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2.  Coxsackievirus A16 induced neurological disorders in young gerbils which could serve as a new animal model for vaccine evaluation 
Scientific Reports  2016;6:34299.
Coxsackievirus A16 (CA16) is one of the major pathogens associated with human hand, foot, and mouth disease (HFMD) in the Asia-pacific region. Although CA16 infections are generally mild, severe neurological manifestations or even death has been reported. Studies on CA16 pathogenesis and vaccine development are severely hampered because the small animal models that are currently available show major limitations. In this study, gerbils (Meriones unguiculatus) were investigated for their suitability as an animal model to study CA16 pathogenesis and vaccine development. Our results showed that gerbils up to the age of 21 days were fully susceptible to CA16 and all died within five days post-infection. CA16 showed a tropism towards the skeletal muscle, spinal cord and brainstem of gerbils, and severe lesions, including necrosis, were observed. In addition, an inactivated CA16 whole-virus vaccine administrated to gerbils was able to provide full protection to the gerbils against lethal doses of CA16 strains. These results demonstrate that gerbils are a suitable animal model to study CA16 infection and vaccine development.
doi:10.1038/srep34299
PMCID: PMC5035925  PMID: 27667023
3.  Circulating miR-185 might be a novel biomarker for clinical outcome in patients with dilated cardiomyopathy 
Scientific Reports  2016;6:33580.
B cells contribute to the development of dilated cardiomyopathy (DCM) by inducing myocyte injuries and myocardial fibrosis. Our recent research indicated that microRNA (miR) -185 participated in human B-cell activation. Thus, this study was aimed to explore the relationship between miR-185 and DCM progression. Forty-one healthy volunteers and fifty newly diagnosed DCM patients were enrolled. The levels of plasma miR-185, TNF-α secreting B cells, and anti-heart autoantibody were detected. We found that the mean levels of plasma miR-185 in DCM patients were significantly higher than those in healthy controls. Furthermore, these DCM patients could be divided into miR-185high and miR-185low groups according to the cluster distribution. During one-year follow-up period, the miR-185high group showed apparent improvements in left ventricular ejection fraction, left ventricular end diastolic diameter, and NT-proBNP, accompanied by significant declines in both cardiovascular mortality and total admissions for heart failure re-hospitalizations. In addition, the levels of anti-β1-AR antibody and TNF-α secreting B cells were also reduced in miR-185high group. These findings suggested that high miR-185 levels might be associated with a favorable prognosis by repressing B cell function in DCM. The findings of this study need to be confirmed with larger sample size and longer duration of observation.
doi:10.1038/srep33580
PMCID: PMC5028782  PMID: 27645404
4.  Retinal transcriptome sequencing sheds light on the adaptation to nocturnal and diurnal lifestyles in raptors 
Scientific Reports  2016;6:33578.
Owls (Strigiformes) represent a fascinating group of birds that are the ecological night-time counterparts to diurnal raptors (Accipitriformes). The nocturnality of owls, unusual within birds, has favored an exceptional visual system that is highly tuned for hunting at night, yet the molecular basis for this adaptation is lacking. Here, using a comparative evolutionary analysis of 120 vision genes obtained by retinal transcriptome sequencing, we found strong positive selection for low-light vision genes in owls, which contributes to their remarkable nocturnal vision. Not surprisingly, we detected gene loss of the violet/ultraviolet-sensitive opsin (SWS1) in all owls we studied, but two other color vision genes, the red-sensitive LWS and the blue-sensitive SWS2, were found to be under strong positive selection, which may be linked to the spectral tunings of these genes toward maximizing photon absorption in crepuscular conditions. We also detected the only other positively selected genes associated with motion detection in falcons and positively selected genes associated with bright-light vision and eye protection in other diurnal raptors (Accipitriformes). Our results suggest the adaptive evolution of vision genes reflect differentiated activity time and distinct hunting behaviors.
doi:10.1038/srep33578
PMCID: PMC5028738  PMID: 27645106
5.  Single-Molecule Imaging Reveals the Activation Dynamics of Intracellular Protein Smad3 on Cell Membrane 
Scientific Reports  2016;6:33469.
Smad3 is an intracellular protein that plays a key role in propagating transforming growth factor β (TGF-β) signals from cell membrane to nucleus. However whether the transient process of Smad3 activation occurs on cell membrane and how it is regulated remains elusive. Using advanced live-cell single-molecule fluorescence microscopy to image and track fluorescent protein-labeled Smad3, we observed and quantified, for the first time, the dynamics of individual Smad3 molecules docking to and activation on the cell membrane. It was found that Smad3 docked to cell membrane in both unstimulated and stimulated cells, but with different diffusion rates and dissociation kinetics. The change in its membrane docking dynamics can be used to study the activation of Smad3. Our results reveal that Smad3 binds with type I TGF-β receptor (TRI) even in unstimulated cells. Its activation is regulated by TRI phosphorylation but independent of receptor endocytosis. This study offers new information on TGF-β/Smad signaling, as well as a new approach to investigate the activation of intracellular signaling proteins for a better understanding of their functions in signal transduction.
doi:10.1038/srep33469
PMCID: PMC5027577  PMID: 27641076
6.  Radiation Changes the Metabolic Profiling of Melanoma Cell Line B16 
PLoS ONE  2016;11(9):e0162917.
