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1.  The Phosphodiesterase-4 (PDE4) Inhibitor Rolipram Decreases Ethanol Seeking and Consumption in Alcohol-preferring Fawn-Hooded Rats 
Alcohol dependence is a complex psychiatric disorder demanding development of novel pharmacotherapies. Since the cyclic AMP (cAMP) signaling cascade has been implicated in mediating behavioral responses to alcohol, key components in this cascade may serve as potential treatment targets. Phosphodiesterase 4 (PDE4), an enzyme that specifically catalyzes the hydrolysis of cAMP, represents as a key point in regulating intracellular cAMP levels. Thus, it was of interest to determine whether PDE4 was involved in the regulation of alcohol use and abuse.
Male Fawn-Hooded (FH/Wjd) rats were tested for 5% (v/v) ethanol and 10% (w/v) sucrose operant oral self-administration following treatment with the selective PDE4 inhibitor rolipram (0.0125, 0.025, or 0.05 mg/kg, s.c.); rolipram at higher doses (0.05, 0.1, and 0.2 mg/kg, s.c.) was tested to determine its impact on the intake of ethanol, sucrose, or water using the two-bottle choice drinking paradigm. Subsequent open-field testing was performed to evaluate the influence of higher doses of rolipram on locomotor activity.
Acute administration of rolipram dose-dependently reduced operant self-administration of 5% ethanol, but had no effect on 10% sucrose responding. Time-course assessment revealed significant decreases in ethanol consumption after rolipram (0.1, 0.2 mg/kg) treatment in continuous- and intermittent-access to ethanol at 5% or 10%, respectively. Moreover, chronic rolipram treatment time-dependently decreased 5% ethanol consumption and preference during treatment days and after the termination of rolipram administration. Rolipram at the highest doses (0.1 and 0.2 mg/kg) did decrease locomotor activity, but the effect lasted only 10 and 20 min, respectively, which did not likely alter long-term ethanol drinking.
These results suggest that PDE4 plays a role in alcohol seeking and consumption behavior. Drugs interfering with PDE4 may be a potential pharmacotherapy for alcohol dependence.
PMCID: PMC4335658  PMID: 22671516
Cyclic AMP Signaling; Phosphodiesterase-4 (PDE4); Rolipram; FH/Wjd Rat; Ethanol Intake
2.  Genetic variants in Fas signaling pathway genes and risk of gastric cancer 
Populations in north central China are at high risk for gastric cancers (GC), and altered FAS-mediated cell signaling and/or apoptosis may contribute to this risk. We examined the association of 554 single nucleotide polymorphisms (SNPs) in 53 Fas signaling-related genes using a pathway-based approach in 1758 GC cases (1126 gastric cardia adenocarcinomas (GCA) and 632 gastric noncardia adenocarcinomas (GNCA)), and 2111 controls from a genome-wide association study (GWAS) of GC in ethnic Chinese. SNP associations with risk of overall GC, GCA and GNCA were evaluated using unconditional logistic regressions controlling for age, sex and study. Gene- and pathway-based associations were tested using the adaptive rank-truncated product (ARTP) method. Statistical significance was evaluated empirically by permutation. Significant pathway-based associations were observed for Fas signaling with risk of overall GC (P = 5.5E-04) and GCA (P = 6.3E-03), but not GNCA (P = 8.1E-02). Among examined genes in the Fas signaling pathway, MAP2K4, FAF1, MAPK8, CASP10, CASP8, CFLAR, MAP2K1, CAP8AP2, PAK2 and IKBKB were associated with risk of GC (nominal P < 0.05), and FAF1 and MAPK8 were significantly associated with risk of both GCA and GNCA (nominal P < 0.05). Our examination of genetic variation in the Fas signaling pathway is consistent with an association of altered Fas signaling and/or apoptosis with risk of GC. As one of the first attempts to investigate a pathway-level association, our results suggest that these genes and the Fas signaling pathway warrant further evaluation in relation to GC risk in other populations.
PMCID: PMC3858487  PMID: 23921907
Gastric cancer; gastric cardia; gastric noncardia; Fas signaling; genetic variants; GWAS; single nucleotide polymorphisms; pathway genes
3.  Giant local circular dichroism within an asymmetric plasmonic nanoparticle trimer 
Scientific Reports  2015;5:8207.
We investigated the near-field response in silver nanoparticle aggregates to the excitation of circular polarized light. In a right-angle trimer system, the local field intensity excited by right-hand circularly polarized light is almost one thousand times larger than the left-hand case. By analyzing the polarization and phase of the local field in plasmonic hotspots, we found this local circular dichroism is originated from the near-field interference excited by orthogonal polarized incident lights. The local circular dichroism can be tuned by the rotation of the third particle, the interparticle distance, and the dielectric environment. This phenomenon could also widely exist in more complicated nanoaggregates. These findings would benefit for resolving light handedness, and enhancing circular dichroism and optical activity.
