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1.  Speckle-type POZ protein, SPOP, is involved in the DNA damage response 
Carcinogenesis  2014;35(8):1691-1697.
We demonstrate that SPOP is a critical component of the DDR. SPOP forms nuclear foci and interacts with the ATM kinase after DNA damage. Depletion of SPOP results in an impaired DDR and hypersensitivity to radiation.
Speckle-type POZ protein (SPOP) is an adaptor of the cullin 3-based ubiquitin ligase responsible for the degradation of oncoproteins frequently overexpressed in many tumor cells. Altered expression and somatic mutations of SPOP have been observed in various tumor types with chromosomal aberrations, indicating a role of SPOP in maintaining genome stability, although a detailed mechanism remains unclear. Here, we show that SPOP is a component of the DNA damage response (DDR). SPOP is recruited to DNA double-strand break sites and it forms nuclear foci after DNA damage. SPOP foci colocalize with γ-H2AX foci and are predominantly dependent on the activity of the ataxia-telangiectasia mutated (ATM) kinase. Furthermore, SPOP interacts with ATM in response to DNA damage. Finally, we demonstrate that knocking down of SPOP resulted in an impaired DDR and a hypersensitivity to ionizing irradiation. Together, we highlight a critical role of SPOP in the DDR.
PMCID: PMC4123640  PMID: 24451148
2.  Optimized Inhibitors of Soluble Epoxide Hydrolase Improve in Vitro Target Residence Time and in Vivo Efficacy 
Journal of Medicinal Chemistry  2014;57(16):7016-7030.
Diabetes is affecting the life of millions of people. A large proportion of diabetic patients suffer from severe complications such as neuropathic pain, and current treatments for these complications have deleterious side effects. Thus, alternate therapeutic strategies are needed. Recently, the elevation of epoxy-fatty acids through inhibition of soluble epoxide hydrolase (sEH) was shown to reduce diabetic neuropathic pain in rodents. In this report, we describe a series of newly synthesized sEH inhibitors with at least 5-fold higher potency and doubled residence time inside both the human and rodent sEH enzyme than previously reported inhibitors. These inhibitors also have better physical properties and optimized pharmacokinetic profiles. The optimized inhibitor selected from this new series displayed improved efficacy of almost 10-fold in relieving pain perception in diabetic neuropathic rats as compared to the approved drug, gabapentin, and previously published sEH inhibitors. Therefore, these new sEH inhibitors could be an attractive alternative to treat diabetic neuropathy in humans.
PMCID: PMC4148150  PMID: 25079952
3.  A New System Identification Approach to Identifying Genetic Variants in Sequencing Studies for A Binary Phenotype 
Human heredity  2014;78(2):104-116.
We propose in this paper a set-valued (SV) system model, which is a generalized form of Logistic (LG) and Probit (Probit) regression, to be considered as a method for discovering genetic variants, especially rare genetic variants in next generation sequencing studies, for a binary phenotype. We propose a new set-valued system identification method to estimate all the underlying key system parameters for the Probit model and compare it with the LG model in the setting of genetic association studies. Across an extensive series of simulation studies, the Probit method maintained Type I error control and had similar or greater power than the LG method which is robust to different distributions of noise: logistic, normal or t distributions. Additionally, the Probit association parameter estimate was 2.7–46.8 fold less variable than the LG log-odds ratio association parameter estimate. Less variability in the association parameter estimate translates to greater power and robustness across the spectrum of minor allele frequencies (MAFs), and these advantages are the most pronounced for rare variants. For instance, in a simulation that generated data from an additive logistic model with odds ratio of 7.4 for a rare single nucleotide polymorphism with a MAF of 0.005 and a sample size of 2300, the Probit method had 60% power whereas the LG method had 25% power at the α=10−6 level. Consistent with these simulation results, the set of variants identified by the LG method was a subset of those identified by the Probit method in two example analyses. Thus, we suggest the Probit method may be a competitive alternative to the LG method in genetic association studies such as candidate gene, genome-wide, or next generation sequencing studies for a binary phenotype.
PMCID: PMC4270367  PMID: 25096228
Set-valued system model; binary phenotype; threshold model; genetic variants; rare variants; next-generation sequencing studies
4.  Heterologous Antigen Selection of Camelid Heavy Chain Single Domain Antibodies against Tetrabromobisphenol A 
Analytical Chemistry  2014;86(16):8296-8302.
