PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (50)
 

Clipboard (0)
None

Select a Filter Below

Year of Publication
1.  Genetic Analysis Identifies DDR2 as a Novel Gene Affecting Bone Mineral Density and Osteoporotic Fractures in Chinese Population 
PLoS ONE  2015;10(2):e0117102.
DDR2 gene, playing an essential role in regulating osteoblast differentiation and chondrocyte maturation, may influence bone mineral density (BMD) and osteoporosis, but the genetic variations actually leading to the association remain to be elucidated. Therefore, the aim of this study was to investigate whether the genetic variants in DDR2 are associated with BMD and fracture risk. This study was performed in three samples from two ethnicities, including 1,300 Chinese Han subjects, 700 Chinese Han subjects (350 with osteoporotic hip fractures and 350 healthy controls) and 2,286 US white subjects. Twenty-eight SNPs in DDR2 were genotyped and tested for associations with hip BMD and fractures. We identified 3 SNPs in DDR2 significantly associated with hip BMD in the Chinese population after multiple testing adjustments, which were rs7521233 (P = 1.06×10−4, β: −0.018 for allele C), rs7553831 (P = 1.30×10−4, β: −0.018 for allele T), and rs6697469 (P = 1.59×10−3, β: −0.015 for allele C), separately. These three SNPs were in high linkage disequilibrium. Haplotype analyses detected two significantly associated haplotypes, including one haplotype in block 2 (P = 9.54×10−4, β: −0.016) where these three SNPs located. SNP rs6697469 was also associated with hip fractures (P = 0.043, OR: 1.42) in the Chinese population. The effect on fracture risk was consistent with its association with lower BMD. However, in the white population, we didn’t observe significant associations with hip BMD. eQTL analyses revealed that SNPs associated with BMD also affected DDR2 mRNA expression levels in Chinese. Our findings, together with the prior biological evidence, suggest that DDR2 could be a new candidate for osteoporosis in Chinese population. Our results also reveal an ethnic difference, which highlights the need for further genetic studies in each ethnic group.
doi:10.1371/journal.pone.0117102
PMCID: PMC4319719  PMID: 25658585
2.  Attenuated Monocyte Apoptosis, a New Mechanism for Osteoporosis Suggested by a Transcriptome-Wide Expression Study of Monocytes 
PLoS ONE  2015;10(2):e0116792.
Background
Osteoporosis is caused by excessive bone resorption (by osteoclasts) over bone formation (by osteoblasts). Monocytes are important to osteoporosis by serving as progenitors of osteoclasts and produce cytokines for osteoclastogenesis.
Aim
To identify osteoporosis-related genes, we performed microarray analyses of monocytes using Affymetrix 1.0 ST arrays in 42 (including 16 pre- and 26 postmenopausal) high hip BMD (bone mineral density) vs. 31 (including 15 pre- and 16 postmenopausal) low hip BMD Caucasian female subjects. Here, high vs. low BMD is defined as belonging to top vs. bottom 30% of BMD values in population.
Method
Differential gene expression analysis in high vs. low BMD subjects was conducted in the total cohort as well as pre- and post-menopausal subjects. Focusing on the top differentially expressed genes identified in the total, the pre- and the postmenopausal subjects (with a p <5E-03), we performed replication of the findings in 3 independent datasets of microarray analyses of monocytes (total N = 125).
Results
We identified (in the 73 subjects) and successfully replicated in all the 3 independent datasets 2 genes, DAXX and PLK3. Interestingly, both genes are apoptosis induction genes and both down-regulated in the low BMD subjects. Moreover, using the top 200 genes identified in the meta-analysis across all of the 4 microarray datasets, GO term enrichment analysis identified a number of terms related to induction of apoptosis, for which the majority of component genes are also down-regulated in the low BMD subjects. Overall, our result may suggest that there might be a decreased apoptosis activity of monocytes in the low BMD subjects.
Conclusion
Our study for the first time suggested a decreased apoptosis rate (hence an increased survival) of monocytes, an important osteoclastogenic cell, as a novel mechanism for osteoporosis.
doi:10.1371/journal.pone.0116792
PMCID: PMC4319757  PMID: 25659073
3.  Determination of Total Tritium in Urine from Residents Living in the Vicinity of Nuclear Power Plants in Qinshan, China 
To estimate the tritium doses of the residents living in the vicinity of a nuclear power plant, urine samples of 34 adults were collected from residents living near the Qinshan nuclear power plant. The tritium-in-urine (HTO plus OBT) was measured by liquid scintillation counting. The doses of tritium-in-urine from participants living at 2, 10 and 22 km were in a range of 1.26–6.73 Bq/L, 1.31–3.09 Bq/L and 2.21–3.81 Bq/L, respectively, while the average activity concentrations of participants from the three groups were 3.53 ± 1.62, 2.09 ± 0.62 and 2.97 ± 0.78 Bq/L, respectively. The personal committed effective doses for males were 2.5 ± 1.7 nSv and for females they were 2.9 ± 1.3 nSv. These results indicate that tritium concentrations in urine samples from residents living at 2 km from a nuclear power plant are significantly higher than those at 10 km. It may be the downwind direction that caused a higher dose in participants living at 22 km. All the measured doses of tritium-in-urine are in a background level range.