PMCID: PMC4314634  PMID: 25644597
4.  Survival outcomes of First Nations patients with oral cavity squamous cell carcinoma (Poliquin 2014) 
Oral cavity squamous cell carcinoma (OCSCC) is the most common head and neck cancer, affecting approximately 2000 Canadians yearly. Analysis of Canadian Cancer Registry data has shown that the incidence of oral cavity cancer is decreasing and survival outcomes are improving.
There are significant health disparities in First Nations (FN) people in Canada. The incidence of cancer in FN groups is significantly lower when compared to the general population, but the cancer-related morbidity and mortality is significantly higher. There is no Canadian literature currently for OCSCC, or any other head and neck cancer, that compares survival outcomes of FN to the overall population. Therefore, the objective of this study is to determine whether there is a difference in epidemiology and survival outcomes between FN and non-FN patients with OCSCC.
This is a retrospective study of a population-based, prospectively-collected database from Alberta Cancer Registry (ACR). Patients with OCSCC, diagnosed and treated in Alberta between 1998 and 2009 were included. ACR data collected included patient gender, age at diagnosis, tobacco and alcohol use, FN status, TNM staging, performance status, date of death, cause of death, and follow-up. FN status was identified through the Alberta Health and Wellness registry and through postal code correlation for those who live on reserves.
A total of 583 patients with OCSCC were included in this study. Of these, 19 were identified as being FN, leaving 564 non-FN patients. When comparing the FN and non-FN groups, there is no significant difference in baseline demographics. Estimated yearly incidences for OCSCC in the Alberta population (all ages) and FN patients are 1.74/100,000 and 1.32/100,000 respectively (p = 0.23). Significant differences are seen in overall survival (OS) (5-year OS 58.1% for non-FN and 33.7% for FN) and for disease-specific survival (DSS) (5-year DSS 67.8% for non-FN and 44.5% for FN). Multivariate analysis confirmed FN patients have a significant increase risk of death in OS and DSS, with hazard ratios of 4.20 (p = 0.01) and 4.57 (p = 0.02), respectively.
The overall survival and disease specific survival are significantly lower in FN patients compared to non-FN patients with OCSCC.
PMCID: PMC4323206  PMID: 25645260
Head and neck cancer; Oral cavity cancer; First Nations
5.  Reduced expression levels of let-7c in human breast cancer patients 
Oncology Letters  2015;9(3):1207-1212.
Circulating microRNAs (miRNAs) are important in the diagnosis of a number of diseases, since serum or plasma miRNAs are more stable compared with miRNA isolated from blood samples. The aim of the present study was to investigate the association between the expression levels of serum let-7c miRNA and the clinical diagnosis of breast cancer (BC). The circulating let-7c levels of 90 BC patients and 64 healthy controls were determined by performing a reverse transcription-quantitative polymerase chain reaction assay. The results demonstrated that let-7c expression was downregulated in the BC tissues compared with the paracarcinoma control tissues. In addition, the let-7c expression in the serum of BC patients was significantly lower compared with the healthy controls (P<0.01). Using a cutoff value of 0.374×103 copies/ml, the serum expression levels of let-7c exhibited 87.5% sensitivity and 78.9% specificity for distinguishing BC patients from healthy controls (area under the receiver operating characteristic curve, 0.848; 95% confidence interval, 0.785–0.911). Furthermore, the results demonstrated that the serum expression levels of let-7c were significantly higher in premenopausal compared with postmenopausal patients (P<0.05), supporting the hypothesis that postmenopausal status may affect the serum expression levels of let-7c. However, no statistically significant differences were detected in the serum levels of let-7c between ER (or PR)-positive and -negative patients. Therefore, the current study hypothesized that serum let-7c may be used as a novel and valuable biomarker for the diagnosis of BC.
PMCID: PMC4315068  PMID: 25663883
circulating miRNA; breast cancer; let-7c; predictive factor; receiver operating characteristic analysis
6.  Age-Related and Depot-Specific Changes in White Adipose Tissue of Growth Hormone Receptor-Null Mice 
Growth hormone receptor-null (GHR−/−) mice are dwarf, insulin sensitive, and long-lived in spite of increased adiposity. However, their adiposity is not uniform, with select white adipose tissue (WAT) depots enlarged. To study WAT depot–specific effects on insulin sensitivity and life span, we analyzed individual WAT depots of 12- and 24-month-old GHR− /− and wild-type (WT) mice, as well as their plasma levels of selected hormones. Adipocyte sizes and plasma insulin, leptin, and adiponectin levels decreased with age in both GHR− /− and WT mice. Two-dimensional gel electrophoresis proteomes of WAT depots were similar among groups, but several proteins involved in endocytosis and/or cytoskeletal organization (Ehd2, S100A10, actin), anticoagulation (S100A10, annexin A5), and age-related conditions (alpha2-macroglobulin, apolipoprotein A-I, transthyretin) showed significant differences between genotypes. Because Ehd2 may regulate endocytosis of Glut4, we measured Glut4 levels in the WAT depots of GHR− /− and WT mice. Inguinal WAT of 12-month-old GHR− /− mice displayed lower levels of Glut4 than WT. Overall, the protein changes detected in this study offer new insights into possible mechanisms contributing to enhanced insulin sensitivity and extended life span in GHR− /− mice.
