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1.  The Cardiopulmonary Effects of Ambient Air Pollution and Mechanistic Pathways: A Comparative Hierarchical Pathway Analysis 
PLoS ONE  2014;9(12):e114913.
Previous studies have investigated the associations between exposure to ambient air pollution and biomarkers of physiological pathways, yet little has been done on the comparison across biomarkers of different pathways to establish the temporal pattern of biological response. In the current study, we aim to compare the relative temporal patterns in responses of candidate pathways to different pollutants. Four biomarkers of pulmonary inflammation and oxidative stress, five biomarkers of systemic inflammation and oxidative stress, ten parameters of autonomic function, and three biomarkers of hemostasis were repeatedly measured in 125 young adults, along with daily concentrations of ambient CO, PM2.5, NO2, SO2, EC, OC, and sulfate, before, during, and after the Beijing Olympics. We used a two-stage modeling approach, including Stage I models to estimate the association between each biomarker and pollutant over each of 7 lags, and Stage II mixed-effect models to describe temporal patterns in the associations when grouping the biomarkers into the four physiological pathways. Our results show that candidate pathway groupings of biomarkers explained a significant amount of variation in the associations for each pollutant, and the temporal patterns of the biomarker-pollutant-lag associations varied across candidate pathways (p<0.0001) and were not linear (from lag 0 to lag 3: p = 0.0629, from lag 3 to lag 6: p = 0.0005). These findings suggest that, among this healthy young adult population, the pulmonary inflammation and oxidative stress pathway is the first to respond to ambient air pollution exposure (within 24 hours) and the hemostasis pathway responds gradually over a 2–3 day period. The initial pulmonary response may contribute to the more gradual systemic changes that likely ultimately involve the cardiovascular system.
doi:10.1371/journal.pone.0114913
PMCID: PMC4264846  PMID: 25502951
2.  Efficacy and Safety of Celecoxib in Chinese Patients with Ankylosing Spondylitis: A 6-Week Randomized, Double-Blinded Study with 6-Week Open-Label Extension Treatment 
Background
Nonsteroidal anti-inflammatory drugs are the first-line option for treating ankylosing spondylitis (AS) in China. However, no large-scale controlled trials have been conducted in this ethnic population.
Objective
To evaluate the efficacy and safety of 6 weeks’ treatment with celecoxib in patients with AS in China.
Methods
This Phase 3, double-blind, parallel-group study randomized patients with AS aged ≥18 to 65 years 1:1 to receive celecoxib 200 mg once daily or diclofenac sustained release 75 mg once daily. After 6 weeks, patients could use celecoxib 400 mg once daily or maintain blinded therapy. The primary efficacy end point was mean change from baseline at Week 6 for Patient’s Global Assessment of Pain Intensity score (100-mm visual analog scale). Noninferiority was established if the upper bound of the CI was <10 mm. Secondary objectives included patients’ and physicians’ assessments of disease activity, change from baseline in C-reactive protein level, and safety.
Results
In the per-protocol analysis set the least squares mean change from baseline in the Patient’s Global Assessment of Pain Intensity score at Week 6 was –23.8 mm and –27.1 mm in patients receiving celecoxib (n = 111) and diclofenac (n = 108), respectively. The 2-sided 95% CI for the treatment difference (celecoxib – diclofenac) was –2.2 to 8.8. Overall, 4.2% and 6.7% of patients in the celecoxib and diclofenac groups, respectively, reported treatment-related adverse events. All were mild to moderate in severity.
Conclusions
Celecoxib 200 mg once daily is noninferior to diclofenac sustained release 75 mg once daily for pain treatment in Chinese patients with AS. ClinicalTrials.gov identifier: NCT00762463.
doi:10.1016/j.curtheres.2014.08.002
PMCID: PMC4266770  PMID: 25516774
ankylosing spondylitis; COX-2 inhibitors; musculoskeletal system; nonsteroidal anti-inflammatory drugs
3.  Angiotensin-Converting Enzyme 2 (ACE2) Activator Diminazene Aceturate Ameliorates Endotoxin-Induced Uveitis in Mice 
Purpose.
Uveitis is a common cause of vision loss. The renin angiotensin system (RAS), which plays a vital role in cardiovascular system, is a potent mediator of inflammation and has been implicated in the pathogenesis of uveitis. A newly identified axis of RAS, ACE2/Ang-(1-7)/Mas, has emerged as a novel target because it counteracts the deleterious effect of angiotensin II. The purpose of this study was to investigate the effect of endogenous ACE2 activation in preventing endotoxin-induced uveitis (EIU) in mice.
Methods.
ACE2 activator diminazene aceturate (DIZE) was administered both systemically and locally. For systemic administration, female BALB/c mice received intraperitoneal injection of DIZE (60 mg/kg body weight [BW]) for 2 days prior to lipopolysaccharide (LPS) intravitreal injection (125 ng) to induce uveitis. For local study, DIZE was given at 0.5, 0.1, and 0 mg/mL as eyedrops six times per day for 2 days before LPS injection. The anterior segment of the mice was examined at 12, 24, 48, and 72 hours after LPS injection, and clinical scores were determined at the same time. Morphology and infiltrating inflammatory cells were evaluated after 24 hours. The mRNA levels of inflammatory cytokines were analyzed by real-time RT-PCR. ACE2 activity was determined using a self-quenching fluorescent substrate.
Results.
At 24 hours, the clinical score of mice treated with DIZE systemically was significantly lower (mean, ∼1.75) than the saline vehicle group (mean, ∼4) (P < 0.001). Histological examination showed 63.4% reduction of infiltrating inflammatory cells in the anterior segment and 57.4% reduction in the posterior segment of DIZE-treated eyes. The number of CD45+ inflammatory cells in the vitreous of the DIZE-treated group was decreased (43.3%) compared to the vehicle group (P < 0.01). The mRNA levels of inflammatory cytokines were significantly reduced in the DIZE-treated group (P < 0.01, P < 0.001). The number of infiltrating inflammatory cells was also significantly reduced in eyes that received topical administration of DIZE: 73.8% reduction in the 0.5 mg/mL group and 51.7% reduction in the 0.1mg/mL group compared to the control group. DIZE treatment resulted in significantly increased ACE2 activity in the retina (P < 0.001).