doi:10.3390/ijerph120100888
PMCID: PMC4306899  PMID: 25602973
urine; tritium; concentration of tritium; committed effective dose
4.  SNP rs6265 Regulates Protein Phosphorylation and Osteoblast Differentiation and Influences BMD in Humans 
Bone Mineral Density (BMD) is major index for diagnosing osteoporosis. PhosSNPs are non-synonymous SNPs that affect protein phosphorylation. The relevance and significance of phosSNPs to BMD and osteoporosis is unknown. This study aims to identify and characterize phosSNPs significant for BMD in humans. We conducted a pilot genome-wide phosSNP association study for BMD in three independent population samples, involving ~5,000 unrelated individuals. We identified and replicated three phosSNPs associated with both spine BMD and hip BMD in Caucasians. Association with hip BMD for one of these phosSNPs, i.e., rs6265 (major/minor allele: G/A) in BDNF gene, was also suggested in Chinese. Consistently in both ethnicities, individuals carrying AA genotype have significant lower hip BMD than carriers of GA and GG genotypes. Through in vitro molecular and cellular studies, we found that compared to osteoblastic cells transfected with wild-type BDNF-Val66 (encoded with allele G at rs6265), transfection of variant BDNF-Met66 (encoded with allele A at rs6265) significantly decreased BDNF protein phosphorylation (at amino acid residue T62), expression of osteoblastic genes (OPN, BMP2, and ALP), and osteoblastic activity. The findings are consistent with and explain our prior observations in general human populations. We conclude that phosSNP rs6265, via regulating BDNF protein phosphorylation and osteoblast differentiation, influence hip BMD in humans. This study represents our first endeavor to dissect the functions of phosSNPs in bone, which might stimulate extended large-scale studies on bone or similar studies on other human complex traits and diseases.
doi:10.1002/jbmr.1997
PMCID: PMC4127979  PMID: 23712400
BMD; SNP; protein phosphorylation; BDNF; osteoblast
5.  Treatment of giant emphysamous bulla with endobronchial valves in patients with chronic obstructive pulmonary disease: a case series 
Journal of Thoracic Disease  2014;6(12):1674-1680.
Background
Giant emphysamtous bulla (GEB) can negatively affect the pulmonary functions of chronic obstructive pulmonary diseases (COPD) patients, including decreased forced expiratory volume in 1 s (FEV1) and increased functional residual capacity (FRC). The aim of this study was to evaluate the efficacy of endobronchial valve (EBV) to treat bullae and to find efficacy predictors of successful treatment.
Methods
Five COPD patients with giant bulla were treated using EBVs. Before the EBV deployment, collateral ventilation (CV) between the targeted and adjacent lobes was evaluated with Chartis system.
Results
In the two patients with negative CV, the mean value of FEV1 increased from 27.1±11.4% of predicted value before EBV treatment to 32.8±12.0% (P>0.05) at 1 month after EBV treatment, than to 31.7±24.5% (P>0.05) at 6 months after EBV treatment. Only one patient, whose bulla occupied the whole right middle lung, displayed sustained improvement of FEV1 at 6 months after EBV treatment. In the three patients with positive CV, the mean value of FEV1 decreased from 28.8±19.0% of predicted value before EBV treatment to 24.8±12.6% (P>0.05) at 1 month after EBV treatment, than to 22.1±10.8% (P>0.05) at 6 months after EBV treatment.
Conclusions
EBV is an effective measure to treat highly selected COPD patients with giant bulla. Although, EBV treatment can achieve transient improvement of lung function at patients with CV negative bulla, long-term benefit was merely observed at the patient with a bulla at right middle lobe (RML).
doi:10.3978/j.issn.2072-1439.2014.11.07
PMCID: PMC4283300  PMID: 25589959
Endobronchial valve (EBV); bulla; chronic obstructive pulmonary diseases (COPD); collateral ventilation (CV)
6.  Percutaneous Vertebroplasty of the Entire Thoracic and Lumbar Vertebrae for Vertebral Compression Fractures Related to Chronic Glucocorticosteriod Use: Case Report and Review of Literature 
Korean Journal of Radiology  2014;15(6):797-801.
Glucocorticosteroid-induced osteoporosis is the most frequent of all secondary types of osteoporosis, and can increase the risk of vertebral compression fractures (VCFs). There are promising additions to current medical treatment for appropriately selected osteoporotic patients. Few studies have reported on the efficiency of percutaneous vertebroplasty (PVP) or kyphoplasty for whole thoracic and lumbar glucocorticosteroid-induced osteoporotic vertebral compression fractures. We report a case of a 67-year-old man with intractable pain caused by successional VCFs treated by PVP.
doi:10.3348/kjr.2014.15.6.797
PMCID: PMC4248636  PMID: 25469092
Percutaneous vertebroplasty; Entire thoracic and lumber vertebra; Osteoporotic vertebral compression fractures; Steroids
7.  The promotion of bone healing by progranulin, a downstream molecule of BMP-2, through interacting with TNF/TNFR signaling 
Biomaterials  2013;34(27):6412-6421.
