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1.  Affibody Modified and Radiolabeled Gold-Iron Oxide Hetero-nanostructures for Tumor PET, Optical and MR Imaging 
Biomaterials  2013;34(11):2796-2806.
A highly monodispersed hetero-nanostructure with two different functional nanomaterials (gold (Au) and iron oxide (Fe3O4, IO)) within one structure was successfully developed as Affibody based trimodality nanoprobe (positron emission tomography, PET; optical imaging; and magnetic resonance imaging, MRI) for imaging of epidermal growth factor receptor (EGFR) positive tumors. Unlike other regular nanostructures with a single component, the Au-IO hetero-nanostructures (Au-IONPs) with unique chemical and physical properties have capability to combine several imaging modalities together to provide complementary information. The IO component within hetero-nanostructures serve as a T2 reporter for MRI; and gold component serve as both optical and PET reporters. Moreover, such hetero-nanoprobes could provide a robust nano-platform for surface-specific modification with both targeting molecules (anti-EGFR Affibody protein) and PET imaging reporters (radiometal 64Cu chelators) in highly efficient and reliable manner. In vitro and in vivo study showed that the resultant nanoprobe provided high specificity, sensitivity, and excellent tumor contrast for both PET and MRI imaging in the human EGFR-expressing cells and tumors. Our study data also highlighted the EGFR targeting efficiency of hetero-nanoparticles and the feasibility for their further theranostic applications.
PMCID: PMC3563754  PMID: 23343632
Au-Fe3O4; Hetero-nanoparticles; Affibody; EGFR; PET; MRI; Optical
2.  Psychotic-affective symptoms and multiple system atrophy expand phenotypes of spinocerebellar ataxia type 2 
BMJ Case Reports  2012;2012:bcr1020115061.
Spinocerebellar ataxia type 2 (SCA2) is a progressive neurodegenerative disorder, characterised by ataxic gait, slow saccades and peripheral neuropathy. Levodopa-responsive parkinsonism could be a clinical phenotype of SCA2, especially those of Chinese origin. In addition to these motor symptoms, SCA2 has been associated with depression and cognitive dysfunction, with only rare reports of psychosis. The authors report the presence of severe psychosis, major depression and multiple system atrophy in affected subjects of a Taiwanese family with intermediate CAG repeats within the ATXN2 gene. The identification of this rare and distinctive SCA2 phenotype expands the current knowledge of the phenotypic variability of SCA2 and suggests that modifier genes could influence the clinical phenotype of SCA2.
PMCID: PMC3316827  PMID: 22605703
3.  Monodispersed bimetallic PdAg nanoparticles with twinned structures: Formation and enhancement for the methanol oxidation 
Scientific Reports  2014;4:4288.
Monodispersed bimetallic PdAg nanoparticles can be fabricated through the emulsion-assisted ethylene glycol (EG) ternary system. Different compositions of bimetallic PdAg nanoparticles, Pd80Ag20, Pd65Ag35 and Pd46Ag54 can be obtained via adjusting the reaction parameters. For the formation process of the bimetallic PdAg nanoparticles, there have two-stage growth processes: firstly, nucleation and growth of the primary nanoclusters; secondly, formation of the secondary nanoparticles with the size-selection and relax process via the coalescence or aggregation of the primary nanoclusters. The as-prepared PdAg can be supported on the carbon black without any post-treatment, which exhibited high electro-oxidation activity towards methanol oxidation under alkaline media. More importantly, carbon-supported Pd80Ag20 nanoparticles reveal distinctly superior activities for the methanol oxidation, even if compared with commercial Pt/C electro-catalyst. It is concluded that the enhanced activity is dependant on the unique twinning structure with heterogeneous phase due to the dominating coalescence growth in EG ternary system.
PMCID: PMC3948072  PMID: 24608736
4.  ArdA proteins from different mobile genetic elements can bind to the EcoKI Type I DNA methyltransferase of E. coli K12☆ 
Biochimica et Biophysica Acta  2014;1844(3):505-511.
Anti-restriction and anti-modification (anti-RM) is the ability to prevent cleavage by DNA restriction–modification (RM) systems of foreign DNA entering a new bacterial host. The evolutionary consequence of anti-RM is the enhanced dissemination of mobile genetic elements. Homologues of ArdA anti-RM proteins are encoded by genes present in many mobile genetic elements such as conjugative plasmids and transposons within bacterial genomes. The ArdA proteins cause anti-RM by mimicking the DNA structure bound by Type I RM enzymes. We have investigated ArdA proteins from the genomes of Enterococcus faecalis V583, Staphylococcus aureus Mu50 and Bacteroides fragilis NCTC 9343, and compared them to the ArdA protein expressed by the conjugative transposon Tn916. We find that despite having very different structural stability and secondary structure content, they can all bind to the EcoKI methyltransferase, a core component of the EcoKI Type I RM system. This finding indicates that the less structured ArdA proteins become fully folded upon binding. The ability of ArdA from diverse mobile elements to inhibit Type I RM systems from other bacteria suggests that they are an advantage for transfer not only between closely-related bacteria but also between more distantly related bacterial species.
