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1.  Effects of chromium-enriched bacillus subtilis KT260179 supplementation on chicken growth performance, plasma lipid parameters, tissue chromium levels, cecal bacterial composition and breast meat quality 
Background
Both chromium (Cr) and probiotic bacillus own the virtues of regulating animal metabolism and meat quality. Purpose of this study was to evaluate the efficiency of supplemental Cr and bacillus in the form of chromium-enriched Bacillus subtilis KT260179 (CEBS) on chicken growth performance, plasma lipid parameters, tissue chromium levels, cecal bacterial composition and breast meat quality.
Methods
Six hundred of 1-day-old Chinese Huainan Partridge chickens were divided into four groups randomly: Control, inorganic Cr, Bacillus subtilis, and CEBS. The feed duration was 56 days.
Results
After 28 days of treatment, broiler feed CEBS or normal B. subtilis had higher body weights than control broiler, and after 56 days, chickens given either CEBS or B. subtilis had greater body weights than control broiler or those given inorganic Cr. Plasma total cholesterol, triglycerides, and low density lipoprotein cholesterol levels declined significantly in the CEBS group compared with the control, whereas plasma high density lipoprotein cholesterol levels increased significantly. The concentration of Cr in blood and breast muscle increased after CEBS and inorganic Cr supplementation. B. subtilis and CEBS supplementation caused a significant increase in the numbers of Lactobacillus and Bifidobacterium in the caecum, while the numbers of Escherichia coli and Salmonella decreased significantly compared to the control. Feed adding CEBS increased the lightness, redness, and yellowness of breast meat, improved the water-holding capacity, decreased the shear force and cooking loss.
Conclusions
In all, CEBS supplementation promoted body growth, improved plasma lipid parameters, increased tissue Cr concentrations, altered cecal bacterial composition and improved breast meat quality.
doi:10.1186/s12944-016-0355-8
PMCID: PMC5100260  PMID: 27821122
Chromium-enriched bacillus subtilis; Chicken; Growth performance; Meat quality; Bacterial composition
2.  Yolk–Shell‐Structured Aluminum Phenylphosphonate Microspheres with Anionic Core and Cationic Shell 
Advanced Science  2016;3(5):1500363.
Spherical materials with yolk‐shell structure have great potential for a wide range of applications. The main advantage of the yolk‐shell geometry is the possibility of introducing different chemical or physical properties within a single particle. Here, a one‐step hydrothermal synthesis route for fabricating amphoteric yolk‐shell structured aluminum phenylphosphonate microspheres using urea as the precipitant is proposed. The resulting microspheres display 3D sphere‐in‐sphere architecture with anionic core and cationic shell. The controllable synthesis of aluminum phosphates with various morphologies is also demonstrated. The anionic core and cationic shell of the aluminum phenylphosphonate microspheres provide docking sites for selective adsorption of both cationic methylene blue and anionic binuclear cobalt phthalocyanine ammonium sulphonate. These new adsorbents can be used for simultaneous capture of both cations and anions from a solution, which make them very attractive for various applications such as environmental remediation of contaminated water.
doi:10.1002/advs.201500363
PMCID: PMC5069564  PMID: 27812467
adsorption; aluminum phenylphosphonate; mesoporous materials; microspheres; yolk‐shell structure
3.  MicroRNA-561 inhibits gastric cancercell proliferation and invasion by downregulating c-Myc expression 
Gastric cancer (GC) causes nearly one million deaths worldwide each year. However, the molecular pathway of GC development remains unclear. Increasing evidences have shown that microRNAs (miRNAs) are highly associated with tumor development. However, relative little is known about the potential role of miRNAs in gastric cancer development. In the present study, we showed that miR-561 was down-regulated frequently in human GCs cell lines and tissues, and its expression was associated with tumor-node-metastasis (pTNM) stage. Enforced expression of miR-561 in GC cells inhibited cell proliferation and invasion in vitro. In contrast, knockdown of miR-561 had the opposite effect on cell proliferation and invasion. Moreover, c-Myc was identified as a potential miR-561 target. Further studies confirmed that miR-561 suppressed the expression of c-Myc by directly binding to its 3’-untranslated region. Restoration of c-Myc in miR-561-overexpressed GC cells reversed the suppressive effects of miR-561 and c-Myc was inversely correlated with miR-561 expression in GC tissues. These results demonstrate that miR-561 acts as a novel tumor suppressor in GC by targeting c-Myc gene and inhibiting GC cells proliferation and invasion. These findings contribute to current understanding of the functions of miR-561 in GC.