PMCID: PMC3859361  PMID: 23873966
Aging; Growth hormone receptor; Adipose tissue depots; Endocytosis; Glut4.
7.  Clinical Characteristics and Impact of Diabetes Mellitus on Outcomes in Patients with Nonvalvular Atrial Fibrillation 
Yonsei Medical Journal  2014;56(1):62-71.
Studies have shown that diabetes mellitus (DM) is a risk factor for cardiovascular disease, including atrial fibrillation (AF); however, the clinical characteristics and prognostic impact of DM in patients with nonvalvular AF have not been well understood in China.
Materials and Methods
Included were 1644 consecutive patients with nonvalvular AF. Endpoints included all-cause mortality, cardiovascular mortality, stroke, major bleeding, and combined endpoint events (CEE) during a 1-year follow-up.
The prevalence of DM was 16.8% in nonvalvular AF patients. Compared with non-diabetic AF patients, diabetic AF patients were older and tended to coexist with other cardiovascular diseases. Most patients with DM (93.5%) were eligible for anticoagulation, as determined by CHADS2 scores. However, only 11.2% of patients received anticoagulation. During a 1-year follow-up, the all-cause mortality and CEE rate in the DM group were significantly higher than those of the non-DM group, while the incidence of stroke was comparable. After multivariate adjustments, DM was still an independent risk factor for 1-year all-cause mortality [hazard ratio (HR)=1.558; 95% confidence interval (CI) 1.126-2.156; p=0.007], cardiovascular mortality (HR=1.615; 95% CI 1.052-2.479; p=0.028), and CEE (HR=1.523; 95% CI 1.098-2.112; p=0.012), yet not for stroke (HR=1.119; 95% CI 0.724-1.728; p=0.614).
DM is a common morbidity coexisting with nonvalvular AF and is associated with an increased risk of 1-year all-cause mortality, cardiovascular mortality, and CEE. However, no increased risk of stroke was found during a 1-year follow-up in patients with AF and DM.
PMCID: PMC4276779  PMID: 25510748
Nonvalvular atrial fibrillation; diabetes mellitus; anticoagulation; outcomes
8.  Efficacy of Combined Vancomycin and Fosfomycin against Methicillin-Resistant Staphylococcus aureus in Biofilms In Vivo 
PLoS ONE  2014;9(12):e113133.
Infection by methicillin-resistant Staphylococcus aureus (MRSA) is a life-threatening condition, and formation of biofilms can lead to treatment failure in a clinical setting. The aim of this study was to demonstrate the in vivo bactericidal effects of a combination of vancomycin (VAN) and fosfomycin (FOS) against MRSA in a rat carboxymethyl cellulose-pouch biofilm model. The results of the time-kill assay showed that the combination therapy was capable of killing at low minimal inhibitory concentrations (MIC) (½× MIC VAN +1× MIC FOS and 1× MIC VAN + 1× MIC FOS). In the in vivo study, a synergistically bactericidal effect was observed when using the combination therapy on MRSA embedded in the mature biofilm model. In comparison with the untreated control group and the groups receiving either VAN or FOS alone, the rats treated with combination therapy had lower MRSA colony counts in exudates from the pouch, lower white blood cell and neutrophil counts, and C-reactive protein (CRP) in peripheral blood. Furthermore, histological analysis of the pouch wall indicated combination therapy resulted in disappearance of biofilm-like structures, marked decrease in necrosis, and formation of granular tissue. In conclusion, the combination of VAN with FOS had a synergistic bactericidal effect on chronic MRSA infection embedded in biofilm, providing an alternative approach to treating this condition.
PMCID: PMC4281042  PMID: 25551618
9.  16p13.3 duplication associated with non-syndromic pierre robin sequence with incomplete penetrance 
Molecular Cytogenetics  2014;7(1):76.
Pierre Robin sequence (PRS) is a condition present at birth. It is characterized by micrognathia, cleft palate, upper airway obstruction, and feeding problems. Multiple etiologies including genetic defects have been documented in patients with syndromic, non-syndromic, and isolated PRS.
