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1.  A longitudinal study about the effect of practicing Yan Xin Qigong on medical care cost with medical claims data 
We use 7-year longitudinal medical claims data and statistical models to study the relationship between practicing Yan Xin Qigong (YXQG), a traditional advanced Chinese Qigong that has been integrated with modern science and technology, and practitioners’ medical care utilization and the associated costs. We find that for the sampled practitioners, their average monthly medical visits and the associated costs are significantly lower after practicing YXQG. After controlling for other factors, the longer of practicing YXQG, the more likely there was a fall in average medical visits and medical costs. The main findings are robust to various estimation methods.
PMCID: PMC4330469
medical care cost; medical care utilization; Yan Xin Qigong; economic impact
2.  Sustained expression of CYPs and DNA adduct accumulation with continuous exposure to PCB126 and PCB153 through a new delivery method: Polymeric implants 
Toxicology reports  2014;1:820-833.
A new delivery method via polymeric implants was used for continuous exposure to PCBs. Female Sprague-Dawley rats received subcutaneous polymeric implants containing PCB126 (0.15% load), PCB153 (5% load), or both, for up to 45 days and release kinetics and tissue distribution were measured. PCB153 tissue levels on day 15 were readily detected in lung, liver, mammary and serum, with highest levels in the mammary tissue. PCB126 was detected only in liver and mammary tissues. However, a completely different pharmacokinetics was observed on co-exposure of PCB153 and PCB126, with a 1.8-fold higher levels of PCB153 in the liver whereas a 1.7-fold lower levels in the mammary tissue. PCB126 and PCB153 caused an increase in expression of key PCB-inducible enzymes, CYP 1A1/2 and 2B1/2, respectively. Serum and liver activities of the antioxidant enzymes, PON1 and PON3, and AhR transcription were also significantly increased by PCB126. 32P-Postlabeling for polar and lipophilic DNA-adducts showed significant quantitative differences: PCB126 increased 8-oxodG, an oxidative DNA lesion, in liver and lung tissues. Adduct levels in the liver remained upregulated up to 45 days, while some lung DNA adducts declined. This is the first demonstration that continuous low-dose exposure to PCBs via implants can produce sustained tissue levels leading to the accumulation of DNA-adducts in target tissue and induction of indicator enzymes. Collectively, these data demonstrate that this exposure model is a promising tool for long-term exposure studies.
doi:10.1016/j.toxrep.2014.09.010
PMCID: PMC4266188  PMID: 25530946
polychlorinated biphenyls (PCBs); PCB126 (3,3’,4,4’,5-pentachlorobiphenyl); PCB153 (2,2’4,4’,5,5’-hexachlorobiphenyl); Polymeric implants; DNA adducts; 32P-Postlabeling; CYPs; paraoxonase 1 (PON1)
3.  Cys-Leukotrienes Promote Fibrosis in a Mouse Model of Eosinophil-Mediated Respiratory Inflammation 
Leukotrienes (i.e., products of the 5-lipoxygenase pathway) are thought to be contributors to lung pathologies. Moreover, eosinophils have been linked with pulmonary leukotriene activities both as potential sources of these mediators and as responding effector cells. The objective of the present study was to define the role(s) of leukotrienes in the lung pathologies accompanying eosinophil-associated chronic respiratory inflammation. A transgenic mouse model of chronic T helper (Th) 2–driven inflammation expressing IL-5 from T cells and human eotaxin-2 locally in the lung (I5/hE2) was used to define potential in vivo relationships among eosinophils, leukotrienes, and chronic Th2-polarized pulmonary inflammation. Airway levels of cys-leukotrienes and leukotriene B4 (LTB4) are both significantly elevated in I5/hE2 mice. The eosinophil-mediated airway hyperresponsiveness (AHR) characteristic of these mice was abolished in the absence of leukotrienes (i.e., 5-lipoxygenase–deficient I5/hE2). More importantly, the loss of leukotrienes led to an unexpectedly significant decrease in collagen deposition (i.e., pulmonary fibrosis) that accompanied elevated levels of IL-4/-13 and TGF-β in the lungs of I5/hE2 mice. Further studies using mice deficient for the LTB4 receptor (BLT-1−/−/I5/hE2) and I5/hE2 animals administered a cys-leukotriene receptor antagonist (montelukast) demonstrated that the AHR and the enhanced pulmonary fibrosis characteristic of the I5/hE2 model were uniquely cys-leukotriene–mediated events. These data demonstrate that, similar to allergen challenge models of wild-type mice, cys-leukotrienes underlie AHR in this transgenic model of severe pulmonary Th2 inflammation. These data also suggest that an underappreciated link exists among eosinophils, cys-leukotriene–mediated events, and fibrotic remodeling associated with elevated levels of IL-4/-13 and TGF-β.
doi:10.1165/rcmb.2013-0009OC
PMCID: PMC3931112  PMID: 23859654
5-lipoxygenase; asthma; eosinophils; montelukast; lung
4.  Maintaining energy homeostasis is an essential component of WldS-mediated axon protection 
Neurobiology of disease  2013;59:69-79.
