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1.  Design and Synthesis of Phenylpyrrolidine Phenylglycinamides As Highly Potent and Selective TF-FVIIa Inhibitors 
ACS Medicinal Chemistry Letters  2013;5(2):188-192.
Inhibitors of the Tissue Factor/Factor VIIa (TF-FVIIa) complex are promising novel anticoagulants that show excellent efficacy and minimal bleeding in preclinical models. On the basis of a zwitterionic phenylglycine acylsulfonamide 1, a phenylglycine benzylamide 2 was shown to possess improved permeability and oral bioavailability. Optimization of the benzylamide, guided by X-ray crystallography, led to a potent TF-FVIIa inhibitor 18i with promising oral bioavailability, but promiscuous activity in an in vitro safety panel of receptors and enzymes. Introducing an acid on the pyrrolidine ring, guided by molecular modeling, resulted in highly potent, selective, and efficacious TF-FVIIa inhibitors with clean in vitro safety profile. The pyrrolidine acid 20 showed a moderate clearance, low volume of distribution, and a short t1/2 in dog PK studies.
doi:10.1021/ml400453z
PMCID: PMC4027585  PMID: 24900796
TF-FVIIa inhibitor; anticoagulant; aminoisoquinoline; phenylpyrrolidine; phenylglycinamide; structure-based drug design
2.  Association of XPC Gene Polymorphisms with Susceptibility to Prostate Cancer: Evidence from 3,936 Subjects 
Aim: Polymorphisms of xeroderma pigmentosum complementation group C (XPC) are thought to have significant effects on prostate cancer (PCa) risk. The aim of our study was to evaluate the impact of XPC gene polymorphisms on PCa risk by using a meta-analysis. Methods: Data were collected from the following electronic databases: PubMed, EMBASE, Elsevier Science Direct, Cochrane Library, and CNKI, with the last report up to April 30, 2013. Odds ratios with 95% confidence intervals were used to assess the strength of the association. Results: A total of five separate case–control studies (1966 cases and 1970 controls) were included in this meta-analysis. Meta-analysis was performed for the rs2228001 and PAT+/−polymorphisms. We did not detect a significant association between rs2228001 polymorphism and PCa (p>0.05). Similar results were found in stratification analyses by ethnicity and tumor stage. We detected a significant association of PAT+/−polymorphism with PCa (p<0.05). In stratification analysis, we did not detect a significant association of PAT+/−polymorphism with risk of bone metastasis in PCa patients (p>0.05). Conclusion: These analyses suggest that XPC gene PAT+/−polymorphism, but not rs2228001, likely contributes to susceptibility to PCa.
doi:10.1089/gtmb.2013.0267
PMCID: PMC3865621  PMID: 24093803
3.  Acute diarrhea and metabolic acidosis caused by tuberculous vesico-rectal fistula 
World Journal of Gastroenterology : WJG  2014;20(41):15462-15466.
Acquired vesico-rectal fistula is an uncommon complication of pelvic malignant tumors, surgical injury, inflammatory disorders such as tuberculosis infection, radiotherapy and less commonly diverticulum of the urinary tract. The fistula is often identified by urinary tract abnormalities such as dysuria, recurrent urinary tract infection, pneumaturia, and fecaluria. Here, we report an unusual case of a patient with a vesico-rectal fistula of tuberculous origin, presenting with severe acute diarrhea, metabolic acidosis, hyperchloremia and hypokalemia while with only mild urinary tract symptoms. The patient was cured by tuberculostatic therapy.
doi:10.3748/wjg.v20.i41.15462
PMCID: PMC4223281  PMID: 25386096
Vesico-rectal fistula; Tuberculous; Diarrhea; Acidosis; Hyperchloremia; Hypokalemia
4.  Iodine nutritional status after the implementation of the new iodized salt concentration standard in Zhejiang Province, China 
BMC Public Health  2014;14(1):836.
Background
Iodine deficiencies were prevalent in China until the introduction of universal salt iodization (USI) in 1995. In 2012, the standard salt iodine concentration was adjusted to 20-30 mg/kg. The success of USI for the control of iodine deficiency disorders requires monitoring its effect at a population level.
