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1.  The structure of an authentic spore photoproduct lesion in DNA suggests a basis for recognition. Corrigendum 
A correction is made to the article by Singh et al. [(2014). Acta Cryst. D70, 752–759].
The article by Singh et al. [ (2014). Acta Cryst. D70, 752–759] is corrected.
PMCID: PMC4030664
spore photoproduct; DNA; host–guest approach; corrigendum
2.  Individual and Center-Level Factors Affecting Mortality Among Extremely Low Birth Weight Infants 
Pediatrics  2013;132(1):e175-e184.
To examine factors affecting center differences in mortality for extremely low birth weight (ELBW) infants.
We analyzed data for 5418 ELBW infants born at 16 Neonatal Research Network centers during 2006–2009. The primary outcomes of early mortality (≤12 hours after birth) and in-hospital mortality were assessed by using multilevel hierarchical models. Models were developed to investigate associations of center rates of selected interventions with mortality while adjusting for patient-level risk factors. These analyses were performed for all gestational ages (GAs) and separately for GAs <25 weeks and ≥25 weeks.
Early and in-hospital mortality rates among centers were 5% to 36% and 11% to 53% for all GAs, 13% to 73% and 28% to 90% for GAs <25 weeks, and 1% to 11% and 7% to 26% for GAs ≥25 weeks, respectively. Center intervention rates significantly predicted both early and in-hospital mortality for infants <25 weeks. For infants ≥25 weeks, intervention rates did not predict mortality. The variance in mortality among centers was significant for all GAs and outcomes. Center use of interventions and patient risk factors explained some but not all of the center variation in mortality rates.
Center intervention rates explain a portion of the center variation in mortality, especially for infants born at <25 weeks’ GA. This finding suggests that deaths may be prevented by standardizing care for very early GA infants. However, differences in patient characteristics and center intervention rates do not account for all of the observed variability in mortality; and for infants with GA ≥25 weeks these differences account for only a small part of the variation in mortality.
PMCID: PMC3691533  PMID: 23753096
mortality rates; outcome; NICU; preterm infants; extremely preterm infants
3.  Dysregulated Expression of FOXM1 Isoforms Drives Progression of Pancreatic Cancer 
Cancer research  2013;73(13):3987-3996.
The transcription factor Forkhead box M1 (FOXM1) plays important roles in oncogenesis. However, the expression statuses of FOXM1 isoforms and their impact on and molecular basis in oncogenesis are unknown. We sought to determine the identities of FOXM1 isoforms in and the impact of their expression on pancreatic cancer development and progression using human tissues, cell lines and animal models. Overexpression of FOXM1 mRNA and protein was pronounced in human pancreatic tumors and cancer cell lines. We identified five FOXM1 isoforms present in pancreatic cancer: FOXM1a, FOXM1b, and FOXM1c along with two isoforms tentatively designated as FOXM1b1 and FOXM1b2 because they were closely related to FOXM1b. Interestingly, FOXM1c was predominantly expressed in pancreatic tumors and cancer cell lines, whereas FOXM1a expression was generally undetectable in them. Functional analysis revealed that FOXM1b, FOXM1b1, FOXM1b2, and FOXM1c but not FOXM1a promoted pancreatic tumor growth and metastasis. Consistently, FOXM1b, FOXM1b1, FOXM1b2, and FOXM1c activated transcription of their typical downstream genes. Also, Sp1 mechanistically activated the FOXM1 promoter, whereas Krüppel-like factor 4 (KLF4) repressed its activity. Finally, we identified an Sp1- and KLF4-binding site in the FOXM1 promoter and demonstrated that both Sp1 and KLF4 protein bound directly to it. Deletion mutation of this binding site significantly attenuated the transcriptional regulation of the FOXM1 promoter positively by Sp1 and negatively by KLF4. We demonstrated that overexpression of specific FOXM1 isoforms critically regulates pancreatic cancer development and progression by enhancing tumor cell invasion and metastasis. Our findings strongly suggest that targeting specific FOXM1 isoforms effectively attenuates pancreatic cancer development and progression.
PMCID: PMC3702645  PMID: 23598278
Progression; angiogenesis; transcription factor; EMT; biomarkers
4.  Outcomes of Small for Gestational Age Infants < 27 Weeks’ Gestation 
The Journal of pediatrics  2013;163(1):55-60.e1-3.
To determine whether small for gestational age (SGA) infants <27 weeks gestation is associated with mortality, morbidity, growth and neurodevelopmental impairment at 18–22 months’ corrected age (CA).
