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1.  Widespread and evolutionary analysis of a MITE family Monkey King in Brassicaceae 
BMC Plant Biology  2015;15:149.
Miniature inverted repeat transposable elements (MITEs) are important components of eukaryotic genomes, with hundreds of families and many copies, which may play important roles in gene regulation and genome evolution. However, few studies have investigated the molecular mechanisms involved. In our previous study, a Tourist-like MITE, Monkey King, was identified from the promoter region of a flowering time gene, BnFLC.A10, in Brassica napus. Based on this MITE, the characteristics and potential roles on gene regulation of the MITE family were analyzed in Brassicaceae.
The characteristics of the Tourist-like MITE family Monkey King in Brassicaceae, including its distribution, copies and insertion sites in the genomes of major Brassicaceae species were analyzed in this study. Monkey King was actively amplified in Brassica after divergence from Arabidopsis, which was indicated by the prompt increase in copy number and by phylogenetic analysis. The genomic variations caused by Monkey King insertions, both intra- and inter-species in Brassica, were traced by PCR amplification. Genomic sequence analysis showed that most complete Monkey King elements are located in gene-rich regions, less than 3kb from genes, in both the B. rapa and A. thaliana genomes. Sixty-seven Brassica expressed sequence tags carrying Monkey King fragments were also identified from the NCBI database. Bisulfite sequencing identified specific DNA methylation of cytosine residues in the Monkey King sequence. A fragment containing putative TATA-box motifs in the MITE sequence could bind with nuclear protein(s) extracted from leaves of B. napus plants. A Monkey King-related microRNA, bna-miR6031, was identified in the microRNA database. In transgenic A. thaliana, when the Monkey King element was inserted upstream of 35S promoter, the promoter activity was weakened.
Monkey King, a Brassicaceae Tourist-like MITE family, has amplified relatively recently and has induced intra- and inter-species genomic variations in Brassica. Monkey King elements are most abundant in the vicinity of genes and may have a substantial effect on genome-wide gene regulation in Brassicaceae. Monkey King insertions potentially regulate gene expression and genome evolution through epigenetic modification and new regulatory motif production.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-015-0490-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4471910  PMID: 26084405
Brassicaceae; Brassica; Miniature inverted repeat transposable elements; Monkey King; Tourist-like MITE; DNA methylation; bna-miR6031
2.  First Demonstration of Antigen Induced Cytokine Expression by CD4-1+ Lymphocytes in a Poikilotherm: Studies in Zebrafish (Danio rerio) 
PLoS ONE  2015;10(6):e0126378.
Adaptive immunity in homeotherms depends greatly on CD4+ Th cells which release cytokines in response to specific antigen stimulation. Whilst bony fish and poikilothermic tetrapods possess cells that express TcR and CD4-related genes (that exist in two forms in teleost fish; termed CD4-1 and CD4-2), to date there is no unequivocal demonstration that cells equivalent to Th exist. Thus, in this study we determined whether CD4-1+ lymphocytes can express cytokines typical of Th cells following antigen specific stimulation, using the zebrafish (Danio rerio). Initially, we analyzed the CD4 locus in zebrafish and found three CD4 homologues, a CD4-1 molecule and two CD4-2 molecules. The zfCD4-1 and zfCD4-2 transcripts were detected in immune organs and were most highly expressed in lymphocytes. A polyclonal antibody to zfCD4-1 was developed and used with an antibody to ZAP70 and revealed double positive cells by immunohistochemistry, and in the Mycobacterium marinum disease model CD4-1+ cells were apparent surrounding the granulomas typical of the infection. Next a prime-boost experiment, using human gamma globulin as antigen, was performed and revealed for the first time in fish that zfCD4-1+ lymphocytes increase the expression of cytokines and master transcription factors relevant to Th1/Th2-type responses as a consequence of boosting with specific antigen.
PMCID: PMC4470515  PMID: 26083432
3.  Enterococcus faecalis Infection Activates Phosphatidylinositol 3-Kinase Signaling To Block Apoptotic Cell Death in Macrophages 
Infection and Immunity  2014;82(12):5132-5142.
Apoptosis is an intrinsic immune defense mechanism in the host response to microbial infection. Not surprisingly, many pathogens have evolved various strategies to manipulate this important pathway to benefit their own survival and dissemination in the host during infection. To our knowledge, no attempts have been made to explore the host cell survival signals modulated by the bacterium Enterococcus faecalis. Here, we show for the first time that during early stages of infection, internalized enterococci can prevent host cell (RAW264.7 cells, primary macrophages, and mouse embryonic fibroblasts [MEFs]) apoptosis induced by a wide spectrum of proapoptotic stimuli. Activation of caspase 3 and cleavage of the caspase 3 substrate poly(ADP-ribose) polymerase were inhibited in E. faecalis-infected cells, indicating that E. faecalis protects macrophages from apoptosis by inhibiting caspase 3 activation. This antiapoptotic activity in E. faecalis-infected cells was dependent on the activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, which resulted in the increased expression of the antiapoptotic factor Bcl-2 and decreased expression of the proapoptotic factor Bax. Further analysis revealed that active E. faecalis physiology was important for inhibition of host cell apoptosis, and this feature seemed to be a strain-independent trait among E. faecalis isolates. Employing a mouse peritonitis model, we also determined that cells collected from the peritoneal lavage fluid of E. faecalis-infected mice showed reduced levels of apoptosis compared to cells from uninfected mice. These results show early modulation of apoptosis during infection and have important implications for enterococcal pathogenesis.