Methods
Two cross sectional surveys of a representative sample of children aged 8–10 years in Zhejiang Province were carried out in 2011 and 2013. Data on participants’ socio-demographic characteristics were collected from the children using a structured questionnaire. Spot urine samples were collected and delivered to local Center for Disease Control and Prevention laboratory for measuring urinary iodine concentration. In 2011, out of 420 selected children aged 8–10 years, 391 were recorded and provided urine samples. In 2013, out of 1560 selected children aged 8–10 years, 1556 were recorded and provided urine samples.
Results
The median urinary iodine concentration of subjects in the 2013 survey was 174.3 μg/L, significantly lower than that of 2011(p = 0.000). The median urinary iodine concentration of subjects living in urban and rural areas in the 2013 survey was 169.0 μg/L, and 186.1 μg/L respectively, significantly lower than that of 2011 only for subjects living in urban areas (p = 0.000). There were no significant differences for subjects living in rural areas in the survey in 2011 and in 2013 (p = 0.086).
Conclusions
At the time the new local iodization policy put forward, iodine nutrition was generally adequate in both urban and rural areas, suggesting that the new policy for adjusting the standard salt iodine concentration is effective. Our data also indicate that the reason people living in urban areas had a lower urinary iodine concentration than people in rural areas may be due to their preference for using non-iodized salt in the last 2 or 3 years. Maintaining USI at an appropriate level is an important part of preventing iodine deficiency disorders and should always be based on regular monitoring and comparison of urinary iodine concentration by province.
doi:10.1186/1471-2458-14-836
PMCID: PMC4139602  PMID: 25118032
Urinary iodine concentration; Comparison; Probability proportional to size sampling; Children
5.  Developmental decline in neuronal regeneration by the progressive change of two intrinsic timers in C. elegans 
Science (New York, N.Y.)  2013;340(6130):372-376.
Like mammalian neurons, C. elegans neurons lose axon regeneration ability as they age, but it is not known why. Here, we report that let-7 contributes to a developmental decline in AVM axon regeneration. In older AVM axons, let-7 inhibits regeneration by down regulating LIN-41, an important AVM axon regeneration-promoting factor. While let-7 inhibits lin-41 expression in older neurons through the lin-41 3'UTR, lin-41 inhibits let-7 expression in younger neurons through Argonaute ALG-1. This reciprocal inhibition ensures axon regeneration is only inhibited in older neurons. These findings show that a let-7-lin-41 regulatory circuit, which was previously shown to control timing of events in mitotic stem cell lineages, is re-utilized in postmitotic neurons to control post-differentiation events.
doi:10.1126/science.1231321
PMCID: PMC4074024  PMID: 23599497
6.  A cross-sectional comparison study on the iodine nutritional status between rural and urban residents in Zhejiang Province, China 
BMJ Open  2014;4(6):e005484.
Objectives
To evaluate the difference of iodine nutritional status between rural and urban residents under the universal salt iodisation policy.
Setting
A multistage cluster sampling technique was employed in the present cross-sectional study. In total, 3300 rural and 3300 urban households were selected where the investigation was conducted.
Participants
A total of 8553 rural and 8909 urban residents participated in this provincial survey.
Primary and secondary outcome measures
Spot urine samples were collected and the iodine concentration in urine was determined by the modified acid-digestion method.
Results
The median urinary iodine concentration of rural residents was 170.1 μg/L, which was higher than that of urban residents with 153.5 μg/L. For school-aged children, middle-aged people and older people, the median urinary iodine concentration of rural residents was 191.2, 160.2 and 154.0 μg/L, respectively, which was higher than that of urban residents with 166.2, 153.8 and 129.5 μg/L, respectively. Risk factors for urinary concentration of rural residents were age (OR=0.99), terrain (OR=0.83), usual intake of pickled products (OR=1.45) and non-iodised salt intake (OR=0.39), while those for urban residents were age (OR=0.99), terrain (OR=0.83), usual intake of aquatic products (OR=1.24) and non-iodised salt intake (OR=0.27) compared with iodised table salt intake.
Conclusions
The median urinary iodine concentration of rural residents was higher than that of urban residents although they were both falls in optimal iodine status as recommended by WHO/UNICEF/International Council for the Control of Iodine Deficiency Disorders. Iodised salt intake is the major factor which influences the iodine nutritional status mostly for rural and urban residents. The ongoing monitoring of population iodine status remains crucially important.
doi:10.1136/bmjopen-2014-005484
PMCID: PMC4078769  PMID: 24969785
NUTRITION & DIETETICS; PUBLIC HEALTH; EPIDEMIOLOGY
7.  Manganese exposure among smelting workers: Relationship between blood manganese–iron ratio and early onset neurobehavioral alterations 
Neurotoxicology  2009;30(6):1214-1222.