•Diverse ArdA proteins all target the EcoKI Type I DNA modification enzyme.•ArdA proteins have variable secondary structure content.•ArdA all bind equally well to EcoKI despite stability variations.
PMCID: PMC3969726  PMID: 24368349
RM, restriction–modification; anti-RM, antirestriction/antimodification; MGE, mobile genetic element; MTase, modification methyltransferase; M subunit, modification subunit; S subunit, sequence specificity subunit; Orf, open reading frame; CD, circular dichroism; GuCl, guanidinium chloride; 2-ME, 2-mercaptoethanol; SEC, size exclusion chromatography; Kd, dissociation constant; DNA methyltransferase; ArdA protein; DNA mimic; Horizontal gene transfer
5.  An Investigation of Factors Affecting Elementary School Students' BMI Values Based on the System Dynamics Modeling 
This study used system dynamics method to investigate the factors affecting elementary school students' BMI values. The construction of the dynamic model is divided into the qualitative causal loop and the quantitative system dynamics modeling. According to the system dynamics modeling, this study consisted of research on the four dimensions: student's personal life style, diet-relevant parenting behaviors, advocacy and implementation of school nutrition education, and students' peer interaction. The results of this study showed that students with more adequate health concepts usually have better eating behaviors and consequently have less chance of becoming obese. In addition, this study also verified that educational attainment and socioeconomic status of parents have a positive correlation with students' amounts of physical activity, and nutrition education has a prominent influence on changing students' high-calorie diets.
PMCID: PMC3950593
6.  The Study of Cooperative Obstacle Avoidance Method for MWSN Based on Flocking Control 
The Scientific World Journal  2014;2014:614346.
Compared with the space fixed feature of traditional wireless sensor network (WSN), mobile WSN has better robustness and adaptability in unknown environment, so that it is always applied in the research of target tracking. In order to reach the target, the nodes group should find a self-adaptive method to avoid the obstacles together in their moving directions. Previous methods, which were based on flocking control model, realized the strategy of obstacle avoidance by means of potential field. However, these may sometimes lead the nodes group to fall into a restricted area like a trap and never get out of it. Based on traditional flocking control model, this paper introduced a new cooperative obstacle avoidance model combined with improved SA obstacle avoidance algorithm. It defined the tangent line of the intersection of node's velocity line and the edge of obstacle as the steering direction. Furthermore, the cooperative obstacle avoidance model was also improved in avoiding complex obstacles. When nodes group encounters mobile obstacles, nodes will predict movement path based on the spatial location and velocity of obstacle. And when nodes group enters concave obstacles, nodes will temporarily ignore the gravity of the target and search path along the edge of the concave obstacles. Simulation results showed that cooperative obstacle avoidance model has significant improvement on average speed and time efficiency in avoiding obstacle compared with the traditional flocking control model. It is more suitable for obstacle avoidance in complex environment.
PMCID: PMC3934532
7.  Hydrogen induced redox mechanism in amorphous carbon resistive random access memory 
We investigated the bipolar resistive switching characteristics of the resistive random access memory (RRAM) device with amorphous carbon layer. Applying a forming voltage, the amorphous carbon layer was carbonized to form a conjugation double bond conductive filament. We proposed a hydrogen redox model to clarify the resistive switch mechanism of high/low resistance states (HRS/LRS) in carbon RRAM. The electrical conduction mechanism of LRS is attributed to conductive sp2 carbon filament with conjugation double bonds by dehydrogenation, while the electrical conduction of HRS resulted from the formation of insulating sp3-type carbon filament through hydrogenation process.
PMCID: PMC3922695  PMID: 24475979
Carbon; Hydrogen redox; Conjugation double bond; RRAM
8.  Cytoprotective effects of urinary trypsin inhibitor on astrocytes injured by sustained compression 
Molecular Biology Reports  2014;41:1311-1316.