PMCID: PMC4249289  PMID: 25267834
4.  Posterior indirect reduction and pedicle screw fixation without laminectomy for Denis type B thoracolumbar burst fractures with incomplete neurologic deficit 
The aim of this study is to evaluate the efficacy of posterior indirect reduction and pedicle screw fixation without laminectomy for the treatment of Denis type B thoracolumbar burst fractures with incomplete neurologic deficit.
From March 2008 to May 2012, 36 consecutive patients of Denis type B thoracolumbar burst with incomplete neurologic deficit were enrolled. All of the patients accepted the treatments of posterior indirect reduction and pedicle screw fixation without laminectomy. Clinical and radiologic outcomes were assessed preoperatively and postoperatively.
Operations were performed in a relatively short time without massive hemorrhage. Their neurologic functions were improved by at least one Frankel grade. The average score of American Spinal Injury Association (ASIA) motor increased from 25.4 ± 10.8 to 42.1 ± 10.5, and the recovery rate of the ASIA score was also increased. The pain level was relieved for all the patients. The local kyphosis angle was reduced from 25.9° ± 3.4° to 6.9° ± 2.2° (P <0.05) and remained 7.9° ± 2.0° (P > 0.05) at the latest follow-up. After the operation, the mean vertebral canal diameter increased from 5.5 ± 1.3 to 11.1 ± 2.2 mm (P < 0.05) and the mean canal stenosis index increased from 32.9 ± 7.8 to 84.8 ± 7.3 % (P < 0.05). There were no serious complications and fixation failures during follow-up.
Denis type B thoracolumbar burst fractures with incomplete neurologic deficit can be effectively treated by posterior indirect reduction and pedicle screw fixation without laminectomy.
PMCID: PMC4458344  PMID: 26021565
Thoracolumbar burst fracture; Posterior approach; Decompression; Neurologic recovery
5.  Morphology and Molecular Mechanisms of Hepatic Injury in Rats under Simulated Weightlessness and the Protective Effects of Resistance Training 
PLoS ONE  2015;10(5):e0127047.
This study investigated the effects of long-term simulated weightlessness on liver morphology, enzymes, glycogen, and apoptosis related proteins by using two-month rat-tail suspension model (TS), and liver injury improvement by rat-tail suspension with resistance training model (TS&RT). Microscopically the livers of TS rats showed massive granular degeneration, chronic inflammation, and portal fibrosis. Mitochondrial and endoplasmic reticulum swelling and loss of membrane integrity were observed by transmission electron microscopy (TEM). The similar, but milder, morphological changes were observed in the livers of TS&RT rats. Serum biochemistry analysis revealed that the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly higher (p<0.05) in TS rats than in controls. The levels of ALT and AST in TS&RT rats were slightly lower than in RT rats, but they were insignificantly higher than in controls. However, both TS and TS&RT rats had significantly lower levels (p<0.05) of serum glucose and hepatic glycogen than in controls. Immunohistochemistry demonstrated that the expressions of Bax, Bcl-2, and active caspase-3 were higher in TS rats than in TS&RT and control rats. Real-time polymerase chain reaction (real-time PCR) showed that TS rats had higher mRNA levels (P < 0.05) of glucose-regulated protein 78 (GRP78) and caspase-12 transcription than in control rats; whereas mRNA expressions of C/EBP homologous protein (CHOP) and c-Jun N-terminal kinase (JNK) were slightly higher in TS rats. TS&RT rats showed no significant differences of above 4 mRNAs compared with the control group. Our results demonstrated that long-term weightlessness caused hepatic injury, and may trigger hepatic apoptosis. Resistance training slightly improved hepatic damage.
PMCID: PMC4441474  PMID: 26000905
6.  High-speed Label-free Functional Photoacoustic Microscopy of Mouse Brain in Action 
Nature methods  2015;12(5):407-410.
We present fast functional photoacoustic microscopy (PAM), which is capable of three-dimensional high-resolution high-speed imaging of the mouse brain, complementary to other imaging modalities. A single-wavelength pulse-width-based method was implemented to image blood oxygenation with capillary-level resolution and a one-dimensional imaging rate of 100 kHz. We applied PAM to image the vascular morphology, blood oxygenation, blood flow, and oxygen metabolism in the brain in both resting and stimulated states.
PMCID: PMC4428901  PMID: 25822799
7.  Investigating Changes in Land Use Cover and Associated Environmental Parameters in Taihu Lake in Recent Decades Using Remote Sensing and Geochemistry 
PLoS ONE  2015;10(4):e0120319.
