 80% and a success rate of 93.3% when excluding the subject with Body Mass Index (BMI) higher than 25. These promising results indicate that pulse-inversion harmonic imaging can significantly improve shear wave motion tracking and thus potentially facilitate more robust assessment of tissue elasticity by SWE.
PMCID: PMC3947393  PMID: 24021638
Harmonic imaging; shear wave elastography; acoustic radiation force; pulse inversion; in vivo human heart; transthoracic scanning; diastolic left ventricle stiffness
7.  Intrastriatal Transplantation of Retinal Pigment Epithelial Cells for the Treatment of Parkinson Disease: In Vivo Longitudinal Molecular Imaging with 18F-P3BZA PET/CT 
Radiology  2014;272(1):174-183.
N-[2-(diethylamino)ethyl]-18F-5-fluoropicolinamide PET/CT is a feasible technique for visualizing and detecting the long-term activity of implanted retinal pigment epithelium cells for the treatment of Parkinson disease in vivo.
To evaluate the performance of N-[2-(diethylamino)ethyl]-18F-5-fluoropicolinamide (18F-P3BZA) for visualizing porcine retinal pigment epithelium (pRPE) cells transplanted in the striatum for the treatment of Parkinson disease and to monitor the long-term activity of implanted pRPE cells by means of 18F-P3BZA positron emission tomography (PET)/computed tomography (CT) in vivo.
Materials and Methods
Animal work was conducted in accordance with the administrative panel on laboratory animal care. In vitro cell uptake of 18F-P3BZA was determined with incubation of melanotic pRPE or amelanotic ARPE-19 cells with 18F-P3BZA. To visualize the implanted pRPE cells in vivo, normal rats (four per group) were injected with pRPE or ARPE-19 cells attached to gelatin microcarriers in the left striatum and with control gelatin microcarriers in the right striatum and followed up with small animal PET/CT. Longitudinal PET/CT scans were acquired in 12 rats up to 16 days after surgery. Postmortem analysis, which included autoradiography and hematoxylin-eosin, Fontana-Masson, and immunofluorescence staining, was performed. Data were compared with the Student t test, analysis of variance, and regression analysis.
18F-P3BZA accumulated in pRPE cells effectively (3.48% of the injected dose [ID] per gram of brain tissue ± 0.58 at 1 hour after injection of the probe at 2 days after surgery in vivo) but not in control ARPE-19 cells (P < .05). Longitudinal PET/CT scans revealed that the activity of implanted pRPE cells decreased over time, as evidenced by a reduction in 18F-P3BZA uptake (3.39% ID/g ± 0.18, 2.49% ID/g ± 0.41, and 1.20% ID/g ± 0.13 at days 2, 9, and 16, respectively; P < .05). Postmortem analysis helped confirm the results of in vivo imaging.
18F-P3BZA PET/CT is a feasible technique for visualizing and detecting the activity of implanted RPE cells in vivo.
© RSNA, 2014
Online supplemental material is available for this article.
PMCID: PMC4264684  PMID: 24758555
8.  Impaired Varus-Valgus Proprioception and Neuromuscular Stabilization in Medial Knee Osteoarthritis 
Journal of biomechanics  2013;47(2):360-366.
Impaired proprioception and poor muscular stabilization in the frontal plane may lead to knee instability during functional activities, a common complaint in persons with knee osteoarthritis (KOA). Understanding these frontal plane neuromechanical properties in KOA will help elucidate the factors contributing to knee instability and aid in the development of targeted intervention strategies. The study objectives were to compare knee varus-valgus proprioception, isometric muscle strength, and active muscular contribution to stability between persons with medial KOA and healthy controls. We evaluated knee frontal plane neuromechanical parameters in 14 participants with medial KOA and 14 age- and gender-matched controls, using a joint driving device (JDD) with a customized motor and a 6-axis force sensor. Analysis of covariance with BMI as a covariate was used to test the differences in varus-valgus neuromechanical parameters between these two groups. The KOA group had impaired varus proprioception acuity (1.08 ± 0.59° vs. 0.69 ± 0.49°, p < 0.05), decreased normalized varus muscle strength (1.31 ± 0.75% vs. 1.79 ± 0.84% body weight, p < 0.05), a trend toward decreased valgus strength (1.29 ± 0.67% vs. 1.88 ± 0.99%, p = 0.054), and impaired ability to actively stabilize the knee in the frontal plane during external perturbation (4.67 ± 2.86 vs. 8.26 ± 5.95 Nm/degree, p < 0.05). The knee frontal plane sensorimotor control system is compromised in persons with medial KOA. Our findings suggest varus-valgus control deficits in both the afferent input (proprioceptive acuity) and muscular effectors (muscle strength and capacity to stabilize the joint).