Radiation therapy can be an effective way to kill cancer cells using ionizing radiation, but some tumors are resistant to radiation therapy and the underlying mechanism still remains elusive. It is therefore necessary to establish an appropriate working model to study and monitor radiation-mediated cancer therapy. In response to cellular stress, the metabolome is the integrated profiling of changes in all metabolites in cells, which can be used to investigate radiation tolerance mechanisms and identify targets for cancer radiation sensibilization. In this study, using 1H nuclear magnetic resonance for untargeted metabolic profiling in radiation-tolerant mouse melanoma cell line B16, we comprehensively investigated changes in metabolites and metabolic network in B16 cells in response to radiation. Principal component analysis and partial least squares discriminant analysis indicated the difference in cellular metabolites between the untreated cells and X-ray radiated cells. In radiated cells, the content of alanine, glutamate, glycine and choline was increased, while the content of leucine, lactate, creatine and creatine phosphate was decreased. Enrichment analysis of metabolic pathway showed that the changes in metabolites were related to multiple metabolic pathways including the metabolism of glycine, arginine, taurine, glycolysis, and gluconeogenesis. Taken together, with cellular metabolome study followed by bioinformatic analysis to profile specific metabolic pathways in response to radiation, we deepened our understanding of radiation-resistant mechanisms and radiation sensibilization in cancer, which may further provide a theoretical and practical basis for personalized cancer therapy.
doi:10.1371/journal.pone.0162917
PMCID: PMC5025142  PMID: 27631970
7.  The critical role of phase difference in gamma oscillation within the temporoparietal network for binding visual working memory 
Scientific Reports  2016;6:32138.
How does the brain enable us to remember two or more object representations in visual working memory (VWM) without confusing them? This “gluing” process, or feature binding, refers to the ability to join certain features together while keeping them segregated from others. Recent neuroimaging research has reported higher BOLD response in the left temporal and parietal cortex during a binding-VWM task. However, less is known about how the two regions work in synchrony to support such process. In this study, we applied transcranial alternating current stimulation (tACS) over the left temporal and parietal cortex in gamma and theta frequency, with a phase difference of either 0° (in-phase) or 180° (anti-phase) to account for the different ways through which neural synchronization may occur. We found no facilitatory or inhibitory effect from sham, theta, and in-phase gamma stimulation. Importantly, there was an enhancement effect from anti-phase gamma tACS that was binding-specific, and such effect was only apparent in low-performing individuals who had room for improvement. Together, these results demonstrate that binding-VWM is supported by a temporally-precise oscillatory mechanism within the gamma frequency range, and that the advantageous 180°-apart phase relationship also implies a possible temporal driver-to-receiver time-lag between the temporal and parietal cortex.
doi:10.1038/srep32138
PMCID: PMC5004173  PMID: 27573864
8.  A novel SoxB2 gene is required for maturation of sperm nucleus during spermiogenesis in the Chinese mitten crab, Eriocheir sinensis 
Scientific Reports  2016;6:32139.
SRY-related HMG box (Sox) genes are characterized by the presence of a DNA-binding HMG domain and involved in a diverse range of developmental processes. In this study, we identified a novel Sox gene, designated as EsSoxB2-1, from the Chinese mitten crab Eriocheir sinensis. The EsSoxB2-1 encodes a protein of 259 amino acids, sharing the highest identity with the beetle Tribolium castaneum SOX21b. Unlike insect Sox21b, however, EsSoxB2-1 is intronless and exhibits a gonad-specific expression pattern at both mRNA and protein level. Two core promoters in 5′ flanking region were demonstrated to be essential for inducing transcriptional regulatory activity. The transcription of EsSoxB2-1 mRNA begins in spermatogonia stage, while the translation of EsSOXB2-1 protein initiates at spermiogenesis stage. Interestingly, EsSOXB2-1 protein was exclusively localized in the nucleus of spermatid and spermatozoa even at the end of acrosome reaction, and was bound to the uncondensed chromatin in nucleoplasm of mature spermatozoa. Knockdown of EsSoxB2-1 by RNAi leads to abnormal transformation of the nucleus during spermiogenesis. Together, these findings demonstrated the requirement of EsSoxB2-1 for the spermatozoa nucleus maturation and also suggested that EsSoxB2-1 would be delivered into fertilized eggs along with chromatins as a paternal transcription factor for regulating early embryonic development.