PMCID: PMC5040678  PMID: 27725860
Gastric cancer; microRNA-561; c-Myc; tumor suppressor
4.  Membrane-associated GRP78 helps subgroup J avian leucosis virus enter cells 
Veterinary Research  2016;47(1):92.
We previously identified chicken Annexin A2 (chANXA2) as a novel receptor for retrovirus avian leucosis virus subgroup J (ALV-J), using a DF1 cell line expressing the viral envelope (env) protein. To further probe whether other proteins participate in virus infection, we investigated several host proteins from co-immunoprecipitation with the DF1 cell line expressing viral env. Mass spectrometry analysis indicates that the chicken glucose-regulation protein 78 (chGRP78) of the DF1 membrane interacted with the ALV-J env protein. The results revealed that antibodies or siRNA to chGRP78 significantly inhibited ALV-J infection and replication, and over-expression of chGRP78 enabled the entry of ALV-J into non-susceptible cells. Taken together, these results are the first to report that chGRP78 functions to help ALV-J enter cells.
doi:10.1186/s13567-016-0373-6
PMCID: PMC5011807  PMID: 27599847
5.  Hepatic ALT isoenzymes are elevated in gluconeogenic conditions including diabetes and suppressed by insulin at the protein level 
Alanine transaminase (ALT) plays an important role in gluconeogenesis by converting alanine into pyruvate for glucose production. Early studies have shown that ALT activities are upregulated in gluconeogenic conditions and may be implicated in the development of diabetes. Since ALT consists of two isoforms, ALT1 and ALT2, with distinctive subcellular and tissue distributions, whether and how they are regulated are largely unknown. In this study, we found that both ALT isoforms in the liver were increased in diabetic GK rats and during fasting. However in ob/ob mice, only ALT2, but not ALT1, protein levels were elevated and the increase of ALT2 is correlated with that of ALT activity. We further demonstrated that, in vitro, both ALT1 and ALT2 were induced by glucocorticoid dexamethasone but suppressed by insulin in Fao hepatoma cells. Finally, we showed that the over-expression of ALT1 and ALT2 in Fao cells directly increased glucose output. Correctively, we have revealed the similarity and difference in the regulation of ALT isoforms in gluconeogenic conditions at the protein level, supporting that ALT isoenzymes play an important role in glucose metabolism and may be implicated the development of insulin resistance and diabetes.
doi:10.1002/dmrr.2655
PMCID: PMC4696510  PMID: 25865565
6.  A Five-Gene Expression Signature Predicts Clinical Outcome of Ovarian Serous Cystadenocarcinoma 
BioMed Research International  2016;2016:6945304.
Ovarian serous cystadenocarcinoma is a common malignant tumor of female genital organs. Treatment is generally less effective as patients are usually diagnosed in the late stage. Therefore, a well-designed prognostic marker provides valuable data for optimizing therapy. In this study, we analyzed 303 samples of ovarian serous cystadenocarcinoma and the corresponding RNA-seq data. We observed the correlation between gene expression and patients' survival and eventually established a risk assessment model of five factors using Cox proportional hazards regression analysis. We found that the survival time in high-risk patients was significantly shorter than in low-risk patients in both training and testing sets after Kaplan-Meier analysis. The AUROC value was 0.67 when predicting the survival time in testing set, which indicates a relatively high specificity and sensitivity. The results suggest diagnostic and therapeutic applications of our five-gene model for ovarian serous cystadenocarcinoma.
doi:10.1155/2016/6945304
PMCID: PMC4949334  PMID: 27478834
7.  Propranolol Targets Hemangioma Stem Cells via cAMP and Mitogen-Activated Protein Kinase Regulation 
Infantile hemangiomas (IHs) are the most common vascular tumor and arise from a hemangioma stem cell (HemSC). Propranolol has proved efficacious against IHs. A selective β2-adrenergic receptor (AR) antagonist mirrored propranolol’s effects on HemSCs. These results show that propranolol acts on HemSCs in IH to suppress proliferation and promote apoptosis in a dose-dependent fashion via β2AR perturbation.
