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1.  Application of levator veli palatini retropositioning combined with Buccinator myomucosal island flap for congenital cleft palate 
Congenital cleft palate causes a serious obstacle to children with regard to language and eating function. The aim of the current study was to examine the clinical application of a type of palatoplasty that has a reduced impact on the maxillary growth and good function in velopharyngeal competence. A total of 37 patients with cleft palate were treated with levator veli palatini retropositioning combined with Buccinator myomucosal island flap. The patients were successfully treated in the first phase and were followed up for 1–3 years. Speech intelligibility was satisfactory and no fistula occurred. In conclusion, the results suggested that levator veli palatini retropositioning combined with the Buccinator myomucosal island flap may restore normal anatomic structure and location of the levator veli palatini, obtain good velopharyngeal competence, and decrease the incidence rate thereof. Thus, levator veli palatini retropositioning combined with the Buccinator myomucosal island flap is a functional procedure for cleft palate repair.
doi:10.3892/etm.2016.3666
PMCID: PMC5038848  PMID: 27698756
cleft palate; levator veli palatini retropositioning; Buccinator myomucosal island flap; velopharyngeal competence
2.  DNA-PK-mediated phosphorylation of EZH2 regulates the DNA damage-induced apoptosis to maintain T-cell genomic integrity 
Wang, Y | Sun, H | Wang, J | Wang, H | Meng, L | Xu, C | Jin, M | Wang, B | Zhang, Y | Zhang, Y | Zhu, T
Cell Death & Disease  2016;7(7):e2316-.
EZH2 is a histone methyltransferase whose functions in stem cells and tumor cells are well established. Accumulating evidence shows that EZH2 has critical roles in T cells and could be a promising therapeutic target for several immune diseases. To further reveal the novel functions of EZH2 in human T cells, protein co-immunoprecipitation combined mass spectrometry was conducted and several previous unknown EZH2-interacting proteins were identified. Of them, we focused on a DNA damage responsive protein, Ku80, because of the limited knowledge regarding EZH2 in the DNA damage response. Then, we demonstrated that instead of being methylated by EZH2, Ku80 bridges the interaction between the DNA-dependent protein kinase (DNA-PK) complex and EZH2, thus facilitating EZH2 phosphorylation. Moreover, EZH2 histone methyltransferase activity was enhanced when Ku80 was knocked down or DNA-PK activity was inhibited, suggesting DNA-PK-mediated EZH2 phosphorylation impairs EZH2 histone methyltransferase activity. On the other hand, EZH2 inhibition increased the DNA damage level at the late phase of T-cell activation, suggesting EZH2 involved in genomic integrity maintenance. In conclusion, our study is the first to demonstrate that EZH2 is phosphorylated by the DNA damage responsive complex DNA-PK and regulates DNA damage-mediated T-cell apoptosis, which reveals a novel functional crosstalk between epigenetic regulation and genomic integrity.
doi:10.1038/cddis.2016.198
PMCID: PMC4973345  PMID: 27468692
3.  Effect of microRNA-21 on the proliferation of human degenerated nucleus pulposus by targeting programmed cell death 4 
This study aims to explore the effect of microRNA-21 (miR-21) on the proliferation of human degenerated nucleus pulposus (NP) by targeting programmed cell death 4 (PDCD4) tumor suppressor. NP tissues were collected from 20 intervertebral disc degeneration (IDD) patients, and from 5 patients with traumatic spine fracture. MiR-21 expressions were tested. NP cells from IDD patients were collected and divided into blank control group, negative control group (transfected with miR-21 negative sequences), miR-21 inhibitor group (transfected with miR-21 inhibitors), miR-21 mimics group (transfected with miR-21 mimics) and PDCD4 siRNA group (transfected with PDCD4 siRNAs). Cell growth was estimated by Cell Counting Kit-8; PDCD4, MMP-2,MMP-9 mRNA expressions were evaluated by qRT-PCR; PDCD4, c-Jun and p-c-Jun expressions were tested using western blot. In IDD patients, the expressions of miR-21 and PDCD4 mRNA were respectively elevated and decreased (both P<0.05). The miR-21 expressions were positively correlated with Pfirrmann grades, but negatively correlated with PDCD4 mRNA (both P<0.001). In miR-21 inhibitor group, cell growth, MMP-2 and MMP-9 mRNA expressions, and p-c-Jun protein expressions were significantly lower, while PDCD4 mRNA and protein expressions were higher than the other groups (all P<0.05). These expressions in the PDCD4 siRNA and miR-21 mimics groups was inverted compared to that in the miR-21 inhibitor group (all P<0.05). MiR-21 could promote the proliferation of human degenerated NP cells by targeting PDCD4, increasing phosphorylation of c-Jun protein, and activating AP-1-dependent transcription of MMPs, indicating that miR-21 may be a crucial biomarker in the pathogenesis of IDD.