doi:10.1038/srep32139
PMCID: PMC4999818  PMID: 27561408
9.  Fast diffusion of silver in TiO2 nanotube arrays 
Summary
Using magnetron sputtering and heat treatment, Ag@TiO2 nanotubes are prepared. The effects of heat-treatment temperature and heating time on the evolution of Ag nanofilms on the surface of TiO2 nanotubes and microstructure of Ag nanofilms are investigated by X-ray diffraction, field emission scanning electron microscopy, and transmission electron microscopy. Ag atoms migrate mainly on the outmost surface of the TiO2 nanotubes, and fast diffusion of Ag atoms is observed. The diffusivity for the diffusion of Ag atoms on the outmost surface of the TiO2 nanotubes at 400 °C is 6.87 × 10−18 m2/s, which is three orders of magnitude larger than the diffusivities for the diffusion of Ag through amorphous TiO2 films. The activation energy for the diffusion of Ag atoms on the outmost surface of the TiO2 nanotubes in the temperature range of 300 to 500 °C is 157 kJ/mol, which is less than that for the lattice diffusion of Ag and larger than that for the grain boundary diffusion. The diffusion of Ag atoms leads to the formation of Ag nanocrystals on the outmost surface of TiO2 nanotubes. Probably there are hardly any Ag nanocrystals formed inside the TiO2 nanotubes through the migration of Ag.
doi:10.3762/bjnano.7.105
PMCID: PMC4979750  PMID: 27547630
activation energy; fast diffusion; magnetron sputtering; silver; TiO2 nanotube
10.  Protective Effects of Berberine on Renal Injury in Streptozotocin (STZ)-Induced Diabetic Mice 
Diabetic nephropathy (DN) is a serious diabetic complication with renal hypertrophy and expansion of extracellular matrices in renal fibrosis. Epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells may be involved in the main mechanism. Berberine (BBR) has been shown to have antifibrotic effects in liver, kidney and lung. However, the mechanism of cytoprotective effects of BBR in DN is still unclear. In this study, we investigated the curative effects of BBR on tubulointerstitial fibrosis in streptozotocin (STZ)-induced diabetic mice and the high glucose (HG)-induced EMT in NRK 52E cells. We found that BBR treatment attenuated renal fibrosis by activating the nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway in the diabetic kidneys. Further revealed that BBR abrogated HG-induced EMT and oxidative stress in relation not only with the activation of Nrf2 and two Nrf2-targeted antioxidative genes (NQO-1 and HO-1), but also with the suppressing the activation of TGF-β/Smad signaling pathway. Importantly, knockdown Nrf2 with siRNA not only abolished the BBR-induced expression of HO-1 and NQO-1 but also removed the inhibitory effect of BBR on HG-induced activation of TGF-β/Smad signaling as well as the anti-fibrosis effects. The data from present study suggest that BBR can ameliorate tubulointerstitial fibrosis in DN by activating Nrf2 pathway and inhibiting TGF-β/Smad/EMT signaling activity.
doi:10.3390/ijms17081327
PMCID: PMC5000724  PMID: 27529235
renal tubular epithelial cells; berberbine; EMT; diabetic nephropathy; Nrf2 pathway; TGF-β/Smad signaling pathway
11.  Early Phthalates Exposure in Pregnant Women Is Associated with Alteration of Thyroid Hormones 
PLoS ONE  2016;11(7):e0159398.
Introduction
Previous studies revealed that phthalate exposure could alter thyroid hormones during the last trimester of pregnancy. However, thyroid hormones are crucial for fetal development during the first trimester. We aimed to clarify the effect of phthalate exposure on thyroid hormones during early pregnancy.
Method
We recruited 97 pregnant women who were offered an amniocentesis during the early trimester from an obstetrics clinic in southern Taiwan from 2013 to 2014. After signing an informed consent form, we collected amniotic fluid and urine samples from pregnant women to analyze 11 metabolites, including mono-ethyl phthalate (MEP), mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-(2-ethylhexyl) phthalate (MEHP), mono-butyl phthalate (MnBP), of 9 phthalates using liquid chromatography/ tandem mass spectrometry. We collected blood samples from each subject to analyze serum thyroid hormones including thyroxine (T4), free T4, and thyroid-binding globulin (TBG).
Results
Three phthalate metabolites were discovered to be >80% in the urine samples of the pregnant women: MEP (88%), MnBP (81%) and MECPP (86%). Median MnBP and MECPP levels in pregnant Taiwanese women were 21.5 and 17.6 μg/g-creatinine, respectively, that decreased after the 2011 Taiwan DEHP scandal. Results of principal component analysis suggested two major sources (DEHP and other phthalates) of phthalates exposure in pregnant women. After adjusting for age, gestational age, TBG, urinary creatinine, and other phthalate metabolites, we found a significantly negative association between urinary MnBP levels and serum T4 (β = –5.41; p-value = 0.012; n = 97) in pregnant women using Bonferroni correction.
Conclusion
We observed a potential change in the thyroid hormones of pregnant women during early pregnancy after DnBP exposure. Additional study is necessitated to clarify these associations.
doi:10.1371/journal.pone.0159398
PMCID: PMC4959782  PMID: 27455052
12.  Gas1 up-regulation is inducible and contributes to cell apoptosis in reactive astrocytes in the substantia nigra of LPS and MPTP models 
Background
Reactive astrogliosis is a remarkable pathogenetic hallmark of the brains of Parkinson’s disease (PD) patients, but its progressive fate and regulation mechanisms are poorly understood. In this study, growth arrest specific 1 (Gas1), a tumor growth suppressor oncogene, was identified as a novel modulator of the cell apoptosis of reactive astrocytes in primary culture and the injured substantia nigra.