Infantile hemangiomas (IHs) are the most common vascular tumor and arise from a hemangioma stem cell (HemSC). Propranolol has proved efficacious for problematic IHs. Propranolol is a nonselective β-adrenergic receptor (βAR) antagonist that can lower cAMP levels and activate the mitogen-activated protein kinase (MAPK) pathway downstream of βARs. We found that HemSCs express β1AR and β2AR in proliferating IHs and determined the role of these βARs and the downstream pathways in mediating propranolol’s effects. In isolated HemSCs, propranolol suppressed cAMP levels and activated extracellular signal-regulated kinase (ERK)1/2 in a dose-dependent fashion. Propranolol, used at doses of <10−4 M, reduced cAMP levels and decreased HemSC proliferation and viability. Propranolol at ≥10−5 M reduced cAMP levels and activated ERK1/2, and this correlated with HemSC apoptosis and cytotoxicity at ≥10−4 M. Stimulation with a βAR agonist, isoprenaline, promoted HemSC proliferation and rescued the antiproliferative effects of propranolol, suggesting that propranolol inhibits βAR signaling in HemSCs. Treatment with a cAMP analog or a MAPK inhibitor partially rescued the HemSC cell viability suppressed by propranolol. A selective β2AR antagonist mirrored propranolol’s effects on HemSCs in a dose-dependent fashion, and a selective β1AR antagonist had no effect, supporting a role for β2AR signaling in IH pathobiology. In a mouse model of IH, propranolol reduced the vessel caliber and blood flow assessed by ultrasound Doppler and increased activation of ERK1/2 in IH cells. We have thus demonstrated that propranolol acts on HemSCs in IH to suppress proliferation and promote apoptosis in a dose-dependent fashion via β2AR perturbation, resulting in reduced cAMP and MAPK activation.
Significance
The present study investigated the action of propranolol in infantile hemangiomas (IHs). IHs are the most common vascular tumor in children and have been proposed to arise from a hemangioma stem cell (HemSC). Propranolol, a nonselective β-adrenergic receptor (βAR) antagonist, has proven efficacy; however, understanding of its mechanism of action on HemSCs is limited. The presented data demonstrate that propranolol, via βAR perturbation, dose dependently suppresses cAMP levels and activated extracellular signal-regulated kinase 1/2. Furthermore, propranolol acts via perturbation of β2AR, and not β1AR, although both receptors are expressed in HemSCs. These results provide important insight into propranolol’s action in IHs and can be used to guide the development of more targeted therapy.
doi:10.5966/sctm.2015-0076
PMCID: PMC4704871  PMID: 26574555
Hemangioma; Propranolol; β-Adrenergic receptor; Cell proliferation; Cell death; Mitogen-activated protein kinase; cAMP; Stem cell
8.  Encapsulation of Fe3O4 Nanoparticles into N, S co-Doped Graphene Sheets with Greatly Enhanced Electrochemical Performance 
Scientific Reports  2016;6:27957.