Humans have had a significant impact on the terrestrial pedosphere through activities such as agriculture and urbanization. The effects of human activities on land use and the related environmental changes were investigated through point and areal studies surrounding Meiliang Bay, which is an open area of extreme eutrophication in Taihu Lake, China. This study used remote sensing and environmental-tracer profiles [total nitrogen (TN), total phosphorus (TP), total organic carbon (TOC), grain size, and geochemical parameters] to determine the causes of changes in land use and the associated environmental parameters. The results of LUCCs (Land use/cover changes) indicate that over the past three decades, total farmland decreased by 862.49 km2, with an annual decrement rate of 28.75 km2/year, and total urbanized land increased by 859.71 km2, with an annual growth rate of 28.66 km2/year. The geochemical results indicate that the trophic state of Taihu Lake was persistently intensifying and that the TN, TP, and TOC concentrations increased twofold, threefold, and twofold, respectively, from 1949 to 2010. The sources of TN, TP, and TOC were highly similar after 1975. However, before 1974, TN and TP originated from different sources than TOC. The grassland and woodland around the lake retain nutrients and sand from the land of study area. The increase in urbanized land and tertiary industries significantly increased the sediment concentrations of TN, TP, and TOC after 1980.
PMCID: PMC4405541  PMID: 25898010
8.  Down-regulation of dual-specificity phosphatase 5 predicts poor prognosis of patients with prostate cancer 
Dual-specificity phosphatase 5 (DUSP5), which specifically inactivates the extracellular signal-regulated kinase (ERK) 1/2 within the mitogen-activated protein kinase (MAPK) signaling, has recently been considered to be a tumor suppressor. However, its role in prostate cancer is still elusive. In this study, we performed immunohistochemistry analysis on human tissue microarray (TMA) to detect the DUSP5 protein expression pattern. The results indicated that DUSP5 was down-regulated in the human prostate cancer relative to the adjacent benign tissues (IRS: PCa = 4.29 ± 1.72 versus Benign = 4.89 ± 1.58, P = 0.04). In addition, when we linked the DUSP5 protein levels to the clinicopathological features of the patients, we found that the downregulation of DUSP5 was significantly associated with advanced pathological stage (P = 0.004) and high Gleason score (P = 0.009). Moreover, we attempted to validate these findings and investigate the prognostic value of DUSP5 in a publicly available microarray-based Taylor Dataset. Statistic analysis demonstrated that the downregulation of DUSP5 was closely correlated with high Gleason score (P = 0.011), positive metastasis (P < 0.001) and biochemical recurrence (BCR) (P = 0.016). More importantly, Kaplan-Meier analysis revealed that significant differences between patients with high and low DUSP5 expression level in regard to the BCR-free survival of overall (P = 0.009), non-metastatic (P = 0.006) and patients with Gleason score 7 (P = 0.044). Multivariate analysis by Cox regression indicated that DUSP5 could be an independent predictor for the risk of BCR (HR: 0.41, 95% CI: 0.2-0.82; P = 0.012). In summary, our findings disclose that DUSP5 may be an important tumor suppressor that inhibits the progression of PCa. The downregulation of DUSP5 may accurately predict poor prognosis in PCa patients.
PMCID: PMC4443163  PMID: 26064329
Prostate cancer; dual-specificity phosphatase 5; tumor suppressor; prognosis
9.  A Study of Tapping by the Unaffected Finger of Patients Presenting with Central and Peripheral Nerve Damage 
Whether the unaffected function of the hand of patients presenting with nerve injury is affected remains inconclusive. We aimed to evaluate whether there are differences in finger tapping following central or peripheral nerve injury compared with the unaffected hand and the ipsilateral hand of a healthy subject.
Thirty right brain stroke patients with hemiplegia, 30 left arm peripheral nerve injury cases, and 60 healthy people were selected. We tested finger tapping of the right hands, and each subject performed the test twice.
Finger tapping following peripheral nerve injury as compared with the unaffected hand and the dominant hand of a healthy person was markedly higher than was found for central nerve injury (P < 0.05). Finger tapping of the male peripheral group’s unaffected hand and the control group’s dominant hand was significantly higher than the central group (P < 0.001). However, finger tapping of the female control group’s dominant hand was significantly higher than the central group’s unaffected hand (P < 0.01, P = 0.002), the peripheral group’s unaffected hand (P < 0.05, P = 0.034).
The unaffected function of the hand of patients with central and peripheral nerve injury was different as compared with the ipsilateral hand of healthy individuals. The rehabilitation therapist should intensify the practice of normal upper limb fine activities and coordination of the patient.
PMCID: PMC4429569  PMID: 26029080
central nerve; peripheral nerve; unaffected hand; dominant hand; finger tapping
10.  Endoscopic findings of gastrointestinal involvement in Chinese patients with Behcet’s disease 
World Journal of Gastroenterology : WJG  2014;20(45):17171-17178.
AIM: To report the incidence, clinical features and outcomes of gastrointestinal (GI) involvement in Behcet’s disease (BD).
METHODS: A total of 168 consecutive patients with BD were screened and upper and lower GI endoscopies were performed in 148 patients. Four hundred age- and sex-matched controls were enrolled for comparison.