doi:10.1590/1414-431X20155020
PMCID: PMC4897996  PMID: 27240294
Intervertebral disc degeneration; MicroRNA-21; Human nucleus pulposus cells; Matrix metalloproteinase-2; Matrix metalloproteinase-9; Target gene
4.  Downregulation of YAP-dependent Nupr1 promotes tumor-repopulating cell growth in soft matrices 
Jia, Q | Zhou, W | Yao, W | Yang, F | Zhang, S | Singh, R | Chen, J | Chen, J J | Zhang, Y | Wei, F | Zhang, Y | Jia, H | Wang, N
Oncogenesis  2016;5(4):e220-.
Despite decades of significant progress in understanding the molecular mechanisms of malignant tumorigenic cells, it remains elusive what these tumorigenic cells are and what controls the growth of these malignant cells. Recently, we have mechanically selected and grown highly malignant and tumorigenic tumor-repopulating cells (TRCs), a small sub-population of cancer cells, by culturing single cancer cells in soft fibrin matrices. However, it is unclear what regulates TRC growth besides Sox2. Here we show that nuclear protein 1 (Nupr1), a protein independent of Sox2, is downregulated in TRCs of melanoma, ovarian cancer and breast cancer cultured in soft fibrin matrices. Nupr1 expression depends on nuclear translocation of YAP that is enriched at the Nupr1 promoter sites; YAP is controlled by Cdc42-mediated F-actin and Lats1 interactions. Nupr1 regulates tumor-suppressor p53 and negatively regulates Nestin and Tert that are independent of Sox2 and promote TRC growth. Silencing Nupr1 increases TRC growth and Nupr1 overexpression inhibits TRC growth in culture and in immune-competent mice. Our results suggest that Nupr1 is a suppressor of growth of highly tumorigenic TRCs and may have a critical role in cancer progression.
doi:10.1038/oncsis.2016.29
PMCID: PMC4848840  PMID: 27089143
5.  Direct frequency comb optical frequency standard based on two-photon transitions of thermal atoms 
Scientific Reports  2015;5:15114.
Optical clocks have been the focus of science and technology research areas due to their capability to provide highest frequency accuracy and stability to date. Their superior frequency performance promises significant advances in the fields of fundamental research as well as practical applications including satellite-based navigation and ranging. In traditional optical clocks, ultrastable optical cavities, laser cooling and particle (atoms or a single ion) trapping techniques are employed to guarantee high stability and accuracy. However, on the other hand, they make optical clocks an entire optical tableful of equipment, and cannot work continuously for a long time; as a result, they restrict optical clocks used as very convenient and compact time-keeping clocks. In this article, we proposed, and experimentally demonstrated, a novel scheme of optical frequency standard based on comb-directly-excited atomic two-photon transitions. By taking advantage of the natural properties of the comb and two-photon transitions, this frequency standard achieves a simplified structure, high robustness as well as decent frequency stability, which promise widespread applications in various scenarios.
doi:10.1038/srep15114
PMCID: PMC4602190  PMID: 26459877
6.  TAp63 suppress metastasis via miR-133b in colon cancer cells 
Lin, C W | Li, X R | Zhang, Y | Hu, G | Guo, Y H | Zhou, J Y | Du, J | Lv, L | Gao, K | Zhang, Y | Deng, H
British Journal of Cancer  2014;110(9):2310-2320.
Background:
TAp63 is a tumour-suppressor protein that is often underexpressed in various types of cancer. It has been shown to activate gene transcription depending on the transcription domain and to be closely related with metastasis. In this study, we demonstrate that TAp63 suppresses metastasis in colon cancer cells through microRNA-133b.
Methods:
We evaluated the correlation of TAp63 and miR-133b with HT-29 and SW-620 cells and investigated the roles of TAp63 in the expression of RhoA, E-cadherin and vimentin. We further investigated the roles of TAp63-mediated invasion and migration of colon cancer cells.
Results:
TAp63 expression is downregulated in colon cancer, and microRNA-133b is a transcriptional target of TAp63. Furthermore, microRNA-133b is essential for the inhibitory effects of TAp63 on RhoA, E-cadherin and vimentin. Moreover, TAp63 inhibits cell migration and invasion through microRNA-133b. Correspondingly, the inhibitory effect of TAp63 on RhoA, E-cadherin, vimentin, migration and invasion can be blocked by the microRNA-133b inhibitor.