Tetrabromobisphenol A (TBBPA) is a ubiquitous flame retardant. A high-throughput immunoassay would allow for monitoring of human and environmental exposures as a part of risk assessment. Naturally occurring antibodies in camelids that are devoid of light chain, show great promise as an efficient tool in monitoring environmental contaminants, but they have been rarely used for small molecules. An alpaca was immunized with a TBBPA hapten coupled to thyroglobulin and a variable domain of heavy chain antibody (VHH) T3–15 highly selective for TBBPA was isolated from a phage displayed VHH library using heterologous coating antigens. Compared to the VHHs isolated using homologous antigens, VHH T3–15 had about a 10-fold improvement in sensitivity in an immunoassay. This assay, under the optimized conditions of 10% methanol in the assay buffer (pH 7.4), had an IC50 for TBBPA of 0.40 ng mL–1 and negligible cross reactivity (<0.1%) with other tested analogues. After heating the VHH at 90 °C for 90 min about 20% of the affinity for coating antigen T3-BSA remained. The recoveries of TBBPA from spiked soil and fetal bovine serum samples ranged from 90.3% to 110.7% by ELISA and agreed well with a liquid chromatography–tandem mass spectrometry method. We conclude the many advantages of VHH make them attractive for the development of immunoassays to small molecules.
PMCID: PMC4139172  PMID: 25068372
5.  Measuring costs of data collection at village clinics by village doctors for a syndromic surveillance system-a cross sectional survey from China 
Studies into the costs of syndromic surveillance systems are rare, especially for estimating the direct costs involved in implementing and maintaining these systems. An Integrated Surveillance System in rural China (ISSC project), with the aim of providing an early warning system for outbreaks, was implemented; village clinics were the main surveillance units. Village doctors expressed their willingness to join in the surveillance if a proper subsidy was provided. This study aims to measure the costs of data collection by village clinics to provide a reference regarding the subsidy level required for village clinics to participate in data collection.
We conducted a cross-sectional survey with a village clinic questionnaire and a staff questionnaire using a purposive sampling strategy. We tracked reported events using the ISSC internal database. Cost data included staff time, and the annual depreciation and opportunity costs of computers. We measured the village doctors’ time costs for data collection by multiplying the number of full time employment equivalents devoted to the surveillance by the village doctors’ annual salaries and benefits, which equaled their net incomes. We estimated the depreciation and opportunity costs of computers by calculating the equivalent annual computer cost and then allocating this to the surveillance based on the percentage usage.
The estimated total annual cost of collecting data was 1,423 Chinese Renminbi (RMB) in 2012 (P25 = 857, P75 = 3284), including 1,250 RMB (P25 = 656, P75 = 3000) staff time costs and 134 RMB (P25 = 101, P75 = 335) depreciation and opportunity costs of computers.
The total costs of collecting data from the village clinics for the syndromic surveillance system was calculated to be low compared with the individual net income in County A.
PMCID: PMC4515002  PMID: 26208506
Rural China; Village clinics; Infectious diseases; Syndromic surveillance system; Data collection; Staff time costs; Depreciation and opportunity costs
6.  Analysis of the TGFβ-induced program in primary airway epithelial cells shows essential role of NF-κB/RelA signaling network in type II epithelial mesenchymal transition 
BMC Genomics  2015;16(1):529.
The airway epithelial cell plays a central role in coordinating the pulmonary response to injury and inflammation. Here, transforming growth factor-β (TGFβ) activates gene expression programs to induce stem cell-like properties, inhibit expression of differentiated epithelial adhesion proteins and express mesenchymal contractile proteins. This process is known as epithelial mesenchymal transition (EMT); although much is known about the role of EMT in cellular metastasis in an oncogene-transformed cell, less is known about Type II EMT, that occurring in normal epithelial cells. In this study, we applied next generation sequencing (RNA-Seq) in primary human airway epithelial cells to understand the gene program controlling Type II EMT and how cytokine-induced inflammation modifies it.
Generalized linear modeling was performed on a two-factor RNA-Seq experiment of 6 treatments of telomerase immortalized human small airway epithelial cells (3 replicates). Using a stringent cut-off, we identified 3,478 differentially expressed genes (DEGs) in response to EMT. Unbiased transcription factor enrichment analysis identified three clusters of EMT regulators, one including SMADs/TP63 and another NF-κB/RelA. Surprisingly, we also observed 527 of the EMT DEGs were also regulated by the TNF-NF-κB/RelA pathway. This Type II EMT program was compared to Type III EMT in TGFβ stimulated A549 alveolar lung cancer cells, revealing significant functional differences. Moreover, we observe that Type II EMT modifies the outcome of the TNF program, reducing IFN signaling and enhancing integrin signaling. We confirmed experimentally that TGFβ-induced the NF-κB/RelA pathway by observing a 2-fold change in NF-κB/RelA nuclear translocation. A small molecule IKK inhibitor blocked TGFβ-induced core transcription factor (SNAIL1, ZEB1 and Twist1) and mesenchymal gene (FN1 and VIM) expression.