Case presentation
We report a 4-year-old boy with a complex small supernumerary marker chromosome (sSMC) who had non-syndromic Pierre Robin sequence (PRS). The complex marker chromosome, der(14)t(14;16)(q11.2;p13.13), was initially identified by routine chromosomal analysis and subsequently characterized by array-comparative genomic hybridization (array CGH) and confirmed by fluorescence in situ hybridization (FISH). Clinical manifestations included micrognathia, U-type cleft palate, bilateral congenital ptosis, upslanted and small eyes, bilateral inguinal hernias, umbilical hernia, bilateral clubfoot, and short fingers and toes. To our best knowledge, this was the first case diagnosed with non-syndromic PRS associated with a complex sSMC, which involved a 3.8 Mb gain in the 14q11.2 region and an 11.8 Mb gain in the 16p13.13-pter region.
We suggest that the duplicated chromosome segment 16p13.3 possibly may be responsible for the phenotypes of our case and also may be a candidate locus of non-syndromic PRS. The duplicated CREBBP gene within chromosome 16p13.3 is associated with incomplete penetrance regarding the mandible development anomalies. Further studies of similar cases are needed to support our findings.
PMCID: PMC4260201  PMID: 25493098
Small supernumerary marker chromosome; Pierre robin sequence; Array CGH; FISH; 16p13.3
10.  Inhibition of phosphodiesterase-4 decreases ethanol intake in mice 
Psychopharmacology  2011;218(2):331-339.
Cyclic AMP (cAMP)-protein kinase A (PKA) signaling has been implicated in the regulation of ethanol consumption. Phosphodiesterase-4 (PDE4) specifically hydrolyzes cAMP and plays a critical role in controlling intracellular cAMP levels in the brain. However, the role of PDE4 in ethanol consumption remains unknown.
To examine whether PDE4 was involved in regulating ethanol intake.
The two-bottle choice paradigm was used to assess intake of ethanol, sucrose, and quinine in C57BL/6J mice treated with the selective PDE4 inhibitor rolipram or Ro 20-1724; locomotor activity was also monitored using the open-field test in mice treated with rolipram.
Administration (i.p.) of either rolipram (0.25 and 0.5 mg/kg) or Ro 20-1724 (10 mg/kg) reduced ethanol intake and preference by 60-80%, but did not alter total fluid intake. In contrast, rolipram even at the higher dose of 0.5 mg/kg was not able to affect intake of sucrose or quinine, alcohol-induced sedation, or blood ethanol elimination. At 0.5 mg/kg, rolipram did decrease locomotor activity, but the effect only lasted for approximately 40 min, which did not likely affect behavior of ethanol drinking.
These results suggest that PDE4 is a novel target for drugs that reduce ethanol intake; PDE4 inhibitors may be used for treatment of alcohol dependence.
PMCID: PMC4210373  PMID: 21509503
Ethanol intake; phosphodiesterase-4 (PDE4); two-bottle choice; rolipram; locomotor activity; sucrose; quinine; cyclic AMP; mice
11.  Metabolic tumour volume as a prognostic factor for oral cavity squamous cell carcinoma treated with primary surgery 
Metabolic tumour volume (MTV) obtained from pre-treatment 18 F-fluorodeoxydeglucose positron emission tomography with computed tomography (PET-CT) has been validated as an independent predictive factor of outcomes in head and neck cancer patients (HNC) treated with primary chemoradiotherapy (CRT). However its role in patients treated with primary surgery has not yet been studied.
To evaluate the prognostic value of MTV in patients treated with primary surgery for oral cavity squamous cell carcinoma (OCSCC).
Demographic and survival data was obtained from patients diagnosed with OCSCC from 2008–2012 in Alberta, Canada. All patients included in the study had PET-CT scan before curative surgical resection. MTV and maximum standardized uptake value (SUVmax) value was delineated from pre-treatment PET-CT scans using Segami Oasis software (Columbus, OH). MTV and SUVmax were divided into intertertile thirds before statistical analysis to allow for in-group comparison of survival.
A total of 80 patients were analyzed using SPSS ver. 20.0 (SPSS Inc, Chicago, IL). Five-year overall, and disease-free survival using Kaplan-Meier curves were 70% and 73% respectively. When the combined SUVmax (tumour primary and locoregional metastasis) was evaluated, it failed to predict overall (HR = 1.0, p = 0.99) or disease-free survival (HR = 1.0, p = 0.227).
Conversely an increase in MTV of 17.5 mL (difference between the highest and lowest MTV tertile) was associated with a 12.4 fold increase in risk of disease recurrence (p < 0.001) and an 11.2 fold increase in the risk of death (p < 0.05).