Decreased cell membrane integrity is a primary pathological change observed in traumatic brain injury (TBI) that activates a number of complex intercellular and intracellular pathological events, leading to further neural injury. In this paper, we assessed the effects of urinary trypsin inhibitor (UTI) on astrocyte membrane integrity by determining the percentage of lactate dehydrogenase (LDH) released after sustained compression injury using a hydrostatic pressure model of mechanical-like TBI. Astrocytes isolated from SD rat pups were injured by sustained compression. At a pressure of 0.3 MPa for 5 min, a significant increase in LDH release was observed compared with control samples. Astrocytes displayed extensive structural disruption of mitochondrial cristae reflected in their swelling. Based on our initial results, injured astrocytes were treated with UTI at a final concentration of 500, 1,000, 3,000 or 5,000 U/ml for 24 h. The percentage of LDH released from injured astrocytes was significantly decreased when 1,000 and 3,000 U/ml of UTI were used. In a separate experiment, astrocytes were treated with UTI at a final concentration of 1,000 U/ml immediately, or at 30 min, 2, 6, or 24 h after sustained compression. The percentage of LDH release was significantly reduced (P < 0.05) when astrocytes were treated with UTI immediately or 30 min later. Together, our results suggest that UTI may have protective effects on astrocytes injured by sustained compression injury. Furthermore, the early administration (<2 h after injury) of UTI may result in a better outcome compared with delayed administration.
PMCID: PMC3933746  PMID: 24385305
Astrocytes; Compression injury; LDH release; UTI; Cytoprotection
9.  Radiolabeled Nanoparticles for Multimodality Tumor Imaging 
Theranostics  2014;4(3):290-306.
Each imaging modality has its own unique strengths. Multimodality imaging, taking advantages of strengths from two or more imaging modalities, can provide overall structural, functional, and molecular information, offering the prospect of improved diagnostic and therapeutic monitoring abilities. The devices of molecular imaging with multimodality and multifunction are of great value for cancer diagnosis and treatment, and greatly accelerate the development of radionuclide-based multimodal molecular imaging. Radiolabeled nanoparticles bearing intrinsic properties have gained great interest in multimodality tumor imaging over the past decade. Significant breakthrough has been made toward the development of various radiolabeled nanoparticles, which can be used as novel cancer diagnostic tools in multimodality imaging systems. It is expected that quantitative multimodality imaging with multifunctional radiolabeled nanoparticles will afford accurate and precise assessment of biological signatures in cancer in a real-time manner and thus, pave the path towards personalized cancer medicine. This review addresses advantages and challenges in developing multimodality imaging probes by using different types of nanoparticles, and summarizes the recent advances in the applications of radiolabeled nanoparticles for multimodal imaging of tumor. The key issues involved in the translation of radiolabeled nanoparticles to the clinic are also discussed.
PMCID: PMC3915092  PMID: 24505237
radiolabeled nanoparticles; molecular imaging; multimodality imaging; tumor diagnosis; cancer; theranostics
10.  Evolving Concepts of Oxidative Stress and Reactive Oxygen Species in Cardiovascular Disease 
Current atherosclerosis reports  2012;14(5):10.1007/s11883-012-0266-8.
Cardiovascular disease continues to be a substantial health-care burden, despite recent treatment advances. Oxidative stress has long been regarded as a key pathophysiological mediator that ultimately leads to CVD including atherosclerosis, hypertension and heart failure. Over the past decade, emerging evidence has shifted our understanding of reactive oxygen species (ROS) from its harmful role to being signaling molecules. Here, we reviewed recent advances in our understanding of ROS that mediate the complex process of cardiovascular diseases, with a focus on major ROS signaling and sources such as mitochondria and NADPH oxidases.
PMCID: PMC3872835  PMID: 22956414
11.  Space electric field concentrated effect for Zr:SiO2 RRAM devices using porous SiO2 buffer layer 
Nanoscale Research Letters  2013;8(1):523.
To improve the operation current lowing of the Zr:SiO2 RRAM devices, a space electric field concentrated effect established by the porous SiO2 buffer layer was investigated and found in this study. The resistive switching properties of the low-resistance state (LRS) and high-resistance state (HRS) in resistive random access memory (RRAM) devices for the single-layer Zr:SiO2 and bilayer Zr:SiO2/porous SiO2 thin films were analyzed and discussed. In addition, the original space charge limited current (SCLC) conduction mechanism in LRS and HRS of the RRAM devices using bilayer Zr:SiO2/porous SiO2 thin films was found. Finally, a space electric field concentrated effect in the bilayer Zr:SiO2/porous SiO2 RRAM devices was also explained and verified by the COMSOL Multiphysics simulation model.
