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1.  Roles of p53 and ASF1A in the Reprogramming of Sheep Kidney Cells to Pluripotent Cells 
Cellular Reprogramming  2015;17(6):441-452.
Abstract
Since the first report of induced pluripotent stem cells (iPSCs) by Takahashi and Yamanaka, numerous attempts have been made to derive iPSCs from other species via the ectopic expression of defined factors. Sheep iPSCs (siPSCs) have significant potential for biotechnology and agriculture. Although several groups have described siPSCs, the reprogramming efficiency was extremely low. The exogenous transgenes could be not silenced in the iPSCs, which hampered their development and application. Here, we report that p53 knockdown and antisilencing function 1A (ASF1A) overexpression promoted iPSC generation from sheep kidney cells (SKCs). Compared with transduction with eight human defined transcription factors (Oct4, Sox2, Klf4, c-Myc, Nanog, Lin28, hTERT, and SV40LT), the additional introduction of p53 RNA interference (RNAi) and/or ASF1A in the presence of small-molecule compounds [vitamin C (Vc) and valproic acid (VPA)] greatly improved the efficiency of sheep iPSC generation. The siPSCs exhibited morphological features similar to mouse embryonic stem cells (ESCs) and were positive for alkaline phosphatase and, pluripotent marker genes (Oct4, Nanog, Sox2, Rex1, TRA-1-60, TRA-1-81, and E-cadherin). Furthermore, these cells exhibited a normal karyotype of 54 chromosomes and were able to differentiate into all three germ layers both in vitro and in vivo. Moreover, the exogenous genes were silenced in siPSCs when p53 small hairpin RNA (shRNA) and ASF1A were added. Our results may help to reveal the role of p53 and ASF1A in sheep somatic cell reprogramming and provide an efficient approach to reprogramming sheep somatic cells.
doi:10.1089/cell.2015.0039
PMCID: PMC4677545  PMID: 26580119
2.  A Dual Color Immunohistochemistry Assay for Measurement of Cereblon in Multiple Myeloma Patient Samples 
Supplemental Digital Content is available in the text.
Clinical interest in the measurement of Cereblon (CRBN), the primary target of the IMiDs immunomodulatory drugs lenalidomide and pomalidomide, has been fueled by its essential requirement for antitumor or immunomodulatory activity of both drugs in multiple myeloma (MM). However, limited analyses of clinical samples for CRBN gene expression or protein levels have utilized unvalidated reagents and assays, raising uncertainty about the interpretation of these results. We previously described a highly specific rabbit monoclonal antibody CRBN65 against 65-76 AA of human Cereblon. Here we describe a validated dual color bright-field Cereblon/CD138 immunohistochemical (IHC) assay utilizing CRBN65 and a commercial mouse monoclonal CD138 antibody. Sensitivity and specificity of the assay was determined and assay precision was shown for both cytoplasmic and nuclear Cereblon in MM bone marrow samples with coefficient of variation values of 5% and 2%, respectively. The dual IHC assay was effective for detecting a continuous range of Cereblon levels in 22 MM patient bone marrow core biopsies and aspirate clots, as shown by average cytoplasmic H-scores ranging from 63 to 267 and nuclear H-scores ranging from 17 to 250. Interpathologist comparison of MM sample H-scores by 3 pathologists demonstrated good concordance (R2=0.73). This dual assay demonstrated superior Cereblon IHC measurement in MM samples compared with the single IHC assay using a published commercial rabbit polyclonal Cereblon antibody and could be used to explore the potential utility of Cereblon as a biomarker in the clinic.
doi:10.1097/PAI.0000000000000246
PMCID: PMC5106091  PMID: 26186254
immunomodulatory drugs; dual; cereblon; myeloma; immunohistochemistry
3.  Abnormal expression of p190RhoGAP in colorectal cancer patients with poor survival 
Purpose: This study aims to investigate the expression and clinical significance of p190RhoGAP, a member of the RhoGAP family, in colorectal cancer (CRC). Methods: The expression p190RhoGAP was detected by RT-PCR, western blot (WB) and immunohistochemistry (IHC) in 14 paired CRCs and matched non-cancerous mucosal tissues. The protein content of p190RhoGAP was identified in 114 CRCs by IHC. In addition, the association of the expression of p190RhoGAP with carcinogenesis, distant metastasis and prognosis was further evaluated. Results: In 14 paired fresh tissues, the mRNA (P<0.0001) and protein (P = 0.003) expression levels of p190RhoGAP were significantly higher in primary CRCs than in paired non-cancerous mucosal tissues; and was consistent with WB results. The expression of p190RhoGAP increased from normal mucosa to adenoma, and became even greater in primary carcinoma (P = 0.001). The expression level of p190RhoGAP was highest in liver metastasis compared to primary carcinoma (P = 0.028). The incidence of p190RhoGAP expression-positive cases was 58.77% in 114 CRC tissues. Furthermore, the enhanced expression of p190RhoGAP was significantly associated with shorter disease-specific survival (P<0.001) and shorter disease-free survival (P<0.001). Cox regression analysis indicated that p190RhoGAP was an independent prognostic parameter for CRC. Conclusion: p190RhoGAP may be an independent predictive factor for the prognosis of CRC, and the abnormal expression of p190RhoGAP may play a crucial role in colorectal carcinogenesis and distant metastasis.
PMCID: PMC5095333  PMID: 27830024
p190rhogap; colorectal cancer; metastasis; poor survival
4.  High Molecular Weight Hyaluronic Acid Inhibits Fibrosis of Endometrium 
Background
Elevated fibrosis has been found in patients with intrauterine adhesion, which indicates that fibrotic factors may play a critical role in formation of intrauterine adhesion. The aim of this study was to identify the effect of hyaluronic acid (HA) at high and low molecular weight on fibrosis of the endometrium in a mouse model of Asherman’s syndrome.