This study shows that MTV is an independent adverse prognostic factor for death and disease recurrence in OCSCC treated with primary surgery.
PMCID: PMC4198685  PMID: 25312990
Metabolic tumour volume; Standardized uptake value; Imaging; Tumour marker; Head and neck cancer
12.  Ytterbium-doped fiber laser passively mode locked by few-layer Molybdenum Disulfide (MoS2) saturable absorber functioned with evanescent field interaction 
Scientific Reports  2014;4:6346.
By coupling few-layer Molybdenum Disulfide (MoS2) with fiber-taper evanescent light field, a new type of MoS2 based nonlinear optical modulating element had been successfully fabricated as a two-dimensional layered saturable absorber with strong light-matter interaction. This MoS2-taper-fiber device is not only capable of passively mode-locking an all-normal-dispersion ytterbium-doped fiber laser and enduring high power laser excitation (up to 1 W), but also functions as a polarization sensitive optical modulating component (that is, different polarized light can induce different nonlinear optical response). Thanks to the combined advantages from the strong nonlinear optical response in MoS2 together with the sufficiently-long-range interaction between light and MoS2, this device allows for the generation of high power stable dissipative solitons at 1042.6 nm with pulse duration of 656 ps and a repetition rate of 6.74 MHz at a pump power of 210 mW. Our work may also constitute the first example of MoS2-enabled wave-guiding photonic device, and potentially give some new insights into two-dimensional layered materials related photonics.
PMCID: PMC4161963  PMID: 25213108
13.  PDE4 as a target for cognition enhancement 
The second messengers cAMP and cGMP mediate fundamental aspects of brain function relevant to memory, learning and cognitive functions. Consequently, cyclic nucleotide phosphodiesterases (PDEs), the enzymes that inactivate the cyclic nucleotides, are promising targets for the development of cognition-enhancing drugs.
Areas covered
PDE4 is the largest of the eleven mammalian PDE families. This review covers the properties and functions of the PDE4 family, highlighting procognitive and memory-enhancing effects associated with their inactivation.
Expert opinion
PAN-selective PDE4 inhibitors exert a number of memory- and cognition-enhancing effects and have neuroprotective and neuroregenerative properties in preclinical models. The major hurdle for their clinical application is to target inhibitors to specific PDE4 isoforms relevant to particular cognitive disorders to realize the therapeutic potential while avoiding side effects, in particular emesis and nausea. The PDE4 family comprises four genes, PDE4A-D, each expressed as multiple variants. Progress to date stems from characterization of rodent models with selective ablation of individual PDE4 subtypes, revealing that individual subtypes exert unique and non-redundant functions in the brain. Thus, targeting specific PDE4 subtypes, as well as splicing variants or conformational states, represents a promising strategy to separate the therapeutic benefits from the side effects of PAN-PDE4 inhibitors.
PMCID: PMC4066988  PMID: 23883342
Alzheimer’s disease; schizophrenia; cognition; memory; cyclic nucleotide; cAMP; phosphodiesterase; PDE4; Rolipram
14.  Fast SAR Image Change Detection Using Bayesian Approach Based Difference Image and Modified Statistical Region Merging 
The Scientific World Journal  2014;2014:862875.
A novel fast SAR image change detection method is presented in this paper. Based on a Bayesian approach, the prior information that speckles follow the Nakagami distribution is incorporated into the difference image (DI) generation process. The new DI performs much better than the familiar log ratio (LR) DI as well as the cumulant based Kullback-Leibler divergence (CKLD) DI. The statistical region merging (SRM) approach is first introduced to change detection context. A new clustering procedure with the region variance as the statistical inference variable is exhibited to tailor SAR image change detection purposes, with only two classes in the final map, the unchanged and changed classes. The most prominent advantages of the proposed modified SRM (MSRM) method are the ability to cope with noise corruption and the quick implementation. Experimental results show that the proposed method is superior in both the change detection accuracy and the operation efficiency.
PMCID: PMC4167452  PMID: 25258740
15.  Comparison of the clinical features and outcomes in two age-groups of elderly patients with atrial fibrillation 
Atrial fibrillation (AF) disproportionately affects older adults. However, direct comparison of clinical features, medical therapy, and outcomes in AF patients aged 65–74 and ≥75 years is rare. The objective of the present study was to evaluate the differences in clinical characteristics and prognosis in these two age-groups of geriatric patients with AF.
Materials and methods
A total of 1,336 individuals aged ≥65 years from a Chinese AF registry were assessed in the present study: 570 were in the 65- to 74-year group, and 766 were in the ≥75-year group. Multivariable Cox hazards regression was performed to analyze the major adverse cardiac events (MACEs) between groups.