PMCID: PMC3881491  PMID: 24330524
RRAM; Porous SiO2; Space charge limited current; Zr
12.  Proteinuria Independently Predicts Unfavorable Outcome of Ischemic Stroke Patients Receiving Intravenous Thrombolysis 
PLoS ONE  2013;8(11):e80527.
Background and Purpose
Patients with low estimated glomerular filtration rate (eGFR) and proteinuria may be at increased risk for stroke. This study investigated whether low eGFR and proteinuria are outcome predictors in stroke patients treated with intravenous thrombolysis.
We studied 432 consecutive stroke patients who received thrombolysis from January 2006 to December 2012, in Taiwan. Unfavorable outcome was defined as modified Rankin scale ≥2 at 3 months after stroke. Proteinuria was classified as negative or trace, mild, and moderate to severe. Using logistic regression analysis, we identified independent factors for unfavorable outcome after thrombolysis.
Of all patients, 32.7% had proteinuria. Patients with proteinuria were older, had higher frequencies of diabetes mellitus, hyperlipidemia, atrial fibrillation, lower eGFR, and greater severity of stroke upon admission than those without proteinuria. Proteinuria, not low eGFR, was an independent predictor for unfavorable outcome for stroke (OR = 2.00 for mild proteinuria, p = 0.035; OR = 2.54 for moderate to severe proteinuria, p = 0.035). However, no clear relationship was found between proteinuria and symptomatic hemorrhage after thrombolysis.
Proteinuria is an independent predictor of unfavorable outcome for acute ischemic stroke in patients treated with intravenous thrombolysis, indicating the crucial role of chronic kidney disease on the effectiveness of thrombolysis.
PMCID: PMC3838417  PMID: 24278288
13.  High performance of graphene oxide-doped silicon oxide-based resistance random access memory 
Nanoscale Research Letters  2013;8(1):497.
In this letter, a double active layer (Zr:SiO x /C:SiO x ) resistive switching memory device with outstanding performance is presented. Through current fitting, hopping conduction mechanism is found in both high-resistance state (HRS) and low-resistance state (LRS) of double active layer RRAM devices. By analyzing Raman and FTIR spectra, we observed that graphene oxide exists in C:SiO x layer. Compared with single Zr:SiO x layer structure, Zr:SiO x /C:SiO x structure has superior performance, including low operating current, improved uniformity in both set and reset processes, and satisfactory endurance characteristics, all of which are attributed to the double-layer structure and the existence of graphene oxide flakes formed by the sputter process.
PMCID: PMC3874615  PMID: 24261454
High performance; Graphene oxide; RRAM; Hopping conduction
14.  TLR4-MyD88/Mal-NF-kB Axis Is Involved in Infection of HSV-2 in Human Cervical Epithelial Cells 
PLoS ONE  2013;8(11):e80327.
We have established an in vitro HSV-2 acute infection model with Human cervical epithelial (HCE cells, the primary target and natural host cells for HSV-2) to investigate the role of TLRs-mediated innate immune response to HSV-2. In current study, we found that HSV-2 infection induced activity of NF-kB reporter and expression of cytokines are TLR4-dependent using approaches with shRNA and TLR4 antagonist. Knockdown experiments demonstrated that the adaptor molecules MyD88 and Mal of the TLRs signaling pathway are required in the HSV-2 induced TLR4-dependent NF-kB activation in HCE cells. Western blot assay suggested that knockdown of TLR4 decreased the phosphorylation of IRAK1 and inhibitor of NF-kB (IkB-α) upon HSV-2 infection. Finally, decreased expression of either TLR4 or MyD88/Mal alone or both significantly abolished productions of IL-6 and IFN-β by ELISA analysis. Taken together, our results from the in vitro infection model reveal for the first time that there exists the pathway via TLR4-Mal/MyD88-IRAK1-NF-kB axis in human cervical epithelial cells in response to HSV-2 infection.
PMCID: PMC3835891  PMID: 24278275
15.  Expression and significance of Kruppel-like factor 6 gene in osteosarcoma 
International Orthopaedics  2012;36(10):2107-2111.
Osteosarcoma is primary malignant tumour of bone. Kruppel-like factor 6 (KLF6) is a tumor suppressor gene frequently inactivated in a number of human cancers and a ubiquitously expressed zinc-finger transcription factor. The present study aimed to first explore the relationship between the expression level of the KLF6 gene in osteosarcoma and the occurrence of bone tumours.
KLF6 mRNA and protein expression levels in osteosarcoma and normal bone tissue were assayed by real-time quantitative PCR and immunohistochemistry. KLF6 mRNA and protein expression levels in osteosarcoma cells and normal osteoblasts were detected by semi-quantitative reverse transcription PCR and Western blotting, respectively.