A biomarker for detection of early onset neurobehavioral alterations in manganism remains unknown. The purpose of this study was to use a neurobehavioral test battery to identify subtle changes in Mn-induced motor and memory dysfunction and to relate the quantifiable neurological dysfunction to an established Mn-exposure index such as blood manganese–iron ratio (MIR). A total of 323 subjects were recruited to control (n = 106), low-exposure (122), and high-exposure (95) groups. The test battery consisted of standard testing procedures including the nine-hole and groove-type steadiness tester, Benton visual retention test, and Purdue pegboard coordination test. No significant health problems or clinically diagnosed neurological dysfunctions were observed. Benton test did not reveal any abnormal memory deficits among Mn-exposed smelters, nor did the groove and nine-hole tests detect any abnormality in dynamic and static steadiness in tested subjects. Purdue pegboard test showed a remarkable age-related decline in fine movement coordination among all study participants regardless of the Mn-exposure condition. Mn exposure significantly exacerbated this age-related deterioration. Statistical modeling revealed that the plasma and erythrocyte MIR (i.e., pMIR and eMIR, respectively) were associated with Purdue pegboard scores. Among all subjects whose MIR were above the cut-off value (COV), pMIR was significantly correlated with pegboard scores (r = −0.261, p = 0.002), whereas for those subjects over the age of 40, the eMIR, but not pMIR, was associated with declined pegboard performance (r = −0.219, p = 0.069). When both factors were taken into account (i.e., age > 40 and MIR > the COV), only pMIR was inversely associated with pegboard scores. Combining their usefulness in Mn-exposure assessment, we recommend that the blood Mn–Fe ratio may serve as a reasonable biomarker not only for assessment of Mn exposure but also for health risk assessment.
doi:10.1016/j.neuro.2009.02.005
PMCID: PMC3983997  PMID: 19963104
Manganese; Manganese–iron ratio; Early onset neurobehavioral alterations; Exposure assessment
8.  Manganese exposure among smelting workers: blood manganese–iron ratio as a novel tool for manganese exposure assessment 
Unexposed control subjects (n = 106), power distributing and office workers (n = 122), and manganese (Mn)-exposed ferroalloy smelter workers (n = 95) were recruited to the control, low and high groups, respectively. Mn concentrations in saliva, plasma, erythrocytes, urine and hair were significantly higher in both exposure groups than in the controls. The Fe concentration in plasma and erythrocytes, however, was significantly lower in Mn-exposed workers than in controls. The airborne Mn levels were significantly associated with Mn/Fe ratio (MIR) of erythrocytes (eMIR) (r = 0.77, p < 0.01) and plasma (pMIR) (r = 0.70, p < 0.01). The results suggest that the MIR may serve as a useful biomarker to distinguish Mn-exposed workers from the unexposed, control population.
doi:10.1080/13547500902730672
PMCID: PMC3980868  PMID: 19283519
Manganese; iron; exposure assessment; Mn-Fe ratio; biomarker; saliva; erythrocyte; smelter
9.  Therapeutic Success of the Ketogenic Diet as a Treatment Option for Epilepsy: a Meta-analysis 
Iranian Journal of Pediatrics  2013;23(6):613-620.
Objective
To systematically evaluate therapeutic success of the ketogenic diet (KD) as a treatment option for epilepsy.
Methods
Using MEDLINE and Google Scholar search, we searched for studies investigating the therapeutic success of ketogenic diet for epilepsy. We estimated therapeutic success rate for ketogenic diet as a treatment option for epilepsy and its 95% CIs using generic inverse variance method.
Findings
A total of 38 studies met the inclusion criteria. In retrospective studies, the weighted success rate of the patients who take the KD as a treatment option for epilepsy was 58.4% (95% confidence interval (95%CI)=48.7% – 69.9%) at 3 months (n=336); 42.8% (95%CI =36.3% – 50.3%) at 6 months (n=492), and 30.1% (95%CI =24.3% – 37.2%) at 12 months (n=387); in prospective studies, weighted success rate was 53.9% (95%CI 45.5% – 63.8%) at 3 months (n=474); 53.2% (95%CI =44.0% – 64.2%) at 6 months (n=321), and 55.0% (95%CI =45.9% – 65.9%) at 12 months (n=347).