WldS mutation protects axons from degeneration in diverse experimental models of neurological disorders, suggesting that the mutation might act on a key step shared by different axon degeneration pathways. Here we test the hypothesis that WldS protects axons by preventing energy deficiency commonly encountered in many diseases. We subjected compartmentally cultured, mouse cortical axons to energy deprivation with 6 mM azide and zero glucose. In wild-type (WT) culture, the treatment, which reduced axon ATP level ([ATP]axon) by 65%, caused immediate axon depolarization followed by gradual free calcium accumulation and subsequent irreversible axon damage. The calcium accumulation resulted from calcium influx partially via L-type voltage-gated calcium channel (L-VGCC). Blocking L-VGCC with nimodipine reduced calcium accumulation and protected axons. Without altering baseline [ATP]axon, the presence of WldS mutation significantly reduced the axon ATP loss and depolarization, restrained the subsequent calcium accumulation, and protected axons against energy deprivation. WldS neurons possessed higher than normal nicotinamide mononucleotide adenylyltransferase (NMNAT) activity. The intrinsic WldS NMNAT activity was required for the WldS-mediated energy preservation and axon protection during but not prior to energy deprivation. NMNAT catalyzes the reversible reaction that produces nicotinamide adenine dinucleotide (NAD) from nicotinamide mononucleotide (NMN). Interestingly, preventing the production of NAD from NMN with FK866 increased [ATP]axon and protected axons from energy deprivation. These results indicate that the WldS mutation dependends on its intrinsic WldS NMNAT acitivity and the subsequent increase in axon ATP but not NAD to protect axons, implicating a novel role of WldS NMNAT in axon bioenergetics and protection.
doi:10.1016/j.nbd.2013.07.007
PMCID: PMC3787137  PMID: 23892229
axon injury; WldS; energy deprivation; ATP; NMNAT; calcium; bioenergetics
5.  Inhibition of x-box binding protein 1 reduces tunicamycin-induced apoptosis in aged murine macrophages 
Aging cell  2013;12(5):794-801.
SUMMARY
Endoplasmic reticulum (ER) stress is induced by the accumulation of unfolded and misfolded proteins in the ER. Although apoptosis induced by ER stress has been implicated in several aging-associated diseases, such as atherosclerosis, it is unclear how aging modifies ER stress response in macrophages. To decipher this relationship, we assessed apoptosis in macrophages isolated from young (6–8 weeks) and aged (16–18 months) mice and exposed the cells to the ER stress inducer tunicamycin. We found that aged macrophages exhibited more apoptosis than young macrophages, which was accompanied by reduced activation of phosphorylated inositol-requiring enzyme-1 (p-IRE1α), one of the three key ER stress signal transducers. Reduced gene expression of x-box binding protein 1 (XBP1), a downstream effector of IRE1α, enhanced p-IRE1α levels and reduced apoptosis in aged, but not young macrophages treated with tunicamycin. These findings delineate a novel, age-dependent interaction by which macrophages undergo apoptosis upon ER stress, and suggest an important protective role of IRE1α in aging-associated ER stress-induced apoptosis. This novel pathway may not only be important in our understanding of longevity, but may also have important implications for pathogenesis and potential treatment of aging-associated diseases in general.
doi:10.1111/acel.12105
PMCID: PMC3773058  PMID: 23711292
Aging; macrophages; endoplasmic reticulum stress; apoptosis
6.  Processes of Sterile Inflammation 
Sterile inflammation occurs in acute conditions such as ischemia reperfusion injury and crystal-induced arthritis, and also with chronic diseases such as particle-induced lung diseases and atherosclerosis. The triggers of sterile inflammation are still being identified and the pathways that transduce sterile inflammatory signals are not completely clear. Currently, most of the innate immune pathways that sense infection have been implicated in sterile inflammation, although distinct signaling pathways of sterile inflammation exist. Whether immune pathology ensues after sterile inflammation depends on the balance of induced inflammatory and resolution pathways. Further identification of the molecular mechanisms of sterile inflammation will lead to novel therapeutics to treat a wide range of diseases.
doi:10.4049/jimmunol.1301539
PMCID: PMC3787118  PMID: 24014880
7.  Alteration in Mir-21/PTEN Expression Modulates Gefitinib Resistance in Non-Small Cell Lung Cancer 
PLoS ONE  2014;9(7):e103305.