Conclusions.
Endogenous ACE2 activation by DIZE has a preventive effect on LPS-induced ocular inflammation in the EIU mouse model. These results support the notions that RAS plays a role in modulating ocular immune response and that enhancing ACE2 provides a novel therapeutic strategy for uveitis.
This study supports the notion that RAS plays a role in modulating ocular immune response and that enhancing ACE2 provides a novel therapeutic strategy for uveitis.
doi:10.1167/iovs.14-13883
PMCID: PMC4062403  PMID: 24854854
uveitis; EIU; angiotensin-converting enzyme 2; renin angiotensin system; diminazene aceturate
4.  Cryo-Electron Microscopy Study of Insect Cell-Expressed Enterovirus 71 and Coxsackievirus A16 Virus-Like Particles Provides a Structural Basis for Vaccine Development 
Journal of Virology  2014;88(11):6444-6452.
ABSTRACT
Enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the two most common etiological agents responsible for the epidemics of hand, foot, and mouth disease (HFMD), a childhood illness with occasional severe neurological complications. A number of vaccine candidates against EV71 or CA16 have been reported; however, no vaccine is currently available for clinical use. Here, we generated a secreted version of EV71 and CA16 virus-like particles (VLPs) using a baculovirus-insect cell expression system and reconstructed the three-dimensional (3D) structures of both VLPs by cryo-electron microscopy (cryo-EM) single-particle analysis at 5.2-Å and 5.5-Å resolutions, respectively. The reconstruction results showed that the cryo-EM structures of EV71 and CA16 VLPs highly resemble the recently published crystal structures for EV71 natural empty particles and CA16 135S-like expanded particles, respectively. Our cryo-EM analysis also revealed that the majority of previously identified linear neutralizing epitopes are well preserved on the surface of EV71 and CA16 VLPs. In addition, both VLPs were able to induce efficiently neutralizing antibodies against various strains of EV71 and CA16 viruses in mouse immunization. These studies provide a structural basis for the development of insect cell-expressed VLP vaccines and for a potential bivalent VLP vaccine against both EV71- and CA16-associated HFMD.
IMPORTANCE The recent outbreaks of hand, foot, and mouth disease (HFMD) in the Asia Pacific region spurred the search for effective vaccines against EV71 and CA16 viruses, the two most common etiological agents responsible for HFMD. In this paper, we show that secreted versions of EV71 and CA16 VLPs generated in the baculovirus-insect cell expression system highly resemble the crystal structures of their viral conterparts and that the majority of previously identified linear neutralizing epitopes are well preserved on the VLP surfaces. In addition, the generated VLPs can efficiently induce neutralizing antibodies against various strains of EV71 and CA16 viruses in mouse immunization. These studies provide a structural basis for the development of insect cell-expressed VLP vaccines and for a potential bivalent VLP vaccine against both EV71- and CA16-associated HFMD.
doi:10.1128/JVI.00200-14
PMCID: PMC4093858  PMID: 24672036
5.  Platelets induce a proinflammatory phenotype in monocytes via the CD147 pathway in rheumatoid arthritis 
Introduction
Activated platelets exert a proinflammatory action that can be largely ascribed to their ability to interact with monocytes. However, the mechanisms that promote dynamic changes in monocyte subsets in rheumatoid arthritis (RA) have not been clearly identified. The aim of this study was to determine whether platelet activation and the consequent formation of monocyte-platelet aggregates (MPA) might induce a proinflammatory phenotype in circulating monocytes in RA.
Methods
The surface phenotype of platelets and the frequencies of monocyte subpopulations in the peripheral blood of RA patients were determined using flow cytometry. Platelets were sorted and co-cultured with monocytes. In addition, monocyte activation was assessed by measuring the nuclear factor kappa B (NF-κB) pathway. The disease activity was evaluated using the 28-joint disease activity score.
Results
Platelet activation, circulating intermediate monocytes (Mon2) and MPA formation were significantly elevated in RA, especially in those with active disease status. Furthermore, Mon2 monocytes showed higher CD147 expression and responded to direct cell contact with activated platelets with higher cytokine production and matrix metallopeptidase 9 (MMP-9) secretion, which increased the expression of CD147. After the addition of specific antibodies for CD147, those effects were abolished. Furthermore, the NF-κB-driven inflammatory pathway may be involved in this process.
Conclusions
These findings indicate an important role of platelet activation and the consequent formation of MPA in the generation of the proinflammatory cytokine milieu and for the promotion and maintenance of the pathogenically relevant Mon2 monocyte compartment in RA, which is likely to play an important role in the pathogenesis of autoimmunity.