Methods
Animal models and cell cultures were utilized in the present study. Lipopolysaccharide (LPS)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated animal models were used to detect Gas1 expression in the brain via immunohistochemistry and western blot. Cell cultures were performed to analyze Gas1 functions in the viability and apoptosis of reactive astrocytes and SH-SY5Y cells by double labeling, CCK-8, LDH, TUNEL, flow cytometry, and siRNA knockdown methods.
Results
Gas1 expressions were significantly elevated in the majority of the reactive astrocytes of the brains with LPS or MPTP insults. In the injured substantia nigras, GFAP-positive astrocytes exhibited higher levels of cleaved caspase-3. In cell culture, the up-regulated Gas1 expression induced apoptosis of reactive astrocytes that were insulted by LPS in combination with interferon-γ and tumor necrosis factor-a. This effect was confirmed through siRNA knockdown of Gas1 gene expression. Finally and interestingly, the potential underlying signaling pathways were evidently related to an increase in the Bax/Bcl-2 ratio, the abundant generation of reactive oxygen species and the activation of cleaved caspase-3.
Conclusions
This study demonstrated that the up-regulation of inducible Gas1 contributed to the apoptosis of reactive astrocytes in the injured nigra. Gas1 signaling may function as a novel regulator of astrogliosis and is thus a potential intervention target for inflammatory events in PD conditions.
Electronic supplementary material
The online version of this article (doi:10.1186/s12974-016-0643-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12974-016-0643-2
PMCID: PMC4938987  PMID: 27391369
Gas1; Astrocytes; Apoptosis; Substantia nigra; Neuroinflammation; Parkinson’s disease
13.  MiR-26a enhances miRNA biogenesis by targeting Lin28B and Zcchc11 to suppress tumor growth and metastasis 
Oncogene  2013;33(34):4296-4306.
Human cancers often exhibit attenuated miRNA biogenesis and global underexpression of miRNAs, thus targeting the miRNA biogenesis pathway represents a novel strategy for cancer therapy. Here, we report that miR-26a enhances miRNA biogenesis, which acts as a common mechanism partially accounting for miR-26a function in diverse cancers, including melamona, prostate and liver cancer. miR-26a was broadly reduced in multiple cancers and overexpression of miR-26a significantly suppressed tumor growth and metastasis both in vitro and in vivo, including melanoma, prostate and liver cancer. Notably, miR-26a overexpression was accompanied by global upregulation of miRNAs, especially let-7, and let-7 expression was concordant with miR-26a expression in cancer cell lines, xenograft tumors and normal human tissues, underscoring their biologic relevance. We showed that miR-26a directly targeted Lin28B and Zcchc11, two critical repressors of let-7 maturation. Furthermore, we have demonstrated that Zcchc11 promoted tumor growth and metastasis and it was prominently overexpressed in human cancers. Our findings thus provide a novel mechanism by which a miRNA acts as a modulator of miRNA biogenesis. These results also define a role of the miR-26a and Zcchc11 in tumorigenesis and metastasis, and have implications to develop new strategies for cancer therapy.
doi:10.1038/onc.2013.385
PMCID: PMC4873289  PMID: 24056962
miR-26a; Zcchc11; let-7; miRNA biogenesis; tumorigenesis; metastasis
14.  PFN2, a novel marker of unfavorable prognosis, is a potential therapeutic target involved in esophageal squamous cell carcinoma 
Background
Esophageal squamous cell carcinoma (ESCC) is one of the most aggressively malignant tumors with dismal prognosis. Profilin 2 (PFN2) is an actin-binding protein that regulates the dynamics of actin polymerization and plays a key role in cell motility. Recently, PFN2 have emerged as significant regulators of cancer processes. However, the clinical significance and biological function of PFN2 in ESCC remain unclear.
Methods
PFN2 protein expression was validated by immunohistochemistry (IHC) on tissue microarray from Chinese Han and Kazakh populations with ESCC. The associations among PFN2 expression, clinicopathological features, and prognosis of ESCC were analyzed. The effects on cell proliferation, invasion and migration were examined using MTT and Transwell assays. Markers of epithelial–mesenchymal transition (EMT) were detected by Western blot analysis.
Results
Compared with normal esophageal epithelium (NEE), PFN2 protein expression was markedly increased in low-grade intraepithelial neoplasia (LGIN), high-grade intraepithelial neoplasia (HGIN), and ESCC, increased gradually from LGIN to ESCC, and finally reached high grade in HGIN in the Han population. Similarly, PFN2 protein was more overexpressed in ESCC than in NEE in the Kazakh population. The results of Western blot analysis also showed that PFN2 expression was significantly higher in the ESCC tissue than in a matched adjacent non-cancerous tissue. PFN2 expression was positively correlated with invasion depth and lymph node metastasis. High PFN2 expression was significantly correlated with short overall survival (OS) (P = 0.023). Cox regression analysis revealed that PFN2 expression was an independent prognostic factor for poor OS in ESCC. Downregulation of PFN2 inhibited, rather than proliferated, cell invasion and migration, as well as induced an EMT phenotype, including increased expression of epithelial marker E-cadherin, decreased mesenchymal marker Vimentin, Snail, Slug and ZEB1, and morphological changes in ESCC cells in vitro.