PMCID: PMC3929588  PMID: 24321442
Knee osteoarthritis; Proprioception; Instability; Varus-valgus motion
9.  Moderate Hypothermia Inhibits Brain Inflammation and Attenuates Stroke-induced Immunodepression in Rats 
CNS neuroscience & therapeutics  2013;20(1):10.1111/cns.12160.
Stroke causes both brain inflammation and immunodepression. Mild to moderate hypothermia is known to attenuate brain inflammation but its role in stroke-induced immunodepression (SIID) of the peripheral immune system remains unknown. This study investigated the effects in rats of moderate intra-ischemic hypothermia on SIID and brain inflammation.
Stroke was induced in rats by permanent distal MCA occlusion combined with transient bilateral CCA occlusion while body temperature was reduced to 30°C. Real-time PCR, flow cytometry, in vitro T cell proliferation assays and confocal microscopy were used to study SIID and brain inflammation.
Brief Intra-Ischemic hypothermia helped maintain certain leukocytes in the peripheral blood and spleen, and enhanced T cell proliferation in vitro and delayed-type hypersensitivity in vivo, suggesting that hypothermia reduces SIID. In contrast, in the brain, brief intra-Ischemic hypothermia inhibited mRNA expression of anti-inflammatory cytokine IL-10 and pro-inflammatory cytokines INF-γ, TNF-α, IL-2, IL-1β and MIP-2. Brief intra-Ischemic hypothermia also attenuated the infiltration of lymphocytes, neutrophils (MPO+ cells) and macrophages (CD68+ cells) into the ischemic brain, suggesting that hypothermia inhibited brain inflammation.
Brief intra-ischemic hypothermia attenuated SIID and protected against acute brain inflammation.
PMCID: PMC3867545  PMID: 23981596
focal cerebral ischemia; hypothermia; inflammation; immunodepression; leukocytes
10.  Akt isoforms differentially protect against stroke-induced neuronal injury by regulating mTOR activities 
Protein kinases Akt1 and Akt3 are considered to be more crucial to brain function than Akt2. We investigated the roles of Akt1 and Akt3 in stroke-induced brain injury and examined their interactions with the Akt/mTOR pathways. Focal ischemia was induced in rats. Lentiviral vectors expressing constitutively active Akt1 and Akt3 (cAkt1 and cAkt3) were injected into the ischemic cortex. Infarct sizes and gene and protein expressions in the Akt/mTOR pathways were evaluated. The results show that Akt1 and Akt3 proteins were degraded as early as 1 hour after stroke, whereas Akt2 proteins remained unchanged until 24 hours after stroke. Lentiviral-mediated overexpression of cAkt1 or cAkt3 reduced neuronal death after in vitro and in vivo ischemia. Interestingly, cAkt3 overexpression resulted in stronger protection than cAkt1 overexpression. Western blot analyses further showed that cAkt3 promoted significantly higher levels of phosphorylated Akt and phosphorylated mTOR than cAkt1. The mTOR inhibitor rapamycin blocked the protective effects of both cAkt1 and cAkt3. In conclusion, Akt isoforms are differentially regulated after stroke and Akt3 offers stronger protection than cAkt1 by maintaining Akt levels and promoting mTOR activity.
PMCID: PMC3851893  PMID: 23942361
Akt1; Akt3; cerebral ischemia; mTOR; stroke
11.  Ischemic postconditioning facilitates brain recovery after stroke by promoting Akt/mTOR activity in nude rats 
Journal of neurochemistry  2013;127(5):723-732.