RESULTS: Fifty-two (35.1%) patients had GI lesions. After a mean follow-up of 10 mo, ileocecal ulcers had been confirmed in 20 patients, including active ulcer(s) in 18 patients, but no ileocecal ulceration was found in controls. GI symptoms were present in 14 patients with active ulcer(s), while 4 patients with smaller ulcer were asymptomatic. Endoscopic features of ileocecal ulcer were: a single ulcer (50%), larger than 1 cm in diameter (72.2%), and round/oval or volcano-type in shape (83.3%). Compared with patients without GI involvement, less ocular lesions, lower levels of albumin, erythrocyte count and hemoglobin, and higher levels of C-reactive protein and erythrocyte sedimentation rate were confirmed in the intestinal BD group. Four patients had esophageal ulcers in the BD group but no case in controls. The other endoscopic findings were similar between the two groups. The prevalence of Helicobacter pylori infection was similar in both groups. Most patients received an immunomodulator and responded well.
CONCLUSION: GI lesions commonly occur in Chinese BD patients. The most frequently involved area is the ileocecal region. Esophageal ulcer might be a rare but unique lesion.
PMCID: PMC4258588  PMID: 25493032
Behcet’s disease; Gastrointestinal involvement; Ulcer; Endoscopy; Case-controlled
11.  Effect of (-)-epigallocatechin-3-gallate in preventing bone loss in ovariectomized rats and possible mechanisms 
Despite recent developments reported in studies of (-)-epigallocatechin-3-gallate (EGCG), its early preventive effect of mitigating bone loss is not well understood. We investigated the effect of EGCG in preventing bone loss in ovariectomized (OVX) female rats, and explored the possible underlying mechanisms. Twelve-week-old female Sprague-Dawley rats, were divided into 3 groups: group A received intraperitoneal EGCG for 12 consecutive weeks, begun 3 days after ovariectomy; group B received ovariectomy alone; group C, received a sham operation. At the end of the experiment, tibias and femurs were harvested for: (1) micro-CT scanning and measurement of bone mineral density (BMD) and bone morphological parameters; (2) a 3-point bending test; (3) HE staining and an immunohistological study investigating Sema4D expression. Results: The BMD and BV/TV of group A were significantly higher than for the OVX group. The trabecular separation (Tb.Sp) of group A was significantly lower than for group B. Results from the 3-point bending test showed no statistical significance among all the groups. Bone histological studies indicated that trabecular bone was denser in group C, while group B had less dense trabecular bone, and the bone morphological status of group A was intermediate between groups A and C. The immunohistological study demonstrated that Sema4D was more highly expressed as a percentage of the brown-stained area in group B than in the other 2 groups. Conclusion: EGCG had a positive effect on mitigating bone loss in ovariectomized rats, and it inhibited Sema4D expression in bone tissue. Early stage supplementation of EGCG at a dose of 10 mg/kg/day after the onset of ovariectomy did not entirely eliminate bone loss.
PMCID: PMC4276187  PMID: 25550929
EGCG; osteoporosis; bone loss; microarchitecture; BMD; Sema4D
12.  Influence of Exercise on Bone Remodeling-Related Hormones and Cytokines in Ovariectomized Rats: A Model of Postmenopausal Osteoporosis 
PLoS ONE  2014;9(11):e112845.
This study aims to explore the effects of exercise on postmenopausal osteoporosis and the mechanisms by which exercise affects bone remodeling. Sixty-three Wistar female rats were randomly divided into five groups: (1) control group, (2) sham-operated group, (3) OVX (Ovariectomy) group, (4) DES-OVX (Diethylstilbestrol-OVX) group, and (5) Ex-OVX (Exercise-OVX) group. The rat osteoporosis model was established through ovariectomy. The Ex-OVX rats were made to run 251.2 meters every day, 6 d/wk for 3 months in a running wheel. Trabecular bone volume (TBV%), total resorption surface (TRS%), trabecular formation surface (TFS%), mineralization rate (MAR), bone cortex mineralization rate (mAR), and osteoid seam width (OSW) were determined by bone histomorphometry. The mRNA and protein levels of interleukin-1β (IL-1β2), interleukin-6 (IL-6), and cyclooxygenase-2 (Cox-2) were determined by in situ hybridization and immunohistochemistry, respectively. Serum levels of estrogen estradiol (E2), calcitonin (CT), osteocalcin (BGP), and parathyroid hormone (PTH) were determined by ELISA assays. The investigation revealed that compared to the control and the sham-operated groups, the OVX group showed significantly lower levels of TBV%, E2, and CT, but much higher levels of TRS%, TFS%, MAR, OSW, BGP, and PTH. The Ex-OVX group showed increased TBV% and serum levels of E2 and CT compared to the OVX group. Ovariectomy also led to a significant increase in IL-1β mRNA and protein levels in the bone marrow and IL-6 and Cox-2 protein levels in tibias. In addition, the Ex-OVX group showed lower levels of IL-1 mRNA and protein, IL-6 mRNA, and Cox-2 mRNA and protein than those in the OVX group. The upshot of the study suggests that exercise can significantly increase bone mass in postmenopausal osteoporosis rat models by inhibiting bone resorption and increasing bone formation, especially in trabecular bones.
PMCID: PMC4231162  PMID: 25393283
13.  Whole exome sequencing reveals novel COL4A3 and COL4A4 mutations and resolves diagnosis in Chinese families with kidney disease 
BMC Nephrology  2014;15:175.