Both the expression of KLF6 mRNA and protein in osteosarcoma cells and tissues were significantly lower than that in normal cells and tumour-adjacent tissues.
KLF6 is a putative tumor suppressor gene involved in osteosarcoma which can be used as a new therapeutic target and an important marker for early diagnosis and postoperative monitoring.
PMCID: PMC3460099  PMID: 22855058
16.  The B7-1 Cytoplasmic Tail Enhances Intracellular Transport and Mammalian Cell Surface Display of Chimeric Proteins in the Absence of a Linear ER Export Motif 
PLoS ONE  2013;8(9):e75084.
Membrane-tethered proteins (mammalian surface display) are increasingly being used for novel therapeutic and biotechnology applications. Maximizing surface expression of chimeric proteins on mammalian cells is important for these applications. We show that the cytoplasmic domain from the B7-1 antigen, a commonly used element for mammalian surface display, can enhance the intracellular transport and surface display of chimeric proteins in a Sar1 and Rab1 dependent fashion. However, mutational, alanine scanning and deletion analysis demonstrate the absence of linear ER export motifs in the B7 cytoplasmic domain. Rather, efficient intracellular transport correlated with the presence of predicted secondary structure in the cytoplasmic tail. Examination of the cytoplasmic domains of 984 human and 782 mouse type I transmembrane proteins revealed that many previously identified ER export motifs are rarely found in the cytoplasmic tail of type I transmembrane proteins. Our results suggest that efficient intracellular transport of B7 chimeric proteins is associated with the structure rather than to the presence of a linear ER export motif in the cytoplasmic tail, and indicate that short (less than ~ 10-20 amino acids) and unstructured cytoplasmic tails should be avoided to express high levels of chimeric proteins on mammalian cells.
PMCID: PMC3779271  PMID: 24073236
17.  Low Modulus Biomimetic Microgel Particles with High Loading of Hemoglobin 
Biomacromolecules  2012;13(9):2748-2759.
We synthesized extremely deformable red blood cell-like microgel particles and loaded them with bovine hemoglobin (Hb) to potentiate oxygen transport. With similar shape and size as red blood cells (RBCs), the particles were fabricated using the PRINT® (Particle Replication In Non-wetting Templates) technique. Low crosslinking of the hydrogel resulted in very low mesh density for these particles, allowing passive diffusion of hemoglobin throughout the particles. Hb was secured in the particles through covalent conjugation of the lysine groups of Hb to carboxyl groups in the particles via EDC/NHS coupling. Confocal microscopy of particles bound to fluorescent dye-labeled Hb confirmed the uniform distribution of Hb throughout the particle interior, as opposed to the surface conjugation only. High loading ratios, up to 5 times the amount of Hb to polymer by weight, were obtained, without a significant effect on particle stability, shape, though particle diameter decreased slightly with Hb conjugation. Analysis of the protein by circular dichroism (CD) spectroscopy showed that the secondary structure of Hb was unperturbed by conjugation to the particles. Methemoglobin in the particles could be maintained at a low level and the loaded Hb could still bind oxygen as studied by UV-vis spectroscopy. Hb-loaded particles with moderate loading ratios demonstrated excellent deformability in microfluidic devices, easily deforming to pass through restricted pores half as wide as the diameter of the particles. The suspension of concentrated particles with Hb concentration of 5.2 g/dL showed comparable viscosity to that of mouse blood, and the particles remained intact even after being sheared at a constant high rate (1,000 1/s) for 10 min. Armed with the ability to control size, shape, deformability, and loading of Hb into RBC mimics, we will discuss the implications for artificial blood.
PMCID: PMC3438367  PMID: 22852860
18.  Assessment and comparison of magnetic nanoparticles as MRI contrast agents in a rodent model of human hepatocellular carcinoma 
The purpose of this study was to synthesize, characterize and tailor the surface properties of magnetic nanoparticles with biocompatible copolymer coatings and to evaluate the efficiency of the resulting nanoconjugates as magnetic resonance imaging (MRI) contrast agents for liver imaging.
Magnetic nanoparticles with core diameters of 10 and 30 nm were synthesized by pyrolysis and were subsequently coated with a copolymer containing either carboxyl (SHP) or methoxy groups (SMG) as termini. All four formulas, and ferumoxides (Feridex I.V.®), were individually injected intravenously into separate, normal Balb/C mice (at 2.5, 1.0, and 0.56 mg Fe/kg), and the animals underwent T2-weighted MRI at multiple time points post injection (p.i.) to evaluate the hepatic uptake and clearance. Furthermore, we compared the abilities of the new formulas and Feridex to detect tumors in an orthotropic Huh7 tumor model.