Material/Methods
Endometrial fibrosis in a mouse model of Asherman’s syndrome was confirmed. Then HA at high and low molecular weight was injected into the uterine cavity. Endometrial fibrosis was compared among the control group, LMW-HA, and HMW-HA group. The extent of endometrial fibrosis was calculated using Masson stain. The fibrosis markers (TGFβ1, CTGF, collagen I, and collagen III) in endometrial tissue were detected using immunohistochemistry and Western blotting.
Results
The ratio of the area with endometrial fibrosis to total endometrial area in the HMW-HA group was significantly decreased compared to the control group (P<0.05). The expression of fibrosis markers (TGFβ1, CTGF, collagen I, and collagen III) in the endometrium was attenuated in the HMW-HA group compared to the control group, but the LMW-HA group had no similar effect.
Conclusions
Hyaluronic acid at high molecular weight may attenuate the degree of endometrial fibrosis after endometrial damage, which may contribute to preventing formation of intrauterine adhesions.
doi:10.12659/MSM.896028
PMCID: PMC5042123  PMID: 27670361
Fibrosis; Gynatresia; Hyaluronic Acid
5.  Ambient-condition growth of high-pressure phase centrosymmetric crystalline KDP microstructures for optical second harmonic generation 
Science Advances  2016;2(8):e1600404.
Exotic nonlinear optical single-crystal microstructures have unique guided-wave and efficient frequency-doubling properties.
Noncentrosymmetric potassium dihydrogen phosphate (KH2PO4 or KDP) in the tetragonal crystal phase is arguably the most extensively studied nonlinear optical crystal in history. It has prolific applications ranging from simple laser pointers to laser inertial confinement fusion systems. Recently, type IV high-pressure KDP crystal sheets with a monoclinic crystal phase having centrosymmetric properties have been observed. However, it was found that this new crystal phase is highly unstable under ambient conditions. We report ambient-condition growth of one-dimensional, self-assembled, single-crystalline KDP hexagonal hollow/solid-core microstructures that have a molecular structure and symmetry identical to the type IV KDP monoclinic crystal that was previously found to exist only at extremely high pressures (>1.6 GPa). Furthermore, we report highly efficient bulk optical second harmonic generation (SHG) from these ambient condition–grown single-crystalline microstructures, even though they have a highly centrosymmetric crystal phase. However, fundamental physics dictates that a bulk optical medium with a significant second-order nonlinear susceptibility supporting SHG must have noncentrosymmetric properties. Laue diffraction analysis reveals a weak symmetry-breaking twin-crystal lattice that, in conjunction with tight confinement of the light field by the tubular structure, is attributed to the significant SHG even with sample volumes <0.001 mm3. A robust polarization-preserving effect is also observed, raising the possibility of advanced optical technological applications.
doi:10.1126/sciadv.1600404
PMCID: PMC5001809  PMID: 27574703
Potassium Di-hydrogen Phosphate; crystal growth; High-pressure; one-dimensional; self-assembly; Centrosymmetric; microstructures; Second harmonic generation
6.  Prevalence of High-Risk Human Papillomavirus (HR-HPV) Genotypes and Multiple Infections in Cervical Abnormalities from Northern Xinjiang, China 
PLoS ONE  2016;11(8):e0160698.
Multiple human papillomavirus (HPV) genotypes often coexist within the cervical epithelia and are frequently detected together in various grades of the cervical neoplasia. To date, only a few reports exist on multiple HPV infections of HPV in Xinjiang Uygur Autonomous Region (XUAR). In the present study, we investigated the prevalence of High-Risk HPV (HR-HPV) genotypes and multiple infections. Cervical cytology samples were collected from 428 women who presented cervical abnormalities. Genotyping of HPV was performed by polymerase chain reaction–sequencing based typing (PCR-SBT) using consensus primers and specific primers. Of them, 166 samples were positive for HPV according to PCR results using the consensus primers. These samples contained cervical abnormalities enriched with inflammation (n = 107), cervical intraepithelial neoplasia (CIN) I (n = 19), CINII-III (n = 9) and cervical cancer (n = 31). Of the 166 HPV positive samples as determined by PCR analysis, 151 were further typed by PCR-SBT using 19 pairs of genotype-specific primers. Using this method, 17 different HR-HPV genotypes were identified. The most frequently observed HPV genotypes were HPV16 (44.0%, 73/166), 53 (28.9%, 48/166), 52 (25.3%, 42/166), 58 (22.3%, 37/166) and 35 (17.5%, 29/166). The proportions of single and multiple infections in the HPV-positive specimens were 34.9% and 65.1%, respectively. Multiple HPV types were most prevalent in the inflammatory state (63.0%), followed by cervical cancer (24.1%), CINI (11.1%), and CINII-III (1.9%). The results of our data analyses suggested that i) multiple HPV infection is not necessarily correlated with the severity of cervical abnormalities; and ii) among the multiple HPV infections, double infections combined with HPV16 is the most common. In addition, L1 full-length sequences of the top five high-risk HPV genotypes were amplified and sequenced. According to the L1 sequence of the epidemic genotypes that were amplified, we found that these genotypes contained the sequence point mutation, and that some of these genotypes further showed amino acid modifications. These results provide a basis for the construction of a polyvalent vaccine that is suitable for use in the XUAR, even in economically challenged communities located in China.
doi:10.1371/journal.pone.0160698
PMCID: PMC4975475  PMID: 27494179
7.  Hepatitis B Virus Middle Protein Enhances IL-6 Production via p38 MAPK/NF-κB Pathways in an ER Stress-Dependent Manner 
PLoS ONE  2016;11(7):e0159089.