Conclusions:
TAp63 and microRNA-133b were able to suppress the metastasis of colon cancer. Both TAp63 and microRNA-133b may be potential biomarkers for diagnosis in colon cancer metastasis and may provide unique therapeutic targets for this common malignancy.
doi:10.1038/bjc.2014.118
PMCID: PMC4007221  PMID: 24594999
TAp63; microRNA-133b; RhoA; colon cancer; metastasis
7.  Peroxisome proliferator-activated receptorβ/δ activation is essential for modulating p-Foxo1/Foxo1 status in functional insulin-positive cell differentiation 
Li, L | Li, T | Zhang, Y | Pan, Z | Wu, B | Huang, X | Zhang, Y | Mei, Y | Ge, L | Shen, G | Ge, R-s | Zhu, D | Lou, Y
Cell Death & Disease  2015;6(4):e1715-.
Peroxisome proliferator-activated receptors (PPARs) participate in energy homeostasis and play essential roles in diabetes therapy through their effects on non-pancreas tissues. Pathological microenvironment may influence the metabolic requirements for the maintenance of stem cell differentiation. Accordingly, understanding the mechanisms of PPARs on pancreatic β-cell differentiation may be helpful to find the underlying targets of disrupted energy homeostasis under the pancreatic disease condition. PPARs are involved in stem cell differentiation via mitochondrial oxidative phosphorylation, but the subtype member activation and the downstream regulation in functional insulin-positive (INS+) cell differentiation remain unclear. Here, we show a novel role of PPARβ/δ activation in determining INS+ cell differentiation and functional maturation. We found PPARβ/δ expression selectively upregulated in mouse embryonic pancreases or stem cells-derived INS+ cells at the pancreatic mature stage in vivo and in vitro. Strikingly, given the inefficiency of generating INS+ cells in vitro, PPARβ/δ activation displayed increasing mouse and human ES cell-derived INS+ cell numbers and insulin secretion. This phenomenon was closely associated with the forkhead box protein O1 (Foxo1) nuclear shuttling, which was dependent on PPARβ/δ downstream PI3K/Akt signaling transduction. The present study reveals the essential role of PPARβ/δ activation on p-Foxo1/Foxo1 status, and in turn, determining INS+ cell generation and insulin secretion via affecting pancreatic and duodenal homeobox-1 expression. The results demonstrate the underlying mechanism by which PPARβ/δ activation promotes functional INS+ cell differentiation. It also provides potential targets for anti-diabetes drug discovery and hopeful clinical applications in human cell therapy.
doi:10.1038/cddis.2015.88
PMCID: PMC4650555  PMID: 25855963
8.  Response to comment on ‘TAp63 suppress metastasis via miR-133b in colon cancer cells' 
Lin, C W | Li, X R | Zhang, Y | Hu, G | Guo, Y H | Zhou, J Y | Du, J | Lv, L | Gao, K | Zhang, Y | Deng, H
British Journal of Cancer  2014;111(12):2369-2370.
doi:10.1038/bjc.2014.389
PMCID: PMC4264430  PMID: 25490679
9.  Histone demethylase Kdm4b functions as a co-factor of C/EBPβ to promote mitotic clonal expansion during differentiation of 3T3-L1 preadipocytes 
Cell Death and Differentiation  2012;19(12):1917-1927.
CCAAT/enhancer-binding protein (C/EBP) β is required for both mitotic clonal expansion (MCE) and terminal adipocyte differentiation of 3T3-L1 preadipocytes. Although the role of C/EBPβ in terminal adipocyte differentiation is well defined, its mechanism of action during MCE is not. In this report, histone demethylase Kdm4b, as well as cell cycle genes Cdc45l (cell division cycle 45 homolog), Mcm3 (mini-chromosome maintenance complex component 3), Gins1 (GINS complex subunit 1) and Cdc25c (cell division cycle 25 homolog c), were identified as potential C/EBPβ target genes during MCE by utilizing promoter-wide chromatin immunoprecipitation (ChIP)-on-chip analysis combined with gene expression microarrays. The expression of Kdm4b is induced during MCE and its induction is dependent on C/EBPβ. ChIP, Electrophoretic Mobility Shift Assay (EMSA) and luciferase assay confirmed that the promoter of Kdm4b is bound and activated by C/EBPβ. Knockdown of Kdm4b impaired MCE. Furthermore, Kdm4b interacted with C/EBPβ and was recruited to the promoters of C/EBPβ-regulated cell cycle genes, including Cdc45l, Mcm3, Gins1, and Cdc25c, demethylated H3K9me3 and activated their transcription. These findings suggest a novel feed forward mechanism involving a DNA binding transcription factor (C/EBPβ) and a chromatin regulator (Kdm4b) in the regulation of MCE by controlling cell cycle gene expression.
doi:10.1038/cdd.2012.75
PMCID: PMC3504706  PMID: 22722334
3T3-L1 preadipocytes; adipocyte differentiation; mitotic clonal expansion; C/EBPβ; Kdm4b; ChIP-on-chip
10.  Acute atrial arrhythmogenesis in murine hearts following enhanced extracellular Ca2+ entry depends on intracellular Ca2+ stores 
Acta Physiologica (Oxford, England)  2010;198(2):143-158.