doi:10.1186/s13075-014-0478-0
PMCID: PMC4298113  PMID: 25404518
6.  Actions of Acute and Chronic Ethanol on Presynaptic Terminals 
This article presents the proceedings of a symposium entitled “The Tipsy Terminal: Presynaptic Effects of Ethanol” (held at the annual meeting of the Research Society on Alcoholism, in Santa Barbara, CA, June 27, 2005). The objective of this symposium was to focus on a cellular site of ethanol action underrepresented in the alcohol literature, but quickly becoming a “hot” topic. The chairs of the session were Marisa Roberto and George Robert Siggins. Our speakers were chosen on the basis of the diverse electrophysiological and other methods used to discern the effects of acute and chronic ethanol on presynaptic terminals and on the basis of significant insights that their data provide for understanding ethanol actions on neurons in general, as mechanisms underlying problematic behavioral effects of alcohol. The 5 presenters drew from their recent studies examining the effects of acute and chronic ethanol using a range of sophisticated methods from electrophysiological analysis of paired-pulse facilitation and spontaneous and miniature synaptic currents (Drs. Weiner, Valenzuela, Zhu, and Morrisett), to direct recording of ion channel activity and peptide release from acutely isolated synaptic terminals (Dr. Treistman), to direct microscopic observation of vesicular release (Dr. Morrisett). They showed that ethanol administration could both increase and decrease the probability of release of different transmitters from synaptic terminals. The effects of ethanol on synaptic terminals could often be correlated with important behavioral or developmental actions of alcohol. These and other novel findings suggest that future analyses of synaptic effects of ethanol should attempt to ascertain, in multiple brain regions, the role of presynaptic terminals, relevant presynaptic receptors and signal transduction linkages, exocytotic mechanisms, and their involvement in alcohol’s behavioral actions. Such studies could lead to new treatment strategies for alcohol intoxication, alcohol abuse, and alcoholism.
doi:10.1111/j.1530-0277.2006.00030.x
PMCID: PMC4115792  PMID: 16441271
Alcohol; Synapses; GABA; Glutamate; Peptides; Intoxication
7.  Sumoylation modulates oxidative stress relevant to the viability and functionality of pancreatic beta cells 
Sumoylation is an evolutionarily conserved regulatory mechanism to play an important role in various cellular processes through modulation of protein localization, stability and functionality. Recent studies including ours have consistently demonstrated that sumoylation provides protection for cells against oxidative stress. Given that pancreatic beta cells are a vulnerable target of oxidative stress, we thus in this minireview, updated the advancement of sumoylation in the regulation of ROS generation, and discussed its impact on several critical signaling pathways relevant to beta cells against oxidative stress and maintenance of functionality. Specifically, we bring together how sumoylation represses intracellular ROS formation, and protects beta cells against oxidative stress through regulating IκB/NFκB, JNK/c-Jun, and Maf/Nrf2 pathways. The tight implication of sumoylation in oxidative stress reflects that it could be an essential mechanism for beta cells to adapt to the detrimental cellular microenvironment.
PMCID: PMC4113497  PMID: 25075252
Sumoylation; beta cell; oxidative stress; ROS; diabetes
8.  Cardiorespiratory Biomarker Responses in Healthy Young Adults to Drastic Air Quality Changes Surrounding the 2008 Beijing Olympics 
Associations between air pollution and cardiorespiratory mortality and morbidity have been well established, but data to support biologic mechanisms underlying these associations are limited. We designed this study to examine several prominently hypothesized mechanisms by assessing Beijing residents’ biologic responses, at the biomarker level, to drastic changes in air quality brought about by unprecedented air pollution control measures implemented during the 2008 Beijing Olympics.
To test the hypothesis that changes in air pollution levels are associated with changes in biomarker levels reflecting inflammation, hemostasis, oxidative stress, and autonomic tone, we recruited and retained 125 nonsmoking adults (19 to 33 years old) free of cardiorespiratory and other chronic diseases. Using the combination of a quasi-experimental design and a panel-study approach, we measured biomarkers of autonomic dysfunction (heart rate [HR*] and heart rate variability [HRV]), of systemic inflammation and oxidative stress (plasma C-reactive protein [CRP], fibrinogen, blood cell counts and differentials, and urinary 8-hydroxy-2′-deoxyguanosine [8-OHdG]), of pulmonary inflammation and oxidative stress (fractional exhaled nitric oxide [FeNO], exhaled breath condensate [EBC] pH, EBC nitrate, EBC nitrite, EBC nitrite+nitrate [sum of the concentrations of nitrite and nitrate], and EBC 8-isoprostane), of hemostasis (platelet activation [plasma sCD62P and sCD40L], platelet aggregation, and von Willebrand factor [vWF]), and of blood pressure (systolic blood pressure [SBP] and diastolic blood pressure [DBP]). These biomarkers were measured on each subject twice before, twice during, and twice after the Beijing Olympics. For each subject, repeated measurements were separated by at least one week to avoid potential residual effects from a prior measurement. We measured a large suite of air pollutants (PM2.5 [particulate matter ≤ 2.5 μm in aerodynamic diameter] and constituents, sulfur dioxide [SO2], carbon monoxide [CO], nitrogen dioxide [NO2], and ozone [O3]) throughout the study at a central Beijing site near the residences and workplaces of the subjects on a daily basis. Total particle number (TPN) was also measured at a separate site. We used a time-series analysis to assess changes in pollutant concentration by period (pre-, during-, and post-Olympics periods). We used mixed-effects models to assess changes in biomarker levels by period and to estimate changes associated with increases in pollutant concentrations, controlling for ambient temperature, relative humidity (RH), sex, and the day of the week of the biomarker measurements. We conducted sensitivity analyses to assess the impact of potential temporal confounding and exposure misclassification.
We observed reductions in mean concentrations for all measured pollutants except O3 from the pre-Olympics period to the during-Olympics period. On average, elemental carbon (EC) changed by −36%, TPN by −22%, SO2 by −60%, CO by −48%, and NO2 by −43% (P < 0.05 for all these pollutants). Reductions were observed in mean concentrations of PM2.5 (by −27%), sulfate (SO42−) (by −13%), and organic carbon (OC) (by −23%); however, these values were not statistically significant. Both 24-hour averages and 1-hour maximums of O3 increased (by 20% and 17%, respectively) from the pre-Olympics to the during-Olympics period. In the post-Olympics period after the pollution control measures were relaxed, mean concentrations of most pollutants (with the exception of SO42− and O3) increased to levels similar to or higher than pre-Olympics levels.