These data indicate that NF-κB/RelA controls a SMAD-independent gene network whose regulation is required for initiation of Type II EMT. Type II EMT dramatically affects the induction and kinetics of TNF-dependent gene networks.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1707-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4506436  PMID: 26187636
Epithelial mesenchymal transition; Transforming growth factor β; Nuclear factor κB; RNA-Seq; Generalized linear modeling; Transcription factor enrichment
7.  A Cell Electrofusion Chip for Somatic Cells Reprogramming 
PLoS ONE  2015;10(7):e0131966.
Cell fusion is a potent approach to explore the mechanisms of somatic cells reprogramming. However, previous fusion methods, such as polyethylene glycol (PEG) mediated cell fusion, are often limited by poor fusion yields. In this study, we developed a simplified cell electrofusion chip, which was based on a micro-cavity/ discrete microelectrode structure to improve the fusion efficiency and to reduce multi-cell electrofusion. Using this chip, we could efficiently fuse NIH3T3 cells and mouse embryonic stem cells (mESCs) to induce somatic cells reprogramming. We also found that fused cells demethylated gradually and 5-hydroxymethylcytosine (5hmC) was involved in the demethylation during the reprogramming. Thus, the cell electrofusion chip would facilitate reprogramming mechanisms research by improving efficiency of cell fusion and reducing workloads.
PMCID: PMC4503441  PMID: 26177036
8.  Association between 25(OH)D Level, Ultraviolet Exposure, Geographical Location, and Inflammatory Bowel Disease Activity: A Systematic Review and Meta-Analysis 
PLoS ONE  2015;10(7):e0132036.
There is no consensus on the vitamin D levels and inflammatory bowel disease (IBD).
To conduct a systematic review and meta-analysis to analyze the relationship between IBD and 25(OH)D, sun exposure, and latitude, and to determine whether vitamin D deficiency affects the severity of IBD.
We searched the PubMed, EBSCO, and databases to identify all studies that assessed the association between 25(OH)D, sun exposure, latitude, and IBD through November 1, 2014, without language restrictions. Studies that compared 25(OH)D levels between IBD patients and controls were selected for inclusion in the meta-analysis. We calculated pooled standardized mean differences (SMDs) and odds ratios (ORs).
Thirteen case-control studies investigating CD and 25(OH)D levels were included, and eight studies part of above studies also investigated the relationship between UC and 25(OH)D. Both CD patients (SMD: 0.26 nmol/L, 95% confidence interval [CI]: 0.09–0.42 nmol/L) and UC patients (SMD: 0.5 nmol/L, 95% CI: 0.15–0.85 nmol/L) had lower levels of 25(OH)D than controls. In addition, CD patients and UC patients were 1.95 times (OR, 1.95; 95% CI, 1.48–2.57) and 2.02 times (OR, 2.02; 95% CI, 1.13–3.60) more likely to be 25(OH)D deficient than controls. We also included 10 studies investigating the relationship between CD activity and vitamin D. Results showed that patients with active CD (CD Activity Index≥150) were more likely to have low vitamin D levels. In addition, whether low sun exposure and high latitude were related to a high morbidity of CD need to be provided more evidence.
Our study shows that IBD patients have lower vitamin D levels. For active CD patients, vitamin D levels were low. These findings suggest that vitamin D may play an important role in the development of IBD, although a direct association could not be determined in our study.
PMCID: PMC4501705  PMID: 26172950
9.  Towards a comprehensive phylogeny of the large temperate genus Pedicularis (Orobanchaceae), with an emphasis on species from the Himalaya-Hengduan Mountains 
BMC Plant Biology  2015;15:176.
Striking interspecific variations in floral traits of the large temperate genus Pedicularis have given rise to controversies concerning infra-generic classifications. To date, phylogenetic relationships within the genus have not been well resolved. The main goal of this study is to construct a backbone phylogeny of Pedicularis, with extensive sampling of species from the Himalaya-Hengduan Mountains. Phylogenetic analyses included 257 species, representing all 13 informal groups and 104 out of 130 series in the classification system of Tsoong, using sequences of the nuclear ribosomal internal transcribed spacer (nrITS) and three plastid regions (matK, rbcL and trnL-F). Bayesian inference and maximum likelihood methods were applied in separate and combined analyses of these datasets.