Resistance to TKI treatment is a major obstacle in effective treatment of NSCLC. Besides EGFR mutation status, the mechanisms involved are largely unknown. Some evidence supports a role for microRNA 21 in modulating drug sensitivity of chemotherapy but its role in NSCLC TKI resistance still remains unexplored. This study aimed to investigate whether NSCLC miR-21 mediated resistance to TKIs also results from Pten targeting. Here, we show miR-21 promotes cancer by negatively regulating Pten expression in human NSCLC tissues: high miR-21 expression levels were associated with shorter DFS in 47 NSCLC patients; high miR-21/low Pten expression levels indicated a poor TKI clinical response and shorter overall survival in another 46 NSCLC patients undergoing TKI treatment. In vitro assays showed that miR-21 was up-regulated concomitantly to down-regulation of Pten in pc-9/GR cells in comparison with pc-9 cells. Moreover, over-expression of miR-21 significantly decreased gefitinib sensitivity by down-regulating Pten expression and activating Akt and ERK pathways in pc-9 cells, while miR-21 knockdown dramatically restored gefitinib sensitivity of pc-9/GR cells by up-regulation of Pten expression and inactivation of AKT and ERK pathways, in vivo and in vitro. We propose alteration of miR-21/Pten expression as a novel mechanism for TKI resistance in NSCLC cancer. Our findings provide a new basis for using miR 21/Pten-based therapeutic strategies to reverse gefitinib resistance in NSCLC.
doi:10.1371/journal.pone.0103305
PMCID: PMC4110008  PMID: 25058005
8.  Temporal scaling in information propagation 
Scientific Reports  2014;4:5334.
For the study of information propagation, one fundamental problem is uncovering universal laws governing the dynamics of information propagation. This problem, from the microscopic perspective, is formulated as estimating the propagation probability that a piece of information propagates from one individual to another. Such a propagation probability generally depends on two major classes of factors: the intrinsic attractiveness of information and the interactions between individuals. Despite the fact that the temporal effect of attractiveness is widely studied, temporal laws underlying individual interactions remain unclear, causing inaccurate prediction of information propagation on evolving social networks. In this report, we empirically study the dynamics of information propagation, using the dataset from a population-scale social media website. We discover a temporal scaling in information propagation: the probability a message propagates between two individuals decays with the length of time latency since their latest interaction, obeying a power-law rule. Leveraging the scaling law, we further propose a temporal model to estimate future propagation probabilities between individuals, reducing the error rate of information propagation prediction from 6.7% to 2.6% and improving viral marketing with 9.7% incremental customers.
doi:10.1038/srep05334
PMCID: PMC4061555  PMID: 24939414
9.  Insulin Regulates Glucose Consumption and Lactate Production through Reactive Oxygen Species and Pyruvate Kinase M2 
Although insulin is known to regulate glucose metabolism and closely associate with liver cancer, the molecular mechanisms still remain to be elucidated. In this study, we attempt to understand the mechanism of insulin in promotion of liver cancer metabolism. We found that insulin increased pyruvate kinase M2 (PKM2) expression through reactive oxygen species (ROS) for regulating glucose consumption and lactate production, key process of glycolysis in hepatocellular carcinoma HepG2 and Bel7402 cells. Interestingly, insulin-induced ROS was found responsible for the suppression of miR-145 and miR-128, and forced expression of either miR-145 or miR-128 was sufficient to abolish insulin-induced PKM2 expression. Furthermore, the knockdown of PKM2 expression also inhibited cancer cell growth and insulin-induced glucose consumption and lactate production, suggesting that PKM2 is a functional downstream effecter of insulin. Taken together, this study would provide a new insight into the mechanism of insulin-induced glycolysis.
doi:10.1155/2014/504953
PMCID: PMC4034658  PMID: 24895527
10.  Bovine Leukemia Virus DNA in Human Breast Tissue 
Emerging Infectious Diseases  2014;20(5):772-782.