Study design
This was a retrospective cohort study from National Institute of Child Health and Human Development Neonatal Research Network’s Generic Database and Follow-up Studies. Infants born at <27 weeks’ gestation from January 2006 to July 2008 were included. SGA was defined as birth weight <10th percentile for gestational age by the Olsen growth curves. Infants with birth weight ≥10th percentile for gestational age were classified as non-SGA. Maternal and infant characteristics, neonatal outcomes and neurodevelopmental data were compared between the groups. Neurodevelopmental impairment was defined as any of the following: cognitive score <70 on BSID III, moderate or severe cerebral palsy, bilateral hearing loss (+/− amplification) or blindness (vision <20/200). Logistic regression analysis evaluated the association between SGA status and death or neurodevelopmental impairment.
There were 385 SGA and 2586 non-SGA infants. Compared with the non-SGA group, mothers of SGA infants were more likely to have higher level of education, prenatal care, cesarean delivery, pregnancy-induced hypertension and antenatal corticosteroid exposure. SGA infants were more likely to have postnatal growth failure, a higher mortality and to have received prolonged mechanical ventilation and postnatal steroids. SGA status was associated with higher odds of death or neurodevelopmental impairment [OR 3.91 (95% CI: 2.91–5.25), P<0.001].
SGA status among infants <27 weeks’ gestation was associated with an increased risk for postnatal steroid use, mortality, growth failure and neurodevelopmental impairment at 18–22 months’ CA.
PMCID: PMC3947828  PMID: 23415614
extremely preterm infants; neurodevelopmental follow-up
5.  Morroniside Improves Microvascular Functional Integrity of the Neurovascular Unit after Cerebral Ischemia 
PLoS ONE  2014;9(6):e101194.
Treating the vascular elements within the neurovascular unit is essential for protecting and repairing the brain after stroke. Acute injury on endothelial systems results in the disruption of blood-brain barrier (BBB), while post-ischemic angiogenesis plays an important role in delayed functional recovery. Here, we considered alterations in microvessel integrity to be targets for brain recovery, and tested the natural compound morroniside as a therapeutic approach to restore the vascular elements of injured tissue in a rat model of focal cerebral ischemia. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) model, and morroniside was then administered intragastrically once a day at doses of 30, 90, and 270 mg/kg. BBB integrity and associated factors were analyzed to identify cerebrovascular permeability 3 days after MCAO. The recruitment of endothelial progenitor cells (EPCs), the expression of angiogenic factors and the new vessel formation in the peri-infarct cortex of rats were examined 7 days after MCAO to identify the angiogenesis. We demonstrated that at 3 days post-ischemia, morroniside preserved neurovascular unit function by ameliorating BBB injury. By 7 days post-ischemia, morroniside amplified angiogenesis, in part by enhancing endothelial progenitor cell proliferation and expression of angiogenic factors. Morever, the increase in the amount of vWF+ vessels induced by ischemia could be extended to 28 days after administration of morroniside, indicating the crucial role of morroniside in angiogenesis during the chronic phase. Taken together, our findings suggested that morroniside might offer a novel therapeutic approach for promoting microvascular integrity recovery and provide a thoroughly new direction for stroke therapy.
PMCID: PMC4076313  PMID: 24979385
6.  Fully motorized optical-resolution photoacoustic microscopy 
Optics letters  2014;39(7):2117-2120.
We have developed fully motorized optical-resolution photoacoustic microscopy (OR-PAM), which integrates five complementary scanning modes and simultaneously provides a high imaging speed and a wide field of view (FOV) with 2.6 µm lateral resolution. With one-dimensional (1D) motion-mode mechanical scanning, we measured the blood flow through a cross section of a blood vessel in vivo. With two-dimensional (2D) optical scanning at a laser repetition rate of 40 kHz, we achieved a 2 kHz B-scan rate over a range of 50 µm with 20 A-lines, and 50 Hz volumetric-scan rate over a FOV of 50×50 µm2 with 400 A-lines, which enabled real-time tracking of cellular dynamics in vivo. With synchronized 1D optical and 2D mechanical hybrid scanning, we imaged a 10×8 mm2 FOV within three minutes, which is 20 times faster than the conventional mechanical scan in our second-generation OR-PAM. With three-dimensional mechanical contour scanning, we maintained the optimal signal-to-noise ratio and spatial resolution of OR-PAM while imaging objects with uneven surfaces, which is essential for quantitative studies.
PMCID: PMC4048805  PMID: 24686689
7.  Interleukin-17A Promotes MUC5AC Expression and Goblet Cell Hyperplasia in Nasal Polyps via the Act1-Mediated Pathway 
PLoS ONE  2014;9(6):e98915.
Recent studies demonstrated that nasal polyps (NP) patients in China and other Asian regions possessed distinct Th17-dominant inflammation and enhanced tissue remodeling. However, the mechanism underlying these observations is not fully understood. This study sought to evaluate the association of interleukin (IL)-17A with MUC5AC expression and goblet cell hyperplasia in Chinese NP patients and to characterize the signaling pathway underlying IL-17A-induced MUC5AC expression in vitro.