Endochondral ossification plays a key role in the bone healing process, which requires normal cartilage callus formation. Progranulin (PGRN) growth factor is known to enhance chondrocyte differentiation and endochondral ossification during development, yet whether PGRN also plays a role in bone regeneration remains unknown. In this study we established surgically-induced bone defect and ectopic bone formation models based on genetically-modified mice. Thereafter, the bone healing process of those mice was analyzed through radiological assays including X-ray and micro CT, and morphological analysis including histology and immunohistochemistry. PGRN deficiency delayed bone healing, while recombinant PGRN enhanced bone regeneration. Moreover, PGRN was required for BMP-2 induction of osteoblastogenesis and ectopic bone formation. Furthermore, the role of PGRN in bone repair was mediated, at least in part, through interacting with TNF-α signaling pathway. PGRN-mediated bone formation depends on TNFR2 but not TNFR1, as PGRN promoted bone regeneration in deficiency of TNFR1 but lost such effect in TNFR2 deficient mice. PGRN blocked TNF-α-induced inflammatory osteoclastogenesis and protected BMP-2 mediated ectopic bone formation in TNFα transgenic mice. Collectively, PGRN acts as a critical mediator of the bone healing process by constituting an interplay network with BMP-2 and TNF-α signaling, and this represents a potential molecular target for treatment of fractures, especially under inflammatory conditions.
doi:10.1016/j.biomaterials.2013.05.030
PMCID: PMC3713419  PMID: 23746860
progranulin; bone repair; BMP-2; TNF-α; endochondral ossification; bone resorption
8.  Gene-gene interaction between RBMS3 and ZNF516 influences bone mineral density 
Osteoporosis is characterized by low bone mineral density (BMD), a highly heritable trait that is determined, in part, by the actions and interactions of multiple genes. While an increasing number of genes have been identified to have independent effects on BMD, few studies have been performed to identify genes that interact with one another to affect BMD. In this study, we performed gene-gene interaction analyses in selected candidate genes in individuals with extremely high vs. low hip BMD (20% tails of the distributions), in two independent US Caucasian samples. The first sample contained 916 unrelated subjects with extreme hip BMD Z-scores selected from a population composed of 2,286 subjects. The second sample consisted of 400 unrelated subjects with extreme hip BMD Z-scores selected from a population composed of 1,000 subjects. Combining results from these two samples, we found one interacting gene pair (RBMS3 vs. ZNF516) which, even after Bonferroni correction for multiple testing, showed consistently significant effects on hip BMD. RMBS3 harbored two SNPs, rs6549904 and rs7640046, both of which had significant interactions with a SNP, rs4891159, located on ZNF516 (P values: 7.04×10−11 and 1.03×10−10). We further validated these results in two additional samples of Caucasian and African descent. The gene pair, RBMS3 vs. ZNF516, was successfully replicated in the Caucasian sample (P values: 8.07×10−3 and 2.91×10−3). For the African sample, a significant interaction was also detected (P values: 0.031 and 0.043), but the direction of the effect was opposite to that observed in the three Caucasian samples. By providing evidence for genetic interactions underlying BMD, this study further delineated the genetic architecture of osteoporosis.
doi:10.1002/jbmr.1788
PMCID: PMC4127986  PMID: 23045156
interaction; association; BMD; osteoporosis
9.  Mechanical Behaviour of Umbrella-Shaped, Ni-Ti Memory Alloy Femoral Head Support Device during Implant Operation: A Finite Element Analysis Study 
PLoS ONE  2014;9(6):e100765.
A new instrument used for treating femoral head osteonecrosis was recently proposed: the umbrella-shaped, Ni-Ti memory femoral head support device. The device has an efficacy rate of 82.35%. Traditional radiographic study provides limited information about the mechanical behaviour of the support device during an implant operation. Thus, this study proposes a finite element analysis method, which includes a 3-step formal head model construction scheme and a unique material assignment strategy for evaluating mechanical behaviour during an implant operation. Four different scenarios with different constraints, initial positions and bone qualities are analyzed using the simulation method. The max radium of the implanted device was consistent with observation data, which confirms the accuracy of the proposed method. To ensure that the device does not unexpectedly open and puncture the femoral head, the constraint on the impact device should be strong. The initial position of sleeve should be in the middle to reduce the damage to the decompression channel. The operation may fail because of poor bone quality caused by severe osteoporosis. The proposed finite element analysis method has proven to be an accurate tool for studying the mechanical behaviour of umbrella-shaped, Ni-Ti memory alloy femoral head support device during an implant operation. The 3-step construct scheme can be implemented with any kind of bone structure meshed with multiple element types.
doi:10.1371/journal.pone.0100765
PMCID: PMC4069114  PMID: 24960038
10.  Progranulin Deficiency Exaggerates, whereas Progranulin-derived Atsttrin Attenuates, Severity of Dermatitis in Mice 
FEBS letters  2013;587(12):1805-1810.