In our population, the older group were more likely to have coronary artery disease, hypertension, previous stroke, cognitive disorder, or chronic obstructive pulmonary disease, and the 65- to 74-year group were more likely to have valvular heart disease, left ventricular systolic dysfunction, or sleep apnea. The older patients had 1.2-fold higher mean CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes, stroke) scores, but less probability of being prescribed drugs. Compared with those aged 65–74 years, the older group had a higher risk of death (hazard ratio 2.881, 95% confidence interval 1.981–4.189; P<0.001) or MACE (hazard ratio 2.202, 95% confidence interval 1.646–2.945; P<0.001) at the 1-year follow-up. In multivariable Cox analyses, secondary AF diagnosis, a history of chronic obstructive pulmonary disease, and left ventricular systolic dysfunction were independent predictors of MACE in the older group.
Patients aged ≥75 years had a worse prognosis than those aged 65–74 years, and were associated with a higher risk of both death and MACE.
PMCID: PMC4136954  PMID: 25143720
atrial fibrillation; geriatric patients; mortality; major adverse cardiac events (MACE)
16.  On the Generalization of Lehmer Problem and High-Dimension Kloosterman Sums 
The Scientific World Journal  2014;2014:726053.
For any fixed integer k ≥ 2 and integer r with (r, p) = 1, it is clear that there exist k integers 1 ≤ ai ≤ p − 1 (i = 1, 2, …, k) such that a1a2 ⋯ ak ≡ r mod p. Let N(k, r; p) denote the number of all (a1, a2, ⋯ ak) such that a1a2 ⋯ ak ≡ r mod p and 2†(a1 + a2 + ⋯ + ak). In this paper, we will use the analytic method and the estimate for high-dimension Kloosterman sums to study the asymptotic properties of N(k, r; p) and give two interesting asymptotic formulae for it.
PMCID: PMC4124714  PMID: 25133256
17.  Critical coupling with graphene-based hyperbolic metamaterials 
Scientific Reports  2014;4:5483.
In order to effectively realize and control the critical coupling, a graphene-based hyperbolic metamaterial has been proposed to replace the absorbing thin film in the critically coupled resonance structure. Our calculations demonstrate that the critical coupling effect (near-perfect light absorption) can be achieved at the near-infrared wavelength by using this layered structure, while the critical coupling frequency can be tuned by varying the Fermi energy level of graphene sheets via electrostatic biasing. Moreover, we show that the critical coupling frequency can be tuned by changing the thickness of the dielectric or layer number of the graphene sheets in the unit cell of the graphene-dielectric HMM. The optimization performance has also been indicated, which may offer an opportunity towards the experimental designs of high efficient graphene based critical coupling devices.
PMCID: PMC4073170  PMID: 24970717
18.  Top-down Proteomics Reveals Concerted Reductions in Myofilament and Z-disc Protein Phosphorylation after Acute Myocardial Infarction* 
Molecular & Cellular Proteomics : MCP  2014;13(10):2752-2764.
Heart failure (HF) is a leading cause of morbidity and mortality worldwide and is most often precipitated by myocardial infarction. However, the molecular changes driving cardiac dysfunction immediately after myocardial infarction remain poorly understood. Myofilament proteins, responsible for cardiac contraction and relaxation, play critical roles in signal reception and transduction in HF. Post-translational modifications of myofilament proteins afford a mechanism for the beat-to-beat regulation of cardiac function. Thus it is of paramount importance to gain a comprehensive understanding of post-translational modifications of myofilament proteins involved in regulating early molecular events in the post-infarcted myocardium. We have developed a novel liquid chromatography–mass spectrometry-based top-down proteomics strategy to comprehensively assess the modifications of key cardiac proteins in the myofilament subproteome extracted from a minimal amount of myocardial tissue with high reproducibility and throughput. The entire procedure, including tissue homogenization, myofilament extraction, and on-line LC/MS, takes less than three hours. Notably, enabled by this novel top-down proteomics technology, we discovered a concerted significant reduction in the phosphorylation of three crucial cardiac proteins in acutely infarcted swine myocardium: cardiac troponin I and myosin regulatory light chain of the myofilaments and, unexpectedly, enigma homolog isoform 2 (ENH2) of the Z-disc. Furthermore, top-down MS allowed us to comprehensively sequence these proteins and pinpoint their phosphorylation sites. For the first time, we have characterized the sequence of ENH2 and identified it as a phosphoprotein. ENH2 is localized at the Z-disc, which has been increasingly recognized for its role as a nodal point in cardiac signaling. Thus our proteomics discovery opens up new avenues for the investigation of concerted signaling between myofilament and Z-disc in the early molecular events that contribute to cardiac dysfunction and progression to HF.
