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1.  PHD2 Silencing Enhances the Survival and Paracrine Function of Transplanted Adipose-Derived Stem Cells in Infarcted Myocardium 
Circulation research  2013;113(3):288-300.
Transplantation of stem cells into damaged hearts has had modest success as a treatment for ischemic heart disease. One of the limitations is the poor stem cell survival in the diseased microenvironment. Prolyl hydroxylase domain protein 2 (PHD2) is a cellular oxygen sensor that regulates two key transcription factors involved in cell survival and inflammation, hypoxia-inducible factor (HIF) and nuclear factor-κB (NF-κB).
We studied if and how PHD2 silencing in human adipose-derived stem cells (ADSCs) enhances their cardioprotective effects after transplantation into infarcted hearts.
Methods and Results
ADSCs were transduced with lentiviral shPHD2 to silence PHD2. ADSCs with or without shPHD2 were transplanted after myocardial infarction (MI) in mice. ADSCs reduced cardiomyocyte apoptosis, fibrosis and infarct size and improved cardiac function. shPHD2-ADSCs exerted significantly more protection. PHD2 silencing induced greater ADSCs survival, which was abolished by shHIF-1α. Conditioned medium (CM) from shPHD2-ADSCs decreased cardiomyocyte apoptosis. Insulin-like growth factor 1 (IGF-1) levels were significantly higher in the CM of shPHD2-ADSCs versus ADSCs, and depletion of IGF-1 attenuated the cardioprotective effects of shPHD2-ADSCs-CM. NF-κB activation was induced by shPHD2 to induce IGF-1 secretion via binding to IGF-1 gene promoter.
PHD2 silencing promotes ADSCs survival in MI hearts and enhances their paracrine function to protect cardiomyocytes. The pro-survival effect of shPHD2 on ADSCs is HIF-1α dependent and the enhanced paracrine function of shPHD2-ADSCs is associated with NF-κB-mediated IGF-1 up-regulation. PHD2 silencing in stem cells may be a novel strategy for enhancing the effectiveness of stem cell therapy after MI.
PMCID: PMC3744216  PMID: 23694817
Myocardial infarction; stem cell; survival; paracrine effect; cardiomyocyte
2.  The Relative Contribution of Paracine Effect versus Direct Differentiation on Adipose-Derived Stem Cell Transplantation Mediated Cardiac Repair 
PLoS ONE  2013;8(3):e59020.
Recent studies have demonstrated that transplantation of adipose-derived stem cell (ADSC) can improve cardiac function in animal models of myocardial infarction (MI). However, the mechanisms underlying the beneficial effect are not fully understood. In this study, we characterized the paracrine effect of transplanted ADSC and investigated its relative importance versus direct differentiation in ADSC transplantation mediated cardiac repair.
Methodology/Principal Findings
MI was experimentally induced in mice by ligation of the left anterior descending coronary artery. Either human ADSC, conditioned medium (CM) collected from the same amount of ADSC or control medium was injected into the peri-infarct region immediately after MI. Compared with the control group, both ADSC and ADSC-CM significantly reduced myocardial infarct size and improved cardiac function. The therapeutic efficacy of ADSC was moderately superior to ADSC-CM. ADSC-CM significantly reduced cardiomyocyte apoptosis in the infarct border zone, to a similar degree with ADSC treatment. ADSC enhanced angiogenesis in the infarct border zone, but to a stronger degree than that seen in the ADSC-CM treatment. ADSC was able to differentiate to endothelial cell and smooth muscle cell in post-MI heart; these ADSC-derived vascular cells amount to about 9% of the enhanced angiogenesis. No cardiomyocyte differentiated from ADSC was found.
ADSC-CM is sufficient to improve cardiac function of infarcted hearts. The therapeutic function of ADSC transplantation is mainly induced by paracrine-mediated cardioprotection and angiogenesis, while ADSC differentiation contributes a minor benefit by being involved in angiogenesis.
Highlights 1 ADSC-CM is sufficient to exert a therapeutic potential. 2. ADSC was able to differentiate to vascular cells but not cardiomyocyte. 3. ADSC derived vascular cells amount to about 9% of the enhanced angiogenesis. 4. Paracrine effect is the major mechanism of ADSC therapeutic function for MI.
PMCID: PMC3602597  PMID: 23527076
3.  Tonic Glutamatergic Input in The Rostral Ventrolateral Medulla is Increased in Rats With Chronic Heart Failure 
Hypertension  2008;53(2):370-374.