Bovine leukemia virus (BLV), a deltaretrovirus, causes B-cell leukemia/lymphoma in cattle and is prevalent in herds globally. A previous finding of antibodies against BLV in humans led us to examine the possibility of human infection with BLV. We focused on breast tissue because, in cattle, BLV DNA and protein have been found to be more abundant in mammary epithelium than in lymphocytes. In human breast tissue specimens, we identified BLV DNA by using nested liquid-phase PCR and DNA sequencing. Variations from the bovine reference sequence were infrequent and limited to base substitutions. In situ PCR and immunohistochemical testing localized BLV to the secretory epithelium of the breast. Our finding of BLV in human tissues indicates a risk for the acquisition and proliferation of this virus in humans. Further research is needed to determine whether BLV may play a direct role in human disease.
doi:10.3201/eid2005.131298
PMCID: PMC4012802  PMID: 24750974
bovine leukemia virus; human; bovine; bovid; breast tissue; viruses; zoonosis; zoonoses; United States; breast cancer; leukemia; lymphoma; cancer; DNA
11.  Laparoscopic ligation of proximal splenic artery aneurysm with splenic function preservation 
Splenic artery aneurysm is one of the most common visceral aneurysms, and patients with this type of aneurysm often present without symptoms. However, when rupture occurs, it can be a catastrophic event. Although most of these aneurysms can be treated with percutaneous embolization, some located in uncommon parts of the splenic artery may make this approach impossible. We present a patient with an aneurysm in the proximal splenic artery, close to the celiac trunk, which was treated by laparoscopic ligation only, without resection of the aneurysm, and with long-term preservation of splenic function.
doi:10.3748/wjg.v20.i16.4835
PMCID: PMC4000525  PMID: 24782641
Laparoscopy; Splenic artery; Aneurysm; Laparoscopic ligation; Splenic function preservation
12.  Comparison of ESWL and Ureteroscopic Holmium Laser lithotripsy in Management of Ureteral Stones 
PLoS ONE  2014;9(2):e87634.
Background
There are many options for urologists to treat ureteral stones that range from 8 mm to 15 mm, including ESWL and ureteroscopic holmium laser lithotripsy. While both ESWL and ureteroscopy are effective and minimally invasive procedures, there is still controversy over which one is more suitable for ureteral stones.
Objective
To perform a retrospective study to compare the efficiency, safety and complications using ESWL vs. ureteroscopic holmium laser lithotripsy in management of ureteral stones.
Methods
Between October 2010 and October 2012, 160 patients who underwent ESWL or ureteroscopic holmium laser lithotripsy at Suzhou municipal hospital for a single radiopaque ureteral stone (the size 8–15 mm) were evaluated. All patients were followed up with ultrasonography for six months. Stone clearance rate, costs and complications were compared.
Results
Similarity in stone clearance rate and treatment time between the two procedures; overall procedural time, analgesia requirement and total cost were significantly different. Renal colic and gross hematuria were more frequent with ESWL while voiding symptoms were more frequent with ureteroscopy. Both procedures used for ureteral stones ranging from 8 to 15 mm were safe and minimally invasive.
Conclusion
ESWL remains first line therapy for proximal ureteral stones while ureteroscopic holmium laser lithotripsy costs more. To determining which one is preferable depends on not only stone characteristics but also patient acceptance and cost-effectiveness ratio.
doi:10.1371/journal.pone.0087634
PMCID: PMC3912003  PMID: 24498344
13.  F-18 Labeled Vasoactive Intestinal Peptide Analogue in the PET Imaging of Colon Carcinoma in Nude Mice 
BioMed Research International  2013;2013:420480.
As large amount of vasoactive intestinal peptide (VIP) receptors are expressed in various tumors and VIP-related diseases, radiolabeled VIP provides a potential PET imaging agent for VIP receptor. However, structural modification of VIP is required before being radiolabeled and used for VIP receptor imaging due to its poor in vivo stability. As a VIP analogue, [R8, 15, 21, L17]-VIP exhibited improved stability and receptor specificity in preliminary studies. In this study, F-18 labeled [R8,15,21, L17]-VIP was produced with the radiochemical yield being as high as 33.6% ± 3% (decay-for-corrected, n = 5) achieved within 100 min, a specific activity of 255 GBq/μmol, and a radiochemical purity as high as 99% as characterized by radioactive HPLC, TLC, and SDS-Page radioautography. A biodistribution study in normal mice also demonstrated fast elimination of F-18 labeled [R8,15,21, L17]-VIP in the blood, liver, and gastrointestinal tracts. A further micro-PET imaging study in C26 colon carcinoma bearing mice confirmed the high tumor specificity, with the tumor/muscle radioactivity uptake ratio being as high as 3.03 at 60 min following injection, and no apparent radioactivity concentration in the intestinal tracts. In addition, blocking experiment and Western Blot test further confirmed its potential in PET imaging of VIP receptor-positive tumor.
doi:10.1155/2013/420480
PMCID: PMC3888718  PMID: 24459669
14.  Prevention of allergic airway hyperresponsiveness and remodeling in mice by Astragaliradix Antiasthmatic decoction 
Background
Astragali radix Antiasthmatic Decoction (AAD), a traditional Chinese medication, is found effective in treating allergic diseases and chronic cough. The purpose of this study is to determine whether this medication could suppress allergen-induced airway hyperresponsiveness (AHR) and remodeling in mice, and its possible mechanisms.