While preconditioning is induced before stroke onset, ischemic postconditioning (IPostC) is performed after reperfusion, which typically refers to a series of mechanical interruption of blood reperfusion after stroke. IPostC is known to reduce infarction in wild type animals. We investigated if IPostC protects against brain injury induced by focal ischemia in T-cell-deficient nude rats and to examine its effects on Akt and the mammalian target of rapamycin (mTOR) pathway. Although IPostC reduced infarct size at 2 days post-stroke in wild type rats, it did not attenuate infarction in nude rats. Despite the unaltered infarct size in nude rats, IPostC increased levels of phosphorylated Akt (p-Akt) and Akt isoforms (Akt1, Akt2, Akt3), and p-mTOR, p-S6K and p-4EBP1 in the mTOR pathway, as well as GAP-43, both in the peri-infarct area and core, 24 hours after stroke. IPostC improved neurological function in nude rats 1–30 days after stroke and reduced the extent of brain damage 30 days after stroke. The mTOR inhibitor rapamycin abolished the long-term protective effects of IPostC. We determined that IPostC did not inhibit acute infarction in nude rats but did provide long-term protection by enhancing Akt and mTOR activity during the acute post-stroke phase.
PMCID: PMC3875603  PMID: 23777415
Stroke; Ischemic postconditioning; T cells; Akt; mTOR
12.  A C-Terminal Proline-Rich Sequence Simultaneously Broadens the Optimal Temperature and pH Ranges and Improves the Catalytic Efficiency of Glycosyl Hydrolase Family 10 Ruminal Xylanases 
Applied and Environmental Microbiology  2014;80(11):3426-3432.
Efficient degradation of plant polysaccharides in rumen requires xylanolytic enzymes with a high catalytic capacity. In this study, a full-length xylanase gene (xynA) was retrieved from the sheep rumen. The deduced XynA sequence contains a putative signal peptide, a catalytic motif of glycoside hydrolase family 10 (GH10), and an extra C-terminal proline-rich sequence without a homolog. To determine its function, both mature XynA and its C terminus-truncated mutant, XynA-Tr, were expressed in Escherichia coli. The C-terminal oligopeptide had significant effects on the function and structure of XynA. Compared with XynA-Tr, XynA exhibited improved specific activity (12-fold) and catalytic efficiency (14-fold), a higher temperature optimum (50°C versus 45°C), and broader ranges of temperature and pH optima (pH 5.0 to 7.5 and 40 to 60°C versus pH 5.5 to 6.5 and 40 to 50°C). Moreover, XynA released more xylose than XynA-Tr when using beech wood xylan and wheat arabinoxylan as the substrate. The underlying mechanisms responsible for these changes were analyzed by substrate binding assay, circular dichroism (CD) spectroscopy, isothermal titration calorimetry (ITC), and xylooligosaccharide hydrolysis. XynA had no ability to bind to any of the tested soluble and insoluble polysaccharides. However, it contained more α helices and had a greater affinity and catalytic efficiency toward xylooligosaccharides, which benefited complete substrate degradation. Similar results were obtained when the C-terminal sequence was fused to another GH10 xylanase from sheep rumen. This study reveals an engineering strategy to improve the catalytic performance of enzymes.
PMCID: PMC4018843  PMID: 24657866
13.  Study on the Traffic Air Pollution inside and outside a Road Tunnel in Shanghai, China 
PLoS ONE  2014;9(11):e112195.
To investigate the vehicle induced air pollution situations both inside and outside the tunnel, the field measurement of the pollutants concentrations and its diurnal variations was performed inside and outside the Xiangyin tunnel in Shanghai from 13:00 on April 24th to 13:00 on April 25th, 2013. The highest hourly average concentrations of pollutants were quantified that CO, NO, NO2 and NOX inside the tunnel were 13.223 mg/m3, 1.829 mg/m3, 0.291 mg/m3 and 3.029 mg/m3, respectively, while the lowest ones were 3.086 mg/m3, 0.344 mg/m3, 0.080 mg/m3 and 0.619 mg/m3. Moreover, the concentrations of pollutants were higher during the daytime, and lower at night, which is relevant to the traffic conditions inside the tunnel. Pollutants concentrations inside the tunnel were much higher than those outside the tunnel. Then in a case of slow wind, the effect of wind is much smaller than the impact of pollution sources. Additionally, the PM2.5 concentrations climbed to the peak sharply (468.45 µg/m3) during the morning rush hours. The concentrations of organic carbon (OC) and elemental carbon (EC) in PM2.5 inside the tunnel were 37.09–99.06 µg/m3 and 22.69–137.99 µg/m3, respectively. Besides, the OC/EC ratio ranged from 0.72 to 2.19 with an average value of 1.34. Compared with the results of other tunnel experiments in Guangzhou and Shenzhen, China, it could be inferred that the proportion of HDVs through the Xiangyin tunnel is relatively lower.