Aim
To investigate the effect of increases in extracellular Ca2+ entry produced by the L-type Ca2+ channel agonist FPL-64176 (FPL) upon acute atrial arrhythmogenesis in intact Langendorff-perfused mouse hearts and its dependence upon diastolic Ca2+ release from sarcoplasmic reticular Ca2+ stores.
Methods
Confocal microscope studies of Fluo-3 fluorescence in isolated atrial myocytes were performed in parallel with electrophysiological examination of Langendorff-perfused mouse hearts.
Results
Atrial myocytes stimulated at 1 Hz and exposed to FPL (0.1 μm) initially showed (<10 min) frequent, often multiple, diastolic peaks following the evoked Ca2+ transients whose amplitudes remained close to control values. With continued pacing (>10 min) this reverted to a regular pattern of evoked transients with increased amplitudes but in which diastolic peaks were absent. Higher FPL concentrations (1.0 μm) produced sustained and irregular patterns of cytosolic Ca2+ activity, independent of pacing. Nifedipine (0.5 μm), and caffeine (1.0 mm) and cyclopiazonic acid (CPA) (0.15 μm) pre-treatments respectively produced immediate and gradual reductions in the F/F0 peaks. Such nifedipine and caffeine, or CPA pre-treatments, abolished, or reduced, the effects of 0.1 and 1.0 μm FPL on cytosolic Ca2+ signals. FPL (1.0 μm) increased the incidence of atrial tachycardia and fibrillation in intact Langendorff-perfused hearts without altering atrial effective refractory periods. These effects were inhibited by nifedipine and caffeine, and reduced by CPA.
Conclusion
Enhanced extracellular Ca2+ entry exerts acute atrial arrhythmogenic effects that is nevertheless dependent upon diastolic Ca2+ release. These findings complement reports that associate established, chronic, atrial arrhythmogenesis with decreased overall inward Ca2+ current.
doi:10.1111/j.1748-1716.2009.02055.x
PMCID: PMC3763207  PMID: 19886909
atrial arrhythmogenesis; Ca2+ homeostasis; calcium entry; murine hearts; store calcium
11.  Inhibition of 12/15-lipoxygenase by baicalein induces microglia PPARβ/δ: a potential therapeutic role for CNS autoimmune disease 
Xu, J | Zhang, Y | Xiao, Y | Ma, S | Liu, Q | Dang, S | Jin, M | Shi, Y | Wan, B | Zhang, Y
Cell Death & Disease  2013;4(4):e569-.
12/15-Lipoxygenase (12/15-LO) is an enzyme that converts polyunsaturated fatty acids into bioactive lipid derivatives. In this study, we showed that inhibition of 12/15-LO by baicalein (BA) significantly attenuated clinical severity of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Inhibited migration of autoimmune T cells into the central nervous system (CNS) by BA treatment could be attributed to reduced activation of microglia, which was indicated by suppressed phagocytosis, and decreased production of proinflammatory cytokines and chemokines in the CNS. We further observed that inhibition of 12/15-LO with BA led to increased expression of peroxisome proliferator-activated receptor (PPAR)β/δ in microglia of EAE mice. This was confirmed in vitro in primary microglia and a microglia cell line, BV2. In addition, we demonstrated that BA did not affect 12/15-LO or 5-lipoxygenase (5-LO) expression in microglia, but significantly decreased 12/15-LO products without influencing the levels of 5-LO metabolites. Moreover, among these compounds only 12/15-LO metabolite 12-hydroxyeicosatetraenoic acid was able to reverse BA-mediated upregulation of PPARβ/δ in BV2 cells. We also showed that inhibition of microglia activation by PPARβ/δ was associated with repressed NF-κB and MAPK activities. Our findings indicate that inhibition of 12/15-LO induces PPARβ/δ, demonstrating important regulatory properties of 12/15-LO in CNS inflammation. This reveals potential therapeutic applications for MS.
doi:10.1038/cddis.2013.86
PMCID: PMC3668632  PMID: 23559003
12/15-LO; PPARβ/δ; baicalein; microglia; EAE
12.  QTL mapping in outbred half-sib families using Bayesian model selection 
Heredity  2011;107(3):265-276.