Thirteen major clades are resolved with strong support, although the backbone of the tree is poorly resolved. There is little consensus between the phylogenetic tree and Tsoong’s classification of Pedicularis. Only two of the 13 groups (15.4 %), and 19 of the 56 series (33.9 %) with more than one sampled species were found to be strictly monophyletic. Most opposite-/whorled-leaved species fall into a single clade, i.e. clade 1, while alternate leaves species occur in the remaining 12 clades. Excluding the widespread P. verticillata in clade 1, species from Europe and North America fall into clades 6–8.
Our results suggest that combinations of morphological and geographic characters associated with strongly supported clades are needed to elucidate a comprehensive global phylogeny of Pedicularis. Alternate leaves are inferred to be plesiomorphic in Pedicularis, with multiple transitions to opposite/whorled phyllotaxy. Alternate-leaved species show high diversity in plant habit and floral forms. In the Himalaya-Hengduan Mountains, geographical barriers may have facilitated diversification of species with long corolla tubes, and the reproductive advantages of beakless galeas in opposite-/whorled-leaved species may boost speciation at high altitude.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-015-0547-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4498522  PMID: 26159907
Adaptive radiation; Floral diversity; Phyllotaxy; Himalaya-Hengduan Mountains; Orobanchaceae; Pedicularis; Phylogenetic analysis
10.  Silencing of Cholinergic Basal Forebrain Neurons Using Archaerhodopsin Prolongs Slow-Wave Sleep in Mice 
PLoS ONE  2015;10(7):e0130130.
The basal forebrain (BF) plays a crucial role in cortical activation. Our previous study showed that activation of cholinergic BF neurons alone is sufficient to suppress slow-wave sleep (SWS) and promote wakefulness and rapid-eye-movement (REM) sleep. However, the exact role of silencing cholinergic BF neurons in the sleep-wake cycle remains unclear. We inhibitied the cholinergic BF neurons genetically targeted with archaerhodopsin (Arch) with yellow light to clarify the role of cholinergic BF neurons in the sleep-wake cycle. Bilateral inactivation of cholinergic BF neurons genetically targeted with archaerhodopsin prolonged SWS and decreased the probability of awakening from SWS in mice. However, silencing these neurons changed neither the duration of wakefulness or REM sleep, nor the probability of transitions to other sleep-wake episodes from wakefulness or REM sleep. Furthermore, silencing these neurons for 6 h within the inactive or active period increased the duration of SWS at the expense of the duration of wakefulness, as well as increasing the number of prolonged SWS episodes (120-240 s). The lost wakefulness was compensated by a delayed increase of wakefulness, so the total duration of SWS and wakefulness during 24 h was kept stable. Our results indicate that the main effect of these neurons is to terminate SWS, whereas wakefulness or REM sleep may be determined by co-operation of the cholinergic BF neurons with other arousal-sleep control systems.
PMCID: PMC4495063  PMID: 26151909
11.  Core-shell Au@Pd nanoparticles with enhanced catalytic activity for oxygen reduction reaction via core-shell Au@Ag/Pd constructions 
Scientific Reports  2015;5:11949.
Core-shell nanoparticles often exhibit improved catalytic properties due to the lattice strain created in these core-shell particles. Herein, we demonstrate the synthesis of core-shell Au@Pd nanoparticles from their core-shell Au@Ag/Pd parents. This strategy begins with the preparation of core-shell Au@Ag nanoparticles in an organic solvent. Then, the pure Ag shells are converted into the shells made of Ag/Pd alloy by galvanic replacement reaction between the Ag shells and Pd2+ precursors. Subsequently, the Ag component is removed from the alloy shell using saturated NaCl solution to form core-shell Au@Pd nanoparticles with an Au core and a Pd shell. In comparison with the core-shell Au@Pd nanoparticles upon directly depositing Pd shell on the Au seeds and commercial Pd/C catalysts, the core-shell Au@Pd nanoparticles via their core-shell Au@Ag/Pd templates display superior activity and durability in catalyzing oxygen reduction reaction, mainly due to the larger lattice tensile effect in Pd shell induced by the Au core and Ag removal.
PMCID: PMC4491719  PMID: 26144550
12.  Deletion of the cyclic di-AMP phosphodiesterase gene (cnpB) in Mycobacterium tuberculosis leads to reduced virulence in a mouse model of infection 
Molecular microbiology  2014;93(1):65-79.