Conclusions
Our findings demonstrate that PFN2 has a novel role in promoting ESCC progression and metastasis and portending a poor prognosis, indicating that PFN2 could act as an early biomarker of high-risk population. Targeting PFN2 may offer a promising therapeutic strategy for ESCC treatment.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-016-0884-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12967-016-0884-y
PMCID: PMC4870769  PMID: 27188458
Profilin 2; ESCC; Precursor lesions; Prognosis; Metastasis
15.  Effect of Elbow Position on Short-segment Nerve Conduction Study in Cubital Tunnel Syndrome 
Chinese Medical Journal  2016;129(9):1028-1035.
Background:
The appropriate elbow position of short-segment nerve conduction study (SSNCS) to diagnose cubital tunnel syndrome (CubTS) is still controversial. The goal of this study was to determine the effect of different elbow positions at full extension and 70° flexion on SSNCS in CubTS.
Methods:
In this cross-sectional study, the clinical data of seventy elbows from 59 CubTS patients between September, 2011 and December, 2014 in the Peking University First Hospital were included as CubTS group. Moreover, thirty healthy volunteers were included as the healthy group. SSNCS were conducted in all subjects at elbow full extension and 70° elbow flexion. Paired nonparametric test, bivariate correlation, Bland–Altman, and Chi-squared test analysis were used to compare the effectiveness of elbow full extension and 70° flexion elbow positions on SSNCS in CubTS patients.
Results:
Data of upper limit was calculated from healthy group, and abnormal latency was judged accordingly. CubTS group's latency and compound muscle action potential (CMAP) of each segment at 70° elbow flexion by SSNCS was compared with full extension position, no statistically significant difference were found (all P > 0.05). Latency and CMAP of each segment at elbow full extension and 70° flexion were correlated (all P < 0.01), except the latency of segment of 4 cm to 6 cm above elbow (P = 0.43), and the latency (P = 0.15) and the CMAP (P = 0.06) of segment of 2 cm to 4 cm below elbow. Bivariate correlation and Bland–Altman analysis proved the correlation between elbow full extension and 70° flexion. Especially in segments across the elbow (2 cm above the elbow and 2 cm below it), latency at elbow full extension and 70° flexion were strong direct associated (r = 0.83, P < 0.01; r = 0.55, P < 0.01), and so did the CMAP (r = 0.49, P < 0.01; r = 0.72, P < 0.01). There was no statistically significant difference in abnormality of each segment at full extension as measured by SSNCS compared with that at 70° flexion (P > 0.05, respectively).
Conclusions:
There was no statistically significant difference in the diagnosis of CubTS with the elbow at full extension compared with that at 70° flexion during SSNCS. We suggest that elbow positon at full extension can also be used during SSNCS.
doi:10.4103/0366-6999.180515
PMCID: PMC4852668  PMID: 27098786
Cubital Tunnel Syndrome; Elbow Position; Inching Test; Short-segment Nerve Conduction Study; Ulnar Nerve
16.  On Holo-Hilbert spectral analysis: a full informational spectral representation for nonlinear and non-stationary data 
The Holo-Hilbert spectral analysis (HHSA) method is introduced to cure the deficiencies of traditional spectral analysis and to give a full informational representation of nonlinear and non-stationary data. It uses a nested empirical mode decomposition and Hilbert–Huang transform (HHT) approach to identify intrinsic amplitude and frequency modulations often present in nonlinear systems. Comparisons are first made with traditional spectrum analysis, which usually achieved its results through convolutional integral transforms based on additive expansions of an a priori determined basis, mostly under linear and stationary assumptions. Thus, for non-stationary processes, the best one could do historically was to use the time–frequency representations, in which the amplitude (or energy density) variation is still represented in terms of time. For nonlinear processes, the data can have both amplitude and frequency modulations (intra-mode and inter-mode) generated by two different mechanisms: linear additive or nonlinear multiplicative processes. As all existing spectral analysis methods are based on additive expansions, either a priori or adaptive, none of them could possibly represent the multiplicative processes. While the earlier adaptive HHT spectral analysis approach could accommodate the intra-wave nonlinearity quite remarkably, it remained that any inter-wave nonlinear multiplicative mechanisms that include cross-scale coupling and phase-lock modulations were left untreated. To resolve the multiplicative processes issue, additional dimensions in the spectrum result are needed to account for the variations in both the amplitude and frequency modulations simultaneously. HHSA accommodates all the processes: additive and multiplicative, intra-mode and inter-mode, stationary and non-stationary, linear and nonlinear interactions. The Holo prefix in HHSA denotes a multiple dimensional representation with both additive and multiplicative capabilities.
doi:10.1098/rsta.2015.0206
PMCID: PMC4792412  PMID: 26953180
Hilbert–Huang transform; nonlinear; non-stationary; empirical mode decomposition; Holo-Hilbert spectrum; Holo-Hilbert spectral analysis
17.  Development of a new outcome prediction model for Chinese patients with penile squamous cell carcinoma based on preoperative serum C-reactive protein, body mass index, and standard pathological risk factors: the TNCB score group system 
Oncotarget  2016;7(15):21023-21033.