Particular N, S co-doped graphene/Fe3O4 hybrids have been successfully synthesized by the combination of a simple hydrothermal process and a subsequent carbonization heat treatment. The nanostructures exhibit a unique composite architecture, with uniformly dispersed Fe3O4 nanoparticles and N, S co-doped graphene encapsulant. The particular porous characteristics with many meso/micro holes/pores, the highly conductive N, S co-doped graphene, as well as the encapsulating N, S co-doped graphene with the high-level nitrogen and sulfur doping, lead to excellent electrochemical performance of the electrode. The N-S-G/Fe3O4 composite electrode exhibits a high initial reversible capacity of 1362.2 mAhg−1, a high reversible specific capacity of 1055.20 mAhg−1 after 100 cycles, and excellent cycling stability and rate capability, with specific capacity of 556.69 mAhg−1 when cycled at the current density of 1000 mAg−1, indicating that the N-S-G/Fe3O4 composite is a promising anode candidate for Li-ion batteries.
doi:10.1038/srep27957
PMCID: PMC4906393  PMID: 27296103
9.  Transarterial administration of integrin inhibitor loaded nanoparticles combined with transarterial chemoembolization for treating hepatocellular carcinoma in a rat model 
World Journal of Gastroenterology  2016;22(21):5042-5049.
AIM: To compare the effect of transarterial chemoembolization (TACE) plus GRGDSP (Gly-Arg-Gly-Asp-Ser-Pro, integrin-inhibitor) loaded nanoparticles with TACE alone or TACE + GRGDSP in a rat model of liver tumor.
METHODS: Morris hepatoma 3924A tumors were implanted in the livers of 30 ACI rats. The ACI rats were divided randomly into three groups (10 animals each). Tumor volume before treatment (V1) was examined by magnetic resonance imaging (MRI), and then, after laparotomy and placement of a PE-10 catheter into the hepatic artery, the following interventional protocols were performed: TACE (mitomycin C + lipiodol + degradable starch microspheres) + GRGDSP loaded nanoparticles for group A; TACE + GRGDSP for group B (control group 1); TACE alone for group C (control group 2). Tumor volume (V2) was assessed by MRI and the mean ratio of the post-treatment to pretreatment tumor volumes (V2/V1) was calculated. Immunohistochemical analysis was performed to assess the quantification of matrix metalloprotein 9 (MMP-9) and vascular endothelial growth factor (VEGF) positive tumor cells in each treatment group.
RESULTS: The mean tumor growth ratios (V2/V1) were 1.3649 ± 0.1194 in group A, 2.0770 ± 0.1595 in group B, and 3.2148 ± 0.1075 in group C. Compared with groups B and C, group A showed a significant reduction in tumor volume. Lower expression of MMP-9 and VEGF in hepatocellular carcinoma was observed in group A than in groups B and C. The angiogenesis of tumor was evaluated using anti-VEGF antibodies, and the metastasis of tumor was assessed using anti-MMP-9 antibody. MMP-9 and VEGF were expressed in all specimens. The immunoexpression of these proteins was confirmed by the presence of red cytoplasmic staining in tumor cells. Lower expression of MMP-9 and VEGF in hepatocellular carcinoma was observed in group A than in groups B and C.
CONCLUSION: Transarterial administration of integrin inhibitor loaded nanoparticles combined with TACE evidently retards tumor growth and intrahepatic metastases compared with TACE alone or TACE plus integrin inhibitor in an animal model of hepatocellular carcinoma.
doi:10.3748/wjg.v22.i21.5042
PMCID: PMC4886379  PMID: 27275096
Hepatocellular carcinoma; Transarterial chemoembolization; Integrin inhibitor; Nanoparticles; Matrix metalloprotein 9; Vascular endothelial growth factor; ACI rats
10.  Epigenetic Silencing of Eyes Absent 4 Gene by Acute Myeloid Leukemia 1-Eight-twenty-one Oncoprotein Contributes to Leukemogenesis in t(8;21) Acute Myeloid Leukemia 
Chinese Medical Journal  2016;129(11):1355-1362.
Background:
The acute myeloid leukemia 1 (AML1)-eight-twenty-one (ETO) fusion protein generated by the t(8;21)(q22;q22) translocation is considered to display a crucial role in leukemogenesis in AML. By focusing on the anti-leukemia effects of eyes absent 4 (EYA4) gene on AML cells, we investigated the biologic and molecular mechanism associated with AML1-ETO expressed in t(8;21) AML.