Tuberculosis (TB) remains a major cause of morbidity and mortality worldwide. The pathogenesis by the causative agent, Mycobacterium tuberculosis, is still not fully understood. We have previously reported that M. tuberculosis Rv3586 (disA) encodes a diadenylate cyclase, which converts ATP to cyclic di-AMP (c-di-AMP). In this study, we demonstrated that a protein encoded by Rv2837c (cnpB) possesses c-di-AMP phosphodiesterase activity and cleaves c-di-AMP exclusively to AMP. Our results showed that in M. tuberculosis, deletion of disA abolished bacterial c-di-AMP production, whereas deletion of cnpB significantly enhanced the bacterial c-di-AMP accumulation and secretion. The c-di-AMP levels in both mutants could be corrected by expressing the respective gene. We also found that macrophages infected with ΔcnpB secreted much higher levels of IFN-β than those infected with the wildtype (WT) or the complemented mutant. Interestingly, mice infected with M. tuberculosis ΔcnpB displayed significantly reduced inflammation, less bacterial burden in the lungs and spleens, and extended survival compared to those infected with the WT or the complemented mutant. These results indicate that deletion of cnpB results in attenuated virulence, which is correlated with elevated c-di-AMP levels.
PMCID: PMC4088933  PMID: 24806618
Mycobacterium tuberculosis; c-di-AMP; phosphodiesterase; diadenylate cyclase; IFN-β; virulence
13.  An Omega-3 Epoxide of Docosahexaenoic Acid Lowers Blood Pressure in Angiotensin-II Dependent Hypertension 
Mediators of anti-hypertensive actions of docosahexaenoic acid (DHA) are largely unknown. The omega-3 epoxide of DHA, 19, 20-EDP (epoxydocosapentaenoic acid) is metabolized by soluble epoxide hydrolase (sEH), which also metabolizes the anti-inflammatory and anti-hypertensive arachidonic acid (ARA) epoxides, EETs (epoxyeicosatrienoic acids). Based in part on plasma levels of EDPs following a DHA-rich diet, we hypothesized that 19, 20-EDP contributes to the anti-hypertensive actions of DHA in angiotensin-II dependent hypertension. Treatment individually with 19, 20-EDP, and a potent sEH inhibitor (sEHI) TPPU (1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea) significantly lowered blood pressure (BP) as compared to angiotensin-II infused animals. The largest reduction in BP was obtained with the combination of 19, 20-EDP and TPPU, which was more efficacious than the combination of 14, 15-EET and TPPU. Oxylipin profiling revealed that 19, 20-EDP and 14, 15-EET infusion affected mostly metabolites of the P450 pathway but also renal levels of prostaglandin-E2. Our findings suggest that 19, 20- EDP is a mediator of the anti-hypertensive effects of DHA in angiotensin-II dependent hypertension. It appears that 19, 20- EDP requires metabolic stabilization with a sEHI to be most effective in lowering BP, although both TPPU and 19, 20- EDP are so effective on their own that demonstrating additive or synergistic interactions is difficult.
PMCID: PMC4092041  PMID: 24691274
Docosahexaenoic acid (DHA); 19, 20-Epoxydocosapentaenoic acid; soluble epoxide hydrolase inhibitors; omega-3 polyunsaturated fatty acids; angiotensin-II dependent hypertension
14.  Seven In Absentia Homolog 2 (SIAH2) downregulation is associated with tamoxifen resistance in MCF-7 breast cancer cells 
The Journal of surgical research  2014;190(1):203-209.
A significant percentage of estrogen receptor (ER)–positive breast cancers are resistant to tamoxifen therapy. Seven in Absentia Homolog 2 (SIAH2), an E3 ubiquitin protein ligase, has been shown to be associated with resistance to antiestrogens. We sought to assess its role in the resistance of a breast cancer cell line, MCF-7, to the ER antagonist, tamoxifen.
Materials and methods
A bioinformatic approach was used for the analysis of SIAH2 expression in breast cancer. MCF-7 and MDA-MB-231, which are ER-positive and -negative breast cancer cell lines, respectively, were used for in vitro studies. SIAH2 and ER-α were selectively knocked down in these cell lines with small-interfering RNAs. Knockdowns were confirmed with Western blot analysis and quantitative real-time polymerase chain reaction. Cells with SIAH2 knockdown were treated with tamoxifen and compared with controls.
Knockdown of SIAH2 followed by treatment with tamoxifen resulted in a significant decrease in the sensitivity of treated ER-positive cells. Of note, knockdown of SIAH2 resulted in downregulation of ER-α, whereas knockdown of ER-α had minimal effect on SIAH2. Consistent with this result, the bioinformatic analysis of clinical data revealed that SIAH2 expression is significantly correlated with ER positivity in human breast cancers, and low SIAH2 expression is associated with a poorer response to tamoxifen.
SIAH2 appears to be an important modulator of tamoxifen sensitivity in ER-positive MCF-7 cells, mediated, at least in part, through regulation of ER-α expression. Low expression of SIAH2 may be one of the mechanisms that contribute to tamoxifen resistance in human breast cancer.