Conclusion
This meta-analysis provides formal statistical support for the efficacy of the ketogenic diet in the treatment of epileptic patients.
PMCID: PMC4025116  PMID: 24910737
Ketogenic Diet; Epilepsy; Meta-Analysis; Children
10.  Geographical Analysis of the Distribution and Spread of Human Rabies in China from 2005 to 2011 
PLoS ONE  2013;8(8):e72352.
Background
Rabies is a significant public health problem in China in that it records the second highest case incidence globally. Surveillance data on canine rabies in China is lacking and human rabies notifications can be a useful indicator of areas where animal and human rabies control could be integrated. Previous spatial epidemiological studies lacked adequate spatial resolution to inform targeted rabies control decisions. We aimed to describe the spatiotemporal distribution of human rabies and model its geographical spread to provide an evidence base to inform future integrated rabies control strategies in China.
Methods
We geo-referenced a total of 17,760 human rabies cases of China from 2005 to 2011. In our spatial analyses we used Gaussian kernel density analysis, average nearest neighbor distance, Spatial Temporal Density-Based Spatial Clustering of Applications with Noise and developed a model of rabies spatiotemporal spread.
Findings
Human rabies cases increased from 2005 to 2007 and decreased during 2008 to 2011 companying change of the spatial distribution. The ANN distance among human rabies cases increased between 2005 and 2011, and the degree of clustering of human rabies cases decreased during that period. A total 480 clusters were detected by ST-DBSCAN, 89.4% clusters initiated before 2007. Most of clusters were mainly found in South of China. The number and duration of cluster decreased significantly after 2008. Areas with the highest density of human rabies cases varied spatially each year and in some areas remained with high outbreak density for several years. Though few places have recovered from human rabies, most of affected places are still suffering from the disease.
Conclusion
Human rabies in mainland China is geographically clustered and its spatial extent changed during 2005 to 2011. The results provide a scientific basis for public health authorities in China to improve human rabies control and prevention program.
doi:10.1371/journal.pone.0072352
PMCID: PMC3753237  PMID: 23991098
11.  The lin-4 microRNA Targets the LIN-14 Transcription Factor to Inhibit Netrin-Mediated Axon Attraction 
Science signaling  2012;5(228):ra43.
lin-4 (miR-125) microRNAs are deeply conserved across animal phylogeny. They are among the first microRNAs discovered and were implicated in regulating developmental timing in C. elegans. In this study, we report that mutations in lin-4 microRNA specifically suppress the AVM axon guidance defects in slt-1 mutants through enhancement of netrin attraction. lin-4 expression in AVM neurons rescued lin-4 mutant phenotypes in AVM axon guidance, suggesting that lin-4 acts cell autonomously in AVM to inhibit its axon attraction to netrin. lin-4 is expressed strongly in the AVM neuron when its axon guidance is underway, and is almost undetectable in the ALM neuron whose axon guidance is netrin independent. The transcription factor lin-14, a necessary target of lin-4 microRNA in the AVM neurons, stimulates netrin-mediated AVM axon ventral guidance. lin-14’s positive effect in netrin attraction is mediated by the receptor unc-40 (DCC) and its cofactor madd-2 functioning through a combination of the unc-34 (Ena) and ced-10 (Rac1)-dependent downstream pathways. lin-14 stimulates netrin-mediated axon attraction in part by enhancing UNC-40 protein expression. Our study indicates that the eventual down-regulation of lin-14 activity in the AVM neurons at the end of axon guidance is caused by lin-4 microRNA inhibition.
doi:10.1126/scisignal.2002437
PMCID: PMC3670680  PMID: 22692424
12.  Altered Functional Connectivity in an Aged Rat Model of Postoperative Cognitive Dysfunction: A Study Using Resting-State Functional MRI 
PLoS ONE  2013;8(5):e64820.
Background
Postoperative cognitive impairment is a common complication after cardiac and major non-cardiac surgery in the elderly, but its causes and mechanisms remain unclear. The purpose of the current study was to use resting-state functional magnetic resonance imaging (fMRI) to explore changes in the functional connectivity, i.e. the synchronization of low frequency fluctuation (LFF), in an animal model of cognitive impairment in aged rats.
