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2.  Aberrant Gene Expression in Humans 
PLoS Genetics  2015;11(1):e1004942.
Gene expression as an intermediate molecular phenotype has been a focus of research interest. In particular, studies of expression quantitative trait loci (eQTL) have offered promise for understanding gene regulation through the discovery of genetic variants that explain variation in gene expression levels. Existing eQTL methods are designed for assessing the effects of common variants, but not rare variants. Here, we address the problem by establishing a novel analytical framework for evaluating the effects of rare or private variants on gene expression. Our method starts from the identification of outlier individuals that show markedly different gene expression from the majority of a population, and then reveals the contributions of private SNPs to the aberrant gene expression in these outliers. Using population-scale mRNA sequencing data, we identify outlier individuals using a multivariate approach. We find that outlier individuals are more readily detected with respect to gene sets that include genes involved in cellular regulation and signal transduction, and less likely to be detected with respect to the gene sets with genes involved in metabolic pathways and other fundamental molecular functions. Analysis of polymorphic data suggests that private SNPs of outlier individuals are enriched in the enhancer and promoter regions of corresponding aberrantly-expressed genes, suggesting a specific regulatory role of private SNPs, while the commonly-occurring regulatory genetic variants (i.e., eQTL SNPs) show little evidence of involvement. Additional data suggest that non-genetic factors may also underlie aberrant gene expression. Taken together, our findings advance a novel viewpoint relevant to situations wherein common eQTLs fail to predict gene expression when heritable, rare inter-individual variation exists. The analytical framework we describe, taking into consideration the reality of differential phenotypic robustness, may be valuable for investigating complex traits and conditions.
Author Summary
The uniqueness of individuals is due to differences in the combination of genetic, epigenetic and environmental determinants. Understanding the genetic basis of phenotypic variation is a key objective in genetics. Gene expression has been considered as an intermediate phenotype, and the association between gene expression and commonly-occurring genetic variants in the general population has been convincingly established. However, there are few methods to assess the impact of rare genetic variants, such as private SNPs, on gene expression. Here we describe a systematic approach, based on the theory of multivariate outlier detection, to identify individuals that show unusual or aberrant gene expression, relative the rest of the study cohort. Through characterizing detected outliers and corresponding gene sets, we are able to identify which gene sets tend to be aberrantly expressed and which individuals show deviant gene expression within a population. One of our major findings is that private SNPs may contribute to aberrant expression in outlier individuals. These private SNPs are more frequently located in the enhancer and promoter regions of genes that are aberrantly expressed, suggesting a possible regulatory function of these SNPs. Overall, our results provide new insight into the determinants of inter-individual variation, which have not been evaluated by large population-level cohort studies.
PMCID: PMC4305293  PMID: 25617623
3.  Carpal Tunnel Syndrome Assessment with Ultrasonography: Value of Inlet-to-Outlet Median Nerve Area Ratio in Patients versus Healthy Volunteers 
PLoS ONE  2015;10(1):e0116777.
To evaluate the diagnostic value of the Inlet-to-outlet median nerve area ratio (IOR) in patients with clinically and electrophysiologically confirmed carpal tunnel syndrome (CTS).
Forty-six wrists in 46 consecutive patients with clinical and electrodiagnostic evidence of CTS and forty-four wrists in 44 healthy volunteers were examined with ultrasonography. The cross-sectional area (CSA) of the median nerve was measured at the carpal tunnel inlet (the level of scaphoid-pisiform) and outlet (the level of the hook of the hamate), and the IOR was calculated for each wrist. Ultrasonography and electrodiagnostic tests were performed under blinded conditions. Electrodiagnostic testing combined with clinical symptoms were considered to be the gold standard test. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic value between the inlet CSA and IOR.
The study population included 16 men and 30 women (mean age, 45.3 years; range, 18–83 years). The control population included 18 men and 26 women (mean age, 50.4 years; range, 18–79 years). The mean inlet CSA was 8.7 mm2 in healthy controls and 14.6mm2 in CTS group (P<0.001). The mean IOR in healthy volunteers (1.0) was smaller than that in patients (1.6, P<0.001). Receiver operating characteristic analysis revealed a diagnostic advantage to using the IOR rather than the inlet CSA (P<0.01). An IOR cutoff value of ≥ 1.3 would yield 93% specificity and 91% sensitivity in the diagnosis of CTS.
The IOR of median nerve area promises to be an effective means in the diagnosis of CTS. A large-scale, randomized controlled trial is required to determine how and when this parameter will be used.