PGRN and its derived engineered protein, Atsttrin, were reported to antagonize TNFα and protect against inflammatory arthritis (Tang, W., et al, Science, 2011). Here we found that PGRN level was also significantly elevated in skin inflammation. PGRN−/− mice exhibited more severe inflammation following induction of oxazolone. In contrast, recombinant Atsttrin protein effectively attenuated inflammation in mice dermatitis model. In addition, the protective role of PGRN and Atsttrin in dermatitis was probably due to their inhibition on NF-κB signaling. Collectively, PGRN, especially its derived engineered protein, Atsttrin, may represent a potential molecular target for prevention and treatment of inflammatory skin diseases.
doi:10.1016/j.febslet.2013.04.037
PMCID: PMC3683372  PMID: 23669357
Progranulin; Atsttrin; dermatitis; NF-κB signaling
11.  Replication of 6 Obesity Genes in a Meta-Analysis of Genome-Wide Association Studies from Diverse Ancestries 
PLoS ONE  2014;9(5):e96149.
Obesity is a major public health problem with a significant genetic component. Multiple DNA polymorphisms/genes have been shown to be strongly associated with obesity, typically in populations of European descent. The aim of this study was to verify the extent to which 6 confirmed obesity genes (FTO, CTNNBL1, ADRB2, LEPR, PPARG and UCP2 genes) could be replicated in 8 different samples (n = 11,161) and to explore whether the same genes contribute to obesity-susceptibility in populations of different ancestries (five Caucasian, one Chinese, one African-American and one Hispanic population). GWAS-based data sets with 1000 G imputed variants were tested for association with obesity phenotypes individually in each population, and subsequently combined in a meta-analysis. Multiple variants at the FTO locus showed significant associations with BMI, fat mass (FM) and percentage of body fat (PBF) in meta-analysis. The strongest association was detected at rs7185735 (P-value = 1.01×10−7 for BMI, 1.80×10−6 for FM, and 5.29×10−4 for PBF). Variants at the CTNNBL1, LEPR and PPARG loci demonstrated nominal association with obesity phenotypes (meta-analysis P-values ranging from 1.15×10−3 to 4.94×10−2). There was no evidence of association with variants at ADRB2 and UCP2 genes. When stratified by sex and ethnicity, FTO variants showed sex-specific and ethnic-specific effects on obesity traits. Thus, it is likely that FTO has an important role in the sex- and ethnic-specific risk of obesity. Our data confirmed the role of FTO, CTNNBL1, LEPR and PPARG in obesity predisposition. These findings enhanced our knowledge of genetic associations between these genes and obesity-related phenotypes, and provided further justification for pursuing functional studies of these genes in the pathophysiology of obesity. Sex and ethnic differences in genetic susceptibility across populations of diverse ancestries may contribute to a more targeted prevention and customized treatment of obesity.
doi:10.1371/journal.pone.0096149
PMCID: PMC4039436  PMID: 24879436
12.  Characterization of the DNA methylome and its interindividual variation in human peripheral blood monocytes 
Epigenomics  2013;5(3):10.2217/epi.13.18.
Aim
Peripheral blood monocytes (PBMs) play multiple and critical roles in the immune response, and abnormalities in PBMs have been linked to a variety of human disorders. However, the DNA methylation landscape in PBMs is largely unknown. In this study, we characterized epigenome-wide DNA methylation profiles in purified PBMs.
Materials & methods
PBMs were isolated from freshly collected peripheral blood from 18 unrelated healthy postmenopausal Caucasian females. Epigenome-wide DNA methylation profiles (the methylome) were characterized by using methylated DNA immunoprecipitation combined with high-throughput sequencing.
Results
Distinct patterns were revealed at different genomic features. For instance, promoters were commonly (~58%) found to be unmethylated; whereas protein coding regions were largely (~84%) methylated. Although CpG-rich and -poor promoters showed distinct methylation patterns, interestingly, a negative correlation between promoter methylation levels and gene transcription levels was consistently observed across promoters with high to low CpG densities. Importantly, we observed substantial interindividual variation in DNA methylation across the individual PBM methylomes and the pattern of this interindividual variation varied between different genomic features, with highly variable regions enriched for repetitive DNA elements. Furthermore, we observed a modest but significant excess (p < 2.2 × 10−16) of genes showing a negative correlation between interindividual promoter methylation and transcription levels. These significant genes were enriched in biological processes that are closely related to PBM functions, suggesting that alteration in DNA methylation is likely to be an important mechanism contributing to the interindividual variation in PBM function, and PBM-related phenotypic and disease-susceptibility variation in humans.
Conclusion
This study represents a comprehensive analysis of the human PBM methylome and its interindividual variation. Our data provide a valuable resource for future epigenomic and multiomic studies, exploring biological and disease-related regulatory mechanisms in PBMs.
doi:10.2217/epi.13.18
PMCID: PMC3874233  PMID: 23750642
DNA methylation; interindividual variation; peripheral blood monocyte
13.  Neural Network L1 Adaptive Control of MIMO Systems with Nonlinear Uncertainty 
The Scientific World Journal  2014;2014:942094.