PMCID: PMC4227705  PMID: 25386920
14.  Ranking candidate genes of esophageal squamous cell carcinomas based on differentially expressed genes and the topological properties of the co-expression network 
The aim of this study was to identify the candidate genes of esophageal squamous cell carcinoma (ESCC).
Gene expression profiling of 17 ESCC samples and 17 adjacent normal samples, GSE20347, was downloaded from Gene Expression Omnibus database. The raw data were preprocessed, and the differentially expressed genes (DEGs) between ESCC and normal samples were identified by using SAM software (false discovery rate <0.001). Then, the co-expression network of DEGs was constructed based on Pearson’s correlation test (r-value ≥0.8). Furthermore, the topological properties of the co-expression network were analyzed through NetworkAnalyzer (default settings) of Cytoscape. The expression fold changes of DEGs and topological properties were utilized to identify the candidate genes of ESCC (Crin score >4), which were further analyzed based on DAVID functional enrichment analysis (P-value <0.05).
A total of 1,063 DEGs were identified, including 490 up-regulated and 573 down-regulated DEGs. Then, the co-expression network of DEGs was constructed, containing 999 nodes and 46,323 edges. Based on the expression fold changes of DEGs and the topological properties of the co-expression network, DEGs were ranked, and the top 24 genes were candidate genes of ESCC, such as CRISP3, EREG, CXCR2, and CRNN. Furthermore, the 24 genes were significantly enriched in bio-functions regarding cell differentiation, glucan biosynthetic process and immune response.
The present study suggested that CRISP3, EREG, CXCR2, and CRNN might be causative genes of ESCC, and play vital roles in the development of ESCC. However, further experimental studies are needed to confirm our results.
Electronic supplementary material
The online version of this article (doi:10.1186/s40001-014-0052-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4223754  PMID: 25358439
Esophageal squamous cell carcinomas; Differentially expressed genes; Topological properties; Co-expression network; Candidate genes
15.  Comb-push Ultrasound Shear Elastography (CUSE) with Various Ultrasound Push Beams 
IEEE transactions on medical imaging  2013;32(8):1435-1447.
Comb-push Ultrasound Shear Elastography (CUSE) has recently been shown to be a fast and accurate two-dimensional (2D) elasticity imaging technique that can provide a full field-of- view (FOV) shear wave speed map with only one rapid data acquisition. The initial version of CUSE was termed U-CUSE because unfocused ultrasound push beams were used. In this paper, we present two new versions of CUSE – Focused CUSE (F-CUSE) and Marching CUSE (M-CUSE), which use focused ultrasound push beams to improve acoustic radiation force penetration and produce stronger shear waves in deep tissues (e.g. kidney and liver). F-CUSE divides transducer elements into several subgroups which transmit multiple focused ultrasound beams simultaneously. M-CUSE uses more elements for each focused push beam and laterally marches the push beams. Both F-CUSE and M-CUSE can generate comb-shaped shear wave fields that have shear wave motion at each imaging pixel location so that a full FOV 2D shear wave speed map can be reconstructed with only one data acquisition. Homogeneous phantom experiments showed that U-CUSE, F-CUSE and M-CUSE can all produce smooth shear wave speed maps with accurate shear wave speed estimates. An inclusion phantom experiment showed that all CUSE methods could provide good contrast between the inclusion and background with sharp boundaries while F-CUSE and M-CUSE require shorter push durations to achieve shear wave speed maps with comparable SNR to U-CUSE. A more challenging inclusion phantom experiment with a very stiff and deep inclusion shows that better shear wave penetration could be gained by using F-CUSE and M-CUSE. Finally, a shallow inclusion experiment showed that good preservations of inclusion shapes could be achieved by both U-CUSE and F-CUSE in the near field. Safety measurements showed that all safety parameters are below FDA regulatory limits for all CUSE methods. These promising results suggest that, using various push beams, CUSE is capable of reconstructing a 2D full FOV shear elasticity map using only one push-detection data acquisition in a wide range of depths for soft tissue elasticity imaging.
