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1.  Control of lipid metabolism by Tachykinin in Drosophila 
Cell reports  2014;9(1):40-47.
Summary
The intestine is a key organ for lipid uptake and distribution, and abnormal intestinal lipid metabolism is associated with obesity and hyperlipidemia. Although multiple regulatory gut hormones secreted from enteroendocrine cells (EEs) regulate systemic lipid homeostasis, such as appetite control and energy balance in adipose tissue, their respective roles regarding lipid metabolism in the intestine are not well understood. We demonstrate that Tachykinins (TKs), one of the most abundant secreted peptides expressed in midgut EEs, regulate intestinal lipid production and subsequently control systemic lipid homeostasis in Drosophila, and that TKs repress lipogenesis in enterocytes (ECs) associated with the TKR99D receptor and PKA signaling. Interestingly, nutrient deprivation enhances the production of TKs in the midgut. Finally, unlike the physiological roles of TKs produced from the brain, gut-derived TKs do not affect behavior, thus demonstrating that gut TK hormones specifically regulate intestinal lipid metabolism without affecting neuronal functions.
doi:10.1016/j.celrep.2014.08.060
PMCID: PMC4325997  PMID: 25263556
2.  Discovery of a New Class of Non-β-lactam Inhibitors of Penicillin-Binding Proteins with Gram-Positive Antibacterial Activity 
Infections caused by hard-to-treat methicillin-resistant Staphylococcus aureus (MRSA) are a serious global public-health concern, as MRSA has become broadly resistant to many classes of antibiotics. We disclose herein the discovery of a new class of non-β-lactam antibiotics, the oxadiazoles, which inhibit penicillin-binding protein 2a (PBP2a) of MRSA. The oxadiazoles show bactericidal activity against vancomycin- and linezolid-resistant MRSA and other Gram-positive bacterial strains, in vivo efficacy in a mouse model of infection, and have 100% oral bioavailability.
doi:10.1021/ja500053x
PMCID: PMC3985699  PMID: 24517363
3.  Label-Free Quantitative Mass Spectrometry Reveals a Panel of Differentially Expressed Proteins in Colorectal Cancer 
BioMed Research International  2015;2015:365068.
To identify potential biomarkers involved in CRC, a shotgun proteomic method was applied to identify soluble proteins in three CRCs and matched normal mucosal tissues using high-performance liquid chromatography and mass spectrometry. Label-free protein profiling of three CRCs and matched normal mucosal tissues were then conducted to quantify and compare proteins. Results showed that 67 of the 784 identified proteins were linked to CRC (28 upregulated and 39 downregulated). Gene Ontology and DAVID databases were searched to identify the location and function of differential proteins that were related to the biological processes of binding, cell structure, signal transduction, cell adhesion, and so on. Among the differentially expressed proteins, tropomyosin-3 (TPM3), endoplasmic reticulum resident protein 29 (ERp29), 18 kDa cationic antimicrobial protein (CAMP), and heat shock 70 kDa protein 8 (HSPA8) were verified to be upregulated in CRC tissue and seven cell lines through western blot analysis. Furthermore, the upregulation of TPM3, ERp29, CAMP, and HSPA8 was validated in 69 CRCs byimmunohistochemistry (IHC) analysis. Combination of TPM3, ERp29, CAMP, and HSPA8 can identify CRC from matched normal mucosal achieving an accuracy of 73.2% using IHC score. These results suggest that TPM3, ERp29, CAMP, and HSPA8 are great potential IHC diagnostic biomarkers for CRC.
doi:10.1155/2015/365068
PMCID: PMC4324820
4.  Enteroendocrine Cells Support Intestinal Stem Cell-Mediated Homeostasis In Drosophila 
Cell reports  2014;9(1):32-39.
SUMMARY
Intestinal stem cells in the adult Drosophila midgut are regulated by growth factors produced from the surrounding niche cells including enterocytes and visceral muscle. The role of the other major cell type, the secretory enteroendocrine cells, in regulating intestinal stem cells remains unclear. We show here that newly eclosed scute loss of function mutant flies are completely devoid of enteroendocrine cells. These enteroendocrine cell-less flies have normal ingestion and fecundity but shorter life span. Moreover, in these newly eclosed mutant flies, the diet-stimulated midgut growth that depends on the insulin-like peptide 3 expression in the surrounding muscle is defective. The depletion of Tachykinin producing enteroendocrine cells or knockdown of Tachykinin leads to a similar although less severe phenotype. These results together establish that enteroendocrine cells serve as an important link between diet and visceral muscle expression of an insulin-like growth factor to stimulate intestinal stem cell proliferation and tissue growth.