PMCID: PMC4189000  PMID: 24969035
19.  Senescent-induced dysregulation of cAMP/CREB signaling and correlations with cognitive decline 
Brain research  2013;1516:93-109.
It is well known that alongside senescence there is a gradual decline in cognitive ability, most noticeably certain kinds of memory such as working, episodic, spatial, and long term memory. However, until recently, not much has been known regarding the specific mechanisms responsible for the decline in cognitive ability with age. Over the past decades, researchers have become more interested in cAMP signaling, and its downstream transcription factor cAMP response element binding protein (CREB) in the context of senescence. However, there is still a lack of understanding on what ultimately causes the cognitive deficits observed with senescence. This review will focus on the changes in intracellular signaling in the brain, more specifically, alterations in cAMP/CREB signaling in aging. In addition, the downstream effects of altered cAMP signaling on cognitive ability with age will be further discussed. Overall, understanding the senescent-related changes that occur in cAMP/CREB signaling could be important for the development of novel drug targets for both healthy aging, and pathological aging such as Alzheimer's disease.
PMCID: PMC3760033  PMID: 23623816
Aging; Memory; Camp; CREB; Phosphodiesterase; Protein kinase A
20.  Interactome Profile of the Host Cellular Proteins and the Nonstructural Protein 2 of Porcine Reproductive and Respiratory Syndrome Virus 
PLoS ONE  2014;9(6):e99176.
The nonstructural protein 2 (NSP2) is considered to be one of crucial viral proteins in the replication and pathogenesis of porcine reproductive and respiratory syndrome virus (PRRSV). In the present study, the host cellular proteins that interact with the NSP2 of PRRSV were immunoprecipitated with anti-Myc antibody from the MARC-145 cells infected by a recombinant PRRSV with 3xMyc tag insertion in its NSP2-coding region, and then 285 cellular proteins interacting with NSP2 were identified by LC-MS/MS. The Gene Ontology and enriched KEGG Pathway bioinformatics analyses indicated that the identified proteins could be assigned to different subcellular locations and functional classes. Functional analysis of the interactome profile highlighted cellular pathways associated with infectious disease, translation, immune system, nervous system and signal transduction. Two interested cellular proteins–BCL2-associated athanogene 6 (BAG6) and apoptosis-inducing factor 1 (AIF1) which may involve in transporting of NSP2 to Endoplasmic reticulum (ER) or PRRSV-driven apoptosis were validated by Western blot. The interactome data between PRRSV NSP2 and cellular proteins contribute to the understanding of the roles of NSP2 in the replication and pathogenesis of PRRSV, and also provide novel cellular target proteins for elucidating the associated molecular mechanisms of the interaction of host cellular proteins with viral proteins in regulating the viral replication.
PMCID: PMC4047090  PMID: 24901321
21.  A Disturbance Rejection Framework for the Study of Traditional Chinese Medicine 
The traditional Chinese medicine (TCM) is explained in the language of engineering cybernetics (EC), an engineering science with the tradition of rigor and long history of practice. The inherent connection is articulated between EC, as a science of interrelations, and the Chinese conception of Wuxing. The combined cybernetic model of Wuxing seems to have significant explaining power for the TCM and could potentially facilitate better communications of the insights of the TCM to the West. In disturbance rejection, an engineering concept, a great metaphor, is found to show how the TCM is practiced, using the liver cancer pathogenesis and treatment as a case study. The results from a series of experimental studies seem to lend support to the cybernetic model of Wuxing and the principles of disturbance rejection.
PMCID: PMC4065676  PMID: 24995034
22.  Transcriptomes and Proteomes Define Gene Expression Progression in Pre-meiotic Maize Anthers 
G3: Genes|Genomes|Genetics  2014;4(6):993-1010.
Plants lack a germ line; consequently, during reproduction adult somatic cells within flowers must switch from mitotic proliferation to meiosis. In maize (Zea mays L.) anthers, hypoxic conditions in the developing tassel trigger pre-meiotic competence in the column of pluripotent progenitor cells in the center of anther lobes, and within 24 hr these newly specified germinal cells have patterned their surrounding neighbors to differentiate as the first somatic niche cells. Transcriptomes were analyzed by microarray hybridization in carefully staged whole anthers during initial specification events, after the separation of germinal and somatic lineages, during the subsequent rapid mitotic proliferation phase, and during final pre-meiotic germinal and somatic cell differentiation. Maize anthers exhibit a highly complex transcriptome constituting nearly three-quarters of annotated maize genes, and expression patterns are dynamic. Laser microdissection was applied to begin assigning transcripts to tissue and cell types and for comparison to transcriptomes of mutants defective in cell fate specification. Whole anther proteomes were analyzed at three developmental stages by mass spectrometric peptide sequencing using size-fractionated proteins to evaluate the timing of protein accumulation relative to transcript abundance. New insights include early and sustained expression of meiosis-associated genes (77.5% of well-annotated meiosis genes are constitutively active in 0.15 mm anthers), an extremely large change in transcript abundances and types a few days before meiosis (including a class of 1340 transcripts absent specifically at 0.4 mm), and the relative disparity between transcript abundance and protein abundance at any one developmental stage (based on 1303 protein-to-transcript comparisons).