Chronic heart failure (CHF) is characterized by increased sympathetic tone. The glutamatergic input in the rostral ventrolateral medulla (RVLM), which is a key region involved in sympathetic outflow, seems not to be involved in the generation of sympathetic tone in the normal state. The aim of this study was to determine the role of the RVLM glutamate receptors in generation of sympathetic tone in CHF. CHF was produced by left coronary artery ligation. Bilateral microinjection of the glutamate receptor antagonist kynurenic acid (KYN), the N-methyl-D-aspartate (NMDA) receptor antagonist D-AP5, or the non-NMDA receptor antagonist CNQX into the RVLM dose-dependently reduced resting blood pressure and renal sympathetic nerve activity in CHF but not in sham rats. Picoinjection of KYN (100 pmol in 5 nl) significantly decreased the basal discharge by 47% in 25 RVLM presympathetic neurons in CHF rats, In contrast, KYN had no effect on the discharge in all 22 RVLM presympathetic neurons tested in sham rats. These data suggest that upregulated glutamate receptors, including NMDA and non-NMDA, in the RVLM are involved in tonic control of elevated sympathetic tone in CHF.
PMCID: PMC3574554  PMID: 19029485
sympathoexcitation; glutamate receptors; micro/picoinjection; extracellular recording; presympathetic neuron
4.  The time interval between hCG priming and oocyte retrieval in ART program: a meta-analysis 
To evaluate the relationship between different hCG priming-to-oocyte retrieval intervals and assisted reproductive technology (ART) outcome.
We systematically searched PubMed, EMBASE, the Cochrane Library, Science Citation Index, Chinese biomedicine (CBM) literature database, and Chinese Journal Full-text Database for randomized controlled trials (RCTs) published up to November 2010. Data was extracted from the studies by two independent reviewers. Statistical analysis was performed with Cochrane Collaboration’s Review Manager (RevMan) 5.0.2. From extracted data, Risk Ratio (RR) with 95% confidence interval (CI) was calculated.
5 RCTs totaling 895 participants were included. Oocyte maturation rate was higher in the long interval group compared with short interval group (RR, 0.67; 95% CI, 0.62–0.73). There were no significant difference between the two groups with regard to fertilization rate (RR, 0.99; 95% CI, 0.94–1.04), implantation rate (RR, 0.91; 95% CI, 0.40–2.04), and pregnancy rate (RR, 0.79; 95% CI, 0.58–1.08).
The percentage of mature (MII) oocytes can be increased by prolonging the interval between hCG priming and oocyte retrieval. The prolonged interval could not increase the fertilization rate, implantation rate, and pregnancy rate. Although there was evidence to confirm the results, they still need to be confirmed by large-sample, multicenter, randomized controlled trials. The time interval dependent mechanisms responsible for ART performance need to be elucidated.
PMCID: PMC3220445  PMID: 21792666
Human chorionic gonadotropin; Oocyte retrieval; Time interval; Infertility; Assisted reproductive technology; Meta-analysis
Hypertension  2008;52(4):708-714.
Up-regulation of Angiotensin type 1 receptors (AT1R) in the rostral ventrolateral medulla (RVLM) contributes to the sympatho-excitation in the chronic heart failure (CHF). However, the role of AT2R is not clear. In this study, we measured AT1R and AT2R protein expression in the RVLM and determined their effects on renal sympathetic nerve activity (RSNA), blood pressure (BP), and heart rate (HR) in anaesthetized sham and CHF rats. We found that: (1) while AT1R expression in the RVLM was up-regulated, the AT2R was significantly down-regulated (CHF: 0.06 ± 0.02 vs sham: 0.15 ± 0.02, P < 0.05); (2) simultaneously stimulating RVLM AT1R and AT2R by Ang II evoked sympatho-excitation, hypertension, and tachycardia in both sham and CHF rats, with greater responses in CHF; (3) stimulating RVLM AT1R with Ang II plus the specific AT2R antagonist PD123319 induced a larger sympatho-excitatory response than simultaneously stimulating AT1R and AT2R in sham rats, but not in CHF; (4) activating RVLM AT2R with CGP42112 induced a sympatho-inhibition, hypotension, and bradycardia only in sham rats (RSNA: 36.4 ± 5.1 % of baseline vs 102 ± 3.9 % of baseline in aCSF, P < 0.05); (5) pretreatment with ETYA, a general inhibitor of AA metabolism, into the RVLM attenuates the CGP42112 induced sympatho-inhibition. These results suggest that AT2R in the RVLM exhibits an inhibitory effect on sympathetic outflow, which is, at least partially, mediated by an AA metabolic pathway. These data implicate a down regulation in the AT2R as a contributory factor in the sympatho-excitation in CHF.