In this article, we propose a model selection method, the Bayesian composite model space approach, to map quantitative trait loci (QTL) in a half-sib population for continuous and binary traits. In our method, the identity-by-descent-based variance component model is used. To demonstrate the performance of this model, the method was applied to map QTL underlying production traits on BTA6 in a Chinese half-sib dairy cattle population. A total of four QTLs were detected, whereas only one QTL was identified using the traditional least square (LS) method. We also conducted two simulation experiments to validate the efficiency of our method. The results suggest that the proposed method based on a multiple-QTL model is efficient in mapping multiple QTL for an outbred half-sib population and is more powerful than the LS method based on a single-QTL model.
doi:10.1038/hdy.2011.15
PMCID: PMC3183946  PMID: 21487433
Bayesian model selection; variance component model; Markov chain Monte Carlo algorithm; QTL mapping
13.  A functionalized single-walled carbon nanotube-induced autophagic cell death in human lung cells through Akt–TSC2-mTOR signaling 
Cell Death & Disease  2011;2(5):e159-.
Nanoparticles are now emerging as a novel class of autophagy activators. Functionalized single-walled carbon nanotubes (f-SWCNTs) are valuable nanomaterials in many industries. This article is designed to assess the autophagic response for f-SWCNTs exposure in vitro and in vivo. A few types of f-SWCNTs were screened in human lung adenocarcinoma A549 cells for the autophagic response and related pathways in vitro. Formation of autophagosomes and LC3-II upregulation were confirmed on the basis of electron microscopy and LC3 western blotting for COOH-CNT, but not for PABS-CNT and PEG-CNT. MTT assay showed marked increase in cell viability, when COOH-CNT was added to cells in the presence of autophagy inhibitor 3MA, ATG6 or TSC2 siRNA. Consistent with the involvement of the Akt–TSC1/2–mTOR pathway, the phosphorylation levels of mTOR, mTOR's substrate S6 and Akt were shown significantly decreased in A549 cells on treatment with COOH-CNT using western blotting. What's more, autophagy inhibitor 3MA significantly reduced the lung edema in vivo. In a word, COOH-CNT induced autophagic cell death in A549 cells through the AKT–TSC2–mTOR pathway and caused acute lung injury in vivo. Inhibition of autophagy significantly reduced COOH-CNT-induced autophagic cell death and ameliorated acute lung injury in mice, suggesting a potential remedy to address the growing concerns on the safety of nanomaterials.
doi:10.1038/cddis.2011.27
PMCID: PMC3122114  PMID: 21593791
SWCNT; autophagy; mTOR; acute lung injury
14.  Electronic Structures of S-Doped Capped C-SWNT from First Principles Study 
Nanoscale Research Letters  2010;5(6):1027-1031.
The semiconducting single-walled carbon nanotube (C-SWNT) has been synthesized by S-doping, and they have extensive potential application in electronic devices. We investigated the electronic structures of S-doped capped (5, 5) C-SWNT with different doping position using first principles calculations. It is found that the electronic structures influence strongly on the workfunction without and with external electric field. It is considered that the extended wave functions at the sidewall of the tube favor for the emission properties. With the S-doping into the C-SWNT, the HOMO and LUMO charges distribution is mainly more localized at the sidewall of the tube and the presence of the unsaturated dangling bond, which are believed to enhance workfunction. When external electric field is applied, the coupled states with mixture of localized and extended states are presented at the cap, which provide the lower workfunction. In addition, the wave functions close to the cap have flowed to the cap as coupled states and to the sidewall of the tube mainly as extended states, which results in the larger workfunction. It is concluded that the S-doped C-SWNT is not incentive to be applied in field emitter fabrication. The results are also helpful to understand and interpret the application in other electronic devices.
doi:10.1007/s11671-010-9594-1
PMCID: PMC2894202  PMID: 20672070
Single-walled carbon nanotube (C-SWNT); Electronic properties; Workfunctions
15.  Significantly enhanced osteoblast response to nano-grained pure tantalum 
Scientific Reports  2017;7:40868.