Concomitantly and consistent with the hypothesis, we observed, from the pre-Olympics to the during-Olympics period, statistically significant (P ≤ 0.05) or marginally significant (0.05 < P < 0.1) decreases in HR (−1 bpm or −1.7% [95% CI, −3.4 to −0.1]), SBP (−1.6 mmHg or − 1.8% [95% CI, −3.9 to 0.4]), 8-OHdG (−58.3% [95% CI, −72.5 to −36.7]), FeNO (−60.3% [95% CI, −66.0 to −53.6]), EBC nitrite (−30.0% [95% CI, −39.3 to −19.3]), EBC nitrate (−21.5% [95% CI, −35.5 to −4.5]), EBC nitrite+nitrate (−17.6% [95% CI, −28.4 to −5.1]), EBC hydrogen ions (−46% [calculated from EBC pH], or +3.5% in EBC pH [95% CI, 2.2 to 4.9]), sCD62P (−34% [95% CI, −38.4 to −29.2]), sCD40L (−5.7% [95% CI, −10.5 to −0.7]), and vWF (−13.1% [95% CI, −18.6 to −7.5]). Moreover, the percentages of above-detection values out of all observations were significantly lower for plasma CRP and EBC 8-isoprostane in the during-Olympics period compared with the pre-Olympics period. In the post-Olympics period, the levels of the following biomarkers reversed (increased, either with or without statistical significance) from those in the during-Olympics period: SBP (10.7% [95% CI, 2.8 to 18.6]), fibrinogen (4.3% [95% CI, −1.7 to 10.2), neutrophil count (4.7% [95% CI, −7.7 to 17.0]), 8-OHdG (315% [95% CI, 62.0 to 962]), FeNO (130% [95% CI, 62.5 to 225]), EBC nitrite (159% [95% CI, 71.8 to 292]), EBC nitrate (161% [95% CI, 48.0 to 362]), EBC nitrite+nitrate (124% [95% CI, 50.9 to 233]), EBC hydrogen ions (146% [calculated from EBC pH] or −4.8% in EBC pH [95% CI, −9.4 to −0.2]), sCD62P (33.7% [95% CI, 17.7 to 51.8]), and sCD40L (9.1% [95% CI, −3.7 to 23.5]).
Furthermore, these biomarkers also showed statistically significant associations with multiple pollutants across different lags after adjusting for meteorologic parameters. The associations were in the directions hypothesized and were consistent with the findings from the comparisons between periods, providing further evidence that the period effects were due to changes in air quality, independent of season and meteorologic conditions or other potential confounders. Contrary to our hypothesis, however, we observed increases in platelet aggregation, red blood cells (RBCs) and white blood cells (WBCs) associated with the during-Olympics period, as well as significant negative associations of these biomarkers with pollutant concentrations. We did not observe significant changes in any of the HRV indices and DBP by period. However, we observed associations between a few HRV indices and pollutant concentrations.
Changes in air pollution levels during the Beijing Olympics were associated with acute changes in biomarkers of pulmonary and systemic inflammation, oxidative stress, and hemostasis and in measures of cardiovascular physiology (HR and SBP) in healthy, young adults. These changes support the prominently hypothesized mechanistic pathways underlying the cardiorespiratory effects of air pollution.
PMCID: PMC4086245  PMID: 23646463
9.  Isolated duodenal myeloid sarcoma associated with the CBFβ/MYH11 fusion gene followed by acute myeloid leukemia progression: A case report and literature review 
Oncology Letters  2014;8(3):1261-1264.
Myeloid sarcoma (MS) is a rare disease that presents as an extramedullary tumorous mass of immature myeloid precursors. The majority of MS are identified in acute myeloid leukemia (AML) patients and rarely present as a primary isolated MS without AML. In addition, inversion of chromosome 16 [inv(16)] and the CBFβ/MYH11 fusion gene are rarely associated with MS. The current study reports a female patient with an isolated duodenal MS, who developed AML-M4 associated with the CBFβ/MYH11 fusion gene and 48,XX,inv(16),+13,+22. A review of previously reported cases of isolated MS with the CBFβ/MYH11 fusion gene was also performed. Isolated MS with the CBFβ/MYH11 fusion gene was often observed in abdominal lesions, with the intestinal tract being the predominantly involved site. In addition, patients with isolated MS with the CBFβ/MYH11 fusion exhibited a high risk of developing systemic AML. The diagnosis of isolated MS may be particularly challenging and, therefore, determining the optimal standard treatment for isolated MS is required.
doi:10.3892/ol.2014.2313
PMCID: PMC4114609  PMID: 25120702
CBFβ/MYH11 fusion gene; acute myeloid leukemia; myeloid sarcoma
10.  New insights into the helical structure of 30-nm chromatin fibers 
Protein & Cell  2014;5(7):489-491.
doi:10.1007/s13238-014-0080-x
PMCID: PMC4085281  PMID: 24969419
11.  New insights into the helical structure of 30-nm chromatin fibers 
Protein & Cell  2014;5(7):489-491.
doi:10.1007/s13238-014-0080-x
PMCID: PMC4085281  PMID: 24969419
12.  Combined Renin Inhibition/(Pro)Renin Receptor Blockade in Diabetic Retinopathy- A Study in Transgenic (mREN2)27 Rats 
PLoS ONE  2014;9(6):e100954.