PMCID: PMC2760297  PMID: 18768398
Angiotensin II type 2 receptor; Angiotensin II type 1 receptor; rostral ventrolateral medulla; sympathetic outflow
6.  2-[3-(Trifluoro­meth­yl)phen­oxy]ethyl 1-oxo-2,6,7-trioxa-1λ5-phosphabicyclo­[2.2.2]octane-4-carboxyl­ate 
In the crystal structure of the title compound, C14H14F3O7P, the central chain, which connects the phosphate bicyclic system and the benzene ring, is made up of an approximately planar C—C(O)—O—C(H2) fragment and a C(H2)—O—C(Ph) link; the mean planes make a dihedral angle of 75.9 (2)°. The F atoms are disordered over two positions; the site occupancy factors are ca 0.6 and 0.4.
PMCID: PMC2960863  PMID: 21201921
7.  Differential effects of cardiac sympathetic afferent stimulation on neurons in the nucleus tractus solitarius 
Neuroscience letters  2006;409(2):146-150.
Activation of the cardiac “sympathetic afferent” reflex (CSAR) has been reported to depress the arterial baroreflex and enhance the arterial chemoreflex via a central mechanism. In the present study, we used single-unit extracellular recording techniques to examine the effects of stimulation of cardiac sympathetic afferents on baro- or chemosensitive neurons in the nucleus tractus solitarius (NTS) in anesthetized rats. Of 54 barosensitive NTS neurons tested for their response to epicardial application of capsaicin (0.4 μg), 38 were significantly (P<0.01) inhibited by 38 % while 16 did not respond. Of 42 NTS chemosensitive neurons tested for their response to capsaicin, 33 were significantly (P<0.01) excited by 47 % while 9 did not respond. In addition, of 12 both barosensitive and chemosensitive NTS neurons tested for capsaicin, 2 were excited, 7 were inhibited, and 3 did not respond. In conclusion, this study indicates that CSAR activation inhibited NTS barosensitive neurons and excited NTS chemosensitive neurons, suggesting that the NTS plays an important role in processing the interactions between these cardiovascular reflexes.
PMCID: PMC1904510  PMID: 17014954
cardiovascular reflexes; sympathetic activity; capsaicin; extracellular recording; baro-/chemosensitive neuron
8.  Exercise Training Prevents Arterial Baroreflex Dysfunction in Rats Treated With Central Angiotensin II 
Hypertension  2007;49(3):519-527.
Angiotensin II (Ang II)–induced arterial baroreflex dysfunction is associated with superoxide generation in the brain. Exercise training (EX) improves baroreflex function and decreases oxidative stress in cardiovascular diseases linked to elevated central Ang II. The aim of this study was to determine whether previous EX prevents baroreflex impairment caused by central administration of exogenous Ang II via an Ang II–superoxide mechanism. Four groups of rats were used: non-EX artificial cerebrospinal fluid infused, non-EX Ang II infused, EX artificial cerebrospinal fluid infused, and EX Ang II infused. Rats were treadmill trained for 3 to 4 weeks and subjected to intracerebroventricular infusion of Ang II over the last 3 days of EX. Twenty-four hours after the end of EX, the arterial baroreflex was assessed in anesthetized rats. Compared with non-EX artificial cerebrospinal fluid–infused rats, Ang II significantly decreased baroreflex sensitivity (maximum gain: 3.0 ± 0.2% of maximum per millimeter of mercury versus 1.6 ± 0.1% of maximum per millimeter of mercury; P < 0.01), which was abolished by acute intracerebroventricular infusion of the Ang II type 1 receptor antagonist losartan and the reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor apocynin. EX prevented the decrease in baroreflex sensitivity and downregulated Ang II type 1 receptor and NADPH oxidase subunit protein expression in the paraventricular nucleus of Ang II–infused rats. Finally, EX decreased superoxide production in the paraventricular nucleus of Ang II–infused rats. These results indicate that EX improves arterial baroreflex function in conditions of high brain Ang II, which is mediated by the central Ang II type 1 receptor and associated with a reduction in central oxidative stress.