TEM revealed a narrow size distribution of both the 10 nm and 30 nm nanoparticles, in contrast to a wide size distribution of Feridex. MTT, apoptosis and Cyclin/DNA flow cytometry assays showed that the polymer coated nanoparticles had no adverse effect on cell growth. Among all the tested formulas, including Feridex, SHP-30 showed the highest macrophage uptake at the in vitro level. In vivo MRI studies on normal mice confirmed the superiority of SHP-30 in inducing hypointensities in the liver tissue, especially at clinical dose (0.56 mg Fe/kg) and 3T field. SHP-30 showed better contrast-to-noise ratio (CNR) than Feridex on the orthotropic Huh7 tumor model.
SHP-30 was found to be an efficient contrast agent for liver MR imaging. The success of this study suggests that by improving the synthetic approach and by tuning the surface properties of IONPs, one can arrive at better formulas than Feridex for clinical practice.
PMCID: PMC3759163  PMID: 22649042
Iron oxide nanoparticle (IONP); hepatocarcinoma (HCC); magnetic resonance imaging (MRI); liver contrast agent
19.  Gene expression profile analysis of human intervertebral disc degeneration 
Genetics and Molecular Biology  2013;36(3):448-454.
In this study, we used microarray analysis to investigate the biogenesis and progression of intervertebral disc degeneration. The gene expression profiles of 37 disc tissue samples obtained from patients with herniated discs and degenerative disc disease collected by the National Cancer Institute Cooperative Tissue Network were analyzed. Differentially expressed genes between more and less degenerated discs were identified by significant analysis of microarray. A total of 555 genes were significantly overexpressed in more degenerated discs with a false discovery rate of < 3%. Functional annotation showed that these genes were significantly associated with membrane-bound vesicles, calcium ion binding and extracellular matrix. Protein-protein interaction analysis showed that these genes, including previously reported genes such as fibronectin, COL2A1 and β-catenin, may play key roles in disc degeneration. Unsupervised clustering indicated that the widely used morphology-based Thompson grading system was only marginally associated with the molecular classification of intervertebral disc degeneration. These findings indicate that detailed, systematic gene analysis may be a useful way of studying the biology of intervertebral disc degeneration.
PMCID: PMC3795174  PMID: 24130454
genes; intervertebral disc degeneration; molecular classification; protein-protein interaction
20.  Post-translational regulation enables robust p53 regulation 
BMC Systems Biology  2013;7:83.
The tumor suppressor protein p53 plays important roles in DNA damage repair, cell cycle arrest and apoptosis. Due to its critical functions, the level of p53 is tightly regulated by a negative feedback mechanism to increase its tolerance towards fluctuations and disturbances. Interestingly, the p53 level is controlled by post-translational regulation rather than transcriptional regulation in this feedback mechanism.
We analyzed the dynamics of this feedback to understand whether post-translational regulation provides any advantages over transcriptional regulation in regard to disturbance rejection. When a disturbance happens, even though negative feedback reduces the steady-state error, it can cause a system to become less stable and transiently overshoots, which may erroneously trigger downstream reactions. Therefore, the system needs to balance the trade-off between steady-state and transient errors. Feedback control and adaptive estimation theories revealed that post-translational regulation achieves a better trade-off than transcriptional regulation, contributing to a more steady level of p53 under the influence of noise and disturbances. Furthermore, post-translational regulation enables cells to respond more promptly to stress conditions with consistent amplitude. However, for better disturbance rejection, the p53- Mdm2 negative feedback has to pay a price of higher stochastic noise.
Our analyses suggest that the p53-Mdm2 feedback favors regulatory mechanisms that provide the optimal trade-offs for dynamic control.
PMCID: PMC3844394  PMID: 23992617
Feedback control theory; p53-Mdm2 feedback loop; Robustness; Disturbance rejection
21.  The Effect of Particle Size on the Biodistribution of Low-modulus Hydrogel PRINT Particles 
There is a growing recognition that the deformability of particles used for drug delivery plays a significant role on their biodistribution and circulation profile. Understanding these effects would provide a crucial tool for the rational design of drug delivery systems. While particles resembling red blood cells (RBCs) in size, shape and deformability have extended circulation times and altered biodistribution profiles compared to rigid, but otherwise similar particles, the in vivo behavior of such highly deformable particles of varied size has not been explored. We report the fabrication of a series of discoid, monodisperse, low-modulus hydrogel particles with diameters ranging from 0.8 to 8.9 μm, spanning sizes smaller than and larger than RBCs. We injected these particles into healthy mice, and tracked their concentration in the blood and their distribution into major organs. These deformable particles all demonstrated some hold up in filtration tissues like the lungs and spleen, followed by release back into the circulation, characterized by decreases in particles in these tissues with concomitant increases in particle concentration in blood. Particles similar to red blood cells in size demonstrated longer circulation times, suggesting that this size and shape of deformable particle is uniquely suited to avoid clearance.