Purpose
To determine the predictive value and feasibility of the new outcome prediction model for Chinese patients with penile squamous cell carcinoma.
Results
The 3-year disease-specific survival (DSS) was 92.3% in patients with < 8.70 mg/L CRP and 54.9% in those with elevated CRP (P < 0.001). The 3-year DSS was 86.5% in patients with a BMI < 22.6 Kg/m2 and 69.9% in those with a higher BMI (P = 0.025). In a multivariate analysis, pathological T stage (P < 0.001), pathological N stage (P = 0.002), BMI (P = 0.002), and CRP (P = 0.004) were independent predictors of DSS. A new scoring model was developed, consisting of BMI, CRP, and tumor T and N classification. In our study, we found that the addition of the above-mentioned parameters significantly increased the predictive accuracy of the system of the American Joint Committee on Cancer (AJCC) anatomic stage group. The accuracy of the new prediction category was verified.
Methods
A total of 172 Chinese patients with penile squamous cell cancer were analyzed retrospectively between November 2005 and November 2014. Statistical data analysis was conducted using the nonparametric method. Survival analysis was performed with the log-rank test and the Cox proportional hazard model. Based on regression estimates of significant parameters in multivariate analysis, a new BMI-, CRP- and pathologic factors-based scoring model was developed to predict disease-specific outcomes. The predictive accuracy of the model was evaluated using the internal and external validation.
Conclusion
The present study demonstrated that the TNCB score group system maybe a precise and easy to use tool for predicting outcomes in Chinese penile squamous cell carcinoma patients.
doi:10.18632/oncotarget.8037
PMCID: PMC4991509  PMID: 26980738
penile neoplasms; neoplasm staging; prognosis; body mass index; C-reactive protein
18.  Small Bowel Cavernous Hemangioma Complicated with Intussusception: Report of an Extremely Rare Case and Review of Literature 
The Indian Journal of Surgery  2014;77(Suppl 1):123-124.
Cavernous hemangioma of the small intestine is a rare disease in adult patients. Intussusception caused by small bowel hemangioma is extremely rare. We report a 20-year-old female presenting with lower abdominal pain and post-prandial bloating. Laboratory studies showed leukocytosis with left shifting and prominent anemia. Computed tomography of the abdomen revealed small bowel intussusception with bowel ischemia. Segmental resection of the intussuscepted jejunum was performed, and the diagnosis of cavernous hemangioma causing intussusception and anemia simultaneously was made.
doi:10.1007/s12262-014-1194-3
PMCID: PMC4425776  PMID: 25972669
Anemia; Cavernous hemangioma; Intussusception; Small bowel hemangioma
19.  Naringenin prevents TGF-β1 secretion from breast cancer and suppresses pulmonary metastasis by inhibiting PKC activation 
Background
Targeting the TGF-β1 pathway for breast cancer metastasis therapy has become an attractive strategy. We have previously demonstrated that naringenin significantly reduced TGF-β1 levels in bleomycin-induced lung fibrosis and effectively prevented pulmonary metastases of tumors. This raised the question of whether naringenin can block TGF-β1 secretion from breast cancer cells and inhibit their pulmonary metastasis.
Methods
We transduced a lentiviral vector encoding the mouse Tgf-β1 gene into mouse breast carcinoma (4T1-Luc2) cells and inoculated the transformant cells (4T1/TGF-β1) into the fourth primary fat pat of Balb/c mice. Pulmonary metastases derived from the primary tumors were monitored using bioluminescent imaging. Spleens, lungs and serum (n = 18–20 per treatment group) were analyzed for immune cell activity and TGF-β1 level. The mechanism whereby naringenin decreases TGF-β1 secretion from breast cancer cells was investigated at different levels, including Tgf-β1 transcription, mRNA stability, translation, and extracellular release.
Results
In contrast to the null-vector control (4T1/RFP) tumors, extensive pulmonary metastases derived from 4T1/TGF-β1 tumors were observed. Administration of the TGF-β1 blocking antibody 1D11 or naringenin showed an inhibition of pulmonary metastasis for both 4T1/TGF-β1 tumors and 4T1/RFP tumors, resulting in increased survival of the mice. Compared with 4T1/RFP bearing mice, systemic immunosuppression in 4T1/TGF-β1 bearing mice was observed, represented by a higher proportion of regulatory T cells and myeloid-derived suppressor cells and a lower proportion of activated T cells and INFγ expression in CD8+ T cells. These metrics were improved by administration of 1D11 or naringenin. However, compared with 1D11, which neutralized secreted TGF-β1 but did not affect intracellular TGF-β1 levels, naringenin reduced the secretion of TGF-β1 from the cells, leading to an accumulation of intracellular TGF-β1. Further experiments revealed that naringenin had no effect on Tgf-β1 transcription, mRNA decay or protein translation, but prevented TGF-β1 transport from the trans-Golgi network by inhibiting PKC activity.