PMCID: PMC4305299  PMID: 25617835
4.  Association between epidermal growth factor receptor mutations and the expression of excision repair cross-complementing protein 1 and ribonucleotide reductase subunit M1 mRNA in patients with non-small cell lung cancer 
The present study aimed to investigate the association between epidermal growth factor receptor (EGFR) gene mutations and excision repair cross-complementing protein 1 (ERCC1) and ribonucleotide reductase subunit M1 (RRM1) mRNA expression in non-small cell lung cancer (NSCLC) tissue. The quantitative polymerase chain reaction was used to detect EGFR mutations, and ERCC1 and RRM1 mRNA expression in 257 cases of NSCLC. In the NSCLC samples the EGFR mutation rate was 49.03% (126/257). The rate was higher in females and non-smoking patients (P<0.05). High expression of ERCC1 mRNA was observed in 47.47% of the samples (122/257), while a high RRM1 mRNA expression was observed in 61.87% of the samples (159/257). In comparison with patients with NSCLC without EGFR mutations, patients with EGFR mutations had significantly lower levels of ERCC1 mRNA expression (P<0.05); however, EGFR mutations and expression levels of RRM1 mRNA were not correlated in NSCLC tissues (P>0.05). In addition, ERCC1 mRNA expression was not correlated with the expression levels of RRM1 mRNA (P>0.05). In conclusion, patients with NSCLC with EGFR mutations tend to have a low expression of ERCC1 mRNA and may potentially benefit from platinum-based chemotherapy.
PMCID: PMC4316980  PMID: 25667646
non-small cell lung cancer; epidermal growth factor receptor; excision repair cross-complementing protein 1; ribonucleotide reductase subunit M1; molecular detection; individualized treatment
5.  Transgenic Mice Overexpressing Amyloid Precursor Protein Exhibit Early Metabolic Deficits and a Pathologically Low Leptin State Associated with Hypothalamic Dysfunction in Arcuate Neuropeptide Y Neurons 
The Journal of Neuroscience  2014;34(27):9096-9106.
Weight loss is a prominent early feature of Alzheimer's disease (AD) that often precedes the cognitive decline and clinical diagnosis. While the exact pathogenesis of AD remains unclear, accumulation of amyloid-β (Aβ) derived from the amyloid precursor protein (APP) in the brain is thought to lead to the neuronal dysfunction and death underlying the dementia. In this study, we examined whether transgenic mice overexpressing the Swedish mutation of APP (Tg2576), recapitulating selected features of AD, have hypothalamic leptin signaling dysfunction leading to early body weight deficits. We found that 3-month-old Tg2576 mice, before amyloid plaque formation, exhibit decreased weight with markedly decreased adiposity, low plasma leptin levels, and increased energy expenditure without alterations in feeding behavior. The expression of the orexigenic neuropeptide Y (NPY) in the hypothalamus to the low leptin state was abnormal at basal and fasting conditions. In addition, arcuate NPY neurons exhibited abnormal electrophysiological responses to leptin in Tg2576 hypothalamic slices or wild-type slices treated with Aβ. Finally, the metabolic deficits worsened as Tg2576 mice aged and amyloid burden increased in the brain. These results indicate that excess Aβ can potentially disrupt hypothalamic arcuate NPY neurons leading to weight loss and a pathologically low leptin state early in the disease process that progressively worsens as the amyloid burden increases. Collectively, these findings suggest that weight loss is an intrinsic pathological feature of Aβ accumulation and identify hypothalamic leptin signaling as a previously unrecognized pathogenic site of action for Aβ.
PMCID: PMC4078086  PMID: 24990930
Alzheimer's disease; amyloid; hypothalamus; leptin; NPY
6.  Protective Effects of Lactobacillus plantarum CCFM8610 against Chronic Cadmium Toxicity in Mice Indicate Routes of Protection besides Intestinal Sequestration 
Applied and Environmental Microbiology  2014;80(13):4063-4071.
Our previous study confirmed the ability of Lactobacillus plantarum CCFM8610 to protect against acute cadmium (Cd) toxicity in mice. This study was designed to evaluate the protective effects of CCFM8610 against chronic Cd toxicity in mice and to gain insights into the protection mode of this strain. Experimental mice were divided into two groups and exposed to Cd for 8 weeks via drinking water or intraperitoneal injection. Both groups were further divided into four subgroups, control, Cd only, CCFM8610 only, and Cd plus CCFM8610. Levels of Cd were measured in the feces, liver, and kidneys, and alterations of several biomarkers of Cd toxicity were noted. The results showed that when Cd was introduced orally, cotreatment with Cd and CCFM8610 effectively decreased intestinal Cd absorption, reduced Cd accumulation in tissue, alleviated tissue oxidative stress, reversed hepatic and renal damage, and ameliorated the corresponding histopathological changes. When Cd was introduced intraperitoneally, administration of CCFM8610 did not have an impact on tissue Cd accumulation or reverse the activities of antioxidant enzymes. However, CCFM8610 still offered protection against oxidative stress and reversed the alterations of Cd toxicity biomarkers and tissue histopathology. These results suggest that CCFM8610 is effective against chronic cadmium toxicity in mice. Besides intestinal Cd sequestration, CCFM8610 treatment offers direct protection against Cd-induced oxidative stress. We also provide evidence that the latter is unlikely to be mediated via protection against Cd-induced alteration of antioxidant enzyme activities.