We enrolled 25 NP patients and 22 normal controls and examined the expression of IL-17A, MUC5AC and act1 in polyp tissues by immunohistochemical (IHC) staining, quantitative polymerase chain reaction (qPCR) and western blot. Moreover, by using an in vitro culture system of polyp epithelial cells (PECs), IL-17A-induced gene expression was screened in cultured PECs by DNA microarray. The expression of IL-17RA, IL-17RC, act1 and MUC5AC and the activation of the MAPK pathway (ERK, p38 and JNK), were further examined in cultured PECs and NCI-H292 cells by qPCR and western blotting, respectively.
We found that increased IL-17A production was significantly correlated with MUC5AC and act1 expression and goblet cell hyperplasia in polyp tissues (p<0.05). IL-17A significantly stimulated the expression of IL-17RA, IL-17RC, act1 and MUC5AC, and the activation of the MAPK pathway in cultured PECs and NCI-H292 cells (p<0.05). In addition, IL-17RA, IL-17RC and act1 siRNA significantly blocked IL-17A-induced MUC5AC production in vitro (p<0.05).
Our results suggest that IL-17A plays a crucial role in stimulating the production of MUC5AC and goblet cell hyperplasia through the act1-mediated signaling pathway and may suggest a promising strategy for the management of Th17-dominant NP patients.
PMCID: PMC4043856  PMID: 24892823
8.  Expression of Chemerin and Its Receptors in Rat Testes and Its Action on Testosterone Secretion 
The Journal of endocrinology  2014;220(2):155-163.
The novel adipokine chemerin plays a role in regulating lipid and carbohydrate metabolism, and recent reports of elevated chemerin levels in polycystic ovarian syndrome elevated chemerin levels with polycystic ovary syndrome and preeclampsia point to an emerging role for chemerin in reproduction. We hypothesized that chemerin, like other adipokines, may function to regulate male gonadal steroidogenesis. Here we show that chemerin and its three receptors chemokine-like receptor 1 (CMKLR1), G-protein coupled receptor 1 (GPR1) and chemokine (C-C motif) receptor-like 2 (CCRL2) were expressed in male reproductive tracts, liver and white adipose tissue. CMKLR1 and GPR1 protein were localized specifically in the Leydig cells of human and rat testes by immunohistochemistry. The expression of chemerin and its receptors in rat testes was developmentally regulated and highly expressed in Leydig cells. In vitro treatment with chemerin suppressed the human chorinoic gonadotropin (hCG)-induced testosterone production from primary Leydig cells, which was accompanied by the inhibition of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) gene and protein expression. The hCG-activated p44/42 mitogen-activated-protein kinase (MAPK) (Erk1/2) pathway in Leydig cells was also inhibited by chemerin co-treatment. Together, these data suggest chemerin is a novel regulator of male gonadal steroidogenesis.
PMCID: PMC3932185  PMID: 24301613
chemerin; steroidogenesis; testosterone; adipokine; Leydig cell
9.  Use of Antihypotensive Therapies in Extremely Preterm Infants 
Pediatrics  2013;131(6):e1865-e1873.
To investigate the relationships among blood pressure (BP) values, antihypotensive therapies, and in-hospital outcomes to identify a BP threshold below which antihypotensive therapies may be beneficial.
Prospective observational study of infants 230/7 to 266/7 weeks’ gestational age. Hourly BP values and antihypotensive therapy use in the first 24 hours were recorded. Low BP was investigated by using 15 definitions. Outcomes were examined by using regression analysis controlling for gestational age, the number of low BP values, and illness severity.
Of 367 infants enrolled, 203 (55%) received at least 1 antihypotensive therapy. Treated infants were more likely to have low BP by any definition (P < .001), but for the 15 definitions of low BP investigated, therapy was not prescribed to 3% to 49% of infants with low BP and, paradoxically, was administered to 28% to 41% of infants without low BP. Treated infants were more likely than untreated infants to develop severe retinopathy of prematurity (15% vs 8%, P = .03) or severe intraventricular hemorrhage (22% vs 11%, P < .01) and less likely to survive (67% vs 78%, P = .02). However, with regression analysis, there were no significant differences between groups in survival or in-hospital morbidity rates.
Factors other than BP contributed to the decision to use antihypotensive therapies. Infant outcomes were not improved with antihypotensive therapy for any of the 15 definitions of low BP investigated.
PMCID: PMC3666108  PMID: 23650301
extremely preterm infant; antihypotensive therapy; blood pressure; hypotension
10.  Endothelial cells enhance prostate cancer metastasis via IL6→androgen receptor→TGFβ→MMP9 signals 
Molecular cancer therapeutics  2013;12(6):1026-1037.