Collagen IV-related nephropathies, including thin basement membrane nephropathy and Alport Syndrome (AS), are caused by defects in the genes COL4A3, COL4A4 and COL4A5. Diagnosis of these conditions can be hindered by variable penetrance and the presence of non-specific clinical or pathological features.
Three families with unexplained inherited kidney disease were recruited from Shanghai, China. Whole exome sequencing (WES) was performed in the index case from each family and co-segregation of candidate pathogenic mutations was tested by Sanger sequencing.
We identified COL4A4 missense variants [c.G2636A (p.Gly879Glu) and c.C4715T (p.Pro1572Leu)] in the 21-year-old male proband from family 1, who had been diagnosed with mesangial proliferative nephropathy at age 14. COL4A4 c.G2636A, a novel variant, co-segregated with renal disease among maternal relatives. COL4A4 c.C4715T has previously been associated with autosomal recessive AS and was inherited from his clinically unaffected father. In family 2, a novel COL4A3 missense mutation c.G2290A (p.Gly997Glu) was identified in a 45-year-old male diagnosed with focal segmental glomerulosclerosis and was present in all his affected family members, who exhibited disease ranging from isolated microscopic hematuria to end stage renal disease (ESRD). In family 3, ESRD occurred in both male and females who were found to harbor a known AS-causing COL4A5 donor splice site mutation (c.687 + 1G > A). None of these variants were detected among 100 healthy Chinese individuals.
WES identified 2 novel and 2 known pathogenic COL4A3/COL4A4/COL4A5 mutations in 3 families with previously unexplained inherited kidney disease. These findings highlight the clinical range of collagen IV-related nephropathies and resolved diagnostic confusion arising from atypical or incomplete clinical/histological findings, allowing appropriate counselling and treatment advice to be given.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2369-15-175) contains supplementary material, which is available to authorized users.
PMCID: PMC4233041  PMID: 25381091
Collagen IV-related nephropathies; Whole exome sequencing; Novel mutation; Misdiagnosis
14.  A TIR Domain Protein from E. faecalis Attenuates MyD88-Mediated Signaling and NF-κB Activation 
PLoS ONE  2014;9(11):e112010.
Toll-like receptor signaling, mediated by functional Toll/interleukin-1 receptor (TIR) domains, plays a critical role in activating the innate immune response responsible for controlling and clearing infection. Bacterial protein mimics of components of this signaling pathway have been identified and function through inhibition of interactions between Toll-like receptors (TLRs) and their adaptor proteins, mediated by TIR domains. A previously uncharacterized gene, which we have named tcpF (for TIR domain-containing protein in E. faecalis) was identified in the genome of Enterococcus faecalis V583, and predicted to encode a protein resembling mammalian and bacterial TIR proteins. We overexpressed and purified TcpF from E. coli and found that the recombinant protein could bind to phosphatidylinositol phosphates in vitro, suggesting a mechanism by which TcpF may be anchored to the plasma membrane in close proximity to TIR domains of TLRs and adaptor proteins. Purified TcpF was also found to interact specifically with the TIR adaptor protein MyD88, and this interaction was dependent on the BB loop domain in the Box 2 region of TcpF. Despite no evidence of TcpF being a secreted protein, recombinant TcpF was effectively able to enter RAW264.7 cells in vitro although the mechanism by which this occurs remains to be determined. Overexpression of TcpF in mammalian cells suppressed the NF-κB activation induced by bacterial lipoteichoic acid. A mutant lacking the tcpF gene was attenuated for survival in macrophages, with increased ability to activate NF-κB compared to the wild type strain. Complementation in trans restored growth, and inhibition of NF-κB, to that of wild type levels. No appreciable difference in bacterial persistence, dissemination or pathogenesis was observed between the wild type and mutant in a mouse peritonitis model however, which suggested either a subtle role for TcpF or functional overlap with other redundant factor(s) in this virulence model.
PMCID: PMC4219826  PMID: 25369374
15.  Changes in motor function in the unaffected hand of stroke patients should not be ignored 
Neural Regeneration Research  2014;9(13):1323-1328.
Motor function changes in the unaffected hand of stroke patients with hemiplegia. These changes are often ignored by clinicians owing to the extent of motor disability of the affected hand. Finger tapping frequency and Lind-mark hand function score showed that the motor function of unaffected hands in stroke patients was poorer than that of a healthy control hand. After 2 weeks of rehabilitation treatment, motor function of the unaffected hand of stroke patients was obviously improved. Therefore, attention should also be paid to motor function in the unaffected hand of stroke patients with hemiplegia during rehabilitation.
PMCID: PMC4160860  PMID: 25221586
nerve regeneration; stroke; unaffected hand; dominant hand; right hand; finger tapping; Lind-mark hand function assessment; rehabilitation training; neural regeneration
16.  Conversion of Human Fibroblasts to Functional Endothelial Cells by Defined Factors 
Transdifferentiation of fibroblasts to endothelial cells (ECs) may provide a novel therapeutic avenue for diseases including ischemia and fibrosis. Here we demonstrate that human fibroblasts can be transdifferentiated into functional ECs by using only two factors, Oct4 and Klf4, under inductive signaling conditions.