PMCID: PMC4215404  PMID: 24656476
Breast cancer; Tamoxifen; Resistance; SIAH2; Estrogen receptor
15.  Histone deacetylases and cardiovascular cell lineage commitment 
World Journal of Stem Cells  2015;7(5):852-858.
Cardiovascular diseases (CVDs), which include all diseases of the heart and circulation system, are the leading cause of deaths on the globally. During the development of CVDs, choric inflammatory, lipid metabolism disorder and endothelial dysfunction are widely recognized risk factors. Recently, the new treatment for CVDs that designed to regenerate the damaged myocardium and injured vascular endothelium and improve recovery by the use of stem cells, attracts more and more public attention. Histone deacetylases (HDACs) are a family of enzymes that remove acetyl groups from lysine residues of histone proteins allowing the histones to wrap the DNA more tightly and commonly known as epigenetic regulators of gene transcription. HDACs play indispensable roles in nearly all biological processes, such as transcriptional regulation, cell cycle progression and developmental events, and have originally shown to be involved in cancer and neurological diseases. HDACs are also found to play crucial roles in cardiovascular diseases by modulating vascular cell homeostasis (e.g., proliferation, migration, and apoptosis of both ECs and SMCs). This review focuses on the roles of different members of HDACs and HDAC inhibitor on stem cell/ progenitor cell differentiation toward vascular cell lineages (endothelial cells, smooth muscle cells and Cardiomyocytes) and its potential therapeutics.
PMCID: PMC4478631  PMID: 26131315
Histone deacetylases; Stem cell; Endothelial cell; Smooth muscle cell; Cardiovascular diseases
16.  Conformational activation of talin by RIAM triggers integrin-mediated cell adhesion 
Nature communications  2014;5:5880.
The membrane localization and activation of cytoskeletal protein talin are key steps to initiate integrin transmembrane receptors activation, which mediates many cellular adhesive responses such as cell migration, spreading, and proliferation. RIAM, a membrane anchor and small GTPase RAP1 effector, is known to bind to the C-terminal rod domain of talin (talin-R) and promote localizations of talin to membrane. Through systematic mapping analysis, we find that RIAM also binds to the N-terminal head of talin (talin-H), a crucial domain involved in binding and activating integrins. We show that the RIAM binding to talin-H sterically occludes the binding of a talin-R domain that otherwise masks the integrin binding site on talin-H. We further provide functional evidence that such RIAM-mediated steric unmasking of talin triggers integrin activation. Our findings thus uncover a novel role for RIAM in conformational regulation of talin during integrin activation and cell adhesion.
PMCID: PMC4432866  PMID: 25520155
RIAM; talin; integrin; NMR
17.  Outbreak of febrile illness caused by coxsackievirus A4 in a nursery school in Beijing, China 
Virology Journal  2015;12:92.
Coxsackievirus A4 (CV-A4) is classified as human enterovirus A according to its serotype. CV-A4, an etiological agent of hand, foot, and mouth disease, affects children worldwide and can circulate in closed environments such as schools and hospitals for long periods.
An outbreak of febrile illness at a nursery school in Beijing, China, was confirmed to be caused by CV-A4. Phylogenetic analysis of the complete genome of the isolated strain showed that the virus belongs to the same cluster as the predominant CV-A4 strain in China. This outbreak was controlled by effective measures.
The early identification of the pathogen and timely intervention may be the most critical factors in controlling an outbreak caused by CV-A4 in a preschool.
PMCID: PMC4495935  PMID: 26084565
Coxsackievirus A4; Outbreak; Preschool; Prevention; Control
18.  Recurrent Thymoma in the Retroperitoneal Space: A Rare Case Report 
Clinics and Practice  2015;5(2):746.
Thymoma is an epithelial neoplasm of the thymus, which commonly lies in the anterior mediastinum and recurrences of thymoma generally are locally, and retroperitoneal recurrence is considered to be rare. A 46-year old Asian woman with invasive thymoma had undergone thymectomy 10 years ago. Computed tomography demonstrated a well-circumscribed mass in the left retroperitoneal space. The patient had not any symptom including myasthenia gravis. Because on the anterior mediastinum area shows no sign of tumor recurrence and the mass adjacent to the vertebral body, neurogenic tumor was suspected. Surgical resection was performed using a retroperitoneal approach, which revealed the tumor adhering neighboring diaphragm. The tumor was histologically diagnosed to be type B1 thymoma according to the World Health Organization classification. The retroperitoneal mass was an unusual local recurrence after thymectomy. The patients whose had under invasive thymectomy should be evaluated carefully when finding retroperitoneal mass during follow-up.