Methods
A mouse model of chronic asthma was used to investigate the effects of AAD on the airway lesions. Mice were sensitized and challenged with ovalbumin (OVA), and the extent of AHR and airway remodeling were characterized. Cells and cytokines in the bronchoalveolar lavage fluid (BALF) were examined.
Results
AAD treatment effectively decreased OVA-induced AHR, eosinophilic airway inflammation, and collagen deposition around the airway. It significantly reduced the levels of IL-13 and TGF-β1, but exerted inconsiderable effect on INF-γ and IL-10.
Conclusions
AAD greatly improves the symptoms of allergic airway remodeling probably through inhibition of Th2 cytokines and TGF-β1.
doi:10.1186/1472-6882-13-369
PMCID: PMC3922862  PMID: 24367979
Astragalus Antiasthmatic Decoction; Airway hyperresponsiveness; Airway remodeling
15.  A ΔclpB Mutant of Francisella tularensis Subspecies holarctica Strain, FSC200, Is a More Effective Live Vaccine than F. tularensis LVS in a Mouse Respiratory Challenge Model of Tularemia 
PLoS ONE  2013;8(11):e78671.
Francisella tularensis subsp. tularensis is a highly virulent pathogen for humans especially if inhaled. Consequently, it is considered to be a potential biothreat agent. An experimental vaccine, F. tularensis live vaccine strain, derived from the less virulent subsp. holarctica, was developed more than 50 years ago, but remains unlicensed. Previously, we developed a novel live vaccine strain, by deleting the chaperonin clpB gene from F. tularensis subsp. tularensis strain, SCHU S4. SCHU S4ΔclpB was less virulent for mice than LVS and a more effective vaccine against respiratory challenge with wild type SCHU S4. In the current study, we were interested to determine whether a similar mutant on the less virulent subsp. holarctica background would also outperform LVS in terms of safety and efficacy. To this end, clpB was deleted from clinical holarctica strain, FSC200. FSC200ΔclpB had a significantly higher intranasal LD50 than LVS for BALB/c mice, but replicated to higher numbers at foci of infection after dermal inoculation. Moreover, FSC200ΔclpB killed SCID mice more rapidly than LVS. However, dermal vaccination of BALB/c mice with the former versus the latter induced greater protection against respiratory challenge with SCHU S4. This increased efficacy was associated with enhanced production of pulmonary IL-17 after SCHU S4 challenge.
doi:10.1371/journal.pone.0078671
PMCID: PMC3827231  PMID: 24236032
16.  BMP12 induces tenogenic differentiation of adipose-derived stromal cells 
PLoS ONE  2013;8(10):e77613.
Adipose-derived stromal cells (ASCs) are pluripotent cells that have the capacity to differentiate into tendon fibroblasts (TFs). They are abundant in adults, easy to access, and are therefore an ideal cell source for tendon tissue engineering. Despite this potential, the molecular cues necessary for tenogenic differentiation of ASCs are unknown. Unlike other bone morphogenetic proteins (BMPs), BMP12, BMP13, and BMP14 have been reported to be less osteo-chondrogenic and to induce tendon rather than bone formation in vivo. This study investigated the effects of BMP12 and BMP14 on ASC differentiation in vitro. In canine ASCs, BMP12 effectively increased the expression of the tendon markers scleraxis and tenomodulin at both mRNA and protein levels. Consistent with these results, BMP12 induced scleraxis promoter driven-GFP and tenomodulin protein expression in mouse ASCs. Although BMP12 also enhanced the expression of the cartilage matrix gene aggrecan in ASCs, the resulting levels remained considerably lower than those detected in tendon fibroblasts. In addition, BMP12 reduced expression of the bone marker osteocalcin, but not the osteogenic transcription factor runx-2. BMP14 exhibited similar, but marginally less potent and selective effects, compared to BMP12. BMPs are known to signal through the canonical Smad pathway and the non-canonical mitogen-activated protein kinase (MAPK) pathway. BMP12 triggered robust phosphorylation of Smad1/5/8 but not Smad2/3 or p38 MAPK in ASCs. The effect was likely conveyed by type I receptors ALK2/3/6, as phosphorylation of Smad1/5/8 was blocked by the ALK2/3/6 inhibitor LDN-193189 but not by the ALK4/5/7 inhibitor SB-505124. Moreover, ALK6 was found to be the most abundant type I receptor in ASCs, with mRNA expression 100 to 10,000 times that of any other type I receptor. Collectively, results support the conclusion that BMP12 induces tenogenic differentiation of ASCs via the Smad1/5/8 pathway.
doi:10.1371/journal.pone.0077613
PMCID: PMC3796462  PMID: 24155967
17.  Cumulative Effect in Information Diffusion: Empirical Study on a Microblogging Network 
PLoS ONE  2013;8(10):e76027.