Methods
Aged (22 months) rats were anaesthetized with 40 µg/kg fentanyl and 500 µg/kg droperidol (intraperitoneal) for splenectomy. Cognitive function was assessed using Y maze prior to operation and on postoperative days 1, 3 and 9. To evaluate functional connectivity, resting-state fMRI data were acquired using a 3T MR imaging system with a 4 channel phase array rat head coil.
Results
Cognitive function was impaired at postoperative days 1 and 3 compared with preoperative. Significant synchronized LFF was detected bilaterally in the primary somatosensory cortex and hippocampus preoperatively. By contrast, no significant LFF synchronization was detected in the right primary somatosensory cortex and right hippocampus on postoperative days 1 and 3, although the pattern of functional connectivity had become almost normal by day 9.
Conclusion
Splenectomy performed under neuroleptic anaesthesia triggers a cognitive decline that is associated with altered spontaneous neuronal activity in the cortex and hippocampus.
doi:10.1371/journal.pone.0064820
PMCID: PMC3667804  PMID: 23738003
13.  Elevated 12-Month and Lifetime Prevalence and Comorbidity Rates of Mood, Anxiety, and Alcohol Use Disorders in Chinese Men Who Have Sex with Men 
PLoS ONE  2013;8(4):e50762.
Background
This study aimed to assess whether Chinese men who have sex with men (MSM) had a significantly elevated prevalence of psychiatric disorders compared to urban males in China.
Methods
807 MSM were recruited using a respondent-driven sampling (RDS) method in urban area of northeast China. Psychiatric disorders were assessed employing the Composite International Diagnostic Interview (CIDI. Version 1.0) according to the criteria of the DSM-III-R.
Results
Chinese MSM had a significantly elevated standardized prevalence ratios (SPR) for lifetime prevalence of any disorder (SPR = 2.8; 95%CI: 2.5–3.2), mood disorder (SPR = 3.0; 95%CI: 2.3–3.7), anxiety disorder (SPR = 5.5; 95% CI: 4.6–6.5), alcohol use disorder (SPR = 2.4, 95%CI: 2.0–2.8), and combination of disorders (SPR = 4.2; 95%CI: 3.4–5.1).
Conclusions
Chinese MSM had significantly elevated prevalence and comorbidity of psychiatric disorders. RDS is a suitable sampling method for psychiatric epidemiological survey in MSM population.
doi:10.1371/journal.pone.0050762
PMCID: PMC3630226  PMID: 23637731
14.  Aggressive natural killer-cell leukemia with jaundice and spontaneous splenic rupture: a case report and review of the literature 
Diagnostic Pathology  2013;8:43.
Aggressive natural killer cell leukemia/lymphoma (ANKL) is a rare aggressive form of NK-cell neoplasm. We report an uncommon case of 36-year-old male who showed jaundice and spontaneous splenic rupture. The diagnosis was established by the biopsy of liver and spleen. The monomorphous medium-size neoplastic cells infiltrated into portal areas and sinus of liver as well as the cords and sinus of the spleen. Necrosis, mitotic figures and significant apoptosis could be seen easily. These neoplastic cells demonstrated a typical immunophenotype of CD3ε+, CD56+, CD16+, Granzyme B+, TIA-1+. T-cell receptor γ (TCR-γ) gene rearrangement analysis showed germline configuration and the result of in situ hybridization for Epstein-Barr virus-encoded RNA (EBER-ISH) was positive. The patient has undergone an aggressive clinical course and died of multi-organ function failure 14 days later after admission. To the best of our knowledge, this is the first case of ANKL with spontaneous splenic rupture, and we should pay more attention to recognize it.
Virtual Slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2048154883890867
doi:10.1186/1746-1596-8-43
PMCID: PMC3599828  PMID: 23510456
Aggressive natural killer-cell leukemia; Jaundice; Spontaneous splenic rupture
15.  The A10389G polymorphism of ND3 gene and breast cancer: A meta-analysis 
Biomedical Reports  2013;1(2):259-264.