Tantalum (Ta) metal is receiving increasing interest as biomaterial for load-bearing orthopedic applications and the synthetic properties of Ta can be tailored by altering its grain structures. This study evaluates the capability of sliding friction treatment (SFT) technique to modulate the comprehensive performances of pure Ta. Specifically, novel nanocrystalline (NC) surface with extremely small grains (average grain size of ≤20 nm) was fabricated on conventional coarse-grained (CG) Ta by SFT. It shows that NC surface possessed higher surface hydrophilicity and enhanced corrosion resistance than CG surface. Additionally, the NC surface adsorbed a notably higher percentage of protein as compared to CG surface. The in vitro results indicated that in the initial culture stages (up to 24 h), the NC surface exhibited considerably enhanced osteoblast adherence and spreading, consistent with demonstrated superior hydrophilicity on NC surface. Furthermore, within the 14 days culture period, NC Ta surface exhibited a remarkable enhancement in osteoblast cell proliferation, maturation and mineralization as compared to CG surface. Ultimately, the improved osteoblast functions together with the good mechanical and anti-corrosion properties render the SFT-processed Ta a promising alternative for the load-bearing bone implant applications.
doi:10.1038/srep40868
PMCID: PMC5233963  PMID: 28084454
16.  Core-shell structured titanium-nitrogen alloys with high strength, high thermal stability and good plasticity 
Scientific Reports  2017;7:40039.
Multifunctional materials with more than two good properties are widely required in modern industries. However, some properties are often trade-off with each other by single microstructural designation. For example, nanostructured materials have high strength, but low ductility and thermal stability. Here by means of spark plasma sintering (SPS) of nitrided Ti particles, we synthesized bulk core-shell structured Ti alloys with isolated soft coarse-grained Ti cores and hard Ti-N solid solution shells. The core-shell Ti alloys exhibit a high yield strength (~1.4 GPa) comparable to that of nanostructured states and high thermal stability (over 1100 °C, 0.71 of melting temperature), contributed by the hard Ti-N shells, as well as a good plasticity (fracture plasticity of 12%) due to the soft Ti cores. Our results demonstrate that this core-shell structure offers a design pathway towards an advanced material with enhancing strength-plasticity-thermal stability synergy.
doi:10.1038/srep40039
PMCID: PMC5216384  PMID: 28059150
17.  Comparison of chemical profiles and effectiveness between Erxian decoction and mixtures of decoctions of its individual herbs: a novel approach for identification of the standard chemicals 
Chinese Medicine  2017;12:1.
Background
Identification of bioactive standard chemicals is a major challenge in the study of the Chinese medicinal formula. In particular, the chemical components may interact differently depending on the preparative methods, therefore affecting the amounts of bioactive components and their pharmacological properties in the medicinal formula. With the use of Erxian decoction (EXD) as a study model—a  well-known Chinese medicinal formula for treating menopausal symptoms, a novel and rapid approach in seeking standard chemicals has been established by differentially comparing the HPLC profiles and the menopause-related biochemical parameters of combined decoction of EXD (EXD-C) and mixtures of the decoctions of its individual herbs (EXD-S).
Methods
The levels of six chemicals, which exerted actions on the HPO axis, have been measured in EXD-C and EXD-S by HPLC. Twelve-month-old female Sprague-Dawley rats were employed and treated with EXD-C and EXD-S. Their endocrine functions after treatment were evaluated by determining the ovarian mRNA levels of aromatase, a key enzyme for estradiol biosynthesis. The effect of the antioxidant regimen was determined by the hepatic superoxide dismutase-1 (SOD), catalase (CAT) and glutathione peroxidase (GPx-1) mRNA levels.
Results
The amounts of mangiferine, ferulic acid, jatrorrhizine and palmatine in EXD-S were twofold higher than those in EXD-C. EXD-S was more effective in stimulating ovarian aromatase and the expression of the antioxidant enzymes compared with EXD-C.
Conclusion
Mangiferine, ferulic acid, jatrorrhizine and palmatine are suitable for use as standard chemicals for quality evaluation of EXD according to our approach. EXD-S could be more effective than EXD-C.
doi:10.1186/s13020-016-0123-8
PMCID: PMC5209811  PMID: 28053654
Standard chemicals; Chinese medicine formula; Erxian decoction; Menopause; Novel approach
18.  The LIM protein Ajuba promotes adipogenesis by enhancing PPARγ and p300/CBP interaction 
Cell Death and Differentiation  2015;23(1):158-168.
Adipocytes play a vital role in energy homeostasis and adipogenesis is a hierarchically regulated cellular differentiation process, in which the precursor mesenchymal stem cells are differentiated into mature adipocytes. Here, we report Ajuba is an important regulator of adipocyte differentiation by functioning as an obligate co-activator of PPARγ. Ajuba binds the DNA-binding domain of PPARγ via its preLIM region in a ligand-independent manner. Depletion of Ajuba in 3T3-L1 cells decreases PPARγ target gene expression and results in delayed adipogenic differentiation. Conversely, stable overexpression of Ajuba in 3T3-L1 cells increases PPARγ target gene expression and accelerates adipogenic differentiation. Mechanistic investigations demonstrate that Ajuba recruits p300/CBP via its LIM domain and facilitates p300/CBP binding to PPARγ. Moreover, Ajuba, PPARγ, p300/CBP can cooperatively occupy the PPARγ target promoters and concomitantly increases histone acetylation at these loci. Collectively, these data suggest that Ajuba is a co-activator constitutively associated with PPARγ and may be a potential therapeutic target for PPARγ-mediated metabolic disorders.
doi:10.1038/cdd.2015.83
PMCID: PMC4815986  PMID: 26113042
19.  Tousled-like kinase mediated a new type of cell death pathway in Drosophila 
Zhang, Y | Cai, R | Zhou, R | Li, Y | Liu, L
Cell Death and Differentiation  2015;23(1):146-157.