doi:10.1016/j.celrep.2014.08.052
PMCID: PMC4198943  PMID: 25263551
Drosophila; DILP3; enteroendocrine cells; homeostasis; intestine; scute; stem cells; Tachykinin
5.  The application of intraoperative transit time flow measurement to accurately assess anastomotic quality in sequential vein grafting 
OBJECTIVES
Intraoperative transit time flow measurement (TTFM) is widely used to assess anastomotic quality in coronary artery bypass grafting (CABG). However, in sequential vein grafting, the flow characteristics collected by the conventional TTFM method are usually associated with total graft flow and might not accurately indicate the quality of every distal anastomosis in a sequential graft. The purpose of our study was to examine a new TTFM method that could assess the quality of each distal anastomosis in a sequential graft more reliably than the conventional TTFM approach.
METHODS
Two TTFM methods were tested in 84 patients who underwent sequential saphenous off-pump CABG in Beijing An Zhen Hospital between April and August 2012. In the conventional TTFM method, normal blood flow in the sequential graft was maintained during the measurement, and the flow probe was placed a few centimetres above the anastomosis to be evaluated. In the new method, blood flow in the sequential graft was temporarily reduced during the measurement by placing an atraumatic bulldog clamp at the graft a few centimetres distal to the anastomosis to be evaluated, while the position of the flow probe remained the same as in the conventional method. This new TTFM method was named the flow reduction TTFM. Graft flow parameters measured by both methods were compared.
RESULTS
Compared with the conventional TTFM, the flow reduction TTFM resulted in significantly lower mean graft blood flow (P < 0.05); in contrast, yielded significantly higher pulsatility index (P < 0.05). Diastolic filling was not significantly different between the two methods and was >50% in both cases. Interestingly, the flow reduction TTFM identified two defective middle distal anastomoses that the conventional TTFM failed to detect. Graft flows near the defective distal anastomoses were improved substantially after revision.
CONCLUSIONS
In this study, we found that temporary reduction of graft flow during TTFM seemed to enhance the sensitivity of TTFM to less-than-critical anastomotic defects in a sequential graft and to improve the overall accuracy of the intraoperative assessment of anastomotic quality in sequential vein grafting.
doi:10.1093/icvts/ivt398
PMCID: PMC3829511  PMID: 24000314
Sequential saphenous coronary artery bypass grafting; Transit time flow measurement; Anastomotic quality
6.  Fundus Camera Guided Photoacoustic Ophthalmoscopy 
Current eye research  2013;38(12):1229-1234.
Purpose
To demonstrate the feasibility of fundus camera guided photoacoustic ophthalmoscopy (PAOM) system and its multimodal imaging capabilities.
Methods
We integrated PAOM and a fundus camera consisting of a white-light illuminator and a high-sensitivity, high-speed CCD. The fundus camera captures both retinal anatomy and PAOM illumination at the same time to provide a real-time feedback when we position the PAOM illuminating light. We applied the integrated system to image rat eyes in vivo and used full-spectrum, visible (VIS), and near infrared (NIR) illuminations in fundus photography.
Results
Both albino and pigmented rat eyes were imaged in vivo. During alignment, different trajectories of PAOM laser scanning were successfully visualized by the fundus camera, which reduced the PAOM alignment time from several minutes to 30 s. In albino eyes, in addition to retinal vessels, main choroidal vessels were observed using VIS-illumination, which is similar to PAOM images. In pigmented eyes, the radial striations of retinal nerve fiber layer were visualized by fundus photography using full-spectrum illumination; meanwhile, PAOM imaged both retinal vessels and the retinal pigmented epithelium melanin distribution.
Conclusions
The results demonstrated that PAOM can be well-integrated with fundus camera without affecting its functionality. The fundus camera guidance is faster and easier comparing with our previous work. The integrated system also set the stage for the next-step verification between oximetry methods based on PAOM and fundus photography.
doi:10.3109/02713683.2013.815219
PMCID: PMC3986591  PMID: 24131226
Fundus camera; multimodal imaging; photoacoustic ophthalmoscopy; retina; retinal imaging
7.  Effects of Phosphorylatable Short Peptide-Conjugated Chitosan-Mediated IL-1Ra and igf-1 Gene Transfer on Articular Cartilage Defects in Rabbits 
PLoS ONE  2014;9(11):e112284.