PMCID: PMC4500877
Thymoma; recurrence; retroperitoneal space
19.  Effect of Acupuncture on Functional Connectivity of Anterior Cingulate Cortex for Bell's Palsy Patients with Different Clinical Duration 
Acupuncture is widely used in the treatment of Bell's palsy (BP) in many countries, but its underlying physiological mechanism remained controversial. In order to explore the potential mechanism, changes of functional connectivity (FC) of anterior cingulate gyrus (ACC) were investigated. We collected 20 healthy (control group) participants and 28 BP patients with different clinical duration accepted resting state functional MRI (rfMRI) scans before and after acupuncture, respectively. The FC of ACC before and after acupuncture was compared with paired t-test and the detailed results are presented in the paper. Our results showed that effects of the acupuncture on FC were closely related to clinical duration in patients with BP, which suggested that brain response to acupuncture was closely connected with the status of brain functional connectivity and implied that acupuncture plays a homeostatic role in the BP treatment.
PMCID: PMC4487273  PMID: 26161125
20.  Efficacy of Acupuncture in Children with Nocturnal Enuresis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials 
Background. Nocturnal enuresis (NE) is recognized as a widespread health problem in young children and adolescents. Clinical researches about acupuncture therapy for nocturnal enuresis are increasing, while systematic reviews assessing the efficacy of acupuncture therapy are still lacking. Objective. This study aims to assess the effectiveness of acupuncture therapy for nocturnal enuresis. Materials and Methods. A comprehensive literature search of 8 databases was performed up to June 2014; randomized controlled trials which compared acupuncture therapy and placebo treatment or pharmacological therapy were identified. A meta-analysis was conducted. Results. This review included 21 RCTs and a total of 1590 subjects. The overall methodological qualities were low. The results of meta-analysis showed that acupuncture therapy was more effective for clinical efficacy when compared with placebo or pharmacological treatment. Adverse events associated with acupuncture therapy were not documented. Conclusion. Based on the findings of this study, we cautiously suggest that acupuncture therapy could improve the clinical efficacy. However, the beneficial effect of acupuncture might be overstated due to low methodological qualities. Rigorous high quality RCTs are urgently needed.
PMCID: PMC4488007  PMID: 26167190
21.  Alternative splicing of VEGFA, APP and NUMB genes in colorectal cancer 
AIM: To investigate alternative splicing in vascular endothelial growth factor A (VEGFA), amyloid beta precursor protein (APP), and Numb homolog (NUMB) in colorectal cancer (CRC).
METHODS: Real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and PCR-restriction fragment length polymorphism analyses were performed to detect the expression of VEGFA, APP, and NUMB mRNA in 20 CRC tissues and matched adjacent normal tissues, as well as their alternative splicing variants.
RESULTS: qRT-PCR analysis revealed that the expression of APP, NUMB, and VEGFA165b mRNA were significantly downregulated, while VEGFA mRNA was upregulated, in CRC tissues (all P < 0.05). PCR-restriction fragment length polymorphism analysis revealed that the expression of VEGFA165a/b in CRC tissues was significantly higher than in adjacent normal tissues (P < 0.05). Compared with adjacent normal tissues, the expression of NUMB-PRRS in CRC tissues was significantly decreased (P < 0.05), and the expression of NUMB-PRRL was increased (P < 0.05).
CONCLUSION: Alternative splicing of VEGFA, APP, and NUMB may regulate the development of CRC, and represent new targets for its diagnosis, prognosis, and treatment.
PMCID: PMC4458765  PMID: 26074693
Alternative splicing; Amyloid beta precursor protein; Colorectal cancer; Numb homolog; Vascular endothelial growth factor A
22.  A Convenient In-Situ Synthesis of Alkenyl Tetrazines for Highly Fluorogenic Bioorthogonal Live-Cell Imaging Probes** 
In spite of the wide application potential of 1,2,4,5-tetrazines, particularly in live-cell and in-vivo imaging, a major limitation has been the lack of practical synthetic methods. Here we report the in situ synthesis of (E)-3-substituted-6-alkenyl-1,2,4,5-tetrazine derivatives via an elimination-Heck cascade reaction. Using this strategy, we provide 24 examples of π-conjugated tetrazine derivatives that can be conveniently prepared from tetrazine building blocks and related halides. These include tetrazine analogs of biological small molecules, highly conjugated buta-1,3-diene substituted tetrazines, and a diverse array of fluorescent probes suitable for live-cell imaging. These highly conjugated probes show dramatic fluorescent turn-on (up to 400-fold) when reacted with dienophiles such as cyclopropenes and trans-cyclooctenes, and we demonstrate their application for live-cell imaging. This work provides an efficient and practical synthetic methodology for tetrazine derivatives and will facilitate the application of conjugated tetrazines, particularly as fluorogenic probes for live-cell imaging.