Conclusions
Naringenin blocks TGF-β1 trafficking from the trans-Golgi network by suppressing PKC activity, resulting in a reduction of TGF-β1 secretion from breast cancer cells. This finding suggests that naringenin may be an attractive therapeutic candidate for TGF-β1 related diseases.
Electronic supplementary material
The online version of this article (doi:10.1186/s13058-016-0698-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13058-016-0698-0
PMCID: PMC4818388  PMID: 27036297
Naringenin; TGF-β1 secretion; Breast cancer metastasis; PKC activation
20.  Treatments for the Fifth Metacarpal Neck Fractures 
Medicine  2016;95(11):e3059.
Abstract
The fifth metacarpal neck fractures (commonly termed boxer's fractures) are the most common type of metacarpal fractures. Many types of treatments are available in clinical practice, some of which have already been compared with other treatments by various researchers. However, a comprehensive treatment comparison is lacking. We estimated the comparative efficacy of different interventions for total complications, through a network meta-analysis of randomized controlled trials.
We conducted a systematic search of the literature through October 2015. The outcome measurements were the total complications. We used a Bayesian network meta-analysis to combine direct and indirect evidence and to estimate the relative effects of treatment.
We identified 6 RCTs registering a total of 288 patients who were eligible for our network meta-analysis. The literature's quality is relatively high. The median Structured Effectiveness for Quality Evaluation of Study score for the included trials was 33.8. The overall methodological quality was high. Of the 6 studies, all were 2-arm controlled trials comparing active intervention. Among the 4 treatments—conservative treatment (CT), antegrade intramedullary nailing (AIMN), transverse pinning (TP) with K-wires, and plate fixation (PF)—CT had the best rankings (ie, lowest risk of total complications), followed by PF, AIMN, and TP (ie, highest risk of total complications). Furthermore, we also presented the results using surface under the cumulative ranking curve. The surface under the cumulative ranking curve probabilities were 94.1%, 52.9%, 37.3%, and 15.7% for CT, PF, AIMN, and TP, respectively.
In conclusion, current evidence suggested that conservative treatment is the optimum treatment for the fifth metacarpal neck fractures because of reduced total complication rates. Moreover, the TP with K-wires is the worst option with highly total complication rates. PF and AIMN therapy should be considered as the first-line choices. Larger and higher-quality randomized controlled trials are required to confirm these conclusions and better inform clinical decision-making.
doi:10.1097/MD.0000000000003059
PMCID: PMC4839910  PMID: 26986129
21.  Contrasting responses of water use efficiency to drought across global terrestrial ecosystems 
Scientific Reports  2016;6:23284.
Drought is an intermittent disturbance of the water cycle that profoundly affects the terrestrial carbon cycle. However, the response of the coupled water and carbon cycles to drought and the underlying mechanisms remain unclear. Here we provide the first global synthesis of the drought effect on ecosystem water use efficiency (WUE = gross primary production (GPP)/evapotranspiration (ET)). Using two observational WUE datasets (i.e., eddy-covariance measurements at 95 sites (526 site-years) and global gridded diagnostic modelling based on existing observation and a data-adaptive machine learning approach), we find a contrasting response of WUE to drought between arid (WUE increases with drought) and semi-arid/sub-humid ecosystems (WUE decreases with drought), which is attributed to different sensitivities of ecosystem processes to changes in hydro-climatic conditions. WUE variability in arid ecosystems is primarily controlled by physical processes (i.e., evaporation), whereas WUE variability in semi-arid/sub-humid regions is mostly regulated by biological processes (i.e., assimilation). We also find that shifts in hydro-climatic conditions over years would intensify the drought effect on WUE. Our findings suggest that future drought events, when coupled with an increase in climate variability, will bring further threats to semi-arid/sub-humid ecosystems and potentially result in biome reorganization, starting with low-productivity and high water-sensitivity grassland.
doi:10.1038/srep23284
PMCID: PMC4794702  PMID: 26983909
22.  Angiotensin II down-regulates nephrin–Akt signaling and induces podocyte injury: roleof c-Abl 
Molecular Biology of the Cell  2016;27(1):197-208.
Ang II plays a vital role in the initiation and progression of proteinuric kidney diseases, but the mechanism is still elusive. It is shown that c-Abl is a molecular chaperone of nephrin signaling and the SHIP2-Akt pathway, and released c-Abl from nephrin is involved in Ang II–induced podocyte injury.