Previously, we reported an improvement in the transfection efficiency of the plasmid DNA-chitosan (pDNA/CS) complex by the utilization of phosphorylatable short peptide-conjugated chitosan (pSP-CS). In this study, we investigated the effects of pSP-CS-mediated gene transfection of interleukin-1 receptor antagonist protein (IL-1Ra) combined with insulin-like growth factor-1 (IGF-1) in rabbit chondrocytes and in a rabbit model of cartilage defects. pBudCE4.1-IL-1Ra+igf-1, pBudCE4.1-IL-1Ra and pBudCE4.1-igf-1 were constructed and combined with pSP-CS to form pDNA/pSP-CS complexes. These complexes were transfected into rabbit primary chondrocytes or injected into the joint cavity. Seven weeks after treatment, all rabbits were sacrificed and analyzed. High levels of IL-1Ra and igf-1 expression were detected both in the cell culture supernatant and in the synovial fluid. In vitro, the transgenic complexes caused significant proliferation of chondrocytes, promotion of glycosaminoglycan (GAG) and collagen II synthesis, and inhibition of chondrocyte apoptosis and nitric oxide (NO) synthesis. In vivo, the exogenous genes resulted in increased collagen II synthesis and reduced NO and GAG concentrations in the synovial fluid; histological studies revealed that pDNA/pSP-CS treatment resulted in varying degrees of hyaline-like cartilage repair and Mankin score decrease. The co-expression of both genes produced greater effects than each single gene alone both in vitro and in vivo. The results suggest that pSP-CS is a good candidate for use in gene therapy for the treatment of cartilage defects and that igf-1 and IL-1Ra co-expression produces promising biologic effects on cartilage defects.
doi:10.1371/journal.pone.0112284
PMCID: PMC4229204  PMID: 25390659
8.  Reflection-mode in vivo photoacoustic microscopy with subwavelength lateral resolution 
Biomedical Optics Express  2014;5(12):4235-4241.
We developed a reflection-mode subwavelength-resolution photoacoustic microscopy system capable of imaging optical absorption contrast in vivo. The simultaneous high-resolution and reflection-mode imaging capacity of the system was enabled by delicately configuring a miniature high-frequency ultrasonic transducer tightly under a water-immersion objective with numerical aperture of 1.0. At 532-nm laser illumination, the lateral resolution of the system was measured to be ~320 nm. With this system, subcellular structures of red blood cells and B16 melanoma cells were resolved ex vivo; microvessels, including individual capillaries, in a mouse ear were clearly imaged label-freely in vivo, using the intrinsic optical absorption from hemoglobin. The current study suggests that, the optical-absorption contrast, subwavelength resolution, and reflection-mode ability of the developed photoacoustic microscopy may empower a wide range of biomedical studies for visualizing cellular and/or subcellular structures.
doi:10.1364/BOE.5.004235
PMCID: PMC4285601  PMID: 25574435
(170.5120) Photoacoustic imaging; (180.0180) Microscopy; (170.3880) Medical and biological imaging
9.  O-Phenyl Carbamate and Phenyl Urea Thiiranes as Selective Matrix Metalloproteinase-2 Inhibitors that Cross the Blood-Brain Barrier 
Journal of medicinal chemistry  2013;56(20):10.1021/jm401217d.
Brain metastasis occurs in 20% to 40% of cancer patients. Treatment is mostly palliative and the inability of most drugs to penetrate the brain presents one of the greatest challenges in the development of therapeutics for brain metastasis. Matrix metalloproteinase-2 (MMP-2) plays important roles in invasion and vascularization of the central nervous system and represents a potential target for treatment of brain metastasis. Carbonate, O-phenyl carbamate, urea, and N-phenyl carbamate derivatives of SB-3CT, a selective and potent gelatinase inhibitor were synthesized and evaluated. The O-phenyl carbamate and urea variants were selective and potent inhibitors of MMP-2. Carbamate 5b was metabolized to the potent gelatinase inhibitor 2, which was present at therapeutic concentrations in the brain. In contrast, phenyl urea 6b crossed the blood-brain barrier, however higher doses would result in therapeutic brain concentrations. Carbamate 5b and urea 6b show potential for intervention of MMP-2-dependent diseases, such as brain metastasis.
doi:10.1021/jm401217d
PMCID: PMC3880597  PMID: 24028490
10.  Muscle Mitohormesis Promotes Longevity via Systemic Repression of Insulin Signaling 
Cell  2013;155(3):10.1016/j.cell.2013.09.021.
Summary
Mitochondrial dysfunction is usually associated with aging. To systematically characterize the compensatory stress signaling cascades triggered in response to muscle mitochondrial perturbation, we analyzed a Drosophila model of muscle mitochondrial injury. We find that mild muscle mitochondrial distress preserves mitochondrial function, impedes the age-dependent deterioration of muscle function and architecture, and prolongs lifespan. Strikingly, this effect is mediated by at least two pro-longevity compensatory signaling modules: one involving a muscle-restricted redox-dependent induction of genes that regulate the mitochondrial unfolded protein response (UPRmt); and another involving the transcriptional induction of the Drosophila ortholog of insulin-like growth factor binding protein 7, which systemically antagonizes insulin signaling, and facilitates mitophagy. Given that several secreted IGF-binding proteins (IGFBPs) exist in mammals, our work raises the possibility that muscle mitochondrial injury in humans may similarly result in the secretion of IGFBPs, with important ramifications for diseases associated with aberrant insulin signaling.
doi:10.1016/j.cell.2013.09.021
PMCID: PMC3856681  PMID: 24243023
11.  Bestrophin 3 Ameliorates TNFα-Induced Inflammation by Inhibiting NF-κB Activation in Endothelial Cells 
PLoS ONE  2014;9(10):e111093.