An indirect adaptive controller is developed for a class of multiple-input multiple-output (MIMO) nonlinear systems with unknown uncertainties. This control system is comprised of an L1 adaptive controller and an auxiliary neural network (NN) compensation controller. The L1 adaptive controller has guaranteed transient response in addition to stable tracking. In this architecture, a low-pass filter is adopted to guarantee fast adaptive rate without generating high-frequency oscillations in control signals. The auxiliary compensation controller is designed to approximate the unknown nonlinear functions by MIMO RBF neural networks to suppress the influence of uncertainties. NN weights are tuned on-line with no prior training and the project operator ensures the weights bounded. The global stability of the closed-system is derived based on the Lyapunov function. Numerical simulations of an MIMO system coupled with nonlinear uncertainties are used to illustrate the practical potential of our theoretical results.
doi:10.1155/2014/942094
PMCID: PMC3988860  PMID: 25147871
14.  Genome-Wide Association Study Identified Copy Number Variants Important for Appendicular Lean Mass 
PLoS ONE  2014;9(3):e89776.
Skeletal muscle is a major component of the human body. Age-related loss of muscle mass and function contributes to some public health problems such as sarcopenia and osteoporosis. Skeletal muscle, mainly composed of appendicular lean mass (ALM), is a heritable trait. Copy number variation (CNV) is a common type of human genome variant which may play an important role in the etiology of many human diseases. In this study, we performed genome-wide association analyses of CNV for ALM in 2,286 Caucasian subjects. We then replicated the major findings in 1,627 Chinese subjects. Two CNVs, CNV1191 and CNV2580, were detected to be associated with ALM (p = 2.26×10−2 and 3.34×10−3, respectively). In the Chinese replication sample, the two CNVs achieved p-values of 3.26×10−2 and 0.107, respectively. CNV1191 covers a gene, GTPase of the immunity-associated protein family (GIMAP1), which is important for skeletal muscle cell survival/death in humans. CNV2580 is located in the Serine hydrolase-like protein (SERHL) gene, which plays an important role in normal peroxisome function and skeletal muscle growth in response to mechanical stimuli. In summary, our study suggested two novel CNVs and the related genes that may contribute to variation in ALM.
doi:10.1371/journal.pone.0089776
PMCID: PMC3953533  PMID: 24626161
15.  Genome-Wide Association Study Identified UQCC Locus for Spine Bone Size in Humans 
Bone  2012;53(1):129-133.
Bone size (BS) contributes significantly to the risk of osteoporotic fracture. Osteoporotic spine fracture is one of the most disabling outcomes of osteoporosis. This study aims to identify genomic loci underlying spine BS variation in humans.
We performed a genome-wide association scan in 2,286 unrelated Caucasians using Affymetrix 6.0 SNP arrays. Areal BS (cm2) at lumbar spine was measured using dual energy X-ray absorptiometry scanners. SNPs of interest were subjected to replication analyses and meta-analyses with additional two independent Caucasian populations (N = 1,000 and 2,503) and one Chinese population (N = 1,627).
In the initial GWAS, 91 SNPs were associated with spine BS (P<1.0E-4). Eight contiguous SNPs were found clustering in a haplotype block within UQCC gene (ubiquinol-cytochrome creductase complex chaperone). Association of the above eight SNPs with spine BS were replicated in one Caucasian and one Chinese populations. Meta-analyses (N = 7,416) generated much stronger association signals for these SNPs (e.g., P = 1.86E-07 for SNP rs6060373), supporting association of UQCC with spine BS across ethnicities.
This study identified a novel locus, i.e., the UQCC gene, for spine BS variation in humans. Future functional studies will contribute to elucidating the mechanisms by which UQCC regulates bone growth and development.
doi:10.1016/j.bone.2012.11.028
PMCID: PMC3682469  PMID: 23207799
Spine bone size; GWAS; UQCC
16.  Suggestion of GLYAT gene underlying variation of bone size and body lean mass as revealed by a bivariate genome-wide association study 
Human genetics  2012;132(2):189-199.
Objective
Bone and muscle, two major tissue types of musculoskeletal system, have strong genetic determination. Abnormality in bone and/or muscle may cause musculoskeletal diseases such as osteoporosis and sarcopenia. Bone size phenotypes (BSPs), such as hip bone size (HBS), appendicular bone size (ABS), are genetically correlated with body lean mass (mainly muscle mass). However, the specific genes shared by these phenotypes are largely unknown. In this study, we aimed to identify the specific genes with pleiotropic effects on BSPs and appendicular lean mass (ALM).
Methods
We performed a bivariate genome-wide association study (GWAS) by analyzing ~690,000 SNPs in 1,627 unrelated Han Chinese adults (802 males and 825 females) followed by a replication study in 2,286 unrelated US Caucasians (558 males and 1728 females).