PMCID: PMC4104127  PMID: 24764312
bioorthogonal; fluorophore; cycloaddition; cellular imaging; heterocycle
23.  Clearance of Pneumocystis murina infection is not dependent on MyD88 
To determine if myeloid differentiation factor 88 (MyD88), which is necessary for signaling by most TLRs and IL-1Rs, is necessary for control of Pneumocystis infection, MyD88-deficient and wild-type mice were infected with Pneumocystis by exposure to infected seeder mice and were followed for up to 106 days. MyD88-deficient mice showed clearance of Pneumocystis and development of anti-Pneumocystis antibody responses with kinetics similar to wild-type mice. Based on expression levels of select genes, MyD88-deficient mice developed immune responses similar to wild-type mice. Thus, MyD88 and the upstream pathways that rely on MyD88 signaling are not required for control of Pneumocystis infection.
PMCID: PMC4071138  PMID: 24680862
Pneumocystis; PCP; MyD88; innate immunity; TLR
24.  Increase of EPA-derived hydroxy, epoxy and dihydroxy fatty acid levels in human plasma after a single dose of long-chain omega-3 PUFA 
Several supplementation studies with long-chain omega-3 polyunsaturated fatty acids (LC n-3 PUFA) describe an increase of EPA-derived hydroxy, epoxy and dihydroxy fatty acids in blood, while changes in levels of other LC n-3 and n-6 PUFA-derived oxylipins were minor. In order to investigate the kinetics of changes in oxylipin levels in response to LC n-3 PUFA ingestion, we conducted a single dose treatment study with healthy subjects.
Subjects and methods
In the present kinetic study, we compared patterns of hydroxy, epoxy and dihydroxy fatty acids in plasma of 6 healthy men before and after 6, 8, 24, and 48 h of fish oil (1008 mg EPA and 672 mg DHA) ingestion. Levels of EPA- as well as other LC PUFA-derived hydroxy, epoxy and dihydroxy fatty acids were analyzed in plasma by LC–MS. Additionally, levels of these oxylipins were compared with their parent PUFA levels in plasma phospholipids.
All EPA-derived oxylipin levels were significantly increased 6 h after LC n-3 PUFA ingestion and gradually drop thereafter reaching the baseline levels about 48 h after treatment. The relative increase in EPA plasma phospholipid levels highly correlated with the increase of plasma EPA-derived oxylipin levels at different time points. In contrast, plasma levels of arachidonic acid- and DHA-derived oxylipins as well as parent PUFA levels in plasma phospholipids were hardly changed.
Discussion and conclusions
Our findings demonstrate that a single dose of LC n-3 PUFAs can rapidly induce a shift in the EPA oxylipin profile of healthy subjects within a few hours. Taking the high biological activity of the EPA-derived epoxy fatty acids into account, even short-term treatment with LC n-3 PUFAs may cause systemic effects, which warrant further investigation.
PMCID: PMC4172375  PMID: 24667634
Oxylipins; Eicosanoids; Arachidonic acid; Eicosapentaenoic acid
25.  Are Podoplanin Gene Polymorphisms Associated with Atopic Dermatitis in Koreans? 
Annals of Dermatology  2015;27(3):275-282.
The histologic characteristics of atopic dermatitis (AD) include perivascular edema and dilated tortuous vessels in the papillary dermis. A single nucleotide polymorphism (SNP) of the fms-related tyrosine kinase 4 (FLT4) gene is associated with AD.
To investigate the associations between podoplanin (PDPN) gene SNPs and AD.
We genotyped 9 SNPs from 5 genes of 1,119 subjects (646 AD patients and 473 controls). We determined the promoter activity of 1 SNP (rs355022) by luciferase assay; this SNP was further investigated using 1,133 independent samples (441 AD patients and 692 controls).
The rs355022 and rs425187 SNPs and the C-A haplotype in the PDPN gene were significantly associated with intrinsic AD in the initial experiment. The rs355022 SNP significantly affected promoter activity in the luciferase assay. However, these results were not replicated in the replication study.
Two SNPs and the C-A haplotype in the PDPN gene are significantly associated with intrinsic AD; although, the results were confirmed by luciferase assay, they could not be replicated with independent samples. Nevertheless, further replication experiments should be performed in future studies.
PMCID: PMC4466280  PMID: 26082584
Atopic dermatitis; Luciferases; Podoplanin protein; Genetic polymorphisms

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