Increasing evidences have suggested vascular endothelial inflammatory processes are the initiator of atherosclerosis. Bestrophin 3 (Best-3) is involved in the regulation of cell proliferation, apoptosis and differentiation of a variety of physiological functions, but its function in cardiovascular system remains unclear. In this study, we investigated the effect of Best-3 on endothelial inflammation. We first demonstrated that Best-3 is expressed in endothelial cells and decreased after tumor necrosis factor-α (TNFα) challenge. Overexpression of Best-3 significantly attenuated TNFα-induced expression of adhesion molecules and chemokines, and subsequently inhibited the adhesion of monocytes to human umbilical vein endothelial cells (HUVECs). Conversely, knockdown of Best-3 with siRNA resulted in an enhancement on TNFα-induced expression of adhesion molecules and chemokines and adhesion of monocytes to HUVECs. Furthermore, overexpression of Best-3 with adenovirus dramatically ameliorated inflammatory response in TNFα-injected mice. Mechanistically, we found up-regulation of Best-3 inhibited TNFα-induced IKKβ and IκBα phosphorylation, IκBα degradation and NF-κB translocation. Our results demonstrated that Best-3 is an endogenous inhibitor of NF-κB signaling pathway in endothelial cells, suggesting that forced Best-3 expression may be a novel approach for the treatment of vascular inflammatory diseases.
doi:10.1371/journal.pone.0111093
PMCID: PMC4203846  PMID: 25329324
12.  Expression of vascular endothelial growth factor C and anti-angiogenesis therapy in endometriosis 
Angiogenesis is an important pathogenesis of Endometriosis. Vascular endothelial growth factor C (VEGF-C) is one of the most important factor in the regulation of both normal and abnormal angiogenesis. Anti-angiogenic treatment of endometriosis is still in the exploratory stage. In this study, we investigate the relationship between VEGF-C and endometriosis, the therapeutic effects of Endostar in the rat endometriosis model. We then demonstrated that Immunohistochemical expression of VEGF-C was higher in endometriotic tissues than in control normal ovary tissues (P < 0.01) and higher in the endomertriosis grade III-IV than in endomertriosis grade I-II (P=0.013). In rat endometriosis model, we observed a significant reduction in the mean volume and weight of the endometriotic implants per rat in the treatment group as compared with the control group. By immunohistochemical evaluation, there was a significant reduction in VEGF-C expression after treatment in all areas examined. VEGF-C may be involved in the pathogenesis of endomertriosis by regulating the angiogenesis. Endostar has therapeutic effects of endometriosis lesions in the rat endometriosis model.
PMCID: PMC4270624  PMID: 25550812
Endomertriosis; VEGF-C; angiogenesis; rat; Endostar
13.  A combined method to quantify the retinal metabolic rate of oxygen using photoacoustic ophthalmoscopy and optical coherence tomography 
Scientific Reports  2014;4:6525.
Quantitatively determining physiological parameters at a microscopic level in the retina furthers the understanding of the molecular pathways of blinding diseases, such as diabetic retinopathy and glaucoma. An essential parameter, which has yet to be quantified noninvasively, is the retinal oxygen metabolic rate (rMRO2). Quantifying rMRO2 is challenging because two parameters, the blood flow rate and hemoglobin oxygen saturation (sO2), must be measured together. We combined photoacoustic ophthalmoscopy (PAOM) with spectral domain-optical coherence tomography (SD-OCT) to tackle this challenge, in which PAOM measured the sO2 and SD-OCT mapped the blood flow rate. We tested the integrated system on normal wild-type rats, in which the measured rMRO2 was 297.86 ± 70.23 nl/minute. This quantitative method may shed new light on both fundamental research and clinical care in ophthalmology in the future.