PMCID: PMC4054212  PMID: 24771031
7.  Association of the four common polymorphisms in interleukin-10 (rs1800890, rs1800896, rs1800871, and rs1800872) with non-Hodgkin’s lymphoma risk: a meta-analysis 
Interleukin-10 (IL-10) single nucleotide polymorphisms (SNPs) have been indicated to be correlated with Non-Hodgkin’s lymphoma (NHL) susceptibility. However, the results of these studies on the association remain inconsistent. This meta-analysis was conducted to derive a more accuracy estimation of the association between the common SNPs (rs1800890, rs1800896, rs1800871 and rs1800872) in IL-10 and NHL risk. Meta-analyses were performed on 21 studies with 7,749 cases and 8584 controls. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the NHL risk. Meta-analyses showed that rs1800890, rs1800871 and rs1800872 polymorphisms had no association with NHL risk. However, rs1800896 polymorphism has association with NHL risk based on the following comparison models (G vs. A: OR = 1.14, 95% CI = 1.00-1.29; AG vs. AA: OR = 1.20, 95% CI = 1.05-1.37; GG+AG vs. AA: OR = 1.22, 95% CI = 1.08-1.39). In the ethnic subgroup analysis, rs1800896 had an increased NHL risk in Caucasians based on the heterozygote model (OR = 1.21, 95% CI = 1.04-1.41) and dominant model (OR = 1.22, 95% CI = 1.00-1.48). When stratified by subtypes, rs1800890, rs1800896 and rs1800872 polymorphisms were found significant association with an increased risk of diffuse large B-cell Lymphoma (DLBCL) in different comparison models, whereas negative results were obtained for Follicular Lymphoma (FL) and chronic lymphocytic Leukemia/small lymphocytic Lymphoma (CLL/SLL) in all genetic models. Our meta-analysis suggested that the rs1800896 polymorphism had an increased risk with NHL susceptibility, where as the rs1800890, rs1800871 and rs1800872 had no association with NHL risk. Among the common subtypes of NHL, three polymorphisms (rs1800890, rs1800896 and rs1800872) had significant association with DLBCL risk.
PMCID: PMC4307416  PMID: 25663969
Non-Hodgkin’s lymphoma; interleukin-10; polymorphism; meta-analysis
8.  Risk factors related to persistent airflow obstruction in severe asthma in Chinese Han population 
Objective: To explore the significance of assessing persistent airway obstruction (PAO) in asthma patients by airway wall remodeling with bronchoscopy, high-resolution computed tomography (HRCT), and biological markers in the induced sputum and serum, exhaled nitric oxide (FENO), and lung function. Methods: The study was conducted in 119 patients with PAO and 125 patients with reversible airway obstruction (RAO). Endobronchial biopsy specimens were analyzed for airway smooth muscle (ASM) area, and reticular basement membrane (RBM) thickness. Airway thickness was also measured by HRCT scanning. Levels of matrix metalloproteases-9 (MMP-9), metalloproteinase 33 (ADAM33), and vascular endothelial growth factor (VEGF) were measured in the induced sputum and serum by enzyme linked immunosorbent assay. Result: PAO was associated with longer disease duration, absence of atopy and rhinitis, and larger ASM area (SMA%) (15.83%±2.32% [n=9] vs. 8.0%±1.68% [n=7], P=0.02), thicker RBM (16.27±2.32 μm [n=9] vs. 8.71±2.41 μm [n=7], P=0.042); No differences in any of the biomarker molecules measured in airway thickness in HRCT, sputum and blood individually between groups were found. Conclusion: Severe asthma patients with longer disease duration and the absence of atopy and rhinitis are more likely to develop PAO in Chines Han population. PAO patients have increased ASM area and RBM thickness appear to be valuable in the evaluation of airway remodeling in asthma patients in Chinese Han population.
PMCID: PMC4307496  PMID: 25664049
Bronchoscopy; high-resolution computed tomography (HRCT); persistent airway obstruction (PAO); reversible airway obstruction (RAO)
9.  Transcutaneous Intraluminal Impedance Measurement for Minimally Invasive Monitoring of Gastric Motility: Validation in Acute Canine Models 
Transcutaneous intraluminal impedance measurement (TIIM) is a new method to cutaneously measure gastric contractions by assessing the attenuation dynamics of a small oscillating voltage emitted by a battery-powered ingestible capsule retained in the stomach. In the present study, we investigated whether TIIM can reliably assess gastric motility in acute canine models. Methods. Eight mongrel dogs were randomly divided into 2 groups: half received an active TIIM pill and half received an identically sized sham capsule. After 24-hour fasting and transoral administration of the pill (active or sham), two force transducers (FT) were sutured onto the antral serosa at laparotomy. After closure, three standard cutaneous electrodes were placed on the abdomen, registering the transluminally emitted voltage. Thirty-minute baseline recordings were followed by pharmacological induction of gastric contractions using neostigmine IV and another 30-minute recording. Normalized one-minute baseline and post-neostigmine gastric motility indices (GMIs) were calculated and Pearson correlation coefficients (PCCs) between cutaneous and FT GMIs were obtained. Statistically significant GMI PCCs were seen in both baseline and post-neostigmine states. There were no significant GMI PCCs in the sham capsule test. Further chronic animal studies of this novel long-term gastric motility measurement technique are needed before testing it on humans.