Dysfunction of renin-angiotensin system (RAS) contributes to the pathogenesis of diabetic retinopathy (DR). Prorenin, the precursor of renin is highly elevated in ocular fluid of diabetic patients with proliferative retinopathy. Prorenin may exert local effects in the eye by binding to the so-called (pro)renin receptor ((P)RR). Here we investigated the combined effects of the renin inhibitor aliskiren and the putative (P)RR blocker handle-region peptide (HRP) on diabetic retinopathy in streptozotocin (STZ)-induced diabetic transgenic (mRen2)27 rats (a model with high plasma prorenin levels) as well as prorenin stimulated cytokine expression in cultured Müller cells. Adult (mRen2)27 rats were randomly divided into the following groups: (1) non-diabetic; (2) diabetic treated with vehicle; (3) diabetic treated with aliskiren (10 mg/kg per day); and (4) diabetic treated with aliskiren+HRP (1 mg/kg per day). Age-matched non-diabetic wildtype Sprague-Dawley rats were used as control. Drugs were administered by osmotic minipumps for three weeks. Transgenic (mRen2)27 rat retinas showed increased apoptotic cell death of both inner retinal neurons and photoreceptors, increased loss of capillaries, as well as increased expression of inflammatory cytokines. These pathological changes were further exacerbated by diabetes. Aliskiren treatment of diabetic (mRen2)27 rats prevented retinal gliosis, and reduced retinal apoptotic cell death, acellular capillaries and the expression of inflammatory cytokines. HRP on top of aliskiren did not provide additional protection. In cultured Müller cells, prorenin significantly increased the expression levels of IL-1α and TNF-α, and this was completely blocked by aliskiren or HRP, their combination, (P)RR siRNA and the AT1R blocker losartan, suggesting that these effects entirely depended on Ang II generation by (P)RR-bound prorenin. In conclusion, the lack of effect of HRP on top of aliskiren, and the Ang II-dependency of the ocular effects of prorenin in vitro, argue against the combined application of (P)RR blockade and renin inhibition in diabetic retinopathy.
doi:10.1371/journal.pone.0100954
PMCID: PMC4072720  PMID: 24968134
13.  Serum Uric Acid Is Associated with Incident Chronic Kidney Disease in Middle-Aged Populations: A Meta-Analysis of 15 Cohort Studies 
PLoS ONE  2014;9(6):e100801.
Background
Mounting evidence indicates that elevated serum uric acid may increase the incidence of chronic kidney disease (CKD). Our goal was to systematically evaluate longitudinal cohort studies for the association of serum uric acid levels and incident CKD.
Methods
We searched electronic databases and the reference lists of relevant articles. The primary outcome was incident CKD, which was defined as an eGFR less than 60 mL/min/1.73 m2 at the follow-up examination. Study-specific risk estimates were combined using random-effects models. The included studies were stratified into subgroups, and meta-regression analyses were performed.
Results
Fifteen unique cohorts with a total of 99,205 individuals and 3,492 incident CKD cases were included. The relative risk of CKD was 1.22 (95% CI 1.16–1.28, I2 = 65.9%) per 1 mg/dL serum uric level increment. This positive association was consistently observed in subgroups stratified according to most of the study-level characteristics. The observed positive association was more pronounced among group with a mean age <60 years (RR 1.26, 95% CI 1.21–1.31), and low-level heterogeneity was observed in the findings for this age group (I2 = 46.4%, P = 0.022). However, no association was observed among studies with a mean age≥60 years (RR 1.04, 95% CI 0.96–1.13), and no evidence of heterogeneity was evident among the studies (I2 = 0%, P = 0.409). This mean age-related difference in the association between serum uric acid levels and CKD was significant (P = 0.004). The sensitivity analysis results were consistent when the analyses were restricted to studies that controlled for proteinuria and metabolic syndrome.
Conclusions
Our meta-analysis demonstrated a positive association between serum uric acid levels and risk of CKD in middle-aged patients independent of established metabolic risk factors. Future randomized, high-quality clinical trials are warranted to determine whether lowering uric acid levels is beneficial in CKD.
doi:10.1371/journal.pone.0100801
PMCID: PMC4069173  PMID: 24959886
14.  Association Between Changes in Air Pollution Levels During the Beijing Olympics and Biomarkers of Inflammation and Thrombosis in Healthy Young Adults 
Context
Air pollution is a risk factor for cardiovascular diseases (CVD), but the underlying biological mechanisms are not well understood.
Objective
To determine whether markers related to CVD pathophysiological pathways (biomarkers for systemic inflammation and thrombosis, heart rate, and blood pressure) are sensitive to changes in air pollution.
Design, Setting, and Participants
Using a quasi-experimental opportunity offered by greatly restricted air pollution emissions during the Beijing Olympics, we measured pollutants daily and the outcomes listed below in 125 healthy young adults before, during, and after the 2008 Olympics (June 2-October 30). We used linear mixed-effects models to estimate the improvement in outcome levels during the Olympics and the anticipated reversal of outcome levels after pollution controls ended to determine whether changes in outcome levels were associated with changes in pollutant concentrations.
Main Outcome Measures
C-reactive protein (CRP), fibrinogen, von Willebrand factor, soluble CD40 ligand (sCD40L), soluble P-selectin (sCD62P) concentrations; white blood cell count (WBC); heart rate; and blood pressure.
Results
Concentrations of particulate and gaseous pollutants decreased substantially (−13% to −60%) from the pre-Olympic period to the during-Olympic period. Using 2-sided tests conducted at the .003 level, we observed statistically significant improvements in sCD62P levels by −34.0% (95% CI, −38.4% to −29.2%; P<.001) from a pre-Olympic mean of 6.29 ng/mL to a during-Olympic mean of 4.16 ng/mL and von Willebrand factor by −13.1% (95% CI, −18.6% to −7.5%; P<.001) from 106.4% to 92.6%. After adjustments for multiple comparisons, changes in the other outcomes were not statistically significant. In the post-Olympic period when pollutant concentrations increased, most outcomes approximated pre-Olympic levels, but only sCD62P and systolic blood pressure were significantly worsened from the during-Olympic period. The fraction of above-detection-limit values for CRP (percentage ≥0.3 mg/L) was reduced from 55% in the pre-Olympic period to 46% in the during-Olympic period and reduced further to 36% in the post-Olympic period. Interquartile range increases in pollutant concentrations were consistently associated with statistically significant increases in fibrinogen, von Wille-brand factor, heart rate, sCD62P, and sCD40L concentrations.