Methods:
Qualitative polymerase chain reaction (PCR), quantitative reverse transcription PCR (RT-PCR), and Western blotting analysis were used to observe the mRNA and protein expression levels of EYA4 in cell lines. Different plasmids (including mutant plasmids) of dual luciferase reporter vector were built to study the binding status of AML1-ETO to the promoter region of EYA4. Chromatin immunoprecipitation assay was used to study the epigenetic silencing mechanism of EYA4. Bisulfite sequencing was applied to detect the methylation status in EYA4 promoter region. The influence of EYA4 gene in the cell proliferation, apoptosis, and cell clone-forming ability was detected by the technique of Cell Counting Kit-8, flow cytometry, and clonogenic assay.
Results:
EYA4 gene was hypermethylated in AML1-ETO+ patients and its expression was down-regulated by 6-fold in Kasumi-1 and SKNO-1 cells, compared to HL-60 and SKNO-1-siA/E cells, respectively. We demonstrated that AML1-ETO triggered the epigenetic silencing of EYA4 gene by binding at AML1-binding sites and recruiting histone deacetylase 1 and DNA methyltransferases. Enhanced EYA4 expression levels inhibited cellular proliferation and suppressed cell colony formation in AML1-ETO+ cell lines. We also found EYA4 transfection increased apoptosis of Kasumi-1 and SKNO-1 cells by 1.6-fold and 1.4-fold compared to negative control, respectively.
Conclusions:
Our study identified EYA4 gene as targets for AML1-ETO and indicated it as a novel tumor suppressor gene. In addition, we provided evidence that EYA4 gene might be a novel therapeutic target and a potential candidate for treating AML1-ETO+ t (8;21) AML.
doi:10.4103/0366-6999.182838
PMCID: PMC4894048  PMID: 27231175
Acute Myeloid Gene 1-Eight-twenty-one; Acute Myeloid Leukemia; Epigenetics; Eyes Absent 4
11.  The Association between Nutritional Markers and Biochemical Parameters and Residual Renal Function in Peritoneal Dialysis Patients 
PLoS ONE  2016;11(6):e0156423.
Residual renal function (RRF) is an important prognostic factor for peritoneal dialysis patients as it influences the quality of life and mortality. This study was conducted to explore the potential factors correlated with RRF. A cross-sectional study was conducted by recruiting 155 patients with residual GFR more than 1mL/min per 1.73m2 at the initiation of peritoneal dialysis. We collected the demographic characteristics, nutritional markers and biochemical parameters of all participants, and analyzed the correlation between these variables and residual GFR as well. The odds ratio of RRF loss associated with each of the nutritional markers and biochemical parameters were estimated by logistic regression model. The residual GFR was negatively correlated with serum phosphate (ORQ3 = 2.67, 95%CI: 1.03–6.92; ORQ4 = 3.45, 95%CI: 1.35–9.04), magnesium (ORQ4 = 3.77, 95%CI: 1.48–3.63), and creatinine (ORQ3 = 2.93, 95%CI: 1.09–7.88; ORQ4 = 8.64 95%CI: 2.79–26.78), while positively associated with normalized protein catabolic rate (ORQ3 = 0.24, 95%CI: 0.09–0.65; ORQ4 = 0.11, 95%CI: 0.03–0.35), 24 hours urine volume(ORQ1 = 22.87, 95%CI: 2.76–189.24; ORQ3 = 0.08, 95%CI: 0.02–0.28) and serum chlorine concentrations (ORQ1 = 5.34, 95%CI: 1.94–14.68; ORQ4 = 0.28, 95%CI: 0.09–0.85), respectively. Our study suggested that the nutritional markers and biochemical parameters, though not all, but at least in part were closely correlated with RRF in peritoneal dialysis patients.
doi:10.1371/journal.pone.0156423
PMCID: PMC4892617  PMID: 27258403
12.  Yolk–Shell Structures: Yolk–Shell Structured Aluminum Phenylphosphonate Microspheres with Anionic Core and Cationic Shell (Adv. Sci. 5/2016) 
Advanced Science  2016;3(5):n/a.