Results
We identified 14 interesting single nucleotide polymorphisms (SNPs) that may contribute to variation of both BSPs and ALM, with p values <10−6 in discovery stage. Among them, the association of three SNPs (rs2507838, rs7116722, and rs11826261) in/near GLYAT (glycine-N-acyltransferase) gene was replicated in US Caucasians, with p values ranging from 1.89×10−3 to 3.71×10−4 for ALM-ABS, from 5.14×10−3 to 1.11×10−2 for ALM-HBS, respectively. Meta-analyses yielded stronger association signals for rs2507838, rs7116722, and rs11826261, with pooled p values of 1.68×10−8, 7.94×10−8, 6.80×10−8 for ALB-ABS and 1.22×10−4, 9.85×10−5, 3.96×10−4 for ALM-HBS, respectively. Haplotype allele ATA based on these three SNPs were also associated with ALM-HBS and ALM-ABS in both discovery and replication samples. Interestingly, GLYAT was previously found to be essential to glucose metabolism and energy metabolism, suggesting the gene’s dual role in both bone development and muscle growth.
Conclusions
Our findings, together with the prior biological evidence, suggest the importance of GLYAT gene in co-regulation of bone phenotypes and body lean mass.
doi:10.1007/s00439-012-1236-5
PMCID: PMC3682481  PMID: 23108985
Bivariate GWAS; Bone size; Lean mass; GLYAT
17.  Total parenteral nutrition caused Wernicke’s encephalopathy accompanied by wet beriberi 
Patient: Female, 17
Final Diagnosis: Wernicke’s encephalopathy
Symptoms: Blurred vision • dizziness • nystygmus • tachycardia
Medication: —
Clinical Procedure: —
Specialty: Neurology
Objective:
Mistake in diagnosis
Background:
Wernicke’s encephalopathy (WE) is an acute and life-threatening illness which is not only seen in alcoholics, but also in persons with poor nutrition lacking thiamine (vitamin B1).
Case Report:
Here, we presented a case of WE in a patient who received parenteral nutrition without complement of thiamine. Besides neuropsychiatric problems, she also manifested prominent cardiovascular abnormalities, which were consistent with wet beriberi.
Conclusions:
This case emphasizes the need for thiamine supplementation in prolonged total parenteral nutrition, and also highlights the awareness of WE in persons with parenteral nutrition lacking thiamine. More importantly, we call for attention to wet beriberi in such persons.
doi:10.12659/AJCR.890041
PMCID: PMC3917879  PMID: 24516692
Parenteral Nutrition; Total – adverse effects; Thiamine Deficiency; Beriberi; Wernicke Encephalopathy
18.  eRF3b, a Biomarker for Hepatocellular Carcinoma, Influences Cell Cycle and Phosphoralation Status of 4E-BP1 
PLoS ONE  2014;9(1):e86371.
Background
Hepatitis B virus (HBV) infection and its sequelae are now recognized as serious problems globally. Our aime is to screen hepatocellular carcinoma (HCC) from chronic hepatitis B (CHB) and identify the characteristics of proteins involved.
Methodology/Principal Findings
We affinity-purified sample serum with weak cation-exchange (WCX) magnetic beads and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) analysis to search for potential markers. The 4210 Da protein, which differed substantially between HCC and CHB isolates, was later identified to be eukaryotic peptide chain release factor GTP-binding subunit eRF3b. Further research showed that eRF3b/GSPT2 was positively expressed in liver tissues. GSPT2 mRNA was, however differentially expressed in blood. Compared with normal controls, the relative expression of GSPT2/18s rRNA was higher in CHB patients than in patients with either LC or HCC (P = 0.035 for CHB vs. LC; P = 0.020 for CHB vs. HCC). The data of further research showed that eRF3b/GSPT2 promoted the entrance of the HepG2 cells into the S-phase and that one of the substrates of the mTOR kinase, 4E-BP1, was hyperphosphorylated in eRF3b-overexpressing HepG2 cells.
Conclusions
Overall, the differentially expressed protein eRF3b, which was discovered as a biomarker for HCC, could change the cell cycle and influence the phosphorylation status of 4E-BP1 on Ser65 in HepG2.
doi:10.1371/journal.pone.0086371
PMCID: PMC3900531  PMID: 24466059
19.  EPAC Inhibition of SUR1 Receptor Increases Glutamate Release and Seizure Vulnerability 
The Journal of Neuroscience  2013;33(20):8861-8865.
EPAC (Exchange Proteins Activated by cAMP) regulates glutamate transmitter release in the central neurons, but a role underlying this regulation has yet to be identified. Here we show that EPAC binds directly to the intracellular loop of an ATP-sensitive potassium (KATP) channel type-1 sulfonylurea receptor (SUR1) receptor consisting of amino acids 859–881 (SUR1859–881). Ablation of EPAC or expression of SUR1859–881, which intercepts EPAC-SUR1 binding, increases the open probability of KATP channels consisting of the Kir6.1 subunit and SUR1. Opening of KATP channels inhibits glutamate release and reduces seizure vulnerability in adult mice. Therefore, EPAC interaction with SUR1 controls seizure susceptibility and possibly acts via regulation of glutamate release.
doi:10.1523/JNEUROSCI.5686-12.2013
PMCID: PMC3865516  PMID: 23678128
20.  The let-7 microRNA Enhances Heme Oxygenase-1 by Suppressing Bach1 and Attenuates Oxidant Injury in Human Hepatocytes 
Biochimica et biophysica acta  2012;1819(11-12):1113-1122.