PMCID: PMC3760382  PMID: 23591479
CUSE; comb-push; ultrasound elastography; shear wave; acoustic radiation force; unfocused ultrasound beam; focused ultrasound beam
16.  Ischemic postconditioning protects against focal cerebral ischemia by inhibiting brain inflammation while attenuating peripheral lymphopenia in mice 
Neuroscience  2013;243:149-157.
Ischemic postconditioning (IPostC) has been shown to attenuate brain injury in rat stroke models, but a mouse model has not been reported. This study establishes an IPostC model in mice and investigates how IPostC affects infiltration of leukocytes in the ischemic brain and lymphopenia associated with stroke-induced immunodepression.
Material and Methods
A total of 125 mice were used. IPostC was performed by a repeated series of brief occlusions of the middle cerebral artery (MCA) after reperfusion, in a focal ischemia model in mice. Infarct sizes, neurological scores, inflammatory brain cells and immune cell populations in lymph nodes, spleen and bone marrow were analyzed with FACS.
IPostC performed immediately, 2 min and 3 hr after reperfusion significantly reduced infarct sizes and attenuated neurological scores as measured up to 3 days post-stroke. In the group with strongest protection, infarct sizes were reduced from 49.6 ± 2.8% (n=16) to 27.9 ± 2.9% (n=10, P<.001). The spared infarct areas were seen in the ischemic penumbra or ischemic margins, i.e., the border zones between the cortical territories of the anterior cerebral artery (ACA) and those of the MCA, as well as in the ventromedial and dorsolateral striatum. FACS analyses showed that IPostC significantly blocked increases in the numbers of microglia (CD45intCD11b+), macrophages (CD45hiCD68+), CD4 T cells (CD45+CD4+) and CD8 T cells (CD45+CD8+) as well as B lymphocytes (CD45+CD19+) in the ischemic brain (n=5/group). Reduced-immune cell numbers in the peripheral blood and spleen were increased by IPostC while immune cell populations in the bone marrow were not altered by IPostC.
IPostC reduced brain infarction and mitigated neurological deficits in mice, likely by blocking infiltration of both innate and adaptive immune cells in the ischemic brain. In addition, IPostC robustly attenuated peripheral lymphopenia and thus improved systemic immunodepression.
PMCID: PMC3735351  PMID: 23590905
cerebral ischemia; postconditioning; infarction size; mouse model
17.  Primary intrathoracic liposarcoma: a clinicopathologic study and prognostic analysis of 23 cases 
Primary intrathoracic liposarcoma is an extremely rare malignancy as well as a rare histologic subtype of intrathoracic sarcoma. Relatively few reports appear in the world literatures. We explored the clinicopathologic features and prognostic factors of this tumor in this study.
We retrospectively analyzed the clinicopathological data of 23 patients with primary intrathoracic liposarcoma who were treated in Shanghai chest Hospital affiliated to Jiao Tong University, from January 2003 to March 2013. These patients were classified into three groups according to the distinct tumor locations, including mediastinum, pleura and lung liposarcoma. Also, these patients could be divided into four types, including well-differentiated, myxoid, dedifferentiated and pleomorphic liposarcoma. The influences of age, sex, tumor size, tumor location, tumor histologic type and therapy on the prognosis of the patients were analyzed.
There were no significant difference for survival among distinct liposarcoma locations. However, significant difference for survival among distinct liposarcoma types were observed. Poor disease-free survival (DFS) was observed in the myxoid, pleomorphic and dedifferentiated types as compared to well-differentiated type (P = 0.038). Inferior overall-survival (OS) was observed in dedifferentiated, pleomorphic and myxoid types relative to well-differentiated type (P = 0.027). The radical surgery was a favorable prognostic factor for OS, as demonstrated by the better OS of the radical surgery group as compared to that of the non-radical surgery group ( P = 0.029). Notably, there were no significant differences for DFS and OS in other clinical parameters including tumor size, gender and age. In addition, radiotherapy and/or chemotherapy could not improve the prognosis of the patients receiving non-radical surgery or suffering from relapse.
The histological type and the radical surgery are the factors that influence the behavior and prognosis of liposarcoma. In general, radiotherapy and chemotherapy are believed to be ineffective therapeutic modalities for survival. So it is essential to completely resect the primary intrathoracic liposarcoma as radical cure of the disease.
PMCID: PMC4088306  PMID: 24993036
Intrathoracic liposarcoma; Histological type; Radical surgery; Overall survival; Disease-free survival
18.  Altered functional brain networks in Prader–Willi syndrome 
NMR in biomedicine  2013;26(6):10.1002/nbm.2900.