PMCID: PMC4276285  PMID: 25574163
10.  Sustained activation of c-Jun N-terminal and extracellular signal-regulated kinases in port-wine stain blood vessels 
Port-wine stain (PWS) is a congenital, progressive vascular malformation but the pathogenesis remains incompletely understood.
We sought to investigate the activation status of various kinases, including extracellular signal-regulated kinase, c-Jun N-terminal kinase, AKT, phosphatidylinositol 3-kinase, P70 ribosomal S6 kinase, and phosphoinositide phospholipase C γ subunit, in PWS biopsy tissues.
Immunohistochemistry was performed on 19 skin biopsy samples from 11 patients with PWS.
c-Jun N-terminal kinase, extracellular signal-regulated kinase, and P70 ribosomal S6 kinase in pediatric and adult PWS blood vessels were consecutively activated. Activation of AKT and phosphatidylinositol 3-kinase was found in many adult hypertrophic PWS blood vessels but not in infants. Phosphoinositide phospholipase C γ subunit showed strong activation in nodular PWS blood vessels.
Infantile PWS sample size was small.
Our data suggest a subsequent activation profile of various kinases during different stages of PWS: (1) c-Jun N-terminal and extracellular signal-regulated kinases are firstly and consecutively activated in all PWS tissues, which may contribute to both the pathogenesis and progressive development of PWS; (2) AKT and phosphatidylinositol 3-kinase are subsequently activated, and are involved in the hypertrophic development of PWS blood vessels; and (3) phosphoinositide phospholipase C γ subunit is activated in the most advanced stage of PWS and may participate in nodular formation.
PMCID: PMC4250318  PMID: 25135651
AKT; c-Jun N-terminal kinase; extracellular signal-regulated kinase; mitogen-activated protein kinase; port-wine stain; vascular malformation
11.  Modeling the mitochondrial cardiomyopathy of Barth syndrome with iPSC and heart-on-chip technologies 
Nature medicine  2014;20(6):616-623.
Studying monogenic mitochondrial cardiomyopathies may yield insights into mitochondrial roles in cardiac development and disease. Here, we combine patient-derived and genetically engineered iPSCs with tissue engineering to elucidate the pathophysiology underlying the cardiomyopathy of Barth syndrome (BTHS), a mitochondrial disorder caused by mutation of the gene Tafazzin (TAZ). Using BTHS iPSC-derived cardiomyocytes (iPSC-CMs), we defined metabolic, structural, and functional abnormalities associated with TAZ mutation. BTHS iPSC-CMs assembled sparse and irregular sarcomeres, and engineered BTHS “heart on chip” tissues contracted weakly. Gene replacement and genome editing demonstrated that TAZ mutation is necessary and sufficient for these phenotypes. Sarcomere assembly and myocardial contraction abnormalities occurred in the context of normal whole cell ATP levels. Excess levels of reactive oxygen species mechanistically linked TAZ mutation to impaired cardiomyocyte function. Our study provides new insights into the pathogenesis of Barth syndrome, suggests new treatment strategies, and advances iPSC-based in vitro modeling of cardiomyopathy.
PMCID: PMC4172922  PMID: 24813252
12.  The differential susceptibilities of MCF-7 and MDA-MB-231 cells to the cytotoxic effects of curcumin are associated with the PI3K/Akt-SKP2-Cip/Kips pathway 
Cancer Cell International  2014;14(1):126.
The mechanism underlying the differential cytotoxicity of curcumin in various cancer types, however, remains largely unclear. The aims of this study is to examine the concentration- and time-related effects of curcumin on two different breast cancer cells, MCF-7 and MDA-MB-231, and investigated the functional changes induced by curcumin treatment, as well as their relationship to the PI3K/Akt-SKP2-Cip/Kips pathway.
First, WST-1 and clonogenic assay were performed to determine the cytotoxicity of curcumin in MCF-7 and MDA-MB-231 cells. Then, the expression of CDK interacting protein/Kinase inhibitory protein (Cip/Kips) members (p27, p21 and p57) and S-phase kinase-associated protein-2 (SKP2) was investigated by QRT PCR and Western Blotting. Curcumin’s effect on PI3K (phosphatidylinositol 3-kinase) /Akt and its substrates Foxo1 and Foxo3a were then studied by Western Blotting. Small interfering RNAs (siRNAs) targeting SKP2 was used to explore the relationship between SKP2 and Cip/Kips members. Finally, WST-1 assay was tested to explore the concomitant treatment with curcumin and the inhibition of PKB or SKP2 signaling on curcumin sensitivity in MCF-7 and MDA-MB-231 cells.