Recent studies have shown that nephrin plays a vital role in angiotensin II (Ang II)–induced podocyte injury and thus contributes to the onset of proteinuria and the progression of renal diseases, but its specific mechanism remains unclear. c-Abl is an SH2/SH3 domain–containing nonreceptor tyrosine kinase that is involved in cell survival and regulation of the cytoskeleton. Phosphorylated nephrin is able to interact with molecules containing SH2/SH3 domains, suggesting that c-Abl may be a downstream molecule of nephrin signaling. Here we report that Ang II–infused rats developed proteinuria and podocyte damage accompanied by nephrin dephosphorylation and minimal interaction between nephrin and c-Abl. In vitro, Ang II induced podocyte injury and nephrin and Akt dephosphorylation, which occurred in tandem with minimal interaction between nephrin and c-Abl. Moreover, Ang II promoted c-Abl phosphorylation and interaction between c-Abl and SH2 domain–containing 5′-inositol phosphatase 2 (SHIP2). c-Abl small interfering RNA (siRNA) and STI571 (c-Abl inhibitor) provided protection against Ang II–induced podocyte injury, suppressed the Ang II-induced c-Abl–SHIP2 interaction and SHIP2 phosphorylation, and maintained a stable level of nephrin phosphorylation. These results indicate that c-Abl is a molecular chaperone of nephrin signaling and the SHIP2-Akt pathway and that the released c-Abl contributes to Ang II–induced podocyte injury.
doi:10.1091/mbc.E15-04-0223
PMCID: PMC4694757  PMID: 26510503
23.  Combination Therapy using Co-encapsulated Resveratrol and Paclitaxel in Liposomes for Drug Resistance Reversal in Breast Cancer Cells in vivo 
Scientific Reports  2016;6:22390.
Multidrug resistance (MDR) is a major impediment to cancer treatment. A promising strategy for treating MDR is the joint delivery of combined anticancer agents to tumor cells in a single nanocarrier. Here, for the first time, Resveratrol (Res) was co-encapsulated with paclitaxel (PTX) in a PEGylated liposome to construct a carrier-delivered form of combination therapy for drug-resistant tumors. The composite liposome had an average diameter of 50 nm with encapsulated efficiencies of above 50%. The studies demonstrated that the composite liposome could generate potent cytotoxicity against the drug-resistant MCF-7/Adr tumor cells in vitro and enhance the bioavailability and the tumor-retention of the drugs in vivo. Moreover, systemic therapy with the composite liposome effectively inhibited drug-resistant tumor in mice (p < 0.01), without any notable increase in the toxicity. These results suggested that the co-delivery of Res and a cytotoxic agent in a nanocarrier may potentially improve the treatment of drug-resistant tumors.
doi:10.1038/srep22390
PMCID: PMC4780086  PMID: 26947928
24.  H19 activates Wnt signaling and promotes osteoblast differentiation by functioning as a competing endogenous RNA 
Scientific Reports  2016;6:20121.
Bone homeostasis is tightly orchestrated and maintained by the balance between osteoblasts and osteoclasts. Recent studies have greatly expanded our understanding of the molecular mechanisms of cellular differentiation. However, the functional roles of non-coding RNAs particularly lncRNAs in remodeling bone architecture remain elusive. In our study, lncRNA H19 was found to be upregulated during osteogenesis in hMSCs. Stable expression of H19 significantly accelerated in vivo and in vitro osteoblast differentiation. Meanwhile, by using bioinformatic investigations and RIP assays combined with luciferase reporter assays, we demonstrated that H19 functioned as an miRNA sponge for miR-141 and miR-22, both of which were negative regulators of osteogenesis and Wnt/β-catenin pathway. Further investigations revealed that H19 antagonized the functions of these two miRNAs and led to de-repression of their shared target gene β-catenin, which eventually activated Wnt/β-catenin pathway and hence potentiated osteogenesis. In addition, we also identified a novel regulatory feedback loop between H19 and its encoded miR-675-5p. And miR-675-5p was found to directly target H19 and counteracted osteoblast differentiation. To sum up, these observations indicate that the lncRNA H19 modulates Wnt/β-catenin pathway by acting as a competing endogenous RNA, which may shed light on the functional role of lncRNAs in coordinating osteogenesis.
doi:10.1038/srep20121
PMCID: PMC4745008  PMID: 26853553
25.  Long noncoding RNA hotair mediated angiogenesis in nasopharyngeal carcinoma by direct and indirect signaling pathways 
Oncotarget  2015;7(4):4712-4723.
Nasopharyngeal carcinoma (NPC), as a unique head and neck cancer type, is particularly prevalent in certain geographic areas such as eastern Asia. Until now, the therapeutic options have been restricted mainly to radiotherapy or chemotherapy. However, the clinical treatment effect remains unsatisfactory even if the combined radio-chemotherapies. Therefore, it is urgently needed to develop effective novel therapies against NPC. In this study, we discovered that lncRNA Hotair was extremely abundant in NPC cells and clinical NPC samples. Further studies showed that Hotair knockdown significantly attenuated both in vitro and in vivo tumor cell growth and angiogenesis. Our study also demonstrated that Hotair promoted angiogenesis through directly activating the transcription of angiogenic factor VEGFA as well as through GRP78-mediated upregulation of VEGFA and Ang2 expression. Therefore, Hotair may serve as a promising diagnostic marker and therapeutic target for NPC patients.
doi:10.18632/oncotarget.6731
PMCID: PMC4826237  PMID: 26717040
Hotair; angiogenesis; nasopharyngeal carcinoma; GRP78

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