doi:10.1038/srep06525
PMCID: PMC4185377  PMID: 25283870
14.  Evaluation of spasticity after stroke by using ultrasound to measure the muscle architecture parameters: a clinical study 
Objective: This study aims to compare the difference and the change trend of Muscle Architecture Parameters (MAP) between spastic and normal muscle tone patients after stroke, and analysis the application and value of Muscle Architecture Parameters in evaluating spasticity after stroke. Methods: 41 stroke patients were divided into spastic group (26 cases), normal muscle tone control group (15 cases). Modified Ashworth Scale (MAS) was applied in both groups for assessing muscle tone of lower limbs (no influence, contralateral). Muscle architectural parameters of ultrasound measurement include muscle thickness, fascicle length and pennation angle. The difference of three muscle architectural parameters between the affected side and the contralateral side in spastic group and the difference of MAS and three muscle architectural parameters between spastic group and normal control group were compared. Results: MAS score, Pennation Angle (PA) and Muscular Thickness (MT) value of MAP in spastic group were significantly higher than the control group, Fascicle length (FL) is significantly lower than the control group (P < 0.05). In spastic group, MAS score, PA and MT value of MAP of affected side muscle was substantially higher than that of contralateral, FL value significantly lower than that of contralateral (P < 0.05). There was positive correlation between MAS and PA and MT but was negative correlation between MAS and FL, rank correlation coefficient test was statistical significant (p < 0.05). Logistic multivariate regression analysis showed that spasticity can lead PA and FL to change (p < 0.05), there is no clear correlation between MT and spasticity occurs (P > 0.05). Conclusion: MAP has a better sensitivity in evaluating muscle tone between spastic patients and non-spastic patients, and degrees of spasticity have a clear corresponding exponential relationship to MAP. Combing MAS and MAP can assess muscle tone more objectively and accurately because subtle changes can be observed by testing values of architecture parameters that compensating for the shortcomings of MAS in reliability and validity. Thus it is helpful for guiding clinical antispastic practice.
PMCID: PMC4211779  PMID: 25356129
Pennation angle; muscular thickness; fascicle length; stroke; spasicity
15.  Pulmonary arteriovenous malformations presenting as refractory heart failure 
Journal of Thoracic Disease  2014;6(9):E169-E172.
A 22-year-old young man with a history of idiopathic dilated cardiomyopathy (IDC) was admitted to our hospital due to difficult-to-control heart failure. A thoracic X-ray showed multiple nodules at the both pulmonary hilus and upper lobe of the right lung. Computed tomography (CT) angiography of the thorax confirmed arteriovenous malformation (AVM). However, effective treatment was impossible due to the poor physical condition; he died a few days later. Here we reported on the case of pulmonary arteriovenous malformations (PAVMs) being misdiagnosed as refractory heart failure.
doi:10.3978/j.issn.2072-1439.2014.07.39
PMCID: PMC4178099  PMID: 25276390
Pulmonary arteriovenous malformations (PAVMs); heart failure; idiopathic dilated cardiomyopathy (IDC)
16.  Precoding Method Interference Management for Quasi-EVD Channel 
The Scientific World Journal  2014;2014:678578.
The Cholesky decomposition-block diagonalization (CD-BD) interference alignment (IA) for a multiuser multiple input multiple output (MU-MIMO) relay system is proposed, which designs precoders for the multiple access channel (MAC) by employing the singular value decomposition (SVD) as well as the mean square error (MSE) detector for the broadcast Hermitian channel (BHC) taken advantage of in our design. Also, in our proposed CD-BD IA algorithm, the relaying function is made use to restructure the quasieigenvalue decomposition (quasi-EVD) equivalent channel. This approach used for the design of BD precoding matrix can significantly reduce the computational complexity and proposed algorithm can address several optimization criteria, which is achieved by designing the precoding matrices in two steps. In the first step, we use Cholesky decomposition to maximize the sum-of-rate (SR) with the minimum mean square error (MMSE) detection. In the next step, we optimize the system BER performance with the overlap of the row spaces spanned by the effective channel matrices of different users. By iterating the closed form of the solution, we are able not only to maximize the achievable sum-of-rate (ASR), but also to minimize the BER performance at a high signal-to-noise ratio (SNR) region.
doi:10.1155/2014/678578
PMCID: PMC4167448  PMID: 25258731
17.  Water-Soluble MMP-9 Inhibitor Prodrug Generates Active Metabolites That Cross the Blood–Brain Barrier 
ACS Chemical Neuroscience  2013;4(8):1168-1173.