Previous studies have reported the association between A10389G polymorphism of the dehydrogenase subunit 3 (ND3) gene and breast cancer risk with conflicting results. To explore this association, we conducted a meta-analysis on 5,580 patients and 5,749 controls from eligible published studies. Six reports (11 study populations) were included in this meta-analysis. Compared with the individuals with the G allele, individuals carrying the A allele did not exhibit increased breast cancer risk. The odds ratio (OR) and 95% confidence interval (CI) were 1.02 and 0.79–1.31, respectively. Stratified analyses were carried out according to ethnicity and source of controls. The corresponding ORs (95% CIs) were 1.20 (0.90–1.86) for African-American, 0.47 (0.03–7.64) for European and 0.89 (0.70–1.14) for mixed populations, respectively. A single study on Asian populations yielded an OR (95% CI) of 0.56 (0.32–1.00). The corresponding ORs (95% CIs) were 1.12 (0.23–5.47) for hospital-based studies, and 0.98 (0.76–1.27) for population-based studies. Only one study did not mention the source of control, the OR (95% CI) of which was 1.80 (1.15–2.82). Results of the present study suggested that the ND3 gene A10389G polymorphism may not be an independent risk factor for breast cancer. However, additional studies should be performed to clarify the possible roles of the ND3 A10398G polymorphism in the etiology of breast cancer.
doi:10.3892/br.2013.58
PMCID: PMC3917039  PMID: 24648932
A10389G polymorphism; dehydrogenase subunit 3 gene; breast cancer; meta-analysis
16.  Screening for urinary biomarkers of steroid-resistant nephrotic syndrome in children 
The present study aimed to screen for urinary biomarkers of steroid-resistant nephrotic syndrome (SRNS) in children. These biomarkers were divided into three groups, the control, the steroid-sensitive nephrotic syndrome (SSNS) and the SRNS groups, which were composed of 45, 32 and 9 children, respectively. Urine samples were obtained and analyzed using Au-chips. Compared with the control group, the peak intensities of four proteins, measured using mass-to-charge ratios, were significantly increased in the primary nephrotic syndrome (PNS; SSNS and SRNS combined) group (P<0.01). The intensity of three and one peaks increased significantly in the SSNS and SRNS groups, respectively, compared with the control (P<0.01). Compared with the SRNS group, the intensity of one protein peak increased in the SSNS group (P<0.01). The diagnostic model was established based on these four protein peaks. The sensitivity and specificity of the model were 88.89 and 93.75%, respectively. Four differentially expressed proteins may consequently serve as urinary biomarkers for SRNS in children.
doi:10.3892/etm.2012.875
PMCID: PMC3570142  PMID: 23403919
urinary proteomics; urine; steroid-resistant; biomarkers; nephrotic syndrome
17.  Dietary Factors Associated with Dental Erosion: A Meta-Analysis 
PLoS ONE  2012;7(8):e42626.
Background
Some diet factors are risk factors for dental erosion.
Methods
We performed computer searches of PubMed, Cochrane Library, EBSCO, CALIS, et al., to search for studies investigating risk factors for dental erosion. For risk factors investigated in a comparative way, we computed pooled odds ratios (ORs) using the Mantel and Haenszel method.
Results
A total of 9 studies met the inclusion criteria, and 6 risk factors were considered, including soft drinks, sports drinks, juice, vitamin C, milk, and yoghourt. The following associations were found for soft drinks (OR = 2.41, 95%CI = 2.03–2.85) and vitamin C (OR = 1.16, 95%CI = 1.10–1.22). While juice (OR = 0.90, 95%CI = 0.25–3.24), sports drinks (OR = 1.58, 95%CI = 0.88–2.85), milk (OR = 0.67, 95%CI = 0.11–4.01), and yoghourt products (OR = 1.05, 95%CI = 0.28–3.96) were not associated with dental erosion.
Conclusions
This meta-analysis provides comprehensive evidence-based assessment of diet-related factors for dental erosion. Preventive strategies should be taken to reduce dental erosion.
doi:10.1371/journal.pone.0042626
PMCID: PMC3432030  PMID: 22952601
18.  Light-regulation of protein dimerization and kinase activity in living cells using photocaged rapamycin and engineered FKBP 
We developed a new system for light-induced protein dimerization in living cells using a novel photocaged analog of rapamycin (pRap) together with an engineered rapamycin binding domain (iFKBP). Using focal adhesion kinase as a target, we demonstrated successful light-mediated regulation of protein interaction and localization in living cells. Modification of this approach enabled light-triggered activation of a protein kinase and initiation of kinase-induced phenotypic changes in vivo.
doi:10.1021/ja109630v
PMCID: PMC3133816  PMID: 21162531
19.  Association of NOD1 (CARD4) insertion/deletion polymorphism with susceptibility to IBD: A meta-analysis 
AIM: To find evidences about whether NOD1/CARD4 insertion/deletion polymorphism is associated with inflammatory bowel disease by meta-analysis.