Approach and Results
To determine if human fibroblasts could be converted into ECs by transient expression of pluripotency factors, human neonatal fibroblasts were transduced with lentiviruses encoding Oct4 and Klf4 in the presence of soluble factors that promote the induction of an endothelial program. After 28 days, clusters of induced endothelial (iEnd) cells appeared and were isolated for further propagation and subsequent characterization. The iEnd cells resembled primary human ECs in their transcriptional signature by expressing endothelial phenotypic markers such as CD31, VE-cadherin, and von Willebrand Factor. Furthermore, the iEnd cells could incorporate acetylated low density lipoprotein, and form vascular structures in vitro and in vivo. When injected into the ischemic limb of mice, the iEnd cells engrafted, increased capillary density, and enhanced tissue perfusion. During the transdifferentiation process, the endogenous pluripotency network was not activated, suggesting that this process bypassed a pluripotent intermediate step.
Pluripotent factor–induced transdifferentiation can be successfully applied for generating functional autologous ECs for therapeutic applications.
PMCID: PMC3898631  PMID: 23520160
angiogenesis; endothelium; peripheral vascular disease; stem cells; transdifferentiation; direct reprogramming
17.  Effect of occipitocervical fusion with screw-rod system for upper cervical spine tumor 
BMC Surgery  2014;14:30.
Craniospinal junction tumors are rare but severe lesions. Surgical stabilization has been established to be an ideal treatment for upper cervical tumor pathology. The purpose of this study was to evaluate the effect of a screw-rod system for occipitocervical fusion.
A total of 24 cases with C1 and C2 cervical tumor underwent occipitocervical fusion with Vertex screw-rod internal fixation from January 2005 to December 2012. Preoperative X-ray and MRI examinations were performed on all patients before the operation, after the operation, and during last follow-up. The JOA score was used to assess neurological function pre and postoperatively.
All the patients were followed up for 6 to 42 months with an average of 24 months. The result of X-ray showed that bony fusion was successful in 18 patients at 3 months and 6 patients at 6 months of follow-ups. There was no deterioration of spinal cord injury. The JOA Scores of neurological function increased significantly.
The screw-rod system offers strong fixation and good fusion for occipitocervical fusion. It is an effective and reliable method for reconstruction of upper cervical spine tumor.
PMCID: PMC4032630  PMID: 24884456
Occipitocervical fusion; Upper cervical spine; Tumor; Reconstruction
18.  Spectral- and time-domain optical coherence tomography measurements of macular thickness in young myopic eyes 
Diagnostic Pathology  2014;9:38.
To evaluate the variation in macular retinal thickness and volume in young Chinese myopic patients using time-domain optical coherence tomography (Stratus TD-OCT) and spectral-domain optical coherence tomography (Cirrus HD-OCT).
Ninety-two eyes of 92 myopic subjects were recruited in this study. Based upon spherical equivalence (SE), subjects were divided into two groups: the low to moderate myopia group (-0.5 D ≤ SE < -6.0 D), and the high myopia group (SE ≥ -6.0 D). Stratus TD-OCT and Cirrus HD-OCT were used to compare macular retinal thickness and volume between the two groups. Bland–Altman analysis and Pearson correlation were used to measure agreement between the two OCT systems.
Average macular retinal thickness and total macular volume measured by Cirrus HD-OCT and Stratus TD-OCT of the low to moderate myopia group were 283.52 ± 12.14 μm and 245.38 ± 8.55 μm, respectively, and 10.08 ± 0.37 mm3 and 6.85 ± 0.26 mm3, respectively, and the high myopia groups were 269.58 ± 10.72 μm and 235.65 ± 7.54 μm, respectively, and 9.71 ± 0.36 mm3 and 6.52 ± 0.25 mm3, respectively. The measurements of the two OCTs showed that macular retinal thickness of the parafovea was significantly lower in the high myopia group compared with the low to moderate myopia group, except at the fovea (all P-values less than 0.001, except at the fovea). Using the Bland–Altman method and Pearson correlation, measurements of macular thickness in nine macular retinal subfields and total macular volumes showed good agreement between the two OCTs in myopic eyes (all P-values less than 0.001), with better agreement in the low to moderate myopia group than in the high myopia group.
The average macular retinal thickness of the fovea did not vary with myopia, while the total volume and retinal thickness of the parafovea were thinner with increasing myopia. There was good agreement between the two OCTs in myopic eyes in all macular subfields, and the Cirrus HD-OCT system provided thicker macular retinal thickness measurements than the Stratus TD-OCT system.
Virtual slides
The virtual slides for this article can be found here:
PMCID: PMC3996088  PMID: 24555908
Myopia; Macular retinal thickness; Optical coherence tomography; Time-domain; Spectral-domain
19.  Dry eye management in a Sjögren’s syndrome mouse model by inhibition of p38-MAPK pathway 
To investigate the therapeutic effect of p38-MAPK inhibitor, SB203580, on dry eye in a mouse model of Sjögren’s syndrome (MRL/lpr mice).
18 female BALB/c mice and 44 female MRL/lpr mice were included. Mice were randomly assigned to the control or treatment group. The expression of phospho-p38 MAPK in lacrimal glands of BALB/c mice was determined by Western blot analysis following IL-1β treatment at various time points. Different doses of SB203580 were injected into lacrimal glands of MRL/lpr mice and phenol red thread test was performed seven days post-injection. Moreover, the levels of acetylcholine and norepinephrine expression in lacrimal glands of MRL/lpr mice were measured using spectrofluoremetric assay and the histopathology of lacrimal glands was also evaluated.