MMP-9 plays a detrimental role in the pathology of several neurological diseases and, thus, represents an important target for intervention. The water-soluble prodrug ND-478 is hydrolyzed to the active MMP-9 inhibitor ND-322, which in turn is N-acetylated to the even more potent metabolite ND-364. We used a sensitive bioanalytical method based on ultraperformance liquid chromatography with multiple-reaction monitoring detection to measure levels of ND-478, ND-322, and ND-364 in plasma and brain after administration of ND-478 and the metabolites. ND-478 did not cross the blood–brain barrier, as was expected; however the active metabolites ND-322 and ND-364 distributed to the brain. The active compound after administration of either ND-478 or ND-322 is likely ND-364. ND-322 is N-acetylated in both brain and liver, but it is so metabolized preferentially in liver. Since N-acetyltransferases involved in the metabolism of ND-322 to ND-364 are polymorphic, direct administration of the N-acetylated ND-364 would achieve the requisite therapeutic levels in the brain.
doi:10.1021/cn400077d
PMCID: PMC3750675  PMID: 23687970
MMP-9 inhibitor; blood−brain barrier; N-acetyltransferase
18.  TAp73 and ΔNp73 Have Opposing Roles in 5-aza-2′-Deoxycytidine-Induced Apoptosis in Breast Cancer Cells 
Molecules and Cells  2014;37(8):605-612.
The p73 gene contains an extrinsic P1 promoter and an intrinsic P2 promoter, controlling the transcription of the pro-apoptotic TAp73 isoform and the anti-apoptotic ΔΝp73 isoform, respectively. The DNA methylation status of both promoters act equally in the epigenetic transcriptional regulation of their relevant isoforms. The aim of this study was to analyze the different effects of these p73 isoforms in 5-aza-2′-deoxycytidine (5-aza-dC)-induced apoptosis in breast cancer cells. We investigated the effects of the DNA demethylation agent, 5-aza-dC, on the T-47D breast cancer cell line, and evaluated the methylation status of the p73 promoters and expression of TAp73 and ΔNp73. Furthermore, we assessed the expression of p53 and p73 isoforms in 5-aza-dC-treated T-47D cells and p53 knockout cells. 5-aza-dC induced significant anti-tumor effects in T-47D cells, including inhibition of cell viability, G1 phase arrest and apoptosis. This was associated with p73 promoter demethylation and a concomitant increase in TAp73 mRNA and protein expression. In contrast, the methylation status of promoter P2 was not associated with ΔNp73 mRNA or protein levels. Furthermore, demethylation of P2 failed to inhibit the expression of ΔNp73 with 5-aza-dC in the p53 knockdown cell model. Our study suggests that demethylation of the P1 and P2 promoters has opposite effects on the expression of p73 isoforms, namely up-regulation of TAp73 and down-regulation of ΔΝp73. We also demonstrate that p53 likely contributes to 5-aza-dC-induced ΔNp73 transcriptional inactivation in breast cancer cells.
doi:10.14348/molcells.2014.0154
PMCID: PMC4145372  PMID: 25134538
5-aza-2′-deoxycytidine; breast cancer; methylation; p53; p73
19.  Transcriptional regulation of the p73 gene by Nrf-2 and promoter CpG methylation in human breast cancer 
Oncotarget  2014;5(16):6909-6922.
To understand the transcriptional regulation of p73 by promoter methylation and Nrf-2 in breast carcinogenesis, ChIP assay indicated that Nrf-2 can bind to both promoters and can activate the transcription of TAp73 and ΔΝp73 in MCF-7 cell line, knockdown of Nrf-2 gene resulted in an abrogation of TAp73 and ΔΝp73 expression in the cells transfected with sh-Nrf-2 as well as Nrf-2 knock out mouse model. However, we found Nrf-2 induced ΔΝp73 expression was abolished with 5-aza-dC treatment, thus lead to a down-regulated ΔΝp73 and an up-regulated TAp73 expression in breast cancer cells lines. Consistent with this model, we detected decreased TAp73 and increased ΔNp73 expression in breast cancer tissue, along with increased TAp73 but decreased ΔNp73 expression in corresponding surrounding noncancerous tissues (NCTs) in a breast cancer tissue assay. A significant inverse correlation was found between TAp73 and ΔNp73 expression in the above tissue-array (P = 0.047) and validated in another set consisting of 128 breast cancer tumor tissue (P = 0.034). Taken together, our findings suggest that Nrf-2 and promoter methylation cooperatively govern the transcriptional regulation of p73, and unbalanced expression of TAp73 and ΔNp73 expression plays a critical role in breast cancer development.
PMCID: PMC4196172  PMID: 25071010
breast cancer; TAp73; ΔNp73; Nrf-2; methylation; transcription
20.  Real-Time Terrain Storage Generation from Multiple Sensors towards Mobile Robot Operation Interface 
The Scientific World Journal  2014;2014:769149.