PMCID: PMC1904508  PMID: 17224469
exercise; baroreflex; sympathetic nerve activity; reactive oxygen species; AT1 receptor
9.  Meeting at the crossroads: common mechanisms in Fragile X and Down syndrome 
Trends in neurosciences  2013;36(12):685-694.
Intellectual disability is characterized by significantly impaired cognitive abilities and is due to various etiological factors, including both genetic and non-genetic causes. Two of the most common genetic forms of intellectual disability are Fragile X syndrome (FXS) and Down syndrome (DS). Recent studies have shown that proteins altered in FXS and DS can physically interact and participate in common signaling pathways regulating dendritic spine development and local protein synthesis, thus supporting the notion that spine dysmorphogenesis and abnormal local protein synthesis may be molecular underpinnings of intellectual disability. Here we review the molecular constituents regulating local protein synthesis and spine morphology and their alterations in FXS and DS. We argue that these changes might ultimately affect synaptic homeostasis and alter cognitive performance.
PMCID: PMC4090020  PMID: 24075449
10.  Scalable Synthesis of Nano-Silicon from Beach Sand for Long Cycle Life Li-ion Batteries 
Scientific Reports  2014;4:5623.
Herein, porous nano-silicon has been synthesized via a highly scalable heat scavenger-assisted magnesiothermic reduction of beach sand. This environmentally benign, highly abundant, and low cost SiO2 source allows for production of nano-silicon at the industry level with excellent electrochemical performance as an anode material for Li-ion batteries. The addition of NaCl, as an effective heat scavenger for the highly exothermic magnesium reduction process, promotes the formation of an interconnected 3D network of nano-silicon with a thickness of 8-10 nm. Carbon coated nano-silicon electrodes achieve remarkable electrochemical performance with a capacity of 1024 mAhg−1 at 2 Ag−1 after 1000 cycles.
PMCID: PMC4085594  PMID: 25001507
11.  Familiarity is related to conceptual implicit memory: An examination of individual differences 
Cognitive neuroscience  2012;3(0):213-214.
Explicit memory is thought to be distinct from implicit memory. However growing evidence indicates that explicit familiarity-based recognition memory judgments rely on the same process that supports conceptual implicit memory. We tested this hypothesis by examining individual differences using a paradigm wherein we measured both familiarity and conceptual implicit memory within the same participants. In Experiments 1a–b, we examined recognition memory confidence ROCs and remember/know responses, respectively, to estimate recollection and familiarity, and used a free association task to measure conceptual implicit memory. Results demonstrated that, across subjects, familiarity, but not recollection, was significantly correlated with conceptual priming. In contrast, in Experiment 2, utilizing a similar paradigm, a comparison of recognition memory ROCs and explicit associative cued recall performance indicated that cued recall was related to both recollection and familiarity. These results are consistent with models assuming that familiarity-based recognition and conceptual implicit memory rely on similar underlying processes.
PMCID: PMC4084411  PMID: 24171740
familiarity; recollection; implicit memory; conceptual priming; associative cued recall
12.  Automated Filtering of Common Mode Artifacts in Multi-Channel Physiological Recordings 
The removal of spatially correlated noise is an important step in processing multi-channel recordings. Here, a technique termed the adaptive common average reference (ACAR) is presented as an effective and simple method for removing this noise. The ACAR is based on a combination of the well-known common average reference (CAR) and an adaptive noise canceling (ANC) filter. In a convergent process, the CAR provides a reference to an ANC filter, which in turn provides feedback to enhance the CAR. This method was effective on both simulated and real data, outperforming the standard CAR when the amplitude or polarity of the noise changes across channels. In many cases the ACAR even outperformed independent component analysis (ICA). On 16 channels of simulated data the ACAR was able to attenuate up to approximately 290 dB of noise and could improve signal quality if the original SNR was as high as 5 dB. With an original SNR of 0 dB, the ACAR improved signal quality with only two data channels and performance improved as the number of channels increased. It also performed well under many different conditions for the structure of the noise and signals. Analysis of contaminated electrocorticographic (ECoG) recordings further showed the effectiveness of the ACAR.
PMCID: PMC4084824  PMID: 23708770
artifact removal; adaptive filtering; multi-channel recording; neural data; common average reference; spatially correlated noise
13.  IL-1β mediates MCP-1 induction by Wnt5a in gastric cancer cells 
BMC Cancer  2014;14:480.