During hepatitis B virus (HBV) infection, three viral envelope proteins of HBV are overexpressed in the endoplasmic reticulum (ER). The large S protein (LHBs) and truncated middle S protein (MHBst) have been documented to play roles in regulating host gene expression and contribute to hepatic disease development. As a predominant protein at the ultrastructural level in biopsy samples taken from viremic patients, the role of the middle S protein (MHBs) remains to be understood despite its high immunogenicity. When we transfected hepatocytes with an enhanced green fluorescent protein (EGFP)-tagged MHBs expressing plasmid, the results showed that expression of MHBs cause an upregulation of IL-6 at the message RNA and protein levels through activating the p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-kappa B (NF-κB) pathways. The use of specific inhibitors of the signaling pathways can diminish this upregulation. The use of BAPTA-AM attenuated the stimulation caused by MHBs. We further found that MHBs accumulated in the endoplasmic reticulum and increased the amount of glucose regulated protein 78 (GRP78/BiP). Our results provide a possibility that MHBs could be involved in liver disease progression.
doi:10.1371/journal.pone.0159089
PMCID: PMC4951109  PMID: 27434097
8.  Blood oxygenation level-dependent magnetic resonance imaging during carbogen breathing: differentiation between prostate cancer and benign prostate hyperplasia and correlation with vessel maturity 
OncoTargets and therapy  2016;9:4143-4150.
Objective
The aim of this study was to investigate whether the blood oxygenation level-dependent (BOLD) contrast magnetic resonance imaging (MRI) can evaluate tumor maturity and preoperatively differentiate prostate cancer (PCa) from benign prostate hyperplasia (BPH).
Patients and methods
BOLD MRI based on transverse relaxation time*-weighted echo planar imaging was performed to assess PCa (19) and BPH (22) responses to carbogen (95% O2 and 5% CO2). The average signal values of PCa and BPH before and after carbogen breathing and the relative increased signal values were computed, respectively. The endothelial-cell marker, CD31, and the pericyte marker, α-smooth muscle actin (mature vessels), were detected with immunofluorescence, and were assessed by microvessel density (MVD) and microvessel pericyte density (MPD). The microvessel pericyte coverage index (MPI) was used to evaluate the degree of vascular maturity. The changed signal from BOLD MRI was correlated with MVD, MPD, and MPI.
Results
After inhaling carbogen, both PCa and BPH showed an increased signal, but a lower slope was found in PCa than that in BPH (P<0.05). PCa had a higher MPD and MVD but a lower MPI than BPH. The increased signal intensity was positively correlated with MPI in PCa and that in BPH (r=0.616, P=0.011; r=0.658, P=0.002); however, there was no correlation between the increased signal intensity and MPD or MVD in PCa than that in BPH (P>0.05).
Conclusion
Our results confirmed that the increased signal values induced by BOLD MRI well differentiated PCa from BPH and had a positive correlation with vessel maturity in both of them. BOLD MRI can be utilized as a surrogate marker for the noninvasive assessment of the degree of vessel maturity.
doi:10.2147/OTT.S105480
PMCID: PMC4939976  PMID: 27462169
BOLD; magnetic resonance imaging; prostate carcinoma; benign prostate hyperplasia; vessel maturity
9.  Finding Clocks in Genes: A Bayesian Approach to Estimate Periodicity 
BioMed Research International  2016;2016:3017475.
Identification of rhythmic gene expression from metabolic cycles to circadian rhythms is crucial for understanding the gene regulatory networks and functions of these biological processes. Recently, two algorithms, JTK_CYCLE and ARSER, have been developed to estimate periodicity of rhythmic gene expression. JTK_CYCLE performs well for long or less noisy time series, while ARSER performs well for detecting a single rhythmic category. However, observing gene expression at high temporal resolution is not always feasible, and many scientists are interested in exploring both ultradian and circadian rhythmic categories simultaneously. In this paper, a new algorithm, named autoregressive Bayesian spectral regression (ABSR), is proposed. It estimates the period of time-course experimental data and classifies gene expression profiles into multiple rhythmic categories simultaneously. Through the simulation studies, it is shown that ABSR substantially improves the accuracy of periodicity estimation and clustering of rhythmic categories as compared to JTK_CYCLE and ARSER for the data with low temporal resolution. Moreover, ABSR is insensitive to rhythmic patterns. This new scheme is applied to existing time-course mouse liver data to estimate period of rhythms and classify the genes into ultradian, circadian, and arrhythmic categories. It is observed that 49.2% of the circadian profiles detected by JTK_CYCLE with 1-hour resolution are also detected by ABSR with only 4-hour resolution.
doi:10.1155/2016/3017475
PMCID: PMC4909896  PMID: 27340654
10.  Effects of common polymorphisms in miR-146a and miR-196a2 on lung cancer susceptibility: a meta-analysis 
Journal of Thoracic Disease  2016;8(6):1297-1305.
Background
MicroRNAs (miRNAs) may play an important role in organ development, cell differentiation, apoptosis, proliferation, cell growth regulation and act as tumor suppressor genes or proto-oncogenes. Single nucleotide polymorphisms (SNPs) in miRNAs are considered to be genetic factors to influence the susceptibility to lung cancer (LC). Rs2910164 in miR-146a and rs11614913 in miR-196a2 are shown to be associated with increased/decreased LC risk. The aim of this meta-analysis was to systematically summarize the possible association.
Methods
The relevant articles were retrieved from several important databases. Studies were selected using specific inclusion and exclusion criteria. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of association between miRNA polymorphism and susceptibility to LC. All analyses were performed using the Stata software.