A mobile robot mounted with multiple sensors is used to rapidly collect 3D point clouds and video images so as to allow accurate terrain modeling. In this study, we develop a real-time terrain storage generation and representation system including a nonground point database (PDB), ground mesh database (MDB), and texture database (TDB). A voxel-based flag map is proposed for incrementally registering large-scale point clouds in a terrain model in real time. We quantize the 3D point clouds into 3D grids of the flag map as a comparative table in order to remove the redundant points. We integrate the large-scale 3D point clouds into a nonground PDB and a node-based terrain mesh using the CPU. Subsequently, we program a graphics processing unit (GPU) to generate the TDB by mapping the triangles in the terrain mesh onto the captured video images. Finally, we produce a nonground voxel map and a ground textured mesh as a terrain reconstruction result. Our proposed methods were tested in an outdoor environment. Our results show that the proposed system was able to rapidly generate terrain storage and provide high resolution terrain representation for mobile mapping services and a graphical user interface between remote operators and mobile robots.
doi:10.1155/2014/769149
PMCID: PMC4101941  PMID: 25101321
21.  Fine Physical and Genetic Mapping of Powdery Mildew Resistance Gene MlIW172 Originating from Wild Emmer (Triticum dicoccoides) 
PLoS ONE  2014;9(6):e100160.
Powdery mildew, caused by Blumeria graminis f. sp. tritici, is one of the most important wheat diseases in the world. In this study, a single dominant powdery mildew resistance gene MlIW172 was identified in the IW172 wild emmer accession and mapped to the distal region of chromosome arm 7AL (bin7AL-16-0.86-0.90) via molecular marker analysis. MlIW172 was closely linked with the RFLP probe Xpsr680-derived STS marker Xmag2185 and the EST markers BE405531 and BE637476. This suggested that MlIW172 might be allelic to the Pm1 locus or a new locus closely linked to Pm1. By screening genomic BAC library of durum wheat cv. Langdon and 7AL-specific BAC library of hexaploid wheat cv. Chinese Spring, and after analyzing genome scaffolds of Triticum urartu containing the marker sequences, additional markers were developed to construct a fine genetic linkage map on the MlIW172 locus region and to delineate the resistance gene within a 0.48 cM interval. Comparative genetics analyses using ESTs and RFLP probe sequences flanking the MlIW172 region against other grass species revealed a general co-linearity in this region with the orthologous genomic regions of rice chromosome 6, Brachypodium chromosome 1, and sorghum chromosome 10. However, orthologous resistance gene-like RGA sequences were only present in wheat and Brachypodium. The BAC contigs and sequence scaffolds that we have developed provide a framework for the physical mapping and map-based cloning of MlIW172.
doi:10.1371/journal.pone.0100160
PMCID: PMC4067302  PMID: 24955773
22.  Oncogenic Fli-1 is a potential prognostic marker for the progression of epithelial ovarian cancer 
BMC Cancer  2014;14:424.
Background
Ovarian cancer is the most lethal gynecologic malignancy, but its etiology remains poorly understood. This study investigated the role of Fli-1 in ovarian carcinogenesis and disease survival.
Methods
Fli-1 protein expression was evaluated by immunohistochemistry in 104 primary epithelial ovarian cancer (EOC) patients with known follow-up data and 20 controls. Correlation between Fli-1 expression and clinical characteristics was evaluated with the logistic regression. Kaplan Meier analysis was used to assess the impact of Fli-1 expression on overall survival (OS) and disease-free survival (DFS). Cell proliferation and migration assay were used to explore the function of Fli-1 in ovarian cancer cells.
Results
Fli-1 was expressed in 74% cases and up-regulated in EOC tissues compared with normal control tissues (p< 0.05). The high expression of Fli-1 was significantly associated with advanced tumor stage, positive lymph nodal involvement, and poor OS and DFS (p< 0.05). Further analysis showed Fli-1 is an independent prognostic factor for OS and DFS. Down-regulation of Fli-1 inhibited cell proliferation but did not affect cell migration in SKOV3 cells.
Conclusions
This study revealed that Fli-1 played an essential role in the development and progression of ovarian cancers. Its overexpression is intimately related to malignant phenotypes and poor clinical outcome, suggesting that Fli-1 is a potential prognostic marker and therapeutic molecular target in ovarian cancer.
doi:10.1186/1471-2407-14-424
PMCID: PMC4089852  PMID: 24923303
Epithelial ovarian cancer (EOC); Fli-1; Tumor stage; Overall survival
23.  Multimodal photoacoustic ophthalmoscopy in mouse 
Journal of biophotonics  2012;6(0):505-512.