Programmed cell death (PCD) has an important role in sculpting organisms during development. However, much remains to be learned about the molecular mechanism of PCD. We found that ectopic expression of tousled-like kinase (tlk) in Drosophila initiated a new type of cell death. Furthermore, the TLK-induced cell death is likely to be independent of the canonical caspase pathway and other known caspase-independent pathways. Genetically, atg2 RNAi could rescue the TLK-induced cell death, and this function of atg2 was likely distinct from its role in autophagy. In the developing retina, loss of tlk resulted in reduced PCD in the interommatidial cells (IOCs). Similarly, an increased number of IOCs was present in the atg2 deletion mutant clones. However, double knockdown of tlk and atg2 by RNAi did not have a synergistic effect. These results suggested that ATG2 may function downstream of TLK. In addition to a role in development, tlk and atg2 RNAi could rescue calcium overload-induced cell death. Together, our results suggest that TLK mediates a new type of cell death pathway that occurs in both development and calcium cytotoxicity.
doi:10.1038/cdd.2015.77
PMCID: PMC4815984  PMID: 26088162
20.  Prevalence of obesity in Malta 
Obesity Science & Practice  2016;2(4):466-470.
Summary
Background
Obesity is a global epidemic with the Mediterranean island of Malta being no exception. The World Health Organization (WHO) has identified Malta as one of the European countries with the highest obesity prevalence.
Method
A cross‐sectional study was conducted (2014–2016) under the auspices of the University of Malta. The prevalence of overweight‐obesity in Malta was calculated and then age stratified for comparisons with previous studies.
Results
The study identified 69.75% (95% CI: 68.32–71.18) of the Maltese population to be either overweight or obese. The men overweight/obese prevalence (76.28% 95% CI: 74.41–78.14) was statistically higher than that for women (63.06% 95% CI: 60.92–65.20) (p = 0.0001). Age stratification revealed that both genders had the highest overweight prevalence rates between 55 and 64 years (Men = 23.25% 95% CI: 20.43–26.33; Women = 24.68% 95% CI: 21.44–28.22). Men obesity prevalence rates were highest in the 35 to 44 years group (22.52% 95% CI: 19.65–25.68) while for women it was highest in the 55 to 64 years group (28.90%, 95% CI: 25.44–30.63).
Conclusion
Over a 35‐year period, an overall decrease in the normal and overweight BMI categories occurred with an increase in the prevalence of obesity. An exception was observed in the women, where the prevalence of normal BMI increased over this time period. Also, it appears that while the total population obesity prevalence increased (for 2016), a percentage of the women have shifted from an obese to an overweight status.
doi:10.1002/osp4.77
PMCID: PMC5192534  PMID: 28090352
Epidemics; Malta; obesity; overweight
21.  RCAD/Ufl1, a Ufm1 E3 ligase, is essential for hematopoietic stem cell function and murine hematopoiesis 
Cell Death and Differentiation  2015;22(12):1922-1934.
The Ufm1 conjugation system is a novel ubiquitin-like modification system, consisting of Ufm1, Uba5 (E1), Ufc1 (E2) and poorly characterized E3 ligase(s). RCAD/Ufl1 (also known as KIAA0776, NLBP and Maxer) was reported to function as a Ufm1 E3 ligase in ufmylation (Ufm1-mediated conjugation) of DDRGK1 and ASC1 proteins. It has also been implicated in estrogen receptor signaling, unfolded protein response (UPR) and neurodegeneration, yet its physiological function remains completely unknown. In this study, we report that RCAD/Ufl1 is essential for embryonic development, hematopoietic stem cell (HSC) survival and erythroid differentiation. Both germ-line and somatic deletion of RCAD/Ufl1 impaired hematopoietic development, resulting in severe anemia, cytopenia and ultimately animal death. Depletion of RCAD/Ufl1 caused elevated endoplasmic reticulum stress and evoked UPR in bone marrow cells. In addition, loss of RCAD/Ufl1 blocked autophagic degradation, increased mitochondrial mass and reactive oxygen species, and led to DNA damage response, p53 activation and enhanced cell death of HSCs. Collectively, our study provides the first genetic evidence for the indispensable role of RCAD/Ufl1 in murine hematopoiesis and development. The finding of RCAD/Ufl1 as a key regulator of cellular stress response sheds a light into the role of a novel protein network including RCAD/Ufl1 and its associated proteins in regulating cellular homeostasis.
doi:10.1038/cdd.2015.51
PMCID: PMC4816109  PMID: 25952549
23.  Enhanced Absorption and Diffusion Properties of Lithium on B,N,VC-decorated Graphene 
Scientific Reports  2016;6:37911.