Results
Seven studies were included in this meta-analysis. There were 3,225 cases and 3,268 controls for SNP rs2910164 and 2,794 cases and 2,840 controls for SNP rs11614913. The significant associations between SNP rs2910164 and LC risk were observed (CC vs. GG: OR =1.30, 95% CI: 1.13–1.50; CC + GC vs. GG: OR =1.15, 95% CI: 1.02–1.29; CC vs. GC + GG: OR =1.27, 95% CI: 1.13–1.42; C vs. G: OR =1.15, 95% CI: 1.08–1.24). SNP rs11614913 was found to be associated with LC risk in most genetic models (TC vs. TT: OR =1.16, 95% CI: 1.02–1.32; CC vs. TT: OR =1.24, 95% CI: 1.06–1.44; CC + TC vs. TT: OR =1.19, 95% CI: 1.06–1.34; C vs. T: OR =1.11, 95% CI: 1.03–1.20). In the subgroup analysis by ethnicity, genotyping method and control characteristics, significantly affected LC risks were also suggested.
Conclusions
The rs2910164 in miR-146a and the rs11614913 in miR-196a2 are likely to be associated with LC risks.
doi:10.21037/jtd.2016.05.02
PMCID: PMC4886023  PMID: 27293850
Lung cancer (LC); microRNA (miRNA); single nucleotide polymorphism (SNP); susceptibility; meta-analysis
11.  Clinical characteristics of fatigued Parkinson’s patients and the response to dopaminergic treatment 
Background
Fatigue, which is commonly observed in Parkinson’s disease (PD), can greatly reduce quality of life and is difficult to treat. We here aimed to investigate the prevalence and characteristics of fatigue among PD patients and to explore an effective strategy to treat PD fatigue.
Method
This was an observational cross-sectional study conducted in northeastern China. We examined fatigue in 222 PD patients from northeastern China using the Parkinson Fatigue Scale-16 (PFS-16). The disease severity, depression, sleep and cognitive functioning were assessed with the Hoehn & Yahr staging (H-Y stage), Unified Parkinson’s Disease Rating Scale (UPDRS), Hamilton Depression Scale (HAMD), Parkinson’s Disease Sleep Scale (PDSS) and Montreal Cognitive Assessment (MoCA) by interview.
Results
The frequency of fatigue in PD patients was 59.46 %. Fatigued patients had longer disease durations and greater disease severity than nonfatigued patients. Additionally, fatigued PD patients scored significantly higher for all motor symptoms, except for tremor, and had more serious depressive symptoms and sleep disturbances than nonfatigued PD patients did. The sleep disturbance severity was an independent factor for fatigue. Furthermore, 43.04 % of fatigued patients taking dopaminergic drugs had fatigue remission. Depression severity was identified as an independent factor for dopaminergic drug non-responsive fatigue.
Conclusions
PD patients with severe sleep disturbances tend to suffer from fatigue. Levodopa improved fatigue only in PD patients with mild depression or no depression, implying that dopaminergic medication is required, but not sufficient, for fatigue suppression in PD patients with moderate or severe depression. Thus, restoring serotonergic neurotransmission as a combination therapy may offer a better strategy for the treatment of fatigue in these patients.
doi:10.1186/s40035-016-0056-2
PMCID: PMC4863328  PMID: 27175281
Parkinson’s disease; Fatigue; Sleep disorder; Depression; Dopaminergic drugs
12.  GS/DBM/PLA porous composite biomaterial for the treatment of infective femoral condyle defect in rats 
A bone defect resulting from open bone trauma may easily become infected; however, the administration of efficacious systemic antibiotics cannot be performed at safe levels. Previous studies have investigated anti-infective biomaterials that incorporate into bone and facilitate the direct application of high-concentration local antibiotics. In the present study, the effect of a novel porous composite with gentamicin sulfate (GS) in treating infected femoral condyle defects was investigated using a rat model. A novel porous composite biomaterial was prepared based on a supercritical carbon dioxide fluid technique that combined GS, demineralized bone matrix (DBM) and polylactic acid (PLA). A rat femoral condyle fracture model of infection was established. The GS/DBM/PLA composite biomaterial was implanted and its physicochemical characteristics, biocompatibility and ability to facilitate repair of infected bone defect were assessed. The GS/DBM/PLA composite biomaterial maintained the antibiotic activity of GS, with good anti-compression strength, porosity and biocompatibility. The results of the animal experiments indicated that the GS/DBM/PLA composite biomaterial exerted marked anti-infective effects and facilitated bone defect repair, while simultaneously controlling infection. Porous GS/DBM/PLA is therefore a promising composite biomaterial for use in bone tissue engineering.
doi:10.3892/etm.2016.3219
PMCID: PMC4887764  PMID: 27284292
bone tissue engineering; infection; bone defect; composite biomaterial
13.  Both Talin-1 and Talin-2 correlate with malignancy potential of the human hepatocellular carcinoma MHCC-97 L cell 
BMC Cancer  2016;16:45.
Background
Talin-1 (TLN-1) and TLN-2 are implicated in many cellular processes, but their roles in hepatocellular carcinoma (HCC) remain unclear. This study aimed to assess cell cycle distribution, anoikis, invasion and migration in human HCC MHCC-97 L cells.
Methods
MHCC-97 L cells, which highly express TLN-1, were transduced with TLN-1 shRNA (experimental group) or scramble shRNA (negative control group); non-transduced MHCC-97 L cells were used as blank controls. TLN-1 and TLN-2 mRNA and protein levels were detected by real-time RT-PCR and western blot, respectively. Then, cell cycle distribution and anoikis were assessed by flow cytometry. In addition, migration and invasion abilities were assessed using Transwell and cell scratch assays. Finally, a xenograft nude mouse model was established to further assess cell tumorigenicity.