Conclusions
Changes in air pollution levels during the Beijing Olympics were associated with acute changes in biomarkers of inflammation and thrombosis and measures of cardiovascular physiology in healthy young persons. These findings are of uncertain clinical significance.
doi:10.1001/jama.2012.3488
PMCID: PMC4049319  PMID: 22665106
15.  Malondialdehyde in exhaled breath condensate and urine as a biomarker of air pollution induced oxidative stress 
Underlying mechanisms by which air pollutants adversely affect human health remain poorly understood. Oxidative stress has been considered as a potential mechanism that may promote lipid peroxidation by reactive oxygen species, leading to the formation of malondialdehyde (MDA) that is excreted in biofluids (e.g., urine and exhaled breath condensate (EBC)). A panel study was conducted to examine whether concentrations of MDA in EBC and urine were associated, respectively, with changes in air pollution levels brought by the Beijing Olympic air pollution control measures. EBC and urine samples from 125 healthy adults were collected twice in each of the pre-, during-, and post-Olympic periods. Period-specific means of MDA and changes in MDA levels associated with increases in 24-h average pollutant concentrations were estimated using linear mixed-effects models. From the pre- to the during-Olympic period, when concentrations of most pollutants decreased, EBC MDA and urinary MDA significantly decreased by 24% (P < 0.0001) and 28% (P = 0.0002), respectively. From the during-Olympic to the post-Olympic period, when concentrations of most pollutants increased, EBC MDA and urinary MDA increased by 28% (P = 0.094) and 55% (P = 0.046), respectively. Furthermore, the largest increases in EBC MDA associated with one interquartile range (IQR) increases in all pollutants but ozone ranged from 10% (95% CI: 2%, 18%) to 19% (95% CI: 14%, 25%). The largest increases in urinary MDA associated with IQR increases in pollutant concentration ranged from 9% (95%: 0.3%, 19%) to 15% (95% CI: 3%, 28%). These findings support the utility of EBC MDA as a biomarker of oxidative stress in the respiratory tract and urinary MDA as a biomarker of systemic oxidative stress in relation to air pollution exposure in healthy young adults. Both EBC and urine samples can be collected noninvasively in the general population.
doi:10.1038/jes.2012.127
PMCID: PMC4049321  PMID: 23321859
The Beijing Olympics; lipid peroxidation; malondialdehyde; oxidative stress; exhaled breath condensate
16.  Measurement of inflammation and oxidative stress following drastic changes in air pollution during the Beijing Olympics: a panel study approach 
Ambient air pollution has been linked to cardiovascular and respiratory morbidity and mortality in epidemiology studies. Frequently, oxidative and nitrosative stress are hypothesized to mediate these pollution effects, however precise mechanisms remain unclear. This paper describes the methodology for a major panel study to examine air pollution effects on these and other mechanistic pathways. The study took place during the drastic air pollution changes accompanying the 2008 Olympics in Beijing, China. After a general description of air pollution health effects, we provide a discussion of panel studies and describe the unique features of this study that make it likely to provide compelling results. This study should lead to a clearer and more precise definition of the role of oxidative and nitrosative stress, as well as other mechanisms, in determining acute morbidity and mortality from air pollution exposure.
doi:10.1111/j.1749-6632.2010.05638.x
PMCID: PMC4049322  PMID: 20716299
panel study; oxidative stress; exhaled breath condensate; 2008 Olympics
17.  Cryo-EM Structure of Isomeric Molluscan Hemocyanin Triggered by Viral Infection 
PLoS ONE  2014;9(6):e98766.
Hemocyanins (Hcs) of arthropods and mollusks function not only as oxygen transporters, but also as phenoloxidases (POs). In invertebrates, PO is an important component in the innate immune cascade, where it functions as the initiator of melanin synthesis, a pigment involved in encapsulating and killing of pathogenic microbes. Although structures of Hc from several species of invertebrates have been reported, the structural basis for how PO activity is triggered by structural changes of Hc in vivo remains poorly understood. Here, we report a 6.8 Å cryo-electron microscopy (cryo-EM) structure of the isomeric form of hemocyanin, which was isolated from Abalone Shriveling syndrome-associated Virus (AbSV) infected abalone (Halitotis diversicolor), and build a pseudoatomic model of isomeric H. diversicolor hemocyanin 1 (HdH1). Our results show that, compared with native form of HdH1, the architecture of isomeric HdH1 turns into a more relaxed form. The interactions between certain functional units (FUs) present in the native form of Hc either decreased or were totally abolished in the isomeric form of Hc. As a result of that, native state Hc switches to its isomeric form, enabling it to play its role in innate immune responses against invading pathogens.
doi:10.1371/journal.pone.0098766
PMCID: PMC4041863  PMID: 24887432
18.  Comparisons of Ultrafine and Fine Particles in Their Associations with Biomarkers Reflecting Physiological Pathways 
Environmental Science & Technology  2014;48(9):5264-5273.
Using a quasi-experimental opportunity offered by greatly restricted air pollution emissions during the Beijing Olympics compared to before and after the Olympics, we conducted the current study to compare ultrafine particles (UFPs) and fine particles (PM2.5) in their associations with biomarkers reflecting multiple pathophysiological pathways linking exposure and cardiorespiratory events. Number concentrations of particles (13.0–764.7 nm) and mass concentrations of PM2.5 were measured at two locations within 9 km from the residence and workplace of 125 participating Beijing residents. Each participant was measured 6 times for biomarkers of autonomic function (heart rate, systolic and diastolic blood pressures), hemostasis (von Willebrand factor, soluble CD40 ligand, and P-selectin), pulmonary inflammation and oxidative stress (exhaled nitric oxide and exhaled breath condensate pH, malondialdehyde, and nitrite), and systemic inflammation and oxidative stress (urinary malondialdehyde and 8-hydroxy-2′-deoxyguanosine, plasma fibrinogen, and white blood cells). Linear mixed models were used to estimate associations of biomarkers with UFPs and PM2.5 measured 1–7 days prior to biomarker measurements (lags). We found that the correlation coefficient for UFPs at two locations (∼9 km apart) was 0.45, and at the same location, the correlation coefficient for PM2.5 vs UFPs was −0.18. Changes in biomarker levels associated with increases in UFPs and PM2.5 were comparable in magnitude. However, associations of certain biomarkers with UFPs had different lag patterns compared to those with PM2.5, suggesting that the ultrafine size fraction (≤100 nm) and the fine size fraction (∼100 nm to 2.5 μm) of PM2.5 are likely to affect PM-induced pathophysiological pathways independently.
doi:10.1021/es5006016
PMCID: PMC4015680  PMID: 24666379
19.  Stochastic Heterogeneous Interaction Promotes Cooperation in Spatial Prisoner's Dilemma Game 
PLoS ONE  2014;9(4):e95169.