We demonstrated MCF-7 and MDA-MB-231 cells exhibited differential responses to curcumin by WST-1 and clonogenic assay (MDA-MB-231 cells was sensitive, and MCF-7 cells was resistant), which were found to be related to the differential curcumin-mediated regulation of SKP2-Cip/Kips (p21 and p27 but not p57) signaling. The differential cellular responses were further linked to the converse effects of curcumin on PI3K/Akt and its substrates Foxo1 and Foxo3a. Importantly, PI3K inhibitor wortmannin could counteract both curcumin-induced phosphorylation of Akt and up-regulation of SKP2 in MCF-7 cells. Subsequent WST-1 assay demonstrated concomitant treatment with curcumin and wortmannin or SKP2 siRNA not only further augmented curcumin sensitivity in MDA-MB-231 cells but also overcame curcumin resistance in MCF-7 cells.
Our study established PI3K/Akt-SKP2-Cip/Kips signaling pathway is involved in the mechanism of action of curcumin and revealed that the discrepant modulation of this pathway by curcumin is responsible for the differential susceptibilities of these two cell types to curcumin.
PMCID: PMC4272549  PMID: 25530715
Curcumin sensitivity; Breast cancer; PI3K; SKP2; FOXO; Cip/Kips
13.  Neural Substrates of View-Invariant Object Recognition Developed without Experiencing Rotations of the Objects 
The Journal of Neuroscience  2014;34(45):15047-15059.
One fails to recognize an unfamiliar object across changes in viewing angle when it must be discriminated from similar distractor objects. View-invariant recognition gradually develops as the viewer repeatedly sees the objects in rotation. It is assumed that different views of each object are associated with one another while their successive appearance is experienced in rotation. However, natural experience of objects also contains ample opportunities to discriminate among objects at each of the multiple viewing angles. Our previous behavioral experiments showed that after experiencing a new set of object stimuli during a task that required only discrimination at each of four viewing angles at 30° intervals, monkeys could recognize the objects across changes in viewing angle up to 60°. By recording activities of neurons from the inferotemporal cortex after various types of preparatory experience, we here found a possible neural substrate for the monkeys' performance. For object sets that the monkeys had experienced during the task that required only discrimination at each of four viewing angles, many inferotemporal neurons showed object selectivity covering multiple views. The degree of view generalization found for these object sets was similar to that found for stimulus sets with which the monkeys had been trained to conduct view-invariant recognition. These results suggest that the experience of discriminating new objects in each of several viewing angles develops the partially view-generalized object selectivity distributed over many neurons in the inferotemporal cortex, which in turn bases the monkeys' emergent capability to discriminate the objects across changes in viewing angle.
PMCID: PMC4220033  PMID: 25378169
monkey inferotemporal cortex; object; view invariance
14.  The Analysis of Hand Movement Distinction Based on Relative Frequency Band Energy Method 
BioMed Research International  2014;2014:781769.
For the purpose of successfully developing a prosthetic control system, many attempts have been made to improve the classification accuracy of surface electromyographic (SEMG) signals. Nevertheless, the effective feature extraction is still a paramount challenge for the classification of SEMG signals. The relative frequency band energy (RFBE) method based on wavelet packet decomposition was proposed for the prosthetic pattern recognition of multichannel SEMG signals. Firstly, the wavelet packet energy of SEMG signals in each subspace was calculated by using wavelet packet decomposition and the RFBE of each frequency band was obtained by the wavelet packet energy. Then, the principal component analysis (PCA) and the Davies-Bouldin (DB) index were used to perform the feature selection. Lastly, the support vector machine (SVM) was applied for the classification of SEMG signals. Our results demonstrated that the RFBE approach was suitable for identifying different types of forearm movements. By comparing with other classification methods, the proposed method achieved higher classification accuracy in terms of the classification of SEMG signals.
PMCID: PMC4238228  PMID: 25431766
15.  NUP98-PHF23 is a chromatin modifying oncoprotein that causes a wide array of leukemias sensitive to inhibition of PHD domain histone reader function 
Cancer discovery  2014;4(5):564-577.
In this report, we show that expression of a NUP98-PHF23 (NP23) fusion, associated with acute myeloid leukemia (AML) in humans, leads to myeloid, erythroid, T-cell, and B-cell leukemia in mice. The leukemic and pre-leukemic tissues display a stem cell-like expression signature including Hoxa, Hoxb, and Meis1 genes. The PHF23 PHD domain is known to bind H3K4me3 residues, and chromatin immunoprecipitation experiments demonstrated that the NP23 protein bound chromatin at a specific subset of H3K4me3 sites, including Hoxa, Hoxb, and Meis1. Treatment of NP23 cells with disulfiram, which inhibits the binding of PHD domains to H3K4me3 residues, rapidly and selectively killed NP23 myeloblasts; cell death was preceded by decreased expression of Hoxa, Hoxb, and Meis1. Furthermore, AML driven by a related fusion gene, NUP98-JARID1A (NJL), was also sensitive to disulfiram. Thus, the NP23 mouse provides a platform to evaluate compounds that disrupt binding of oncogenic PHD proteins to H3K4me3.
PMCID: PMC4018760  PMID: 24535671
NUP98-PHF23; AML; HOXA9; disulfiram; BAHCC1; NUP98-JARID1A; epigenetic therapy
16.  Tudor: a versatile family of histone methylation ‘readers’ 
Trends in biochemical sciences  2013;38(11):10.1016/j.tibs.2013.08.002.