Results
Compared with the blank and negative control groups, TLN-1/2 mRNA and protein levels were significantly reduced in the experiment group. TLN-1/2 knockdown cells showed significantly more cells in the G0/G1 phase (79.24 %) in comparison with both blank (65.36 %) and negative (62.69 %) control groups; conversely, less cells were found in G2/M and S phases in the experimental group compared with controls. Moreover, anoikis was enhanced (P < 0.05), while invasion and migration abilities were reduced (P < 0.05) in TLN-1/2 knockdown cells compared with controls. TLN-1/2 knockdown inhibited MHCC-97 L cell migration (Percentage of wound healing area: experimental group: 32.6 ± 0.7 % vs. negative controls: 50.1 ± 0.6 % and blank controls: 53.6 ± 0.6 %, both P < 0.01). Finally, the tumors obtained with TLN-1/2 knockdown cells were smaller (P < 0.05) compared with controls.
Conclusion
Both TLN-1 and TLN-2 levels correlate with tumorigenicity in human HCC, indicating that these molecules constitute important molecular targets for the diagnosis and/or treatment of HCC.
doi:10.1186/s12885-016-2076-9
PMCID: PMC4730717  PMID: 26822056
Hepatocellular carcinoma (HCC); Talin-1; Talin-2; Migration; Invasion; Cell cycle arrest
14.  Age-related decline in white matter integrity in a mouse model of tauopathy: an in vivo diffusion tensor magnetic resonance imaging study 
Neurobiology of aging  2013;35(6):1364-1374.
Elevated expression of human hyperphosphorylated tau is associated with neuronal loss and white matter (WM) pathology in Alzheimer’s disease (AD) and related neurodegenerative disorders. Using in vivo diffusion tensor magnetic resonance imaging (DT-MRI) at 11.1 Tesla we measured age-related alterations in WM diffusion anisotropy indices in a mouse model of human tauopathy (rTg4510) and nontransgenic (nonTg) control mice at the age of 2.5, 4.5, and 8 months. Similar to previous DT-MRI studies in AD subjects, 8-month-old rTg4510 mice showed lower fractional anisotropy (FA) values in WM structures than nonTg. The low WM FA in rTg4510 mice was observed in the genu and splenium of the corpus callosum, anterior commissure, fimbria, and internal capsule and was associated with a higher radial diffusivity than nonTg. Interestingly, rTg4510 mice showed lower estimates for the mode of anisotropy than controls at 2.5 months suggesting that changes in this diffusivity metric are detectable at an early stage preceding severe tauopathy. Immunogold electron microscopy partly supports our diffusion tensor imaging findings. At the age of 4 months, rTg4510 mice show axonal tau inclusions and unmyelinated processes. At later ages (12 months and 14 months) we observed inclusions in myelin sheath, axons, and unmyelinated processes, and a “disorganized” pattern of myelinated fiber arrangement with enlarged inter-axonal spaces in rTg4510 but not in nonTg mice. Our data support a role for the progression of tau pathology in reduced WM integrity measured by DT-MRI. Further in vivo DT-MRI studies in the rTg4510 mouse should help better discern the detailed mechanisms of reduced FA and anisotropy mode, and the specific role of tau during neurodegeneration.
doi:10.1016/j.neurobiolaging.2013.12.009
PMCID: PMC4729397  PMID: 24411290
Tauopathy; Neurodegenerative disease; Alzheimer’s disease; FTDP-17; rTg4510; Diffusion tensor MRI; White matter integrity; Electron microscopy; Ultrastructure
15.  Neuroprotective effect of Shenqi Fuzheng injection pretreatment in aged rats with cerebral ischemia/reperfusion injury 
Neural Regeneration Research  2016;11(1):94-100.
Shenqi Fuzheng injection is extracted from the Chinese herbs Radix Astragali and Radix Codonopsis. The aim of the present study was to investigate the neuroprotective effects of Shenqi Fuzheng injection in cerebral ischemia and reperfusion. Aged rats (20–22 months) were divided into three groups: sham, model, and treatment. Shenqi Fuzheng injection or saline (40 mL/kg) was injected into the tail vein daily for 1 week, after which a cerebral ischemia/reperfusion injury model was established. Compared with model rats that received saline, rats in the treatment group had smaller infarct volumes, lower brain water and malondialdehyde content, lower brain Ca2+ levels, lower activities of serum lactate dehydrogenase and creatine kinase, and higher superoxide dismutase activity. In addition, the treatment group showed less damage to the brain tissue ultrastructure and better neurological function. Our findings indicate that Shenqi Fuzheng injection exerts neuroprotective effects in aged rats with cerebral ischemia/reperfusion injury, and that the underlying mechanism relies on oxygen free radical scavenging and inhibition of brain Ca2+ accumulation.