Both Wnt5a overexpression and macrophage infiltration have been implicated in inflammation and cancer. The aim of this study is to reveal the involvement of Wnt5a in macrophage recruitment in gastric cancer.
mRNA expression in gastric cancer tissues and cells was investigated by real-time PCR. Protein secretion by gastric cancer cells was determined by ELISA. PcDNA3.1-Wnt5a expression vector and Wnt5a siRNA vector were used to overexpress and silence Wnt5a expression in gastric cells, respectively. Macrophage migration was analyzed by transwell, and macrophage cytoskeleton was stained with FITC-phalloidin.
Wnt5a was overexpressed in gastric cancer tissues, and correlated with monocyte chemotactic protein 1 (MCP-1) and interleukin 1β (IL-1β), respectively. In gastric cancer cells, Wnt5a induced MCP-1 expression, which was mediated by IL-1β. Conditioned medium from gastric cancer cells transfected with Wnt5a stimulated macrophage chemotaxis and cytoskeletal changes via MCP-1, which were suppressed by recombinant IL-1 receptor antagonist (rIL-1Ra).
These results suggest that Wnt5a is involved in macrophage recruitment by upregulating MCP-1, and IL-1Ra may be used to inhibit macrophage recruitment in gastric cancer.
PMCID: PMC4086280  PMID: 24993819
15.  Prospective study of restless legs syndrome and mortality among men 
Neurology  2013;81(1):52-59.
To prospectively examine whether men with restless legs syndrome (RLS) had an increased risk of mortality.
This was a prospective cohort study of 18,425 US men free of diabetes, arthritis, and renal failure in the Health Professionals Follow-up Study (HPFS). In 2002, RLS was assessed using a set of standardized questions. Deaths were identified from state vital statistics records, the National Death Index, family reports, and the postal system.
During 8 years of follow-up (2002–2010), we documented 2,765 deaths. In an age-adjusted model, RLS was associated with a 39% increased risk of mortality (hazard ratio [HR] = 1.39; 95% confidence interval [CI] 1.19–1.62; p < 0.0001). The association between RLS and mortality was slightly attenuated after further adjustment for body mass index, lifestyle factors, chronic conditions, sleep duration, and other sleep-related disorders (adjusted HR = 1.30; 95% CI 1.11–1.52; p = 0.003). When we further excluded those with major chronic conditions (e.g., cancer, high blood pressure, cardiovascular disease, and other comorbidities), the adjusted HR was 1.92 (95% CI 1.03–3.56; p = 0.04). The interactions between RLS and other risk factors (older age, overweight, short sleep duration, smoking, low physical activity, and unhealthy diet) in relation to total mortality risk were not significant (p for interaction >0.2 for all).
We observed that men with RLS had a higher overall mortality and this association was independent of known risk factors. The increased mortality in RLS was more frequently associated with respiratory disease, endocrine disease, nutritional/metabolic disease, and immunologic disorders. Future research exploring the pathophysiologic relationship between these disorders and RLS is warranted.
PMCID: PMC3770202  PMID: 23761622
17.  Increasing use of atypical antipsychotics and anticonvulsants during pregnancy 
To quantify maternal use of atypical antipsychotics, typical antipsychotics, anticonvulsants and lithium during pregnancy.
Tennessee birth and death records were linked to Tennessee Medicaid data to conduct a retrospective cohort study of 296,817 women enrolled in Tennessee Medicaid throughout pregnancy who had a live birth or fetal death from 1985 to 2005.
During the study time period, the adjusted rate of use of any study medication during pregnancy increased from nearly 14 to 31 per 1,000 pregnancies (β = 0.08, 95% CI = 0.07, 0.09). Significant increases were reported in use of anticonvulsants alone among mothers with pain and other psychiatric disorders, atypical antipsychotics alone among mothers with bipolar disorders, schizophrenia, unipolar depressive disorders, and other psychiatric disorders, and more than one studied medication for mothers with epilepsy, pain disorders, bipolar disorders, unipolar depressive disorders, and other psychiatric disorders. Significant decreases were reported in use of lithium alone and typical antipsychotics alone for all clinically meaningful diagnosis groups.
There was a substantial increase in use of atypical antipsychotics alone, anticonvulsants alone, and medications from multiple studied categories among Tennessee Medicaid-insured pregnant women during the study period. Further examination of the maternal and fetal consequences of exposure to these medications during pregnancy is warranted.