PMCID: PMC3416965  PMID: 22705460
hydrogel; deformability; biodistribution; long circulating; biomimetic
22.  An Activatable Near Infrared Fluorescent Probe for In Vivo Imaging of Fibroblast Activation Protein-alpha 
Bioconjugate chemistry  2012;23(8):1704-1711.
Fibroblast activation protein-alpha (FAPα) is a cell surface glycoprotein which is selectively expressed by tumor-associated fibroblasts in malignant tumors but rarely on normal tissues. FAPα has also been reported to promote tumor growth and invasion and therefore has been of increasing interest as a promising target for designing tumor-targeted drugs and imaging agents. Although medicinal study on FAPα inhibitors has led to the discovery of many FAPα-targeting inhibitors including a drug candidate in a phase II clinical trial, the development of imaging probes to monitor the expression and activity of FAPα in vivo has largely lagged behind. Herein we report an activatable near infrared (NIR) fluorescent probe (ANPFAP) for in vivo optical imaging of FAPα. The ANPFAP consists of a NIR dye (Cy5.5) and a quencher dye (QSY21) which are linked together by a short peptide sequence (KGPGPNQC) specific for FAPα cleavage. Because of the efficient fluorescence resonance energy transfer (FRET) between Cy5.5 and QSY21 in ANPFAP, high contrast on the NIR fluorescence signal can be achieved after the cleavage of the peptide sequence by FAPα both in vitro and in vivo. In vitro assay on ANPFAP indicated the specificity of the probe to FAPα. The in vivo optical imaging using ANPFAP showed fast tumor uptake as well as high tumor to background contrast on U87MG tumor models with FAPα expression, while much lower signal and tumor contrast were observed in the C6 tumor without FAPα expression, demonstrating the in vivo targeting specificity of the ANPFAP. Ex vivo imaging also demonstrated ANPFAP had high tumor uptake at 4 h post injection. Collectively, these results indicated that ANPFAP could serve as a useful NIR optical probe for early detection of FAPα expressing tumors.
PMCID: PMC3419799  PMID: 22812530
FAPα; NIRF; glioma; activatable probe; optical imaging
23.  A global change in RNA polymerase II pausing during the Drosophila midblastula transition 
eLife  2013;2:e00861.
Massive zygotic transcription begins in many organisms during the midblastula transition when the cell cycle of the dividing egg slows down. A few genes are transcribed before this stage but how this differential activation is accomplished is still an open question. We have performed ChIP-seq experiments on tightly staged Drosophila embryos and show that massive recruitment of RNA polymerase II (Pol II) with widespread pausing occurs de novo during the midblastula transition. However, ∼100 genes are strongly occupied by Pol II before this timepoint and most of them do not show Pol II pausing, consistent with a requirement for rapid transcription during the fast nuclear cycles. This global change in Pol II pausing correlates with distinct core promoter elements and associates a TATA-enriched promoter with the rapid early transcription. This suggests that promoters are differentially used during the zygotic genome activation, presumably because they have distinct dynamic properties.
eLife digest
Fertilized eggs—zygotes—develop into embryos via several distinct stages. In many animals, the zygote initially undergoes rapid rounds of genome replication; however, this hectic activity is not controlled by the zygote itself. Instead, the mother deposits RNA molecules in the egg as it forms inside her, and after the egg has been fertilized, these RNA molecules are translated into proteins that guide the development of the early embryo. Only at a stage called midblastula transition does the zygote take over control by transcribing its own RNA molecules.
Fruit flies start to transcribe their own genes en masse after completing thirteen rounds of DNA replication. However, some genes are already transcribed during the rapid cycles of DNA replication earlier in development. How these early genes are transcribed, and how the embryo shifts to more widespread transcription during the midblastula transition, are not well understood. In particular, it is not known if the molecular machinery needed to transcribe the genes is recruited a long time before transcription starts, or if it is recruited ‘just in time’. Here, Chen et al. explore how genes are switched on in the fruit fly zygote.