The Tudor domain comprises a family of motifs that mediate protein-protein interactions required for various DNA-templated biological processes. Emerging evidence demonstrates a versatility of the Tudor family domains by identifying their specific interactions to a wide variety of histone methylation marks. Here, we discuss novel functions of a number of Tudor-containing proteins (including JMJD2A, 53BP1, SGF29, Spindlin1, UHRF1, PHF1, PHF19 and SHH1) in ‘reading’ unique methylation events on histones in order to facilitate DNA damage repair or regulate transcription. This review covers our recent understanding of the molecular bases for histone-Tudor interactions and their biological outcomes. As deregulation of Tudor-containing proteins is associated with certain human disorders, pharmacological targeting of Tudor interactions could provide new avenues for therapeutic intervention.
PMCID: PMC3830939  PMID: 24035451
histone methylation; epigenetic ‘reader’; Tudor domain; JMJD2A; 53BP1; SGF29; Spindlin1; UHRF1; PHF1; PHF19; SHH1
17.  A single-nucleotide polymorphism of miR-146a and psoriasis: an association and functional study 
Epidermal growth factor receptor (EGFR), which is overexpressed in psoriatic lesions, has been proven to contribute to the hyperproliferation of keratinocytes in psoriasis. Single nucleotide polymorphisms (SNPs) involved in miRNAs that can regulate the expression of EGFR could potentially influence the development of psoriasis. The present study investigated the association between a functional SNP of rs2910164 in miR-146a and the risk of psoriasis in the Chinese Han population. A total of 521 Han Chinese patients with psoriasis and 582 healthy controls were recruited in this study. The miR-146a rs2910164 SNP was genotyped by polymerase chain reaction-restriction fragment length polymorphism. Overall, a significantly increased risk of psoriasis was associated with the rs2910164 miR-146a CG and GG genotypes (adjusted OR, 1.38; 95% CI, 1.06–1.80). Furthermore, the rs2910164G allele in miR-146a attenuated its inhibitory regulation on the expression of EGFR as well as the proliferation of human keratinocytes, and lowered the level of miR-146a in the psoriatic lesions. These findings indicate that the rs2910164G allele in miR-146a weakens its suppression on the proliferation of keratinocytes probably through the decreased inhibition of the target gene, EGFR, which may account for the increased risk of psoriasis in this study population.
PMCID: PMC4224556  PMID: 25209759
psoriasis; microRNA; SNP; miR-146a; EGFR
18.  Paradoxical role of CBX8 in proliferation and metastasis of colorectal cancer 
Oncotarget  2014;5(21):10778-10790.
The effect of polycomb chromobox (Cbx) proteins in cancer is context-dependent. The Chromobox homolog 8 (CBX8) was originally characterized as a transcriptional repressor, which inhibits cell proliferation in Ink4a-Arf-dependent and -independent manner. However, the role of CBX8 in colorectal cancer remains unknown. Here, we found that high CBX8 expression was associated with a low rate of distant metastasis and good prognosis in CRC patients, even though CBX8 was up-regulated in CRC cell lines and clinical samples. Knockdown of CBX8 inhibited CRC proliferation in vitro and in vivo, mostly by increasing p53 and its downstream effectors. However, knockdown of CBX8 enhanced CRC migration, invasion and metastasis in vitro and in vivo, in part through direct up-regulation of integrin β4 (ITGB4) that in turn decreased RhoA activity. Collectively, the knockdown of CBX8 inhibited CRC proliferation, while promoting its metastasis, thus exerting paradoxical effects in CRC progression.
PMCID: PMC4279409  PMID: 25360999
CBX8; Polycomb Group protein; colorectal cancer; metastasis; proliferation; p53; integrin
19.  Proteomics of protein post-translational modifications implicated in neurodegeneration 
Mass spectrometry (MS)-based proteomics has developed into a battery of approaches that is exceedingly adept at identifying with high mass accuracy and precision any of the following: oxidative damage to proteins (redox proteomics), phosphorylation (phosphoproteomics), ubiquitination (diglycine remnant proteomics), protein fragmentation (degradomics), and other posttranslational modifications (PTMs). Many studies have linked these PTMs to pathogenic mechanisms of neurodegeneration. To date, identifying PTMs on specific pathology-associated proteins has proven to be a valuable step in the evaluation of functional alteration of proteins and also elucidates biochemical and structural explanations for possible pathophysiological mechanisms of neurodegenerative diseases. This review provides an overview of methods applicable to the identification and quantification of PTMs on proteins and enumerates historic, recent, and potential future research endeavours in the field of proteomics furthering the understanding of PTM roles in the pathogenesis of neurodegeneration.
PMCID: PMC4323146  PMID: 25671099
Proteomics; Protein posttranslational modifications; Neurodegeneration; Alzheimer’s disease; Parkinson’s disease
20.  Integrin β3 Is Required in Infection and Proliferation of Classical Swine Fever Virus 
PLoS ONE  2014;9(10):e110911.