While the potential roles of endothelial cells (ECs) in the microvascules of prostate cancer (PCa) during angiogenesis have been documented, their direct impacts on the PCa metastasis remain unclear. We found that the CD31-positive and CD34-positive ECs are increased in PCa compared to the normal tissues and these ECs cells were decreased upon castration, gradually recovered with time, and become increased after PCa progresses into the castration resistant stage, suggesting a potential linkage of these ECs with androgen deprivation therapy. The in vitro invasion assays demonstrated that the co-culture of ECs with PCa cells significantly enhanced the invasion ability of the PCa cells. Mechanism dissection found that co-culture of PCa cells with ECs led to increased IL-6 secretion from ECs, which might result in down-regulation of AR signaling in PCa cells, and then the activation of TGF-β/MMP9 signaling. The consequences of the IL-6→androgen receptor→TGFβ→MMP9 signaling pathway might then trigger the increased invasion of PCa cells. Blocking the IL-6→androgen receptor→TGFβ→MMP9 signaling pathway either by IL-6 antibody, AR-siRNA, or TGF-β1 inhibitor all interrupted the ability of ECs to influence PCa invasion. These results, for the first time, revealed the important roles of ECs within the PCa microenvironment to promote the PCa metastasis, and provide new potential targets of IL-6→androgen receptor→TGFβ→MMP9 signals to battle the PCa metastasis.
PMCID: PMC3782851  PMID: 23536722
prostate cancer metastasis; endothelial cells; androgen receptor; microvascules; invasion
11.  Acyl-coenzyme A synthetases in metabolic control 
Current opinion in lipidology  2010;21(3):212-217.
Purpose of review
The 11 long-chain (ACSL) and very long chain acyl-coenzyme A (acyl-CoA) synthetases [(ACSVL)/fatty acid transport protein] are receiving considerable attention because it has become apparent that their individual functions are not redundant.
Recent findings
Recent studies have focused on the structure of the acyl-CoA synthetases, their post-translational modification, their ability to activate fatty acids of varying chain lengths, and their role in directing fatty acids into different metabolic pathways. An unsettled controversy focuses on the ACSVL isoforms and whether these have both enzymatic and transport functions. Another issue is whether conversion of a fatty acid to an acyl-CoA produces an increase in the AMP/ATP ratio that is sufficient to activate AMP-activated kinase.
FuturestudiesarerequiredtodeterminethesubcellularlocationofeachACSLandACSVL isoform and the functional importance of phosphorylation and acetylation. Purification and crystallization of mammalian ACSL and ACSVL isoforms is needed to confirm the mechanism of action and discover how these enzymesdiffer in their affinity for fatty acids of differentchainlengths.Functionally,itwillbeimportanttolearnhowtheACSLisoformscan direct their acyl-CoA products toward independent downstream pathways.
PMCID: PMC4040134  PMID: 20480548
β-oxidation; acyl-CoA synthetase; AMP-activated kinase; fatty acid; fatty acid transport protein; glycerolipid synthesis
12.  Trait impulsivity and impaired prefrontal impulse inhibition function in adolescents with internet gaming addiction revealed by a Go/No-Go fMRI study 
Recent studies suggest that Internet gaming addiction (IGA) is an impulse disorder, or is at least related to impulse control disorders. In the present study, we hypothesized that different facets of trait impulsivity may be specifically linked to the brain regions with impaired impulse inhibition function in IGA adolescents.
Seventeen adolescents with IGA and seventeen healthy controls were scanned during performance of a response-inhibition Go/No-Go task using a 3.0 T MRI scanner. The Barratt Impulsiveness Scale (BIS)-11 was used to assess impulsivity.
There were no differences in the behavioral performance on the Go/No-Go task between the groups. However, the IGA group was significantly hyperactive during No-Go trials in the left superior medial frontal gyrus, right anterior cingulate cortex, right superior/middle frontal gyrus, left inferior parietal lobule, left precentral gyrus, and left precuneus and cuneus. Further, the bilateral middle temporal gyrus, bilateral inferior temporal gyrus, and right superior parietal lobule were significantly hypoactive during No-Go trials. Activation of the left superior medial frontal gyrus was positively associated with BIS-11 and Chen Internet Addiction Scale (CIAS) total score across IGA participants.
Our data suggest that the prefrontal cortex may be involved in the circuit modulating impulsivity, while its impaired function may relate to high impulsivity in adolescents with IGA, which may contribute directly to the Internet addiction process.