doi:10.4103/1673-5374.175052
PMCID: PMC4774243  PMID: 26981095
nerve regeneration; cerebral ischemia/reperfusion; Shenqi Fuzheng injection; aged rats; neurological function; Ca2+; oxygen free radicals; NSFC grant; neural regeneration
16.  Isolation and Identification of Lactic Acid Bacteria from Traditional Dairy Products in Baotou and Bayannur of Midwestern Inner Mongolia and q-PCR Analysis of Predominant Species 
In this study, traditional culture method and 16S rRNA gene analysis were applied to reveal the composition and diversity of lactic acid bacteria (LAB) of fermented cow milk, huruud and urum from Baotou and Bayannur of midwestern Inner Mongolia. Also, the quantitative results of dominant LAB species in three different types of dairy products from Baotou and Bayannur were gained by quantitative polymerase chain reaction (q-PCR) technology. Two hundred and two LAB strains isolated from sixty-six samples were identified and classified into four genera, namely Enterococcus, Lactococcus, Lactobacillus, Leuconostoc, and twenty-one species and subspecies. From these isolates, Lactococcus lactis subsp. lactis (32.18%), Lactobacillus plantarum (12.38%) and Leuconosto mesenteroides (11.39%) were considered as the dominated LAB species under the condition of cultivating in MRS and M17 medium. And the q-PCR results revealed that the number of dominant species varied from samples to samples and from region to region. This study clearly shows the composition and diversity of LAB existing in fermented cow milk, huruud and urum, which could be considered as valuable resources for LAB isolation and further probiotic selection.
doi:10.5851/kosfa.2016.36.4.499
PMCID: PMC5018510  PMID: 27621691
lactic acid bacteria; traditional dairy products; 16S rRNA gene; q-PCR
17.  Female genetic distribution bias in mitochondrial genome observed in Parkinson’s Disease patients in northern China 
Scientific Reports  2015;5:17170.
Genetic polymorphisms associated with susceptibility to Parkinson’s disease (PD) have been described in mitochondrial DNA (mtDNA). To explore the potential contribution of mtDNA mutations to the risk of PD in a Chinese population, we examined the linkage relationship between several single nucleotide polymorphisms (SNPs) and haplotypes in mtDNA and PD. We genotyped 5 SNPs located on coding genes using PCR-RFLP analysis. A specific allele 10398G demonstrated an increased risk of PD (OR 1.30; 95% CI 0.95–1.76; P = 0.013). After stratification by gender, the increased risk appeared to be more significant in females (OR 1.91; 95% CI 1.16–3.16; P = 0.001). But the significance only appeared in females under Bonferroni correction. No significant differences were detected for other SNPs (T4336C, G5460A, G9055A, and G13708A). Individual haplotype composed of 4336T-5460G-9055G-10398A-13708G was found to be associated with protective effect regarding PD (P = 0.0025). The haplotypes 4336T-5460G-9055G-10398G-13708G and 4336T-5460G-9055G-10398A-13708G were more significantly associated in females (P = 0.0036 for risk and P = 0.0006 for protective effects). These data suggest that the A10398G and two haplotypes coupled with 10398A or 10398G are closely associated with susceptibility to PD in a northern Chinese population. This association demonstrated a female genetic distribution bias.
doi:10.1038/srep17170
PMCID: PMC4658531  PMID: 26602989
18.  Structural insights into HetR−PatS interaction involved in cyanobacterial pattern formation 
Scientific Reports  2015;5:16470.
The one-dimensional pattern of heterocyst in the model cyanobacterium Anabaena sp. PCC 7120 is coordinated by the transcription factor HetR and PatS peptide. Here we report the complex structures of HetR binding to DNA, and its hood domain (HetRHood) binding to a PatS-derived hexapeptide (PatS6) at 2.80 and 2.10 Å, respectively. The intertwined HetR dimer possesses a couple of novel HTH motifs, each of which consists of two canonical α-helices in the DNA-binding domain and an auxiliary α-helix from the flap domain of the neighboring subunit. Two PatS6 peptides bind to the lateral clefts of HetRHood, and trigger significant conformational changes of the flap domain, resulting in dissociation of the auxiliary α-helix and eventually release of HetR from the DNA major grove. These findings provide the structural insights into a prokaryotic example of Turing model.
doi:10.1038/srep16470
PMCID: PMC4649674  PMID: 26576507
19.  Serum vitamin D3 does not correlate with liver fibrosis in chronic hepatitis C 
World Journal of Gastroenterology : WJG  2015;21(39):11152-11159.
AIM: To investigate the relationship between serum vitamin D3 levels and liver fibrosis or inflammation in treatment-naive Chinese patients with chronic hepatitis C (CHC).
METHODS: From July 2010 to June 2011, we enrolled 122 CHC patients and 11 healthy controls from Dingxi city, Gansu Province, China. The patients were infected with Hepatitis C virus (HCV) during blood cell re-transfusion following plasma donation in 1992-1995, and had never received antiviral treatment. At present, all the patients except two underwent liver biopsy with ultrasound guidance. The Scheuer Scoring System was used to evaluate hepatic inflammation and the Metavir Scoring System was used to evaluate hepatic fibrosis. Twelve-hour overnight fasting blood samples were collected in the morning of the day of biopsy. Serum levels of alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, cholinesterase, prothrombin activity, albumin, γ-glutamyl transpeptidase, hemoglobin, calcium and phosphorus were determined. Serum HCV RNA levels were measured by real-time PCR. Serum levels of 25-hydroxyvitamin D3 [25(OH)D3] and 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] were measured by high-performance liquid chromatography tandem mass spectrometry.
RESULTS: Serum levels of 25(OH)D3 but not 24,25(OH)2D3 were significantly lower in CHC patients than in control subjects. Serum 25(OH)D3 levels did not correlate with liver fibrosis, inflammation, patient age, or levels of alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin, prothrombin activity, cholinesterase or HCV RNA. However, serum 25(OH)D3 levels did correlate with serum 24,25(OH)2D3 levels. Serum 25(OH)D3 and 24,25(OH)2D3 levels, and the 25(OH)D3/24,25(OH)2D3 ratio, have no difference among the fibrosis stages or inflammation grades.