Previous studies mostly investigate player's cooperative behavior as affected by game time-scale or individual diversity. In this paper, by involving both time-scale and diversity simultaneously, we explore the effect of stochastic heterogeneous interaction. In our model, the occurrence of game interaction between each pair of linked player obeys a random probability, which is further described by certain distributions. Simulations on a 4-neighbor square lattice show that the cooperation level is remarkably promoted when stochastic heterogeneous interaction is considered. The results are then explained by investigating the mean payoffs, the mean boundary payoffs and the transition probabilities between cooperators and defectors. We also show some typical snapshots and evolution time series of the system. Finally, the 8-neighbor square lattice and BA scale-free network results indicate that the stochastic heterogeneous interaction can be robust against different network topologies. Our work may sharpen the understanding of the joint effect of game time-scale and individual diversity on spatial games.
doi:10.1371/journal.pone.0095169
PMCID: PMC3997352  PMID: 24759921
20.  Chinese SLE Treatment and Research Group Registry: III. Association of Autoantibodies with Clinical Manifestations in Chinese Patients with Systemic Lupus Erythematosus 
Journal of Immunology Research  2014;2014:809389.
We investigated the characteristics of Chinese SLE patients by analyzing the association between specific autoantibodies and clinical manifestations of 2104 SLE patients from registry data of CSTAR cohort. Significant (P < 0.05) associations were found between anti-Sm antibody, anti-rRNP antibody, and malar rash; between anti-RNP antibody, anti-SSA antibody, and pulmonary arterial hypertension (PAH); between anti-SSB antibody and hematologic involvement; and between anti-dsDNA antibody and nephropathy. APL antibody was associated with hematologic involvement, interstitial lung disease, and a lower prevalence of oral ulcerations (P < 0.05). Associations were also found between anti-dsDNA antibody and a lower prevalence of photosensitivity, and between anti-SSA antibody and a lower prevalence of nephropathy (P < 0.05). Most of these findings were consistent with other studies in the literature but this study is the first report on the association between anti-SSA and a lower prevalence of nephropathy. The correlations of specific autoantibodies and clinical manifestations could provide clues for physicians to predict organ damages in SLE patients. We suggest that a thorough screening of autoantibodies should be carried out when the diagnosis of SLE is established, and repeated echocardiography annually in SLE patients with anti-RNP or anti-SSA antibody should be performed.
doi:10.1155/2014/809389
PMCID: PMC4017718  PMID: 24864270
21.  Mechanism of the Rpn13-induced activation of Uch37 
Protein & Cell  2014;5(8):616-630.
Uch37 is a de-ubiquitinating enzyme that is activated by Rpn13 and involved in the proteasomal degradation of proteins. The full-length Uch37 was shown to exhibit low iso-peptidase activity and is thought to be auto-inhibited. Structural comparisons revealed that within a homo-dimer of Uch37, each of the catalytic domains was blocking the other’s ubiquitin (Ub)-binding site. This blockage likely prevented Ub from entering the active site of Uch37 and might form the basis of auto-inhibition. To understand the mode of auto-inhibition clearly and shed light on the activation mechanism of Uch37 by Rpn13, we investigated the Uch37-Rpn13 complex using a combination of mutagenesis, biochemical, NMR, and small-angle X-ray scattering (SAXS) techniques. Our results also proved that Uch37 oligomerized in solution and had very low activity against the fluorogenic substrate ubiquitin-7-amino-4-methylcoumarin (Ub-AMC) of de-ubiquitinating enzymes. Uch37ΔHb,Hc,KEKE, a truncation removal of the C-terminal extension region (residues 256–329) converted oligomeric Uch37 into a monomeric form that exhibited iso-peptidase activity comparable to that of a truncation-containing the Uch37 catalytic domain only. We also demonstrated that Rpn13C (Rpn13 residues 270–407) could disrupt the oligomerization of Uch37 by sequestering Uch37 and forming a Uch37-Rpn13 complex. Uch37 was activated in such a complex, exhibiting 12-fold-higher activity than Uch37 alone. Time-resolved SAXS (TR-SAXS) and FRET experiments supported the proposed mode of auto-inhibition and the activation mechanism of Uch37 by Rpn13. Rpn13 activated Uch37 by forming a 1:1 stoichiometric complex in which the active site of Uch37 was accessible to Ub.
Electronic supplementary material
The online version of this article (doi:10.1007/s13238-014-0046-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s13238-014-0046-z
PMCID: PMC4130924  PMID: 24752541
Uch37-Rpn13 complex; de-ubiquitination; SAXS analysis; oligomerization; iso-peptidase
22.  Mechanism of the Rpn13-induced activation of Uch37 
Protein & Cell  2014;5(8):616-630.