PMCID: PMC4050412  PMID: 24885073
Internet addiction; Response inhibition; fMRI; Go/No-Go
13.  Oxidation and Reduction of the 5-(2’-Deoxyuridinyl)methyl Radical** 
Sleeping beauty: The 5-(2’-Deoxyuridinyl) methyl radical 1 is a key intermediate in the thymine oxidative reaction mediated by reactive oxygen species. Evidence is presented that 1 is prone to both oxidation and reduction reactions at the absence of O2. These results question the current paradigm and suggest that the redox chemistry of 1, which has been largely overlooked in the past, may play a major role in determining the fate of 1.
PMCID: PMC3689432  PMID: 23589226
DNA; photochemistry; radicals; reaction mechanisms; thymine
14.  High Metastaticgastric and Breast Cancer Cells Consume Oleic Acid in an AMPK Dependent Manner 
PLoS ONE  2014;9(5):e97330.
Gastric cancer and breast cancer have a clear tendency toward metastasis and invasion to the microenvironment predominantly composed of adipocytes. Oleic acid is an abundant monounsaturated fatty acid that releases from adipocytes and impinges on different energy metabolism responses. The effect and underlying mechanisms of oleic acid on highly metastatic cancer cells are not completely understood. We reported that AMP-activated protein kinase (AMPK) was obviously activated in highly aggressive carcinoma cell lines treated by oleic acid, including gastric carcinoma HGC-27 and breast carcinoma MDA-MB-231 cell lines. AMPK enhanced the rates of fatty acid oxidation and ATP production and thus significantly promoted cancer growth and migration under serum deprivation. Inactivation of AMPK attenuated these activities of oleic acid. Oleic acid inhibited cancer cell growth and survival in low metastatic carcinoma cells, such as gastric carcinoma SGC7901 and breast carcinoma MCF-7 cell lines. Pharmacological activation of AMPK rescued the cell viability by maintained ATP levels by increasing fatty acid β-oxidation. These results indicate that highly metastatic carcinoma cells could consume oleic acid to maintain malignancy in an AMPK-dependent manner. Our findings demonstrate the important contribution of fatty acid oxidation to cancer cell function.
PMCID: PMC4019637  PMID: 24823908
15.  Glucose Biosensor Based on a Glassy Carbon Electrode Modified with Polythionine and Multiwalled Carbon Nanotubes 
PLoS ONE  2014;9(5):e95030.
A novel glucose biosensor was fabricated. The first layer of the biosensor was polythionine, which was formed by the electrochemical polymerisation of the thionine monomer on a glassy carbon electrode. The remaining layers were coated with chitosan-MWCNTs, GOx, and the chitosan-PTFE film in sequence. The MWCNTs embedded in FAD were like “conductive wires” connecting FAD with electrode, reduced the distance between them and were propitious to fast direct electron transfer. Combining with good electrical conductivity of PTH and MWCNTs, the current response was enlarged. The sensor was a parallel multi-component reaction system (PMRS) and excellent electrocatalytic performance for glucose could be obtained without a mediator. The glucose sensor had a working voltage of −0.42 V, an optimum working temperature of 25°C, an optimum working pH of 7.0, and the best percentage of polytetrafluoroethylene emulsion (PTFE) in the outer composite film was 2%. Under the optimised conditions, the biosensor displayed a high sensitivity of 2.80 µA mM−1 cm−2 and a low detection limit of 5 µM (S/N = 3), with a response time of less than 15 s and a linear range of 0.04 mM to 2.5 mM. Furthermore, the fabricated biosensor had a good selectivity, reproducibility, and long-term stability, indicating that the novel CTS+PTFE/GOx/MWCNTs/PTH composite is a promising material for immobilization of biomolecules and fabrication of third generation biosensors.
PMCID: PMC4015890  PMID: 24816121
16.  A Radical Transfer Pathway in Spore Photoproduct Lyase 
Biochemistry  2013;52(18):3041-3050.
Spore photoproduct lyase (SPL) repairs a covalent UV-induced thymine dimer, spore photoproduct (SP), in germinating endospores and is responsible for endospores’ strong UV resistance. SPL is a radical SAM enzyme, which uses a [4Fe-4S]1+ cluster to reduce the S-adenosyl-L-methionine (SAM), generating a catalytic 5′-deoxyadenosyl radical (5′-dA•). This in turn abstracts an H atom from SP, generating an SP radical that undergoes β scission to form a repaired 5′-thymine and a 3′-thymine allylic radical. Recent biochemical and structural data suggest that a conserved cysteine donates an H atom to the thymine radical, resulting in a putative thiyl radical. Here we present structural and biochemical data which suggest that two conserved tyrosines are also critical in enzyme catalysis. One (Y99(Bs) in Bacillus subtilis SPL) is downstream of the cysteine, suggesting that SPL uses a novel hydrogen atom transfer (HAT) pathway with a pair of cysteine-tyrosine residues to regenerate SAM. The other tyrosine (Y97(Bs)) has a structural role to facilitate SAM binding; it may also contribute to the SAM regeneration process by interacting with the putative •Y99(Bs) and/or 5′-dA• intermediates to lower the energy barrier for the second H-abstraction step. Our results indicate that SPL is the first member of the radical SAM superfamily (comprising more than 44,000 members) to bear a catalytically operating HAT chain.