PMCID: PMC3888313  PMID: 23124892
anticonvulsants; antipsychotics; fetal effects; lithium; pregnancy
18.  Swine Cone and Rod Precursors Arise Sequentially and Display Sequential and Transient Integration and Differentiation Potential Following Transplantation 
We followed cone and rod development in the pig and we correlated development with the potential for cone and rod precursor integration and differentiation following subretinal transplantation.
Rod and cone precursors were identified during development by their position in the outer retina and by immunostaining for markers of differentiation. Embryonic retinal cells from green fluorescent protein (GFP)+ transgenic pigs at different developmental stages were transplanted into adult retinas and integration and differentiation was followed and quantified by immunostaining for markers of cone and rod differentiation.
Pig cones and rods are spatially segregated, allowing us to follow rod and cone development in situ. Gestation in the pig is 114 days. By embryonic day (E) 50, postmitotic cone progenitors had formed the outer two rows of the retina. These cone progenitors are marked by expression of Islet1 (ISL1) and Recoverin (RCVRN) (at this embryonic stage, RCVRN exclusively marks these cone precursors). By contrast, postmitotic neural retina leucine zipper (NRL)+ rod precursors, located interior to the cone precursors, did not appear until E65. At E50, before NRL+ rod precursors are evident, transplanted cells gave rise almost exclusively to cones. At, E57, transplanted cells gave rise to equal numbers of rods and cones, but by E65, transplanted cells gave rise almost exclusively to rods. Transplantation of cells at E85 or E105, as precursors initiate opsin expression, led to few integrated cells.
Consistent with their sequential appearances in embryonic retina, these results demonstrate sequential and surprisingly narrow developmental windows for integration/differentiation of cone and rod precursors following transplantation.
We demonstrate sequential and surprisingly narrow windows for differentiation of embryonic rod and cone progenitors into rods and cones following subretinal transplantation.
PMCID: PMC3894797  PMID: 24327609
retinal transplantation; cones; precursors
19.  Oligomerization transforms human APOBEC3G from an efficient enzyme to a slowly dissociating nucleic acid binding protein 
Nature chemistry  2013;6(1):28-33.
The human APOBEC3 proteins are a family of DNA-editing enzymes that play an important role in the innate immune response and have broad activity against retroviruses and retrotransposons. APOBEC3G is a member of this family that inhibits HIV-1 replication in the absence of the viral infectivity factor Vif. Inhibition of HIV replication occurs by both deamination of viral single-stranded DNA and a deamination-independent mechanism. Efficient deamination requires rapid binding to and dissociation from ssDNA. However, a relatively slow dissociation rate is required for the proposed deaminase-independent roadblock mechanism in which APOBEC3G binds the viral template strand and blocks reverse transcriptase-catalyzed DNA elongation. Here we show that APOBEC3G initially binds ssDNA with rapid on-off rates and subsequently converts to a slowly dissociating mode. In contrast, an oligomerization-deficient APOBEC3G mutant did not exhibit a slow off rate. We propose that catalytically active monomers or dimers slowly oligomerize on the viral genome and inhibit reverse transcription.
PMCID: PMC3950479  PMID: 24345943
APOBEC; DNA binding; HIV-1; restriction factor; roadblock mechanism; optical tweezers; single molecule force spectroscopy
20.  Using the emerging Collaborative Cross to probe the immune system 
Genes and immunity  2013;15(1):38-46.
The Collaborative Cross (CC) is an emerging panel of recombinant inbred mouse strains. Each strain is genetically distinct but all descended from the same eight inbred founders. In 66 strains from incipient lines of the CC (pre-CC), as well as the 8 CC founders and some of their F1 offspring, we examined subsets of lymphocytes and antigen-presenting cells. We found significant variation among the founders, with even greater diversity in the pre-CC. Genome-wide association using inferred haplotypes detected highly significant loci controlling B-to-T cell ratio, CD8 T-cell numbers, CD11c and CD23 expression. Comparison of overall strain effects in the CC founders with strain effects at QTL in the pre-CC revealed sharp contrasts in the genetic architecture of two traits with significant loci: variation in CD23 can be explained largely by additive genetics at one locus, whereas variation in B-to-T ratio has a more complex etiology. For CD23, we found a strong QTL whose confidence interval contained the CD23 structural gene Fcer2a. Our data on the pre-CC demonstrate the utility of the CC for studying immunophenotypes and the value of integrating founder, CC, and F1 data. The extreme immunophenotypes observed could have pleiotropic effects in other CC experiments.