Cumulative effect in social contagion underlies many studies on the spread of innovation, behavior, and influence. However, few large-scale empirical studies are conducted to validate the existence of cumulative effect in information diffusion on social networks. In this paper, using the population-scale dataset from the largest Chinese microblogging website, we conduct a comprehensive study on the cumulative effect in information diffusion. We base our study on the diffusion network of message, where nodes are the involved users and links characterize forwarding relationship among them. We find that multiple exposures to the same message indeed increase the possibility of forwarding it. However, additional exposures cannot further improve the chance of forwarding when the number of exposures crosses its peak at two. This finding questions the cumulative effect hypothesis in information diffusion. Furthermore, to clarify the forwarding preference among users, we investigate both structural motif in the diffusion network and temporal pattern in information diffusion process. Findings provide some insights for understanding the variation of message popularity and explain the characteristics of diffusion network.
doi:10.1371/journal.pone.0076027
PMCID: PMC3788071  PMID: 24098422
18.  Creatine pretreatment protects cortical axons from energy depletion in vitro 
Neurobiology of Disease  2012;47(2):184-193.
Creatine is a natural nitrogenous guanidino compound involved in bioenergy metabolism. Although creatine has been shown to protect neurons of the central nervous system (CNS) from experimental hypoxia/ischemia, it remains unclear if creatine may also protect CNS axons, and if the potential axonal protection depends on glial cells. To evaluate the direct impact of creatine on CNS axons, cortical axons were cultured in a separate compartment from their somas and proximal neurites using a modified two-compartment culture device. Axons in the axon compartment were subjected to acute energy depletion, an in vitro model of white matter ischemia, by exposure to 6 mM sodium azide for 30 min in the absence of glucose and pyruvate. Energy depletion reduced axonal ATP by 65%, depolarized axonal resting potential, and damaged 75% of axons. Application of creatine (10 mM) to both compartments of the culture at 24 h prior to energy depletion significantly reduced axonal damage by 50%. In line with the role of creatine in the bioenergy metabolism, this application also alleviated the axonal ATP loss and depolarization. Inhibition of axonal depolarization by blocking sodium influx with tetrodotoxin also effectively reduced the axonal damage caused by energy depletion. Further study revealed that the creatine effect was independent of glial cells, as axonal protection was sustained even when creatine was applied only to the axon compartment (free from somas and glial cells) for as little as 2 h. In contrast, application of creatine after energy depletion did not protect axons. The data provide the first evidence that creatine pretreatment may directly protect CNS axons from energy deficiency.
doi:10.1016/j.nbd.2012.03.037
PMCID: PMC3367034  PMID: 22521466
creatine; energy depletion; ischemia; axonal injury; ATP; white matter; compartmental culture
19.  Regulation of paraoxonase 1 (PON1) in PCB 126-exposed male Sprague Dawley rats 
Toxicology Letters  2012;209(3):291-298.
3,3′,4,4′,5-Pentachlorobiphenyl (PCB 126), an aryl hydrocarbon receptor (AhR) agonist and most potent dioxin-like PCB congener, significantly alters gene expression, lipid metabolism, and oxidative stress in the liver. PON1, an antioxidant and anti-atherogenic enzyme, is produced in the liver and secreted into the blood where it is incorporated into high density lipoprotein (HDL) and protects LDL and cellular membranes against lipid peroxidation. To explore the regulation of PON1, male Sprague-Dawley rats were treated with ip injections of 0, 1 or 5 μmol/kg PCB 126 and euthanized up to two weeks afterwards. Serum total and HDL-cholesterol were increased by low dose and decreased by high dose exposure, while LDL-cholesterol was unchanged. PCB 126 significantly increased hepatic PON1 gene expression and liver and serum PON1 activities. Liver and serum thiobarbituric acid reactive substances levels were not elevated except for high dose and long exposure times. Serum antioxidant capacity was unchanged across all exposure doses and time points. This study, the first describing the regulation of gene expression of PON1 by a PCB congener, raises interesting questions whether elevated PON1 is able to ameliorate PCB 126-induced lipid peroxidation and whether serum PON1 levels may serve as a new biomarker of exposure to dioxin-like compounds.