METHODS: We surveyed the studies on the association of NOD1/CARD4 insertion/deletion polymorphism with inflammatory bowel disease in PubMed. Meta-analysis was performed for genotypes GG/T vs T/T, GG/GG vs T/T, GG/T + GG/GG vs T/T, GG/GG vs T/T + GG/T, and GG allele vs T allele in a fixed/random effect model.
RESULTS: We identified 8 studies (6439 cases and 4798 controls) in Caucasian populations using PubMed search. We found no association between NOD1/CARD4 insertion/deletion polymorphism and inflammatory bowel disease, Crohn’s disease, and ulcerative colitis. Stratification of cases by age showed that NOD1/CARD4 insertion/deletion polymorphism was associated with inflammatory bowel disease in younger age group at onset (< 40 years) (GG vs T: OR = 0.68, 95% CI: 0.50-0.93, P = 0.02; GG/T + GG/GG vs T/T: OR = 0.71, 95% CI: 0.59-0.85, P = 0.0003).
CONCLUSION: This meta-analysis demonstrates an association between NOD1/CARD4 insertion/deletion polymorphism and inflammatory bowel disease in the younger age group at onset (< 40 years) in Caucasian populations.
doi:10.3748/wjg.v16.i34.4348
PMCID: PMC2937117  PMID: 20818820
NOD1; CARD4; Genetic polymorphisms; Inflammatory bowel disease; Meta-analysis
20.  Blocking and triggering of plant immunity by Pseudomonas syringae effector AvrPto 
Plant Signaling & Behavior  2008;3(8):583-585.
Bacterial effectors are double-edged swords that enhance bacterial virulence in susceptible plants while trigger resistance in plants carrying cognate resistance proteins. A well-known example of this is Pseudomonas syringae protein AvrPto that is delivered into plant cells through the type III secretion system. AvrPto inhibits immune responses in Arabidopsis plants but triggers resistance in some tomato plants carrying cognate resistance proteins Pto, a serine/threonine kinase, and Prf, a nucleotide-binding leucine-rich repeat protein. In a recent structural study we showed that AvrPto is an inhibitor of the Pto protein kinase. Because Pto closely resemble the kinase domain of receptor kinases, which include pattern recognition receptors (PRRs) crucial for plants to detect invading pathogens, we tested the possibility that PRRs such as FLS2 and EFR are targeted by AvrPto in susceptible plants. Indeed, AvrPto is capable of binding the FLS2 and EFR kinases to block plant immune responses when expressed in protoplasts. In Arabidopsis plants containing FLS2, the P. syringae strain lacking avrPto is compromised in its ability to multiply. However, the defect of the avrPto-deletion strain was alleviated in fls2 plants, indicating a role of AvrPto in overcoming FLS2-mediated resistance. Interestingly, the FLS2-AvrPto and Pto-AvrPto interactions share significant similarity, raising the tantalizing possibility that Pto has evolved as a molecular decoy of the intended targets of AvrPto.
PMCID: PMC2634504  PMID: 19704476
Pseudomonas syringae; innate immunity; virulence; disease resistance; FLS2
21.  Enthalpy (ΔH) and Entropy (ΔS) for π-Stacking Interactions in near-Sandwich Configurations: The Relative Importance of Electrostatic, Dispersive, and Charge-Transfer Effects 
The Journal of organic chemistry  2007;72(7):2469-2475.