Prader–Willi syndrome (PWS) is a genetic imprinting disorder characterized mainly by hyperphagia and early childhood obesity. Previous functional neuroimaging studies used visual stimuli to examine abnormal activities in the eating-related neural circuitry of patients with PWS. It was found that patients with PWS exhibited both excessive hunger and hyperphagia consistently, even in situations without any food stimulation. In the present study, we employed resting-state functional MRI techniques to investigate abnormal brain networks related to eating disorders in children with PWS. First, we applied amplitude of low-frequency fluctuation analysis to define the regions of interest that showed significant alterations in resting-state brain activity levels in patients compared with their sibling control group. We then applied a functional connectivity (FC) analysis to these regions of interest in order to characterize interactions among the brain regions. Our results demonstrated that patients with PWS showed decreased FC strength in the medial prefrontal cortex (MPFC)/inferior parietal lobe (IPL), MPFC/precuneus, IPL/precuneus and IPL/hippocampus in the default mode network; decreased FC strength in the pre-/postcentral gyri and dorsolateral prefrontal cortex (DLPFC)/orbitofrontal cortex (OFC) in the motor sensory network and prefrontal cortex network, respectively; and increased FC strength in the anterior cingulate cortex/insula, ventrolateral prefrontal cortex (VLPFC)/OFC and DLPFC/VLPFC in the core network and prefrontal cortex network, respectively. These findings indicate that there are FC alterations among the brain regions implicated in eating as well as rewarding, even during the resting state, which may provide further evidence supporting the use of PWS as a model to study obesity and to provide information on potential neural targets for the medical treatment of overeating.
PMCID: PMC3776442  PMID: 23335390
Prader; Willi syndrome; eating disorder; obesity; amplitude of low-frequency fluctuation; resting-state networks; functional MRI
19.  Factors that predict lymph node status in clinical stage T1aN0M0 lung adenocarcinomas 
To identify patients in whom systematic lymph node dissection would be suitable, preoperative diagnosis of the biological invasiveness of lung adenocarcinomas through the classification of these T1aN0M0 lung adenocarcinomas into several subgroups may be warranted. In this retrospective study, we sought to determine predictive factors of lymph node status in clinical stage T1aN0M0 lung adenocarcinomas.
We retrospectively reviewed the records of 273 consecutive patients undergone surgical resection of clinical stage T1aN0M0 lung adenocarcinomas at Shanghai Chest Hospital, from January 2011 to December 2012. Preoperative computed tomography findings of all 273 patients were reviewed and their tumors categorized as pure GGO, GGO with minimal solid components (<5 mm), part-solid (solid parts >5 mm), or purely solid. Relevant clinicopathologic features were investigated to identify predictors of hilar or mediastinal lymph node metastasis using univariate or multiple variable analysis.
Among the 273 eligible clinical stage T1aN0M0 lung adenocarcinomas examined on thin-section CT, 103 (37.7%) were pure GGO, 118 (43.2%) GGO with minimal solid components, 13 (4.8%) part-solid (solid parts >5 mm, five GGO predominant and eight solid predominant), and 39 (14.3%) pure solid. There were 18 (6.6%) patients with lymph node metastasis. Incidence of N1 and N2 nodal involvement was 11 (6.6%) and seven (2.6%) patients, respectively. All patients with pure GGO and GGO with minimal solid components (<5 mm) tumors were pathologically staged N0. Multivariate analyses showed that the following factors significantly predicted lymph node metastasis for T1a lung adenocarcinomas: symptoms at presentation, GGO status, and abnormal carcinoembryonic antigen (CEA) titer. Multivariate analyses also showed that the following factors significantly predicted lymph node metastasis for pure solid tumors: air bronchogram sign, tumor size, symptoms at presentation, and abnormal CEA titer.
The patients of clinical stage T1aN0M0 lung adenocarcinomas with pure GGO and GGO with minimal solid components tumors were pathologically staged N0 and systematic lymph node dissection should be avoided. But systematic lymph node dissection should be performed for pure solid tumors or part-solid, especially in patients with CEA greater than 5 ng/mL or symptoms at presentation, because of the high possibility of lymph node involvement.