doi:10.1016/j.toxlet.2012.01.003
PMCID: PMC3288253  PMID: 22266287
Paraoxonase 1; PCB 126; TBARS; rat; liver; AhR; plasma lipids
20.  Methicillin-Resistant Staphylococcus aureus Carriage among Students at a Historically Black University: A Case Study 
Background. Black people in the USA is afflicted with a higher rate of methicillin-resistant Staphylococcus aureus (MRSA) infection. This study determined the prevalence of MRSA carriage among black college students at a university setting. Methods. Hand and nasal swabs were collected and screened for MRSA by mannitol fermentation, coagulase, and DNase activities and their resistance to oxacillin. MRSA isolates were analyzed for antimicrobial resistance pattern, genetic profile for staphylococcal cassette chromosome mec (SCCmec) type, pulsed-field type, multilocus sequence type (ST), and the presence of Panton-Valentine leukocidin (PVL) gene. Results. MRSA was isolated from 1 of the 312 (0.3%) hand swabs and 2 of the 310 (0.65%) nasal swabs, respectively. All isolates lack multidrug resistance and have type IV SCCmec, characteristic of community-associated MRSA. These isolates were a ST8-MRSA-IVa-PVL(+) (USA300 strain), a ST8-MRSA-IVb-PVL(−), and a new MLST, ST2562-MRSA-IV-PVL(−), identified in this study. These isolates were thus not transmitted among students. Conclusion. We found a low rate of MRSA carriage among students in a black university. Our finding highlights the need of future study which involves multiinstitutions and other ethnic group to assess the association of black race with MRSA carriage.
doi:10.1155/2013/979734
PMCID: PMC3563209  PMID: 23401691
21.  Aging enhances the basal production of IL-6 and CCL2 in vascular smooth muscle cells 
Objective
Increased circulating cytokine levels are a prominent feature of aging that may contribute to atherosclerosis. However, the role vascular cells play in chronic inflammation induced by aging is not clear. Here, we examined the role of aging on inflammatory responses of vascular cells.
Methods and Results
In an ex vivo culture system, we examined the inflammatory response of aortas from young (2-4 months) and aged (16-18 months) mice under non-stimulatory conditions. We found that basal levels of interleukin (IL)-6 were increased in aged aortas. Aged aortic vascular smooth muscle cells (VSMC) exhibited a higher basal secretion of IL-6 than young VSMC. Gene and protein expression analysis revealed that aged VSMC exhibited upregulation of chemokines (e.g. CCL2), adhesion molecules (e.g., ICAM1), and innate immune receptors (e.g., Toll like receptor [TLR] 4), which all contribute to atherosclerosis. Using VSMC from aged TL4-/- and Myd88-/- mice, we demonstrate that signaling via TLR4 and its signal adaptor, MyD88, are in part responsible for the age-elevated basal IL-6 response.
Conclusion
Aging induces a proinflammatory phenotype in VSMC due in part to increased signaling of TLR4 and MyD88. Our results provide a potential explanation as to why aging leads to chronic inflammation and enhanced atherosclerosis.
doi:10.1161/ATVBAHA.111.236349
PMCID: PMC3241880  PMID: 22034510
aging; atherosclerosis; inflammation; mouse; vascular smooth muscle cells
22.  Degree-Strength Correlation Reveals Anomalous Trading Behavior 
PLoS ONE  2012;7(10):e45598.
Manipulation is an important issue for both developed and emerging stock markets. Many efforts have been made to detect manipulation in stock markets. However, it is still an open problem to identify the fraudulent traders, especially when they collude with each other. In this paper, we focus on the problem of identifying the anomalous traders using the transaction data of eight manipulated stocks and forty-four non-manipulated stocks during a one-year period. By analyzing the trading networks of stocks, we find that the trading networks of manipulated stocks exhibit significantly higher degree-strength correlation than the trading networks of non-manipulated stocks and the randomized trading networks. We further propose a method to detect anomalous traders of manipulated stocks based on statistical significance analysis of degree-strength correlation. Experimental results demonstrate that our method is effective at distinguishing the manipulated stocks from non-manipulated ones. Our method outperforms the traditional weight-threshold method at identifying the anomalous traders in manipulated stocks. More importantly, our method is difficult to be fooled by colluded traders.