The let-7 microRNA (miRNA) plays important roles in human liver development and disease such as hepatocellular carcinoma, liver fibrosis and hepatitis wherein oxidative stress accelerates the progression of these diseases. To date, the role of the let-7 miRNA family in modulation of heme oxygenase 1 (HMOX1), a key cytoprotective enzyme, remains unknown. Our aims were to determine whether let-7 miRNA directly regulates Bach1, a transcriptional repressor of the HMOX1 gene, and whether indirect up-regulation of HMOX1 by let-7 miRNA attenuates oxidant injury in human hepatocytes. The effects of let-7 miRNA on Bach1 and HMOX1 gene expression in Huh-7 and HepG2 cells were determined by real-time qRT-PCR, Western blot, and luciferase reporter assays. Dual luciferase reporter assays revealed that let-7b, let-7c, or miR-98 significantly decreased Bach1 3’-untranslated region (3’-UTR)-dependent luciferase activity but not mutant Bach1 3’-UTR-dependent luciferase activity, whereas mutant let-7 miRNA containing base complementarity with mutant Bach1 3’-UTR restored its effect on mutant reporter activity. let-7b, let-7c, or miR-98 down-regulated Bach1 protein levels by 50–70%, and subsequently up-regulated HMOX1 gene expression by 3–4 fold, compared with non-specific controls. Furthermore, Huh-7 cells transfected with let-7b, let-7c or miR-98 mimic showed increased resistance against oxidant injury induced by tert-butyl-hydroperoxide (tBuOOH), whereas the protection was abrogated by over-expression of Bach1. In conclusion, let-7 miRNA directly acts on the 3’-UTR of Bach1 and negatively regulates expression of this protein, and thereby up-regulates HMOX1 gene expression. Over-expression of the let-7 miRNA family members may represent a novel approach to protecting human hepatocytes from oxidant injury.
doi:10.1016/j.bbagrm.2012.06.001
PMCID: PMC3480558  PMID: 22698995
let-7; HMOX1; Bach1; microRNA; oxidative stress; Huh-7 cell
21.  Expression of Tau40 Induces Activation of Cultured Rat Microglial Cells 
PLoS ONE  2013;8(10):e76057.
Accumulation of microtubule-associated protein tau has been observed in the brain of aging and tauopathies. Tau was observed in microglia, but its role is not illustrated. By immunofluorescence staining and the fractal dimension value assay in the present study, we observed that microglia were activated in the brains of rats and mice during aging, simultaneously, the immunoreactivities of total tau and the phosphorylated tau were significantly enhanced in the activated microglia. Furtherly by transient transfection of tau40 (human 2N/4R tau) into the cultured rat microglia, we demonstrated that expression of tau40 increased the level of Iba1, indicating activation of microglia. Moreover, expression of tau40 significantly enhanced the membranous localization of the phosphorylated tau at Ser396 in microglia possibly by a mechanism involving protein phosphatase 2A, extracellular signal-regulated kinase and glycogen synthase kinase-3β. It was also found that expression of tau40 promoted microglial migration and phagocytosis, but not proliferation. And we observed increased secretion of several cytokines, including interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor-α and nitric oxide after the expression of tau40. These data suggest a novel role of human 2N/4R tau in microglial activation.
doi:10.1371/journal.pone.0076057
PMCID: PMC3795725  PMID: 24146816
22.  Melatonin in Alzheimer’s Disease 
Alzheimer’s disease (AD), an age-related neurodegenerative disorder with progressive cognition deficit, is characterized by extracellular senile plaques (SP) of aggregated β-amyloid (Aβ) and intracellular neurofibrillary tangles, mainly containing the hyperphosphorylated microtubule-associated protein tau. Multiple factors contribute to the etiology of AD in terms of initiation and progression. Melatonin is an endogenously produced hormone in the brain and decreases during aging and in patients with AD. Data from clinical trials indicate that melatonin supplementation improves sleep, ameliorates sundowning and slows down the progression of cognitive impairment in AD patients. Melatonin efficiently protects neuronal cells from Aβ-mediated toxicity via antioxidant and anti-amyloid properties. It not only inhibits Aβ generation, but also arrests the formation of amyloid fibrils by a structure-dependent interaction with Aβ. Our studies have demonstrated that melatonin efficiently attenuates Alzheimer-like tau hyperphosphorylation. Although the exact mechanism is still not fully understood, a direct regulatory influence of melatonin on the activities of protein kinases and protein phosphatases is proposed. Additionally, melatonin also plays a role in protecting the cholinergic system and in anti-inflammation. The aim of this review is to stimulate interest in melatonin as a potentially useful agent in the prevention and treatment of AD.
doi:10.3390/ijms140714575
PMCID: PMC3742260  PMID: 23857055
Alzheimer’s disease; melatonin; tau hyperphosphorylation; beta amyloid; antioxidation; cholinergic; neuroinflammation
23.  Comprehensive Characterization of Human Genome Variation by High Coverage Whole-Genome Sequencing of Forty Four Caucasians 
PLoS ONE  2013;8(4):e59494.