PMCID: PMC4065268  PMID: 24939185
archesporial cell; cell fate specification; Multiple archesporial cells 1; mac1; pre-meiotic development; genetics of sex
23.  The Effect of Amino Density on the Attachment, Migration, and Differentiation of Rat Neural Stem Cells In Vitro 
Molecules and Cells  2013;35(5):436-443.
Artificial extracellular matrices play important roles in the regulation of stem cell behavior. To generate materials for tissue engineering, active functional groups, such as amino, carboxyl, and hydroxyl, are often introduced to change the properties of the biomaterial surface. In this study, we chemically modified coverslips to create surfaces with different amino densities and investigated the adhesion, migration, and differentiation of neural stem cells (NSCs) under serum-free culture conditions. We observed that a higher amino density significantly promoted NSCs attachment, enhanced neuronal differentiation and promoted excitatory synapse formation in vitro. These results indicate that the amino density significantly affected the biological behavior of NSCs. Thus, the density and impact of functional groups in extracellular matrices should be considered in the research and development of materials for tissue engineering.
PMCID: PMC3887867  PMID: 23639969
biocompatible; cell adhesion molecular; cell migration assays; coated materials; neural stem cells
24.  Functional Subpopulations of V3 Interneurons in the Mature Mouse Spinal Cord 
The Journal of Neuroscience  2013;33(47):18553-18565.
V3 interneurons (INs) are a major group of excitatory commissural interneurons in the spinal cord, and they are essential for producing a stable and robust locomotor rhythm. V3 INs are generated from the ventral-most progenitor domain, p3, but migrate dorsally and laterally during postmitotic development. At birth, they are located in distinctive clusters in the ventral horn and deep dorsal horn. To assess the heterogeneity of this genetically identified group of spinal INs, we combined patch-clamp recording and anatomical tracing with cluster analysis. We examined electrophysiological and morphological properties of mature V3 INs identified by their expression of tdTomato fluorescent proteins in Sim1Cre/+; Rosafloxstop26TdTom mice. We identified two V3 subpopulations with distinct intrinsic properties and spatial distribution patterns. Ventral V3 INs, primarily located in lamina VIII, possess a few branching processes and were capable of generating rapid tonic firing spikes. By contrast, dorsal V3 INs exhibited a more complex morphology and relatively slow average spike frequency with strong adaptation, and they also displayed large sag voltages and post-inhibitory rebound potentials. Our data suggested that hyperpolarization-activated cation channel currents and T-type calcium channel currents may account for some of the membrane properties of V3 INs. Finally, we observed that ventral and dorsal V3 INs were active in different ways during running and swimming, indicating that ventral V3 INs may act as premotor neurons and dorsal V3 INs as relay neurons mediating sensory inputs. Together, we detected two physiologically and topographically distinct subgroups of V3 INs, each likely playing different roles in locomotor activities.
PMCID: PMC3894417  PMID: 24259577
25.  The Impact of Antibody Selection on the Detection of Cardiac Troponin I 
Cardiac troponin I (cTnI) is the current standard biomarker for diagnosing acute myocardial infarction and for risk-stratification of acute coronary syndromes in patients. However it remains unclear how the epitope specificity of antibodies in immunoassays influences the detection of various modified forms of cTnI.
Four mouse anti-human cTnI monoclonal antibodies targeting different regions of human cTnI were chosen for immunoaffinity purification of cTnI from human and swine cardiac tissue. High-resolution intact protein mass spectrometry was employed to assess the comparative performance of these four antibodies in detecting modified forms of cTnI.
Our data revealed that antibody selection significantly impacts the relative protein yield of cTn from immunoaffinity purification. Remarkably, a single amino acid variation in cTnI (G->S) in the epitope region completely abolished the binding between monoclonal antibody 560 and swine cTnI in solution. Moreover, proteolytic degradation around the epitope region severely compromised the detection of proteolytic fragment forms of cTnI by monoclonal antibodies. In contrast, the phosphorylation status near the epitope region did not significantly affect the antibody recognition of cTnI.
Caution needs to be taken in the interpretation of the data produced by immuno-assays with monoclonal antibodies against various epitopes of cTnI.
PMCID: PMC3631584  PMID: 23107929
cardiac troponin; mass spectrometry; epitope; immunoassays; biomarker; acute myocardial infarction

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