PMCID: PMC3666868  PMID: 23607538
17.  The Impact of Body Mass Index on Short- and Long-Term Outcomes in Patients Undergoing Coronary Artery Graft Bypass 
PLoS ONE  2014;9(4):e95223.
This study was designed to investigate the impact of body mass index (BMI) on short- and long-term outcomes after initial revascularization with coronary artery bypass graft (CABG) surgery.
4916 Chinese who consecutively underwent isolated, primary CABG at the Cardiovascular Institute of Fuwai Hospital from January 1, 1999 to December 31, 2005 were included in this study. They were classified based on BMI as follows: underweight: <18.5 kg/m2, normal weight: 18.5 to 23.9 kg/m2, overweight: 24 to 27.9 kg/m2, obesity: 28 to 32 kg/m2, and severe obesity: >32 kg/m2. Short (in-hospital) and long-term (5-years) major post-operative complications and mortalities were compared among various BMI groups after initial revascularization.
Multiple regression analysis of five years follow-up of clinical end points indicated that various BMI groups were not associated with significant differences in 5 years mortality and MACCE, however, old age, smoking, hypertension, myocardial infarction and heart failure were the risk factor for the mortality.
In this large-scale study with long term follow-up after primary CABG in an exclusively ethnic Chinese population, we found that different BMI groups were not significantly associated with 5-years mortality and MACCE, however, old age, smoking, hypertension, myocardial infarction and heart failure were the risk factors of post-operative mortality, and old age, hypertension and heart failure increased the rate of MACCE.
PMCID: PMC3994030  PMID: 24752323
18.  Chemical syntheses of oligodeoxyribonucleotides containing spore photoproduct 
The Journal of organic chemistry  2013;78(7):3021-3029.
5-(α-Thyminyl)-5,6-dihydrothymine, also called spore photoproduct or SP, is commonly found in the genomic DNA of UV irradiated bacterial endospores. Despite the fact that SP was discovered nearly 50 years ago, its biochemical impact is still largely unclear due to the difficulty to prepare SP containing oligonucleotide in high purity. Here, we report the first synthesis of the phosphoramidite derivative of dinucleotide SP TpT, which enables successful incorporation of SP TpT into oligodeoxyribonucleotides with high efficiency via standard solid phase synthesis. This result provides the scientific community a reliable means to prepare SP containing oligonucleotides, laying the foundation for future SP biochemical studies. Thermal denaturation studies of the SP containing oligonucleotide found that SP destabilizes the duplex by 10–20 kJ/mole, suggesting that its presence in the spore genomic DNA may alter the DNA local conformation.
PMCID: PMC3633573  PMID: 23506239
19.  Propylisopropylacetic acid (PIA), a constitutional isomer of valproic acid, uncompetitively inhibits arachidonic acid acylation by rat acyl-CoA synthetase 4: a potential drug for bipolar disorder 
Biochimica et biophysica acta  2013;1831(4):880-886.
Mood stabilizers used for treating bipolar disorder (BD) selectively downregulate arachidonic acid (AA) turnover (deacylation-reacylation) in brain phospholipids, when given chronically to rats. In vitro studies suggest that one of these, valproic acid (VPA), which is teratogenic, reduces AA turnover by inhibiting the brain acyl-CoA synthetase (Acsl)-4 mediated acylation of AA to AA-CoA. We tested whether non-teratogenic VPA analogues might also inhibit Acsl-4 catalyzed acylation, and thus have potential anti-BD action.
Rat Acsl4-flag protein was expressed in E. coli, and the ability of three VPA analogues, propylisopropylacetic acid (PIA), propylisopropylacetamide (PID) and N-methyl-2,2,3,3-tetramethylcyclopropanecarboxamide (MTMCD), and of sodium butyrate, to inhibit conversion of AA to AA-CoA by Acsl4 was quantified using Michaelis-Menten kinetics.
Acsl4-mediated conversion of AA to AA-CoA in vitro was inhibited uncompetitively by PIA, with a Ki of 11.4 mM compared to a published Ki of 25 mM for VPA, while PID, MTMCD and sodium butyrate had no inhibitory effect.
PIA's ability to inhibit conversion of AA to AA-CoA by Acsl4 in vitro suggests that, like VPA, PIA may reduce AA turnover in brain phospholipids in unanesthetized rats, and if so, may be effective as a non-teratogenic mood stabilizer in BD patients.