PMCID: PMC4004367  PMID: 24195963
Collaborative Cross; FcεR; QTL
21.  ABCG1 rs57137919G>A Polymorphism Is Functionally Associated with Varying Gene Expression and Apoptosis of Macrophages 
PLoS ONE  2014;9(6):e97044.
ATP-binding cassette transporter G1 (ABCG1) is a transmembrane cholesterol transporter involved in macrophage sterol homeostasis, reverse cholesterol transport (RCT), and atherosclerosis. The role of ABCG1 in atherosclerosis remains controversial, especially in animal models. Our previous study showed that single nucleotide polymorphism rs57137919 (-367G>A) in the ABCG1 promoter region was associated with reduced risk for atherosclerotic coronary artery disease (CAD). This study was designed to provide functional evidence for the role of rs57137919G>A in atherosclerosis in humans. We combined in vitro and ex vivo studies using cell lines and human monocyte-derived macrophages to investigate the functional consequences of the promoter polymorphism by observing the effects of the rs57137919A allele on promoter activity, transcription factor binding, gene expression, cholesterol efflux, and apoptosis levels. The results showed that the rs57137919A allele was significantly associated with decreased ABCG1 gene expression possibly due to the impaired ability of protein-DNA binding. ABCG1-mediated cholesterol efflux decreased by 23% with rs57137919 A/A versus the G/G genotype. Cholesterol-loaded macrophage apoptosis was induced 2-fold with the A/A genotype compared with the G/G genotype. Proapoptotic genes Bok and Bid mRNA levels were significantly increased in macrophages from the A/A genotype compared with those from the G/G genotype. These findings demonstrated that the ABCG1 promoter rs57137919G>A variant had an allele-specific effect on ABCG1 expression and was associated with an increased apoptosis in cholesterol-loaded macrophages, providing functional evidence to explain the reduced risk for atherosclerosis in subjects with the ABCG1 promoter rs57137919A allele as reported in our previous study.
PMCID: PMC4074052  PMID: 24972087
22.  Meta-Analysis of Randomized Controlled Trials Comparing EX-PRESS Implantation with Trabeculectomy for Open-Angle Glaucoma 
PLoS ONE  2014;9(6):e100578.
To evaluate the efficacy and safety of EX-PRESS implantation compared with trabeculectomy for uncontrolled open-angle glaucoma.
Pertinent randomized controlled trials were identified through systematic searches of the PubMed, EMBASE, and Cochrane Library. The efficacy measures utilized were the weighted mean differences (WMDs) for the intraocular pressure reduction (IOPR), the reduction in glaucoma medications, the change of visual acuity, and the relative risks (RRs) for operative success rates. The safety measures utilized were RRs for postoperative complications. The pooled effects were calculated using the random-effects model.
Four randomized controlled trials of 292 eyes were included in this meta-analysis. The WMDs of the IOPR comparing the EX-PRESS with trabeculectomy were −0.25 (95% Cl: −3.61 to 3.11) at 6 month, 0.053 (−4.31 to 4.42) at 12 months, 0.81 (−4.06 to 5.67) at 24 months, and 0.20 (−2.11 to 2.51) at final follow-up. There was no statistically significance for IOPR at any point after surgery. There were also no significant differences in the reduction in glaucoma medications or visual acuity between the groups. The pooled relative risks comparing EX-PRESS with Trabeculectomy were 1.36 (1.11 to 1.66) for the complete operative success rate and 1.05 (0.94 to 1.17) for the qualified operative success rate. EX-PRESS and Trabeculectomy were associated with similar incidences in most complications with the exception of hyphema, with pooled RR being 0.18 (0.046 to 0.66).
EX-PRESS implantation and trabeculectomy have similar efficacy in IOP-lowering, medication reduction, vision recovery, and qualified operative success rates. EX-PRESS associated with higher rates of complete operative success and fewer hyphema than with Trabeculectomy. However, these should be interpreted with caution because of the inherent limitations of the included studies.
PMCID: PMC4074054  PMID: 24972022
23.  The Anorectic Actions of the TGFβ Cytokine MIC-1/GDF15 Require an Intact Brainstem Area Postrema and Nucleus of the Solitary Tract 
PLoS ONE  2014;9(6):e100370.