Photoacoustic ophthalmoscopy (PAOM) is a novel imaging technology that measures optical absorption in the retina. The capability of PAOM can be further enhanced if it could image mouse eyes, because mouse models are widely used for various retinal diseases. The challenges in achieving high-quality imaging of mouse retina, however, come from the much smaller eyeball size. Here, we report an optimized imaging system, which integrates PAOM, spectral-domain optical coherence tomography (SD-OCT), and autofluorescence-scanning laser ophthalmoscopy (AF-SLO), for mouse eyes. Its multimodal capability was demonstrated by imaging transgenic Nrl-GFP mice that express green fluorescent protein (GFP) in photoreceptors. SD-OCT provided guidance of optical alignment for PAOM and AF-SLO, and complementary contrast with high depth-resolution retinal cross sections. PAOM visualized the retinal vasculature and retinal pigment epithelium melanin, and AF-SLO measured GFP-expressing in retinal photoreceptors. The in vivo imaging results were verified by histology and confocal microscopy.
doi:10.1002/jbio.201200061
PMCID: PMC3986594  PMID: 22649053
Photoacoustic ophthalmoscopy; optical coherence tomography; scanning laser ophthalmoscopy; retinal imaging
24.  Acetylation-Mediated Proteasomal Degradation of Core Histones during DNA Repair and Spermatogenesis 
Cell  2013;153(5):1012-1024.
SUMMARY
Histone acetylation plays critical roles in chromatin remodeling, DNA repair, and epigenetic regulation of gene expression, but the underlying mechanisms are unclear. Proteasomes usually catalyze ATP- and polyubiquitin-dependent proteolysis. Here we show that the proteasomes containing the activator PA200 catalyze the polyubiquitin-independent degradation of histones. Most proteasomes in mammalian testes (“spermatoproteasomes”) contain a spermatid/sperm-specific α-subunit α4s/PSMA8 and/or the catalytic β-subunits of immunoproteasomes in addition to PA200. Deletion of PA200 in mice abolishes acetylation-dependent degradation of somatic core histones during DNA double-strand breaks, and delays core histone disappearance in elongated spermatids. Purified PA200 greatly promotes ATP-independent proteasomal degradation of the acetylated core histones, but not polyubiquitinated proteins. Furthermore, acetylation on histones is required for their binding to the bromodomain-like regions in PA200 and its yeast ortholog, Blm10. Thus, PA200/Blm10 specifically targets the core histones for acetylation-mediated degradation by proteasomes, providing mechanisms by which acetylation regulates histone degradation, DNA repair, and spermatogenesis.
doi:10.1016/j.cell.2013.04.032
PMCID: PMC3983474  PMID: 23706739
25.  Aerobic Exercise Inhibits Sympathetic Nerve Sprouting and Restores β-Adrenergic Receptor Balance in Rats with Myocardial Infarction 
PLoS ONE  2014;9(5):e97810.
Background
Cardiac sympathetic nerve sprouting and the dysregulation of β-adrenergic receptor (β-AR) play a critical role in the deterioration of cardiac function after myocardial infarction (MI). Growing evidence indicates that exercise provides protection against MI. The aims of this study were to investigate whether aerobic exercise following MI could inhibit sympathetic nerve sprouting and restore the balance of β3-AR/β1-AR.
Methods
Male Sprague-Dawley rats were divided into three groups: sham-operated control group (SC), MI group (MI), and MI with aerobic exercise group (ME). The rats in ME group were assigned to 8 weeks of exercise protocol (16 m/min, 50 min/d, 5 d/wk). The expression of nerve growth factor (NGF), the sympathetic nerve marker-tyrosine hydroxylase (TH), the nerve sprouting marker-growth associated protein 43 (GAP43), and β1- and β2-AR expression in the peri-infarct area of the left ventricle (LV) were measured by Western blot and immunohistochemistry, while β3-AR expression was determined by Western blot and immunofluorescence. Endothelial nitric oxide synthase (NOS2), phospho-NOS2 (p-NOS2), and neuronal nitric oxide synthase (NOS1) were measured by Western blot.
Results
MI increased LV end-diastolic pressure (LVEDP), and decreased LV systolic pressure (LVSP). Compared with the MI group, aerobic exercise significantly decreased LVEDP and increased LVSP. The protein expression of TH, GAP43 and NGF was significantly increased after MI, which was normalized by exercise. Compared with the SC group, the ratios of β2-AR/β1-AR and β3-AR/β1-AR were elevated in the MI group, and the protein expression of β3-AR and NOS1 increased after MI. Compared with the MI group, the ratios of β2-AR/β1-AR and β3-AR/β1-AR were normalized in the ME group, while the protein expression of β3-AR and NOS1 significantly increased, and NOS2 was activated by exercise.
Conclusions
Aerobic exercise inhibits cardiac sympathetic nerve sprouting, restores β3-AR/β1-AR balance and increases β3-AR expression through the activation of NOS2 and NOS1 after myocardial infarction.
doi:10.1371/journal.pone.0097810
PMCID: PMC4026473  PMID: 24842290

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