Whole genome sequencing studies are essential to obtain a comprehensive understanding of the vast pattern of human genomic variations. Here we report the results of a high-coverage whole genome sequencing study for 44 unrelated healthy Caucasian adults, each sequenced to over 50-fold coverage (averaging 65.8×). We identified approximately 11 million single nucleotide polymorphisms (SNPs), 2.8 million short insertions and deletions, and over 500,000 block substitutions. We showed that, although previous studies, including the 1000 Genomes Project Phase 1 study, have catalogued the vast majority of common SNPs, many of the low-frequency and rare variants remain undiscovered. For instance, approximately 1.4 million SNPs and 1.3 million short indels that we found were novel to both the dbSNP and the 1000 Genomes Project Phase 1 data sets, and the majority of which (∼96%) have a minor allele frequency less than 5%. On average, each individual genome carried ∼3.3 million SNPs and ∼492,000 indels/block substitutions, including approximately 179 variants that were predicted to cause loss of function of the gene products. Moreover, each individual genome carried an average of 44 such loss-of-function variants in a homozygous state, which would completely “knock out” the corresponding genes. Across all the 44 genomes, a total of 182 genes were “knocked-out” in at least one individual genome, among which 46 genes were “knocked out” in over 30% of our samples, suggesting that a number of genes are commonly “knocked-out” in general populations. Gene ontology analysis suggested that these commonly “knocked-out” genes are enriched in biological process related to antigen processing and immune response. Our results contribute towards a comprehensive characterization of human genomic variation, especially for less-common and rare variants, and provide an invaluable resource for future genetic studies of human variation and diseases.
doi:10.1371/journal.pone.0059494
PMCID: PMC3618277  PMID: 23577066
24.  Bivariate Genome-Wide Association Analyses Identified Genes with Pleiotropic Effects for Femoral Neck Bone Geometry and Age at Menarche 
PLoS ONE  2013;8(4):e60362.
Femoral neck geometric parameters (FNGPs), which include cortical thickness (CT), periosteal diameter (W), buckling ratio (BR), cross-sectional area (CSA), and section modulus (Z), contribute to bone strength and may predict hip fracture risk. Age at menarche (AAM) is an important risk factor for osteoporosis and bone fractures in women. Some FNGPs are genetically correlated with AAM. In this study, we performed a bivariate genome-wide association study (GWAS) to identify new candidate genes responsible for both FNGPs and AAM. In the discovery stage, we tested 760,794 SNPs in 1,728 unrelated Caucasian subject, followed by replication analyses in independent samples of US Caucasians (with 501 subjects) and Chinese (with 826 subjects). We found six SNPs that were associated with FNGPs and AAM. These SNPs are located in three genes (i.e. NRCAM, IDS and LOC148145), suggesting these three genes may co-regulate FNGPs and AAM. Our findings may help improve the understanding of genetic architecture and pathophysiological mechanisms underlying both osteoporosis and AAM.
doi:10.1371/journal.pone.0060362
PMCID: PMC3617200  PMID: 23593202
25.  Heme status affects human hepatic messenger RNA and microRNA expression 
AIM: To assess effects of heme on messenger RNA (mRNA) and microRNA (miRNA) profiles of liver cells derived from humans.
METHODS: We exposed human hepatoma cell line Huh-7 cells to excess iron protoporphyrin (heme) (10 μmol/L) or induced heme deficiency by addition of 4, 6-dioxoheptanoic acid (500 μmol/L), a potent inhibitor of aminolevulinic acid dehydratase, for 6 h or 24 h. We harvested total RNA from the cells and performed both mRNA and miRNA array analyses, with use of Affymetrix chips, reagents, and instruments (human genome U133 plus 2.0 and miRNA 2.0 arrays). We assessed changes and their significance and interrelationships with Target Scan, Pathway Studios, and Ingenuity software.
RESULTS: Changes in mRNA levels were most numerous and striking at 6 h after heme treatment but were similar and still numerous at 24 h. After 6 h of heme exposure, the increase in heme oxygenase 1 gene expression was 60-fold by mRNA and 88-fold by quantitative reverse transcription-polymerase chain reaction. We found striking changes, especially up-regulation by heme of nuclear erythroid-2 related factor-mediated oxidative stress responses, protein ubiquitination, glucocorticoid signaling, P53 signaling, and changes in RNAs that regulate intermediary metabolism. Fewer mRNAs were down-regulated by heme, and the fold decreases were less exuberant than were the increases. Notable decreases after 24 h of heme exposure were patatin-like phospholipase domain-containing protein 3 (-6.5-fold), neuronal PAS domain protein 2 (-1.93-fold), and protoporphyrinogen oxidase (-1.7-fold).
CONCLUSION: Heme excess exhibits several toxic effects on liver and kidney, which deserve study in humans and in animal models of the human porphyrias or other disorders.
doi:10.3748/wjg.v19.i10.1593
PMCID: PMC3602476  PMID: 23538684
Delta-aminolevulinic acid synthase; Heme; Heat shock proteins; Hepatotoxicity; Messenger RNA; MicroRNA

Results 1-25 (50)