Genes are transcribed by a protein complex called RNA polymerase, which binds to DNA sequences, called promoters, within the genes. Chen et al. used a technique called ChIP-Seq to determine how much RNA polymerase was bound to the DNA before, during and after the midblastula transition. Before the transition—from about eight rounds of DNA replication onward—RNA polymerase was bound to only about 100 genes, and was active in most of these cases. In contrast, after the transition, RNA polymerase had been recruited to the promoters of around 4000 genes (fruit flies have a total of about 14,000 genes). However, it was often found in a paused, rather than active, form, at these genes, which is thought to help ensure that their transcription can occur on a precise schedule.
Chen et al. then used computer analyses to test the theory that differences in the DNA sequences of the gene promoters might determine which genes the RNA polymerase bound to, and whether or not the polymerase underwent pausing or became active immediately. Strikingly, there were clear differences in the sequence motifs that recruited RNA polymerase to the promoters of genes that were transcribed immediately and those that showed pausing of the polymerase. Moreover, genes that were transcribed before the midblastula transition were shorter, on average, than those transcribed after. This suggests that transcription during the rapid genome replication cycles has to occur quickly and therefore lacks pausing. Together, these findings present a biological rationale for differences in how genes are first transcribed during fruit fly development.
PMCID: PMC3743134  PMID: 23951546
transcription; ChIP-seq; promoters; chromatin; zygotic genome activation; RNA polymerase pausing; D. melanogaster
24.  Characterization of Tumor Suppressive Function of cornulin in Esophageal Squamous Cell Carcinoma 
PLoS ONE  2013;8(7):e68838.
By using cDNA microarray analysis, we identified cornulin (CRNN) gene was frequently downregulated in esophageal squamous cell carcinoma (ESCC). In the present study, we investigated the role of CRNN in ESCC development. The results showed that CRNN was frequently downregulated in primary ESCCs in both mRNA level (26/56, 46.4%) and protein level (137/249, 55%), which was significantly associated with lymph node metastases (P=0.027), advanced clinical stage (P=0.039), and overall survival rate (P<0.001). Multivariate analysis indicated that the CRNN downregulation was an independent prognostic factor for ESCC. Functional studies with both in vitro and in vivo assays demonstrated that CRNN had strong tumor suppressive ability in ESCC cells. The tumor-suppressive mechanism of CRNN was associated with its role in cell cycle arrest at G1/S checkpoint by upregulating expressions of P21WAF1/CIP1 and Rb. Silencing CRNN expression by RNA interference could effectively inhibit its tumor suppressive effect. In conclusion, our findings demonstrate that CRNN is a tumor suppressor gene that plays a critical tumor suppressive role in ESCC.
PMCID: PMC3722219  PMID: 23894350
25.  Single-Row or Double-Row Fixation Technique for Full-Thickness Rotator Cuff Tears: A Meta-Analysis 
PLoS ONE  2013;8(7):e68515.
The single-row and double-row fixation techniques have been widely used for rotator cuff tears. However, whether the double-row technique produces superior clinical or anatomic outcomes is still considered controversial. This study aims to use meta-analysis to compare the clinical and anatomical outcomes between the two techniques.
The Pubmed, Embase, and Cochrane library databases were searched for relevant studies published before November 1, 2012. Studies clearly reporting a comparison of the single-row and double-row techniques were selected. The Constant, ASES, and UCLA scale systems and the rotator cuff integrity rate were evaluated. The weighted mean differences and relative risks were calculated using a fixed-effects or random-effects model.
Eight studies were included in this meta-analysis. The weighted mean differences of the ASES (−0.84; P = 0.04; I2 = 0%) and UCLA (−0.75; P = 0.007; I2 = 0%) scales were significantly low in the single-row group for full-thickness rotator cuff tears. For tear sizes smaller than 3 cm, no significant difference was found between the groups no matter in Constant (P = 0.95; I2 = 0%), ASES (P = 0.77; I2 = 0%), or UCLA (P = 0.24; I2 = 13%) scales. For tear sizes larger than 3 cm, the ASES (−1.95; P = 0.001; I2 = 49%) and UCLA (−1.17; P = 0.006; I2 = 0%) scales were markedly lower in the single-row group. The integrity of the rotator cuff (0.81; P = 0.0004; I2 = 10%) was greater and the partial thickness retear rate (1.93; P = 0.007; I2 = 10%) was less in the double-row group. Full-thickness retears showed no difference between the groups (P = 0.15; I2 = 0%).
The meta-analysis suggests that the double-row fixation technique increases post-operative rotator cuff integrity and improves the clinical outcomes, especially for full-thickness rotator cuff tears larger than 3 cm. For tear sizes smaller than 3 cm, there was no difference in the clinical outcomes between the two techniques.
Level of Evidence
Level I.
PMCID: PMC3708899  PMID: 23874649

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