Uch37 is a de-ubiquitinating enzyme that is activated by Rpn13 and involved in the proteasomal degradation of proteins. The full-length Uch37 was shown to exhibit low iso-peptidase activity and is thought to be auto-inhibited. Structural comparisons revealed that within a homo-dimer of Uch37, each of the catalytic domains was blocking the other’s ubiquitin (Ub)-binding site. This blockage likely prevented Ub from entering the active site of Uch37 and might form the basis of auto-inhibition. To understand the mode of auto-inhibition clearly and shed light on the activation mechanism of Uch37 by Rpn13, we investigated the Uch37-Rpn13 complex using a combination of mutagenesis, biochemical, NMR, and small-angle X-ray scattering (SAXS) techniques. Our results also proved that Uch37 oligomerized in solution and had very low activity against the fluorogenic substrate ubiquitin-7-amino-4-methylcoumarin (Ub-AMC) of de-ubiquitinating enzymes. Uch37ΔHb,Hc,KEKE, a truncation removal of the C-terminal extension region (residues 256–329) converted oligomeric Uch37 into a monomeric form that exhibited iso-peptidase activity comparable to that of a truncation-containing the Uch37 catalytic domain only. We also demonstrated that Rpn13C (Rpn13 residues 270–407) could disrupt the oligomerization of Uch37 by sequestering Uch37 and forming a Uch37-Rpn13 complex. Uch37 was activated in such a complex, exhibiting 12-fold-higher activity than Uch37 alone. Time-resolved SAXS (TR-SAXS) and FRET experiments supported the proposed mode of auto-inhibition and the activation mechanism of Uch37 by Rpn13. Rpn13 activated Uch37 by forming a 1:1 stoichiometric complex in which the active site of Uch37 was accessible to Ub.
Electronic supplementary material
The online version of this article (doi:10.1007/s13238-014-0046-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s13238-014-0046-z
PMCID: PMC4130924  PMID: 24752541
Uch37-Rpn13 complex; de-ubiquitination; SAXS analysis; oligomerization; iso-peptidase
23.  Primary testicular lymphoma with subcutaneous masses as the sole manifestation of the first relapse and central nervous system lymphoma as the second relapse: A case report and literature review 
Oncology Letters  2014;7(6):1881-1884.
Primary testicular lymphoma (PTL) accounts for ~1% of all non-Hodgkin’s lymphomas and has a marked tendency for systemic relapse. The current study presents a unique case of testicular diffuse large B-cell lymphoma of non-germinal center B-cell subtype, with subcutaneous masses as the sole manifestation of the first relapse and central nervous system lymphoma as the second relapse. Subcutaneous relapse and subsequent brain relapse are extremely rare signs of PTL dissemination. The patient received methotrexate-based combined chemotherapy and achieved a partial response. This case presents a rare pattern of treatment failure in this malignant clinical entity.
doi:10.3892/ol.2014.2052
PMCID: PMC4049739  PMID: 24932252
primary testicular lymphoma; subcutaneous soft tissue; relapse
24.  Whole-genome analysis of 5-hydroxymethylcytosine and 5-methylcytosine at base resolution in the human brain 
Genome Biology  2014;15(3):R49.
Background
5-methylcytosine (mC) can be oxidized by the tet methylcytosine dioxygenase (Tet) family of enzymes to 5-hydroxymethylcytosine (hmC), which is an intermediate of mC demethylation and may also be a stable epigenetic modification that influences chromatin structure. hmC is particularly abundant in mammalian brains but its function is currently unknown. A high-resolution hydroxymethylome map is required to fully understand the function of hmC in the human brain.
Results
We present genome-wide and single-base resolution maps of hmC and mC in the human brain by combined application of Tet-assisted bisulfite sequencing and bisulfite sequencing. We demonstrate that hmCs increase markedly from the fetal to the adult stage, and in the adult brain, 13% of all CpGs are highly hydroxymethylated with strong enrichment at genic regions and distal regulatory elements. Notably, hmC peaks are identified at the 5′splicing sites at the exon-intron boundary, suggesting a mechanistic link between hmC and splicing. We report a surprising transcription-correlated hmC bias toward the sense strand and an mC bias toward the antisense strand of gene bodies. Furthermore, hmC is negatively correlated with H3K27me3-marked and H3K9me3-marked repressive genomic regions, and is more enriched at poised enhancers than active enhancers.
Conclusions
We provide single-base resolution hmC and mC maps in the human brain and our data imply novel roles of hmC in regulating splicing and gene expression. Hydroxymethylation is the main modification status for a large portion of CpGs situated at poised enhancers and actively transcribed regions, suggesting its roles in epigenetic tuning at these regions.
doi:10.1186/gb-2014-15-3-r49
PMCID: PMC4053808  PMID: 24594098
25.  Cordycepin activates AMP-activated protein kinase (AMPK) via interaction with the γ1 subunit 
Cordycepin is a bioactive component of the fungus Cordyceps militaris. Previously, we showed that cordycepin can alleviate hyperlipidemia through enhancing the phosphorylation of AMP-activated protein kinase (AMPK), but the mechanism of this stimulation is unknown. Here, we investigated the potential mechanisms of cordycepin-induced AMPK activation in HepG2 cells. Treatment with cordycepin largely reduced oleic acid (OA)-elicited intracellular lipid accumulation and increased AMPK activity in a dose-dependent manner. Cordycepin-induced AMPK activation was not accompanied by changes in either the intracellular levels of AMP or the AMP/ATP ratio, nor was it influenced by calmodulin-dependent protein kinase kinase (CaMKK) inhibition; however, this activation was significantly suppressed by liver kinase B1 (LKB1) knockdown. Molecular docking, fluorescent and circular dichroism measurements showed that cordycepin interacted with the γ1 subunit of AMPK. Knockdown of AMPKγ1 by siRNA substantially abolished the effects of cordycepin on AMPK activation and lipid regulation. The modulating effects of cordycepin on the mRNA levels of key lipid regulatory genes were also largely reversed when AMPKγ1 expression was inhibited. Together, these data suggest that cordycepin may inhibit intracellular lipid accumulation through activation of AMPK via interaction with the γ1 subunit.
doi:10.1111/jcmm.12187
PMCID: PMC3930416  PMID: 24286368
Cordycepin; AMPK; LKB1; Molecular docking

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