Interactions between two aromatic rings with various substituents in a near-sandwich configuration have been quantitatively studied using the triptycene derived molecular models. This model system allows a stacking arrangement of two arenes to assume a near perfect face-to-face configuration in its ground state conformation. Comparing to our previous study of the parallel displaced configuration, repulsive interactions are predominant for most arenes currently studied. However, if one arene is strongly electron-deficient (Ar2 = pentafluorobenzoate), attractive interactions were observed regardless of the character of the other arene (Ar1). For stacking interactions between Me2NC6H4 and C6F5CO groups, a ΔH of −1.84 ± 0.2 kcal/mol and a ΔS of −2.9 ± 0.8 cal/mol·K were determined. The general trend in the attractive stacking interaction towards a pentafluorobenzoate is Me2NC6H4 > Me3C6H2> Me2C6H3> MeC6H4 > MeOC6H4 > C6H5 > O2NC6H4. The observed trend is consistent with a donor-acceptor relationship and the acceptor is a C6F5CO group.
doi:10.1021/jo062526t
PMCID: PMC2631381  PMID: 17338571
22.  A Quantitative Study on the in-vitro and in-vivo Acetylation of High Mobility Group A1 Proteins 
High mobility group (HMG) A1 proteins are subject to a number of post-translational modifications, which may regulate their function in gene transcription and other cellular processes. We examined, by using mass spectrometry, the acetylation of HMGA1a and HMGA1b proteins induced by histone acetyltransferases p300 and PCAF in vitro and in PC-3 human prostate cancer cells in vivo. It turned out that five lysine residues in HMGA1a, i.e., Lys-14, Lys-64, Lys-66, Lys-70, and Lys-73, could be acetylated by both p300 and PCAF. We further quantified the level of acetylation by analyzing, with LC-MS/MS, the proteolytic peptides of the in-vitro or in-vivo acetylated HMGA1 proteins where the unmodified lysine residues were chemically derivatized with a perdeuterated acetyl group. Quantification results revealed that p300 and PCAF exhibited different site preferences for the acetylation; the preference of p300 acetylation followed the order of Lys-64~Lys-70 > Lys-66 > Lys-14~Lys73, whereas the selectivity of PCAF acetylation followed the sequence of Lys-70~Lys-73 > Lys-64~Lys-66 > Lys-14. HMGA1b was acetylated in a very similar fashion as HMGA1a. We also demonstrated that C-terminal phosphorylation of HMGA1 proteins did not affect the in-vitro acetylation of the two proteins by either p300 or PCAF. Moreover, we examined the acetylation of lysine residues in HMGA1a and HMGA1b isolated from PC-3 human prostate cancer cells. Our results showed that all the above five lysine residues were also acetylated in vivo, with Lys-64, Lys-66 and Lys-70 in HMGA1a exhibiting higher levels of acetylation than Lys-14 and Lys-73.
doi:10.1016/j.jasms.2007.05.020
PMCID: PMC2020522  PMID: 17627840
23.  Diffusion tensor imaging of the brain in patients with Alzheimer’s disease and cerebrovascular lesions 
Background: Recent autopsy study showed a high incidence of cerebrovascular lesions in Alzheimer’s disease (AD). To assess the impact of cerebrovascular pathology in AD, we used diffusion tensor imaging (DTI) to study AD patients with and without cerebrovascular lesions. Materials and Methods: Conventional and DTI scans were obtained from 10 patients with probable AD, 10 AD/V patients (probable AD with cerebrovascular lesions) and ten normal controls. Mean diffusivity (D) and fractional anisotropy (FA) values of some structures involved with AD pathology were measured. Results: D value was higher in AD patients than in controls in hippocampus and the cingulate gyrus. In AD/V patients, increased D value was found in the same structures and also in the thalamus and basal ganglia compared to controls. There was a significant difference of D value between AD and AD/V patients. FA value reduced in the white matter of left inferior temporal gyrus and in the bilateral middle cingulate gyrus in patients with AD/V compared with controls. The MMSE (mini-mental state examination) score significantly correlated with FA value in the right hippocampus (r=0.639, P<0.019), in the right anterior cingulate gyrus (r=0.587, P<0.035) and in left parahippocampal gyrus (r=0.559, P<0.047). Conclusion: Cerebrovascular pathology had stronger impact on the D value than the AD pathology alone did. Elevated D value in thalamic and basal ganglia may contribute to cognitive decline in AD/V patients. Reduced FA values in AD/V patients may indicate that cerebrovascular pathology induced more severe white matter damage than the AD pathology alone did.
doi:10.1631/jzus.2007.B0242
PMCID: PMC1838832  PMID: 17444598
Diffusion tensor imaging (DTI); Alzheimer’s disease (AD); Cerebrovascular; Magnetic resonance imaging (MRI)

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