PMCID: PMC3945801  PMID: 24559138
Lymph node; Lung adenocarcinomas; Stage small non-small cell lung cancer
20.  The protective effects of T cell deficiency against brain injury are ischemic model-dependent in rats 
Neurochemistry international  2012;62(3):265-270.
Previous studies have reported that T cell deficiency reduced infarct sizes after transient middle cerebral artery (MCA) suture occlusion in mice. However, how reperfusion and different models affect the detrimental effects of T cells have not been studied. We investigated the effects of T cell deficiency in nude rats using two stroke models and compared their infarct sizes with those in WT rats. In the distal MCA occlusion (MCAo) model, the distal MCA was permanently occluded and the bilateral common carotid arteries (CCAs) were transiently occluded for 60 min. In the suture MCAo model, the MCA was transiently occluded for 100 min by the insertion of a monofilament suture. Our results showed that T cell deficiency resulted in about a 50% reduction in infarct size in the suture MCAo model, whereas it had no effect in the distal MCAo model, suggesting the protective effects of T cell deficiency are dependent on the ischemic model used. We further found more total T cells, CD4 T cells and CD8 T cells in the ischemic brains of WT rats in the suture MCAo model than in the distal MCAo model. In addition, we detected more CD68-expressing macrophages in the ischemic brains of WT rats than in nude rats in the suture MCAo but not the distal MCAo model. Lymphocyte reconstitution in nude rats resulted in larger infarct sizes in the suture MCAo, but not in the distal MCAo stroke model. The results of regional CBF measurement indicated a total reperfusion in the MCAo model but only a partial reperfusion in the distal MCAo model. In conclusion, the protective effects of T cell deficiency on brain injury are dependent on the ischemic model used; likely associated with different degrees of reperfusion.
PMCID: PMC3581747  PMID: 23228347
Stroke; focal ischemia; nude rats T cells
21.  Hurdles to clear before clinical translation of ischemic postconditioning against stroke 
Translational stroke research  2013;4(1):63-70.
Ischemic postconditioning has been established for its protective effects against stroke in animal models. It is performed after post-stroke reperfusion and refers to a series of induced ischemia or a single brief one. This review article addresses major hurdles in clinical translation of ischemic postconditioning to stroke patients, including potential hazards, the lack of well-defined protective paradigms, and the paucity of deeply-understood protective mechanisms. A hormetic model, often used in toxicology to describe a dose-dependent response to a toxic agent, is suggested to study both beneficial and detrimental effects of ischemic postconditioning. Experimental strategies are discussed, including how to define the hazards of ischemic (homologous) postconditioning and the possibility of employing non-ischemic (heterologous) postconditioning to facilitate clinical translation. This review concludes that a more detailed assessment of ischemic postconditioning and studies of a broad range of heterologous postconditioning models are warranted for future clinical translation.
PMCID: PMC3601799  PMID: 23524538
ischemic postconditioning; preconditioning; stroke; hormesis; clinical translation
22.  A Part-Based Probabilistic Model for Object Detection with Occlusion 
PLoS ONE  2014;9(1):e84624.
The part-based method has been a fast rising framework for object detection. It is attracting more and more attention for its detection precision and partial robustness to the occlusion. However, little research has been focused on the problem of occlusion overlapping of the part regions, which can reduce the performance of the system. This paper proposes a part-based probabilistic model and the corresponding inference algorithm for the problem of the part occlusion. The model is based on the Bayesian theory integrally and aims to be robust to the large occlusion. In the stage of the model construction, all of the parts constitute the vertex set of a fully connected graph, and a binary variable is assigned to each part to indicate its occlusion status. In addition, we introduce a penalty term to regularize the argument space of the objective function. Thus, the part detection is formulated as an optimization problem, which is divided into two alternative procedures: the outer inference and the inner inference. A stochastic tentative method is employed in the outer inference to determine the occlusion status for each part. In the inner inference, the gradient descent algorithm is employed to find the optimal positions of the parts, in term of the current occlusion status. Experiments were carried out on the Caltech database. The results demonstrated that the proposed method achieves a strong robustness to the occlusion.
PMCID: PMC3894947  PMID: 24465420
23.  Safety and efficacy of thoracoscopic wedge resection for elderly high-risk patients with stage I peripheral non-small-cell lung cancer 
Elderly patients with severe cardiopulmonary and other system dysfunctions are unable to tolerate pulmonary lobectomy. This study aimed to evaluate the risk and efficacy of wedge resection under video-assisted thoracoscopic surgery (VATS) on elderly high-risk patients with stage I peripheral non-small-cell lung cancer (PNSCLC).