Classical Swine Fever (CSF) is a highly infectious fatal pig disease, resulting in huge economic loss to the swine industry. Integrins are membrane-bound signal mediators, expressed on a variety of cell surfaces and are known as receptors or co-receptors for many viruses. However, the role of integrin β3 in CSFV infection is unknown. Here, through quantitive PCR, immunofluorescence (IFC) and immunocytohistochemistry (ICC), we revealed that ST (swine testicles epithelial) cells have a prominent advantage in CSFV proliferation as compared to EC (swine umbilical vein endothelial cell), IEC (swine intestinal epithelial cell) and PK (porcine kidney epithelial) cells. Meanwhile, ST cells had remarkably more integrin β3 expression as compared to EC, IEC and PK cells, which was positively correlated with CSFV infection and proliferation. Integrin β3 was up-regulated post CSFV infection in all the four cell lines, while the CSFV proliferation rate was decreased in integrin β3 function-blocked cells. ShRNA1755 dramatically decreased integrin β3, with a deficiency of 96% at the mRNA level and 80% at the protein level. CSFV proliferation was dramatically reduced in integrin β3 constantly-defected cells (ICDC), with the deficiencies of 92.6%, 99% and 81.7% at 24 h, 48 h and 72 h post CSFV infection, respectively. These results demonstrate that integrin β3 is required in CSFV infection and proliferation, which provide a new insight into the mechanism of CSFV infection.
PMCID: PMC4207786  PMID: 25340775
21.  Signature Gene Expression Reveals Novel Clues to the Molecular Mechanisms of Dimorphic Transition in Penicillium marneffei 
PLoS Genetics  2014;10(10):e1004662.
Systemic dimorphic fungi cause more than one million new infections each year, ranking them among the significant public health challenges currently encountered. Penicillium marneffei is a systemic dimorphic fungus endemic to Southeast Asia. The temperature-dependent dimorphic phase transition between mycelium and yeast is considered crucial for the pathogenicity and transmission of P. marneffei, but the underlying mechanisms are still poorly understood. Here, we re-sequenced P. marneffei strain PM1 using multiple sequencing platforms and assembled the genome using hybrid genome assembly. We determined gene expression levels using RNA sequencing at the mycelial and yeast phases of P. marneffei, as well as during phase transition. We classified 2,718 genes with variable expression across conditions into 14 distinct groups, each marked by a signature expression pattern implicated at a certain stage in the dimorphic life cycle. Genes with the same expression patterns tend to be clustered together on the genome, suggesting orchestrated regulations of the transcriptional activities of neighboring genes. Using qRT-PCR, we validated expression levels of all genes in one of clusters highly expressed during the yeast-to-mycelium transition. These included madsA, a gene encoding MADS-box transcription factor whose gene family is exclusively expanded in P. marneffei. Over-expression of madsA drove P. marneffei to undergo mycelial growth at 37°C, a condition that restricts the wild-type in the yeast phase. Furthermore, analyses of signature expression patterns suggested diverse roles of secreted proteins at different developmental stages and the potential importance of non-coding RNAs in mycelium-to-yeast transition. We also showed that RNA structural transition in response to temperature changes may be related to the control of thermal dimorphism. Together, our findings have revealed multiple molecular mechanisms that may underlie the dimorphic transition in P. marneffei, providing a powerful foundation for identifying molecular targets for mechanism-based interventions.
Author Summary
Penicillium marneffei is a significant dimorphic fungal pathogen capable of causing lethal systemic infections. It grows in a yeast-like form at mammalian body temperature and a mold-like form at ambient temperature. The thermal dimorphism of P. marneffei is closely related to its virulence. In the present study, we re-sequenced the genome of P. marneffei using Illumina and PacBio sequencing technologies, and simultaneously assembled these newly sequenced reads in different lengths with previously obtained Sanger sequences. This hybrid assembly greatly improved the quality of the genome sequences. Next, we used RNA-seq to measure the global gene expression of P. marneffei at different phases and during dimorphic phase transitions. We found that 27% of genes showed signature expression patterns, suggesting that these genes function at different stages in the life cycle of P. marneffei. Moreover, genes with same expression patterns tend to be clustered together as neighbors to each other in the genome, suggesting an orchestrated transcriptional regulation for multiple neighboring genes. Over-expression of the MADS-box transcription factor, madsA, located in one of these clusters, confirms the function of this gene in driving the yeast-to-mycelia phase transition irrespective of the temperature cues. Our data also implies diverse roles of secreted proteins and non-coding RNAs in dimorphic transition in P. marneffei.
PMCID: PMC4199489  PMID: 25330172
22.  Changes in the Mechanical Properties and Composition of Bone during Microdamage Repair 
PLoS ONE  2014;9(10):e108324.