CONCLUSION: We found that serum levels of 25(OH)D3 and its degradation metabolite 24,25(OH)2D3 did not correlate with liver fibrosis in treatment-naive Chinese patient with CHC.
doi:10.3748/wjg.v21.i39.11152
PMCID: PMC4607912  PMID: 26494969
Hepatitis C virus; 25-Hydroxyvitamin D3; 24,25-Dihydroxyvitamin D3; Fibrosis; Inflammation
20.  Repeated intra-nigrostriatal injection of phorbol myristate acetate induces microglial senescence in adult rats 
Molecular Medicine Reports  2015;12(5):7271-7278.
Phorbol myristate acetate (PMA), as a potent tumor promoter, may induce microglial senescence. The present study investigated the effect of PMA infection on microglial senescence. From 58 male Sprague-Dawley rats, 10 were randomly selected and divided into a PMA injection group, containing five rats (0.5 µg/µl PMA) and a control group, containing five rats (commensurable 0.9% saline). Immunofluorescent staining of Iba-1 and enzyme-linked immunosorbent assay analyses of the expression levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1 β were performed in these two groups. The remaining 48 rats were randomly divided into the following three groups, each containing 16 rats: Repeated injection control group (commensurable normal saline, once a week for 4 weeks), single PMA injection group (0.5 µg/µl PMA, once in the first week) and repeated injection PMA group (0.5 µg/µl PMA, once a week for 4 weeks). The expression levels of p21, detected using double immunofluorescence staining with Iba-1, and β-galactosidase, via double immunohistochemical staining of Iba-1, were examined in these three groups. The results indicated that a single injection of PMA did not change the microglial morphology and had no significant effects on the expression levels of TNF-α and IL-1β, compared with the control group (P>0.05). Following four repeated injections of PMA, the microglia in the substantia nigra presented with features of senescence, characterized by increased expression levels of β-galactosidase (P<0.001) and p21 (P<0.001), compared with the repeated injection control group. In conclusion, repeated intra-nigrostriatal treatment with PMA induced microglial senescence with increased expression levels of β-galactosidase and p21 in the substantia nigra of the rats.
doi:10.3892/mmr.2015.4412
PMCID: PMC4626136  PMID: 26459397
microglia; senescence; substantia nigra; phorbol myristate acetate
21.  Expression of CD44 and CD29 by PEComa cells suggests their possible origin of mesenchymal stem cells 
Background: Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal tumor composed of histologically and immunohistochemically distinctive perivascular epithelioid cells. The perivascular epithelioid cell (PEC) co-expresses melanocytic and muscle markers. Since no normal counterpart to the PEC has ever been identified in any normal tissue, the cell origin of these tumors is still uncertain. Although, several hypotheses have recently been advanced to explain the histogenesis of PEComa, it remains unclear. Methods: The aim of this study was to discuss whether differential expression of stem cell-associated proteins could be used to aid in determining the histogenesis of PEComa. For this purpose, we detected the immunoexpression of 5 kinds of stem cell markers on PEComas, including CD29, CD44, CD133, ALDH1, and nestin. In addition to observed histopathologic morphology, we also performed PEComa relevant clinical diagnostic markers (HMB-45, SMA, melan-A, Desmin, Ki-67, S-100 and TFE3) to identify whether they belonged to PEComas. Results: Our study included 13 PEComa samples, and we obtained positive immunoexpression results as follows: CD29 (13/13), CD44 (8/13), ALDH1 (10/13), nestin (1/13), and CD133 (0/13). Conclusions: Since CD44 and CD29 are surface proteins associated with MSCs, these results suggest that PEComa might arise from MSCs. However, whether MSCs are the origin of PEComa needs to be further explored in the future.
PMCID: PMC4680442  PMID: 26722497
Perivascular epithelioid cell tumor; stem cell markers; mesenchymal stem cells
22.  Thyroid Volume and Its Relation to Anthropometric Measures in a Healthy Cuban Population 
European Thyroid Journal  2015;4(1):55-61.
Objectives
The aim of this study was to describe the thyroid volume in healthy adults by ultrasound and to correlate this volume with some anthropometric measures and other differentiated thyroid cancer risk factors.
Study Design
Thyroid volume and anthropometric measures were recorded in a sample of 100 healthy adults, including 21 men and 79 women aged 18-50 years, living in a non-iodine-deficient area of Havana city.
Results
The average thyroid volume was 6.6 ± 0.26 ml; it was higher in men (7.3 ml) than in women (6.4 ml; p = 0.15). In the univariate analysis, thyroid volume was correlated with all anthropometric measures, but in the multivariate analysis, body surface area was found to be the only significant anthropometric parameter. Thyroid volume was also higher in current or former smokers and in persons with blood group AB or B.
Conclusion
Specific reference values of thyroid volume as a function of body surface area could be used for evaluating thyroid volume in clinical practice. The relation between body surface area and thyroid volume is coherent with what is known about the relation of thyroid volume to thyroid cancer risk, but the same is not true about the relation between thyroid volume and smoking habit.
doi:10.1159/000371346
PMCID: PMC4404892  PMID: 25960963
Thyroid volume; Ultrasound; Thyroid cancer risk factors; Case-control study
23.  Morphologic patterns and imaging features of intracranial hemangiopericytomas: a retrospective analysis 
OncoTargets and therapy  2015;8:2169-2178.
Objectives
Hemangiopericytomas (HPCs) are rare intracranial tumors. Their differential diagnosis using computed tomography (CT) and magnetic resonance imaging (MRI) is difficult because of similarities in morphologic features with other intracranial tumors and meningiomas.
Methods
We retrospectively analyzed the clinical data and CT and MRI findings of 32 patients diagnosed with HPCs via histopathology. We evaluated the location, shape, morphologic patterns, density, and signal intensity of the tumors and classified them into four types.