The expression of p-p38 MAPK in lacrimal glands of BALB/c mice gradually increased following incubation with IL-1β ex vivo. Injection of SB203580 into lacrimal glands significantly improved the results of phenol red thread test in MRL/lpr mice. In addition, the secretions of acetylcholine and norepinephrine increased significantly compared to the control group. Less lymphocytes infiltration was observed in pathological section of lacrimal glands following SB203580 injection.
Our results indicate that the activation of p38-MAPK pathway plays an important role in dry eye of a Sjögren’s syndrome mouse model. Inhibition of p38-MAPK pathway by SB203580 might have potential therapeutic effect on Sjögren’s syndrome associated dry eye.
Virtual slides
The virtual slides for this article can be found here:
PMCID: PMC3976089  PMID: 24443980
Sjögren’s syndrome; Dry eye; Interleukin-1β; p38-MAPK pathway
20.  Effect of aerobic exercise and low carbohydrate diet on pre-diabetic non-alcoholic fatty liver disease in postmenopausal women and middle aged men – the role of gut microbiota composition: study protocol for the AELC randomized controlled trial 
BMC Public Health  2014;14:48.
Pre-diabetes and non-alcoholic fatty liver disease (NAFLD) are associated with an unhealthy lifestyle and pose extremely high costs to the healthcare system. In this study, we aim to explore whether individualized aerobic exercise (AEx) and low carbohydrate diet (LCh) intervention affect hepatic fat content (HFC) in pre-diabetes via modification of gut microbiota composition and other post-interventional effects.
A 6-month randomized intervention with 6-month follow-up is conducted from January 2013 to December 2015. The target sample size for intervention is 200 postmenopausal women and middle-aged men aged 50–65 year-old with pre-diabetes and NAFLD. The qualified subjects are randomized into 4 groups with 50 subjects in each group: 1 = AEx, 2 = LCh, 3 = AEx + LCh, and 4 = control. In addition, two age-matched reference groups (5 = pre-diabetes without NAFLD (n = 50) and 6 = Healthy without pre-diabetes or NAFLD (n = 50)) are included. The exercise program consists of progressive and variable aerobic exercise (intensity of 60 to 75% of initial fitness level, 3–5 times/week and 30–60 min/time). The diet program includes dietary consultation plus supplementation with a special lunch meal (40% of total energy intake/day) which aims to reduce the amount of carbohydrate consumption (30%). The control and reference groups are advised to maintain their habitual habits during the intervention. The primary outcome measures are HFC, serum metabolomics and gut microbiota composition. The secondary outcome measures include body composition and cytokines. In addition, socio-psychological aspects, social support, physical activity and diet will be performed by means of questionnaire and interview.
Specific individualized exercise and diet intervention in this study offers a more efficient approach for liver fat reduction and diabetes prevention via modification of gut microbiota composition. Besides, the study explores the importance of incorporating fitness assessment and exercise in the management of patients with pre-diabetes and fatty liver disorders. If our program is shown to be effective, it will open new strategies to combat these chronic diseases.
Trial registration
Current Controlled Trials: ISRCTN42622771.
PMCID: PMC3897962  PMID: 24438438
Liver fat content; Glucose metabolism; Lipid metabolism; Gut microbiota; Metabonomics; Human; Clinical setting
21.  Impact and clinical significance of pedicle length on spinal canal and intervertebral foramen area 
The aim of this study was to measure changes in the cross-sectional area of the spinal canal and the area of the intervertebral foramen for each pedicle segment before and after the pedicle extension using computer-simulated transpedicular osteotomy to provide a theoretical basis for clinical decompression in the lumbar spinal canal. Using spiral CT scanning of the original lumbar spine, a finite element model was established. The pedicle was cut and extended by 2 mm, 4 mm, 6 mm, and 8 mm for respective modeling. The changes in the area of each plane of the vertebral canal and the area of the intervertebral foramen were measured. With the gradual extension of the pedicle, the areas of the spinal canal and intervertebral foramen also significantly increased compared with those of the original lumbar spine (P<0.05). The extension of the pedicle using transpedicular osteotomy can significantly increase the cross-sectional area of the lumbar canal and the area of the intervertebral foramen. This finding provides a new theoretically practicable method for the clinical decompression of the lumbar spinal canal.
PMCID: PMC3902255  PMID: 24482703
Spinal stenosis; pedicle length; finite element method; osteotomy
22.  Monitoring somatosensory evoked potentials in spinal cord ischemia-reperfusion injury 
Neural Regeneration Research  2013;8(33):3087-3094.