Systematic first-principles calculations were performed to investigate the adsorption and diffusion of Li on different graphene layers with B/N-doping and/or C-vacancy, so as to understand why doping heteroatoms in graphene anode could significantly improve the performance of lithium-ion batteries. We found that the formation of single or double carbon vacancies in graphene are critical for the adsorption of Li atoms. While the N-doping facilitates the formation of vacancies, it introduces over binding issue and hinders the Li diffusion. The presence of B takes the excessive electrons from Li and N and reduces the energy barrier of Li diffusion on substrates. We perceive that these clear insights are crucial for the further development of graphene based anode materials for lithium-ion batteries.
doi:10.1038/srep37911
PMCID: PMC5126578  PMID: 27897202
24.  First-Principles Studies on the Structural Stability of Spinel ZnCo2O4 as an Electrode Material for Lithium-ion Batteries 
Scientific Reports  2016;6:36717.
Systematic first principles calculations were performed for ZnCo2O4 to clarify its structural and electronic properties, and particularly the structural stability as an electrode material for lithium-ion batteries. For samples with low Li concentration, e.g., LinZnCo2O4 with n < 1, Li atoms take the center of oxygen octahedra and may diffuse rapidly. Structure distortions and volume expansions can be observed in LinZnCo2O4 with n > 1 and amorphous structures eventually prevail. The AIMD simulations for Li9ZnCo2O4 suggest the formation of Li2O, Co3O4 and LiZn local compounds or alloys. In particular, the formation of Zn-Co aggregations and the losing of ZnO pairs are identified as the possible reasons that are responsible to the Li capacity fading in ZnCo2O4 anodes.
doi:10.1038/srep36717
PMCID: PMC5101478  PMID: 27827419
25.  Characterization of Tamyb10 allelic variants and development of STS marker for pre-harvest sprouting resistance in Chinese bread wheat 
Molecular Breeding  2016;36(11):148.
Wheat grain color does not only affect the brightness of flour but also seed dormancy and pre-harvest sprouting (PHS) tolerance. The transcription factor Tamyb10 is an important candidate for R-1 gene, and the expression of its homologs determines wheat seed coat color. In the present study, the allelic variations of Tamyb10 were explored in a set of Chinese bread wheat varieties and advanced lines with different PHS tolerance, and a sequenced-tagged site (STS) marker for Tamyb10-D1 gene was developed, designated as Tamyb10D, which could be used as an efficient and reliable marker to evaluate the depth dormancy of wheat seeds. Using the marker Tamyb10D, 1629- and 1178-bp PCR fragments were amplified from the tolerant varieties, whereas a 1178-bp fragment was from the susceptible ones. Of the Chinese bread wheat varieties and advanced lines, 103 were used to validate the relationship between the polymorphic fragments of Tamyb10D and PHS tolerance. Statistical analysis indicated that Tamyb10D was significantly (P < 0.001) associated with depth of seed dormancy in these germplasms. To further confirm the association between allelic variants of Tamyb10-D1 and PHS tolerance, 200 recombinant inbred lines (RILs) from the cross between Zhongyou 9507 (1178-bp fragment) and Yangxiaomai (1178- and 1629-bp fragments) were genotyped using the marker Tamyb10D. General linear model analysis indicated that variation in Tamyb10-D1 had a significant (P < 0.001) association with the germination index (GI) values, explaining 13.7, 4.7, and 9.8 % of the phenotypic variation in GI in Shijiazhuang, Beijing, and the averaged data from those environments, respectively. In addition, among the 103 wheat varieties, 8 Tamyb10 genotypes (Tamybl0-A1, Tamybl0-B1, and Tamyb10-D1 loci) were detected, namely, aaa, aab, aba, abb, baa, bab, bba, and bbb, and these were significantly associated with GI value.
doi:10.1007/s11032-016-0573-9
PMCID: PMC5097096  PMID: 27942244
Allelic variation; Germination index (GI); Tamyb10-D1; Triticum aestivum

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