Macrophage inhibitory cytokine-1 (MIC-1/GDF15) modulates food intake and body weight under physiological and pathological conditions by acting on the hypothalamus and brainstem. When overexpressed in disease, such as in advanced cancer, elevated serum MIC-1/GDF15 levels lead to an anorexia/cachexia syndrome. To gain a better understanding of its actions in the brainstem we studied MIC-1/GDF15 induced neuronal activation identified by induction of Fos protein. Intraperitoneal injection of human MIC-1/GDF15 in mice activated brainstem neurons in the area postrema (AP) and the medial (m) portion of the nucleus of the solitary tract (NTS), which did not stain with tyrosine hydroxylase (TH). To determine the importance of these brainstem nuclei in the anorexigenic effect of MIC-1/GDF15, we ablated the AP alone or the AP and the NTS. The latter combined lesion completely reversed the anorexigenic effects of MIC-1/GDF15. Altogether, this study identified neurons in the AP and/or NTS, as being critical for the regulation of food intake and body weight by MIC-1/GDF15.
PMCID: PMC4074070  PMID: 24971956
24.  Meta-Analysis of the Association between Lumican Gene Polymorphisms and Susceptibility to High Myopia 
PLoS ONE  2014;9(6):e98748.
Many studies have evaluated the association between lumican (LUM) gene polymorphisms and high myopia. However, the results remain controversial. This meta-analysis aims to comprehensively evaluate the relationship between two common LUM polymorphisms (rs3759223 and rs3759222) and the risk of high myopia.
A comprehensive literature search for studies published up until September of 2013 was performed. Data were extracted independently by two investigators, and the weighted Odds Ratios (ORs) and 95% Confidence Intervals (CIs) for the associations were obtained by using a random-effects model.
Eight studies (1425cases and 1271 controls) were identified for the analysis of the association between rs3759223 polymorphism and high myopia. The results indicated that rs3759223 polymorphism was associated with high myopia under a recessive model (OR = 1.71, 95%CI 1.04–2.81). Further subgroup analysis indicated that this polymorphism was associated with high myopia among Chinese people in the additive model (OR = 1.17, 95%CI 1.06–1.29) and a recessive model (OR = 1.75, 95%CI 1.00–3.06) with control group coming from hospital based population. Four studies (1024 cases and 1163 controls) were identified for the analysis of the association between rs3759222 polymorphism and high myopia. The results indicated that rs3759222 polymorphism was not associated with high myopia in all genetic models, even the subgroup analysis couldn't provide relative proof to assure the outcome.
This meta-analysis suggests that LUM polymorphisms are associated with the risk of high myopia. However, well-designed studies with larger sample sizes and more ethnic groups are required to further validate this association.
PMCID: PMC4067286  PMID: 24956166
25.  Characterization of the Ectodomain of the Envelope Protein of Dengue Virus Type 4: Expression, Membrane Association, Secretion and Particle Formation in the Absence of Precursor Membrane Protein 
PLoS ONE  2014;9(6):e100641.
The envelope (E) of dengue virus (DENV) is the major target of neutralizing antibodies and vaccine development. After biosynthesis E protein forms a heterodimer with precursor membrane (prM) protein. Recent reports of infection enhancement by anti-prM monoclonal antibodies (mAbs) suggest anti-prM responses could be potentially harmful. Previously, we studied a series of C-terminal truncation constructs expressing DENV type 4 prM/E or E proteins and found the ectodomain of E protein alone could be recognized by all 12 mAbs tested, suggesting E protein ectodomain as a potential subunit immunogen without inducing anti-prM response. The characteristics of DENV E protein ectodomain in the absence of prM protein remains largely unknown.
Methodology/Principal Findings
In this study, we investigated the expression, membrane association, glycosylation pattern, secretion and particle formation of E protein ectodomain of DENV4 in the presence or absence of prM protein. E protein ectodomain associated with membrane in or beyond trans-Golgi and contained primarily complex glycans, whereas full-length E protein associated with ER membrane and contained high mannose glycans. In the absence of prM protein, E protein ectodomain can secrete as well as form particles of approximately 49 nm in diameter, as revealed by sucrose gradient ultracentrifugation with or without detergent and electron microscopy. Mutational analysis revealed that the secretion of E protein ectodomain was affected by N-linked glycosylation and could be restored by treatment with ammonia chloride.
Considering the enhancement of DENV infectivity by anti-prM antibodies, our findings provide new insights into the expression and secretion of E protein ectodomain in the absence of prM protein and contribute to future subunit vaccine design.
PMCID: PMC4065094  PMID: 24950216

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