PMCID: PMC3593989  PMID: 23354024
bipolar disorder; valproate; arachidonic acid; acyl-CoA synthetase 4; mood stabilizer; Acsl4; brain; MTMCD; N-methyl-2,2,3,3-tetramethylcyclopropanecarboxamide; PIA; propylisopropylacetic; PID; propylisopropylacetamide; rat; butyrate; inhibition; uncompetitive; enzyme; anticonvulsant
20.  Parvoviral Left-End Hairpin Ears Are Essential during Infection for Establishing a Functional Intranuclear Transcription Template and for Efficient Progeny Genome Encapsidation 
Journal of Virology  2013;87(19):10501-10514.
The 121-nucleotide left-end telomere of Minute Virus of Mice (MVM) can be folded into a Y-shaped hairpin with short axial ears that are highly conserved within genus Parvovirus. To explore their potential role(s) during infection, we constructed infectious plasmid clones that lacked one or other ear. Although these were nonviable when transfected into A9 cells, excision of the viral genome and DNA amplification appeared normal, and viral transcripts and proteins were expressed, but progeny virion production was minimal, supporting the idea of a potential role for the ears in genome packaging. To circumvent the absence of progeny that confounded further analysis of these mutants, plasmids were transfected into 293T cells both with and without an adenovirus helper construct, generating single bursts of progeny. These virions bound to A9 cells and were internalized but failed to initiate viral transcription, protein expression, or DNA replication. No defects in mutant virion stability or function could be detected in vitro. Significantly, mutant capsid gene expression and DNA replication could be rescued by coinfection with wild-type virions carrying a replication-competent, capsid-gene-replacement vector. To pinpoint where such complementation occurred, prior transfection of plasmids expressing only MVM nonstructural proteins was explored. NS1 alone, but not NS2, rescued transcription and protein expression from both P4 and P38 promoters, whereas NS1 molecules deleted for their C-terminal transactivation domain did not. These results suggest that the mutant virions reach the nucleus, uncoat, and are converted to duplex DNA but require an intact left-end hairpin structure to form the initiating transcription complex.
PMCID: PMC3807388  PMID: 23903839
21.  Optical Sensor Based on a Single CdS Nanobelt 
Sensors (Basel, Switzerland)  2014;14(4):7332-7341.
In this paper, an optical sensor based on a cadmium sulfide (CdS) nanobelt has been developed. The CdS nanobelt was synthesized by the vapor phase transportation (VPT) method. X-Ray Diffraction (XRD) and Transmission Electron Microscopy (TEM) results revealed that the nanobelt had a hexagonal wurtzite structure of CdS and presented good crystal quality. A single nanobelt Schottky contact optical sensor was fabricated by the electron beam lithography (EBL) technique, and the device current-voltage results showed back-to-back Schottky diode characteristics. The photosensitivity, dark current and the decay time of the sensor were 4 × 104, 31 ms and 0.2 pA, respectively. The high photosensitivity and the short decay time were because of the exponential dependence of photocurrent on the number of the surface charges and the configuration of the back to back Schottky junctions.
PMCID: PMC4029630  PMID: 24763211
CdS; nanobelt; optical sensor; Schottky contact; photosensitivity
22.  Association of LOX-1 gene polymorphisms with cerebral infarction in northern Chinese Han population 
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) plays an important role in the pathophysiology of atherosclerosis and thrombosis. This study is aimed at evaluating the potential association of 3’-UTR-C188T and G501C in LOX-1 gene with cerebral infarction.
A total of 386 patients with cerebral infarction and 386 healthy controls were included in the study, which were unrelated Chinese Han population in the Liaoning Province of northern China. The single nucleotide polymorphisms, 3’-UTR-C188T and G501C, were analyzed by polymerase chain reaction–ligation detection reaction method.
The frequencies of CC + GC genotype, GC genotype and C allele of G501C in the patients with cerebral infarction were significantly higher than those in the controls (P < 0.01, P < 0.01, P = 0.04, respectively). The correlation still remained after adjusting for confounding risk factors of cerebral infarction. In addition, no significant association was observed between 3’-UTR-C188T and cerebral infarction.
The study indicated that the G501C variant in LOX-1 gene may be associated with susceptibility to cerebral infarction, independent of other common risk factors, in northern Chinese Han population.