Under normal conditions, loading activities result in microdamage in the living skeleton, which is repaired by bone remodeling. However, microdamage accumulation can affect the mechanical properties of bone and increase the risk of fracture. This study aimed to determine the effect of microdamage on the mechanical properties and composition of bone. Fourteen male goats aged 28 months were used in the present study. Cortical bone screws were placed in the tibiae to induce microdamage around the implant. The goats were euthanized, and 3 bone segments with the screws in each goat were removed at 0 days, 21 days, 4 months, and 8 months after implantation. The bone segments were used for observing microdamage and bone remodeling, as well as nanoindentation and bone composition, separately. Two regions were measured: the first region (R1), located 1.5 mm from the interface between the screw hole and bone; and the second region (R2), located>1.5 mm from the bone-screw interface. Both diffuse and linear microdamage decreased significantly with increasing time after surgery, with the diffuse microdamage disappearing after 8 months. Thus, screw implantation results in increased bone remodeling either in the proximal or distal cortical bone, which repairs the microdamage. Moreover, bone hardness and elastic modulus decreased with microdamage repair, especially in the proximal bone tissue. Bone composition changed greatly during the production and repair of microdamage, especially for the C (Carbon) and Ca (Calcium) in the R1 region. In conclusion, the presence of mechanical microdamage accelerates bone remodeling either in the proximal or distal cortical bone. The bone hardness and elastic modulus decreased with microdamage repair, with the micromechanical properties being restored on complete repair of the microdamage. Changes in bone composition may contribute to changes in bone mechanical properties.
PMCID: PMC4196754  PMID: 25313565
23.  Misdiagnosis of bilateral tubal pregnancy: a case report 
The incidence of bilateral tubal pregnancy is rising due to the increase of pelvic inflammatory disease and assisted reproductive techniques. Because the clinical manifestations of bilateral tubal pregnancy are not specific, we often ignore inspection of the other fallopian tube when focusing on the lesions, which may cause misdiagnosis.
Case presentation
A 33-year-old Chinese woman presented with vaginal bleeding after menopause and with an abnormality found by transvaginal ultrasound scan for which she underwent laparoscopy and salpingectomy. Unfortunately, she had to undergo a repetitive laparoscopic salpingotomy for the other tubal pregnancy due to misdiagnosis of her bilateral tubal pregnancy.
The incidence of unusual presentations of ectopic pregnancies has risen. Surgeons should always keep in mind the possibility of bilateral tubal pregnancy. An attentive examination of the pelvis, especially the two fallopian tubes, is necessary to avoid missing bilateral tubal pregnancy.
PMCID: PMC4198979  PMID: 25312677
Bilateral tubal pregnancy; Laparoscopy; Misdiagnosis
24.  Effects of Temperature on Chronic Trapezius Myofascial Pain Syndrome during Dry Needling Therapy 
The purpose of this study was to investigate the effects of temperature on chronic trapezius myofascial pain syndrome during dry needling therapy. Sixty patients were randomized into two groups of dry needling (DN) alone (group A) and DN combined with heat therapy group (group B). Each patient was treated once and the therapeutic effect was assessed by the visual analogue scale (VAS), pressure pain threshold (PPT), and the 36-item short form health survey (SF-36) at seven days, one month, and three months after treatment. Evaluation based on VAS and PPT showed that the pain of patients in groups A and B was significantly (P < 0.05) relieved at seven days, one month, and three months after treatment Compared to before treatment. There was significantly (P < 0.05) less pain in group B than group A at one and three months after treatment. The SF-36 evaluation demonstrated that the physical condition of patients in both groups showed significant (P < 0.05) improvement at one month and three months after treatment than before treatment. Our study suggests that both DN and DN heating therapy were effective in the treatment of trapezius MPS, and that DN heating therapy had better long-term effects than DN therapy.
PMCID: PMC4212540  PMID: 25383083
25.  Cantharidin induces G2/M phase arrest and apoptosis in human gastric cancer SGC-7901 and BGC-823 cells 
Oncology Letters  2014;8(6):2721-2726.
The aim of the present study was to investigate the effect of cantharidin (CTD) on human gastric cancer cells and to explore the underlying mechanisms of these effects. The human gastric cancer SGC-7901 and BGC-823 cell lines were treated with CTD. MTS assays were then employed to examine cellular proliferation, flow cytometry was used to analyze the cell cycle and apoptosis, and western blot analysis was used to determine protein expression levels. It was found that CTD inhibited the proliferation of the human gastric cancer SGC-7901 and BGC-823 cells in a dose- and time-dependent manner in vitro. CTD also induced G2/M phase arrest and cellular apoptosis in a dose-dependent manner. In addition, CTD increased the levels of p21, caspase-7, -8 and -9, activated caspase-3, poly ADP ribose polymerase and Bad, but decreased the levels of cyclin-dependent kinase 1, cyclin A and B, B-cell lymphoma-2 (Bcl-2) and Bid. The present results suggested that CTD may inhibit the proliferation of human gastric cancer SGC-7901 and BGC-823 cells in vitro by inducing G2/M phase arrest and cell apoptosis. CTD may induce cellular G2/M phase arrest by regulating cycle-associated proteins and induce apoptosis by activating a caspase cascade or regulating the Bcl-2 family proteins.
PMCID: PMC4214476  PMID: 25364455
cantharidin; gastric cancer; G2/M phase arrest; apoptosis; caspase; Bcl-2 family

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