Elderly patients (≥70 years) with suspected PNSCLC were divided into high-risk group and conventional risk group. The high-risk patients confirmed in stage I by the examination of positron emission tomography computed tomography (PET-CT) and the postoperative patients in stage I PNSCLC with negative incisal margin were treated with VATS wedge resection. The conventional risk patients were treated with VATS radical resection and systematic lymphadenectomy. The clinical and pathological data were recorded. The total survival, tumor-free survival, recurrence time and style of patients were followed up.
The operative time and blood loss of the VATS wedge resection group (69.4 ± 15.5 min, 52.1 ± 11.2 ml) were significantly less than those of the VATS radical resection group (128 ± 35.5 min, 217.9 ± 87.1 ml). Neither groups had postoperative death. The overall and tumor-free survival rate of the VATS wedge resection group within three years were 66.7% and 60.0%, and those of the VATS radical resection group were 93.8% and 94.1%, without significant difference (P > 0.05). The recurrence rates of the VATS wedge resection group and VATS radical resection group were 14.3% and 3.0%, without significant difference (P > 0.05).
It is safe, minimally invasive and meaningful to perform VATS wedge resection on the elderly high-risk patients with stage I PNSCLC.
PMCID: PMC3896765  PMID: 24359930
Elderly; Early lung cancer; Thoracoscope
24.  NADPH oxidase modulates MHC class II antigen presentation by B cells 
Phagocyte NADPH oxidase plays a key role in pathogen clearance via reactive oxygen species (ROS) production. Defects in oxidase function result in chronic granulomatous disease (CGD) with hallmark recurrent microbial infections and inflammation. The oxidase′s role in the adaptive immune response is not well-understood. Class II presentation of cytoplasmic and exogenous Ag to CD4+ T cells was impaired in human B cells with reduced oxidase p40phox subunit expression. Naturally arising mutations which compromise p40phox function in a CGD patient also perturbed class II Ag presentation and intracellular ROS production. Reconstitution of patient B cells with wild-type, but not a mutant, p40phox allele restored exogenous Ag presentation and intracellular ROS generation. Remarkably, class II presentation of epitopes from membrane Ag was robust in p40phox-deficient B cells. These studies reveal a role for NADPH oxidase and p40phox in skewing epitope selection and T cell recognition of self Ag.
PMCID: PMC3466399  PMID: 22984083
Human B cells; MHC class II presentation; NADPH oxidase
25.  Four Common Vascular Endothelial Growth Factor Polymorphisms (−2578C>A, −460C>T, +936C>T, and +405G>C) in Susceptibility to Lung Cancer: A Meta-Analysis 
PLoS ONE  2013;8(10):e75123.
Background and Objective
Vascular endothelial growth factor (VEGF) is one of the key initiators and regulators of angiogenesis and it plays a vital role in the onset and development of malignancy. The association between VEGF gene polymorphisms and lung cancer risk has been extensively studied in recent years, but currently available results remain controversial or ambiguous. The aim of this meta-analysis is to investigate the associations between four common VEGF polymorphisms (i.e., −2578C>A, −460C>T, +936C>T and +405C>G) and lung cancer risk.
A comprehensive search was conducted to identify all eligible studies to estimate the association between VEGF polymorphisms and lung cancer risk. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of this association.
A total of 14 published case-control studies with 4,664 cases and 4,571 control subjects were identified. Our meta-analysis provides strong evidence that VEGF −2578C>A polymorphism is capable of increasing lung cancer susceptibility, especially among smokers and lung squamous cell carcinoma (SCC) patients. Additionally, for +936C>T polymorphism, increased lung cancer susceptibility was only observed among lung adenocarcinoma patients. In contrast, VEGF −460C>T polymorphism may be a protective factor among nonsmokers and SCC patients. Nevertheless, we did not find any association between +405C>G polymorphism and lung cancer risk, even when the groups were stratified by ethnicity, smoking status or histological type.
This meta-analysis recommends more investigations into the relationship between −2578C>A and −460C>T lung cancer risks. More detailed and well-designed studies should be conducted to identify the causal variants and the underlying mechanisms of the possible associations.
PMCID: PMC3788083  PMID: 24098368

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