PMCID: PMC3994314  PMID: 24661313
LOX-1; Ox-LDL; Polymorphisms; Cerebral infarction; Atherosclerosis
23.  Increased Tbx1 expression may play a role via TGFβ-Smad2/3 signaling pathway in acute kidney injury induced by gentamicin 
T-box 1 (Tbx1) gene is closely involved in embryonic kidney development. To explore the role of Tbx1 in acute kidney injury (AKI) and the underlying mechanism, we detected the expression of Tbx1 and components of transforming growth factor-beta (TGF-β) signaling pathways including TGF-β, phosphorylated Smad2/3 (p-Smad2/3) and phosphorylated Smad1/5/8 (p-Smad1/5/8) in kidney tissues derived from a rat model for AKI induced by gentamicin (GM). Apoptosis of renal cells was assessed by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL), along with the expression of two essential genes involved in apoptosis, caspase-3 and Bcl-2. Correlation between Tbx1 expression and the number of TUNEL-positive cells was analyzed by a Spearman test. Expression of TGF-β, p-Smad2/3 and p-Smad1/5/8 in Tbx1-knockdown NRK cells was also analyzed by real-time RT-PCR and Western blotting. Markedly increased Tbx1 expression was found in the injured kidney tissues, which has activated the TGFβ-Smad2/3 pathway whilst suppressed Smad1/5/8 expression. Conversely, decreased TGF-β and p-Smad2/3 levels, and elevated p-Smad1/5/8 levels were detected in Tbx1-knockdown NRK cells. More apoptotic cells were detected in the injured kidneys, which has well correlated with the expression of Tbx1. Expression of caspase-3 was markedly increased, while Bcl-2 was decreased in the injured kidney tissues. Above findings suggested that activation of Tbx1 is involved in AKI through the TGFβ-Smad2/3 pathway. Tbx1 expression may therefore serve as a marker for AKI, and Tbx1-blocking therapies may provide an option for treating GM-induced nephropathy.
PMCID: PMC4014240  PMID: 24817956
Acute kidney injury; gentamicin; Smad1/5/8; Smad2/3; Tbx1; TGF-β
24.  FANCM and FAAP24 Maintain Genome Stability via Cooperative as well as Unique Functions 
Molecular cell  2013;49(5):997-1009.
The DNA remodeling enzyme FANCM and its DNA-binding partner, FAAP24, constitute a complex involved in the activation of Fanconi Anemia (FA) DNA damage response mechanism, but neither gene has distinct patient mutants. In this study, we created isogenic models for both FANCM and FAAP24 and investigated their integrated functions in DNA damage response. We found that FANCM and FAAP24 coordinately facilitate FA pathway activation and suppress sister chromatid exchange. Importantly, we show that FANCM and FAAP24 possess non-overlapping functions such that FAAP24 promotes ATR-mediated checkpoint activation particularly in response to DNA crosslinking agents, whereas FANCM participates in recombination-independent interstrand crosslink repair by facilitating recruitment of lesion incision activities which requires its translocase activity. Our data suggest that FANCM and FAAP24 play multiple while not fully epistatic roles in maintaining genomic integrity.
PMCID: PMC3595374  PMID: 23333308
25.  Epithelial cell adhesion molecule aptamer functionalized PLGA-lecithin-curcumin-PEG nanoparticles for targeted drug delivery to human colorectal adenocarcinoma cells 
To improve the efficacy of drug delivery, active targeted nanotechnology-based drug delivery systems are gaining considerable attention as they have the potential to reduce side effects, minimize toxicity, and improve efficacy of anticancer treatment. In this work CUR-NPs (curcumin-loaded lipid-polymer-lecithin hybrid nanoparticles) were synthesized and functionalized with ribonucleic acid (RNA) Aptamers (Apts) against epithelial cell adhesion molecule (EpCAM) for targeted delivery to colorectal adenocarcinoma cells. These CUR-encapsulated bioconjugates (Apt-CUR-NPs) were characterized for particle size, zeta potential, drug encapsulation, stability, and release. The in vitro specific cell binding, cellular uptake, and cytotoxicity of Apt-CUR-NPs were also studied. The Apt-CUR-NP bioconjugates exhibited increased binding to HT29 colon cancer cells and enhancement in cellular uptake when compared to CUR-NPs functionalized with a control Apt (P<0.01). Furthermore, a substantial improvement in cytotoxicity was achieved toward HT29 cells with Apt-CUR-NP bioconjugates. The encapsulation of CUR in Apt-CUR-NPs resulted in the increased bioavailability of delivered CUR over a period of 24 hours compared to that of free CUR in vivo. These results show that the EpCAM Apt-functionalized CUR-NPs enhance the targeting and drug delivery of CUR to colorectal cancer cells. Further development of CUR-encapsulated, nanosized carriers will lead to improved targeted delivery of novel chemotherapeutic agents to colorectal cancer cells.
PMCID: PMC3937189  PMID: 24591829
PLGA-lecithin-PEG nanoparticles; curcumin; EpCAM; aptamer; targeted drug delivery

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