doi:10.1371/journal.pone.0045598
PMCID: PMC3474833  PMID: 23082114
23.  An age-specific CD8+ T-cell pathway that impairs the effectiveness of strategies to prolong allograft survival1 
Age-related decline in immunity can impair cell-mediated responses during an infection, malignancy, and acute allograft rejection. Although much research has been allocated to understand the immune responses that impact the former two conditions, the cellular mechanisms by which aging impacts the immune acceptance of organ allografts are not completely clear. In this study, we examined how recipient age impacts the efficacy of therapies that modulate immune recognition of allografts using an immunogenic murine skin transplant model. We found that costimulatory blockade-based treatment failed to extend allograft survival in older recipients to the same extent as that observed in younger recipients. CD8+ T-cells were critical for the inability of aged recipients to achieve maximal allograft survival. Although aged mice displayed a larger number of effector memory T-cells prior to transplantation, these cells did not exhibit enhanced alloreactivity compared to young memory T-cells. In contrast, naïve aged CD8+ T-cells exhibited enhanced IFN-γ production to allostimulation compared to young naïve T-cells. Our results provide evidence that aging enhances CD8+ T-cell alloreactivity. This could impair the ability of costimulatory blockade-based therapies to prolong allograft survival. Thus, targeting CD8+ T cells in humans may be a way to improve outcomes in older patients requiring immune modulatory therapy.
doi:10.4049/jimmunol.1100441
PMCID: PMC3178732  PMID: 21873523
24.  Strict evolutionary conservation followed rapid gene loss on human and rhesus Y chromosomes 
Nature  2012;483(7387):82-86.
The human X and Y chromosomes evolved from an ordinary pair of autosomes during the past 200–300 million years1–3. Due to genetic decay, the human MSY (male-specific region of Y chromosome) retains only three percent of the ancestral autosomes’ genes4,5. This evolutionary decay was driven by a series of five “stratification” events. Each event suppressed X-Y crossing over within a chromosome segment or “stratum”, incorporated that segment into the MSY, and subjected its genes to the erosive forces that attend the absence of crossing over2,6. The last of these events occurred 30 million years ago (mya), or 5 million years before the human and Old World monkey (OWM) lineages diverged. Although speculation abounds regarding ongoing decay and looming extinction of the human Y chromosome7–10, remarkably little is known about how many MSY genes were lost in the human lineage in the 25 million years that have followed its separation from the OWM lineage. To explore this question, we sequenced the MSY of the rhesus macaque, an OWM, and compared it to the human MSY. We discovered that, during the last 25 million years, MSY gene loss in the human lineage was limited to the youngest stratum (stratum 5), which comprises three percent of the human MSY. Within the older strata, which collectively comprise the bulk of the human MSY, gene loss evidently ceased more than 25 mya. Likewise, the rhesus MSY has not lost any older genes (from strata 1–4) during the past 25 million years, despite major structural differences from the human MSY. The rhesus MSY is simpler, with few amplified gene families or palindromes that might enable intrachromosomal recombination and repair. We present an empirical reconstruction of human MSY evolution in which each stratum transitioned from rapid, exponential loss of ancestral genes to strict conservation through purifying selection.
doi:10.1038/nature10843
PMCID: PMC3292678  PMID: 22367542
25.  Haptoglobin activates innate immunity to enhance acute transplant rejection in mice 
Immune tolerance to transplanted organs is impaired when the innate immune system is activated in response to the tissue necrosis that occurs during harvesting and implantation procedures. A key molecule in this immune pathway is the intracellular TLR signal adaptor known as myeloid differentiation primary response gene 88 (MyD88). After transplantation, MyD88 induces DC maturation as well as the production of inflammatory mediators, such as IL-6 and TNF-α. However, upstream activators of MyD88 function in response to transplantation have not been identified. Here, we show that haptoglobin, an acute phase protein, is an initiator of this MyD88-dependent inflammatory process in a mouse model of skin transplantation. Necrotic lysates from transplanted skin elicited higher inflammatory responses in DCs than did nontransplanted lysates, suggesting DC-mediated responses are triggered by factors released during transplantation. Analysis of transplanted lysates identified haptoglobin as one of the proteins upregulated during transplantation. Expression of donor haptoglobin enhanced the onset of acute skin transplant rejection, whereas haptoglobin-deficient skin grafts showed delayed acute rejection and antidonor T cell priming in a MyD88-dependent graft rejection model. Thus, our results show that haptoglobin release following skin necrosis contributes to accelerated transplant rejection, with potential implications for the development of localized immunosuppressive therapies.
doi:10.1172/JCI58344
PMCID: PMC3248290  PMID: 22156194

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