Results
The number of tumors analyzed was 32; 29 were supratentorial and three were infratentorial. Eighteen tumors were lobular, while 14 were oval in shape. Further, 28 tumors had cystic areas, and 16 had signal-void vessels. Among the 20 tumors that had been scanned by MRI; eleven showed isointensity, eight slight hyperintensity, and one slight hypointensity on T1-weighted image. Moreover, 12 showed isointensity, and eight showed slight hyperintensity on T2-weighted image and T2-weighted-fluid-attenuated-inversion recovery. Diffusion-weighted images showed isointensity (9/13) or slight hyperintensity (4/13). Of the 15 tumors scanned by contrast-enhanced MRI, one showed poor enhancement; six, moderate enhancement; and eight, intense enhancement. Only one tumor exhibited the “dural tail” sign. Moreover, calcification was observed in just one tumor on CT imaging (1/22). All tumors (5/5) showed intense enhancement on CT angiography, whereas some exhibited dual blood supply (2/5).
Conclusion
We conclude that tumors present outside the brain parenchyma, with isointense to slightly intense regions on MRI scans, oval/lobular shape, well-/ill-defined margins, signal-void vessels, apparent cystic areas, dual blood supply, and intense enhancement on CT or MRI scans, but without calcification or a “dural tail” sign, may be diagnosed as HPCs.
doi:10.2147/OTT.S85971
PMCID: PMC4550184  PMID: 26347312
hemangiopericytoma; computed tomography; magnetic resonance imaging
24.  Impact of a Mandatory Prescription Drug Monitoring Program on Prescription of Opioid Analgesics by Dentists 
PLoS ONE  2015;10(8):e0135957.
Prescription Drug Monitoring Programs (PDMP) are statewide databases that collect data on prescription of controlled substances. New York State mandates prescribers to consult the PDMP registry before prescribing a controlled substance such as opioid analgesics. The effect of mandatory PDMP on opioid drug prescriptions by dentists is not known. This study investigates the impact of mandatory PDMP on frequency and quantity of opioid prescriptions by dentists in a dental urgent care center. Based on the sample size estimate, we collected patient records of a 3-month period before and two consecutive 3-month periods after the mandatory PDMP implementation and analyzed the data on number of visits, treatment types and drug prescriptions using Chi-square tests. For patients who were prescribed pain medications, 452 (30.6%), 190 (14.1%), and 140 (9.6%) received opioid analgesics in the three study periods respectively, signifying a statistically significant reduction in the number of opioid prescriptions after implementation of the mandatory PDMP (p<0.05). Total numbers of prescribed opioid pills in a 3-month period decreased from 5096 to 1120, signifying a 78% reduction in absolute quantity. Prescriptions for non-opioid analgesics acetaminophen increased during the same periods (p<0.05). We conclude that the mandatory PDMP significantly affected the prescription pattern for pain medications by dentists. Such change in prescription pattern represents a shift towards the evidence-based prescription practices for acute postoperative pain.
doi:10.1371/journal.pone.0135957
PMCID: PMC4537135  PMID: 26274819
25.  Changes of Serotonin (5-HT), 5-HT2A Receptor, and 5-HT Transporter in the Sprague-Dawley Rats of Depression, Myocardial Infarction and Myocardial Infarction Co-exist with Depression 
Chinese Medical Journal  2015;128(14):1905-1909.
Background:
To evaluate whether serotonin (5-HT), 5-HT2A receptor (5-HT2AR), and 5-HT transporter (serotonin transporter [SERT]) are associated with different disease states of depression, myocardial infarction (MI) and MI co-exist with depression in Sprague-Dawley rats.
Methods:
After established the animal model of four groups include control, depression, MI and MI with depression, we measured 5-HT, 5-HT2AR and SERT from serum and platelet lysate.
Results:
The serum concentration of 5-HT in depression rats decreased significantly compared with the control group (303.25 ± 9.99 vs. 352.98 ± 13.73; P = 0.000), while that in MI group increased (381.78 ± 14.17 vs. 352.98 ± 13.73; P = 0.000). However, the depression + MI group had no change compared with control group (360.62 ± 11.40 vs. 352.98 ± 13.73; P = 0.036). The changes of the platelet concentration of 5-HT in the depression, MI, and depression + MI group were different from that of serum. The levels of 5-HT in above three groups were lower than that in the control group (380.40 ± 17.90, 387.75 ± 22.28, 246.40 ± 18.99 vs. 500.29 ± 20.91; P = 0.000). The platelet lysate concentration of 5-HT2AR increased in depression group, MI group, and depression + MI group compared with the control group (370.75 ± 14.75, 393.47 ± 15.73, 446.66 ± 18.86 vs. 273.66 ± 16.90; P = 0.000). The serum and platelet concentration of SERT in the depression group, MI group and depression + MI group were all increased compared with the control group (527.51 ± 28.32, 602.02 ± 23.32, 734.76 ± 29.59 vs. 490.56 ± 16.90; P = 0.047, P = 0.000, P = 0.000 in each and 906.38 ± 51.84, 897.33 ± 60.34, 1030.17 ± 58.73 vs. 708.62 ± 51.15; P = 0.000 in each).
Conclusions:
The concentration of 5-HT2AR in platelet lysate and SERT in serum and platelet may be involved in the pathway of MI with depression. Further studies should examine whether elevated 5-HT2AR and SERT may contribute to the biomarker in MI patients with depression.
doi:10.4103/0366-6999.160526
PMCID: PMC4717933  PMID: 26168831
5-HT; 5-HT2A Receptor; Depression; Myocardial Infarction; Serotonin Transporter

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