It remains unclear whether spinal cord ischemia-reperfusion injury caused by ischemia and other non-mechanical factors can be monitored by somatosensory evoked potentials. Therefore, we monitored spinal cord ischemia-reperfusion injury in rabbits using somatosensory evoked potential detection technology. The results showed that the somatosensory evoked potential latency was significantly prolonged and the amplitude significantly reduced until it disappeared during the period of spinal cord ischemia. After reperfusion for 30–180 minutes, the amplitude and latency began to gradually recover; at 360 minutes of reperfusion, the latency showed no significant difference compared with the pre-ischemic value, while the somatosensory evoked potential amplitude in-creased, and severe hindlimb motor dysfunctions were detected. Experimental findings suggest that changes in somatosensory evoked potential latency can reflect the degree of spinal cord ischemic injury, while the amplitude variations are indicators of the late spinal cord reperfusion injury, which provide evidence for the assessment of limb motor function and avoid iatrogenic spinal cord injury.
PMCID: PMC4158706  PMID: 25206629
neural regeneration; spinal cord injury; somatosensory evoked potentials; spinal cord; ischemia; reperfusion; iatrogenic spinal cord injury; histopathology; abdominal aorta occlusion model; latency; grants-supported paper; neuroregeneration
23.  Intracellular Interferons in Fish: A Unique Means to Combat Viral Infection 
PLoS Pathogens  2013;9(11):e1003736.
We demonstrate for the first time in vertebrates, that alternative splicing of interferon (IFN) genes can lead to a functional intracellular IFN (iIFN). Fish IFN genes possess introns and in rainbow trout three alternatively spliced transcripts of the IFN1 gene exist. Two of the encoded IFNs are predicted to lack a signal peptide. When overexpressed these iIFNs induce antiviral responses. Variants of the two IFNR receptor chains (IFNAR1 and IFNAR2) lacking a signal peptide are also present in trout. Transfection of HEK 293T cells with the iIFN and iIFNR molecules results in STAT phosphorylation and induction of antiviral genes. These results show that fish possess a functioning iIFN system that may act as a novel defence to combat viral infection.
Author Summary
The type I interferon (IFN) family consists of multiple members which are encoded by intronless genes in reptiles, birds and mammals but intron-containing genes in amphibians and fish. They coordinate antiviral defence by binding to cell surface receptors. Here, we demonstrate for the first time in vertebrates, that intracellular IFNs can be produced from alternatively spliced IFN transcripts and are able to elicit cellular responses through intracellular IFN receptors. This functional intracellular IFN system in fish may play a significant role in activating antiviral pathways in cells infected with virus or in neighbouring cells, and represents a novel defence to combat viral pathogens.
PMCID: PMC3828176  PMID: 24244163
24.  Bone transport combined with locking plate and bone grafting for treatment of nonunion of the ulna: a case report 
Study design: Nonunion complicating ulna fracture surgery in one patient. OBJECTIVE: To treat nonunion of the ulna using bone transport combined with locking plate and bone grafting. Methods: A 54-year-old male patient developing nonunion of the ulna 3 years after left ulna fracture surgery was included in this study. Bone transport combined with locking plate and bone grafting was applied to treat the patient, with the purpose of achieving the goal of bone healing at the site where nonunion occurred. Results: Postoperative imaging data of the patient suggested bone healing at the site where nonunion and bone transport (by osteotomy) occurred. The patient had no special chief complaints and his forearm rotation functions were normal. Conclusion: Bone transport combined with locking plate and bone grafting can provide a new option for treatment of nonunion of the ulna.
PMCID: PMC3832341  PMID: 24260610
Nonunion; bone transport; ulna fracture; locking plate
25.  ¹H NMR-based metabolic profiling of human rectal cancer tissue 
Molecular Cancer  2013;12:121.
Rectal cancer is one of the most prevalent tumor types. Understanding the metabolic profile of rectal cancer is important for developing therapeutic approaches and molecular diagnosis.
Here, we report a metabonomics profiling of tissue samples on a large cohort of human rectal cancer subjects (n = 127) and normal controls (n = 43) using 1H nuclear magnetic resonance (1H NMR) based metabonomics assay, which is a highly sensitive and non-destructive method for the biomarker identification in biological systems. Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA) and orthogonal projection to latent structure with discriminant analysis (OPLS-DA) were applied to analyze the 1H-NMR profiling data to identify the distinguishing metabolites of rectal cancer.
Excellent separation was obtained and distinguishing metabolites were observed among the different stages of rectal cancer tissues (stage I = 35; stage II = 37; stage III = 37 and stage IV = 18) and normal controls. A total of 38 differential metabolites were identified, 16 of which were closely correlated with the stage of rectal cancer. The up-regulation of 10 metabolites, including lactate, threonine, acetate, glutathione, uracil, succinate, serine, formate, lysine and tyrosine, were detected in the cancer tissues. On the other hand, 6 metabolites, including myo-inositol, taurine, phosphocreatine, creatine, betaine and dimethylglycine were decreased in cancer tissues. These modified metabolites revealed disturbance of energy, amino acids, ketone body and choline metabolism, which may be correlated with the progression of human rectal cancer.
Our findings firstly identify the distinguishing metabolites in different stages of rectal cancer tissues, indicating possibility of the attribution of metabolites disturbance to the progression of rectal cancer. The altered metabolites may be as potential biomarkers, which would provide a promising molecular diagnostic approach for clinical diagnosis of human rectal cancer. The role and underlying mechanism of metabolites in rectal cancer progression are worth being further investigated.
PMCID: PMC3819675  PMID: 24138801

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