In article 1500363, X. Shi, J. Liu, and co‐workers describe a new method for the synthesis of amphoteric yolk‐shell structured aluminum phenylphosphonate microspheres with mesoporous shells, overcoming the challenges of precise synthetization of particles with incompatible cores and shells. These microspheres can be used for selective adsorption of cationic and anionic molecules, and provides insight into synthesis of a new family of yolk‐shell particles.
doi:10.1002/advs.201670023
PMCID: PMC5115540
adsorption; aluminum phenylphosphonate; mesoporous materials; microspheres; yolk‐shell structure
13.  Vectorial strain gauge method using single flexible orthogonal polydimethylsiloxane gratings 
Scientific Reports  2016;6:23606.
A vectorial strain gauge method using a single sensing element is reported based on the double-sided polydimethylsiloxane (PDMS) Fraunhofer diffraction gratings structures. Using O2 plasma treatment steps, orthogonal wrinkled gratings were fabricated on both sides of a pre-strained PDMS film. Diffracted laser spots from this structure have been used to experimentally demonstrate, that any applied strain can be quantitatively characterized in both the x and y directions with an error of less than 0.6% and with a gauge factor of approximately 10. This simple and low cost technology which is completely different from the traditional vectorial strain gauge method, can be applied to surface vectorial strain measurement and multi-axis integrated mechanical sensors.
doi:10.1038/srep23606
PMCID: PMC4804235  PMID: 27005493
14.  Yolk–Shell‐Structured Aluminum Phenylphosphonate Microspheres with Anionic Core and Cationic Shell 
Advanced Science  2016;3(5):1500363.
Spherical materials with yolk‐shell structure have great potential for a wide range of applications. The main advantage of the yolk‐shell geometry is the possibility of introducing different chemical or physical properties within a single particle. Here, a one‐step hydrothermal synthesis route for fabricating amphoteric yolk‐shell structured aluminum phenylphosphonate microspheres using urea as the precipitant is proposed. The resulting microspheres display 3D sphere‐in‐sphere architecture with anionic core and cationic shell. The controllable synthesis of aluminum phosphates with various morphologies is also demonstrated. The anionic core and cationic shell of the aluminum phenylphosphonate microspheres provide docking sites for selective adsorption of both cationic methylene blue and anionic binuclear cobalt phthalocyanine ammonium sulphonate. These new adsorbents can be used for simultaneous capture of both cations and anions from a solution, which make them very attractive for various applications such as environmental remediation of contaminated water.
doi:10.1002/advs.201500363
PMCID: PMC5069564  PMID: 27812467
adsorption; aluminum phenylphosphonate; mesoporous materials; microspheres; yolk‐shell structure
15.  Facile Synthesis of Coaxial CNTs/MnOx-Carbon Hybrid Nanofibers and Their Greatly Enhanced Lithium Storage Performance 
Scientific Reports  2015;5:17473.
Carbon nanotubes (CNTs)/MnOx-Carbon hybrid nanofibers have been successfully synthesized by the combination of a liquid chemical redox reaction (LCRR) and a subsequent carbonization heat treatment. The nanostructures exhibit a unique one-dimensional core/shell architecture, with one-dimensional CNTs encapsulated inside and a MnOx-carbon composite nanoparticle layer on the outside. The particular porous characteristics with many meso/micro holes/pores, the highly conductive one-dimensional CNT core, as well as the encapsulating carbon matrix on the outside of the MnOx nanoparticles, lead to excellent electrochemical performance of the electrode. The CNTs/MnOx-Carbon hybrid nanofibers exhibit a high initial reversible capacity of 762.9 mAhg−1, a high reversible specific capacity of 560.5 mAhg−1 after 100 cycles, and excellent cycling stability and rate capability, with specific capacity of 396.2 mAhg−1 when cycled at the current density of 1000 mAg−1, indicating that the CNTs/MnOx-Carbon hybrid nanofibers are a promising anode candidate for Li-ion batteries.
doi:10.1038/srep17473
PMCID: PMC4664925  PMID: 26621615
16.  Cross-talk between PRMT1-mediated methylation and ubiquitylation on RBM15 controls RNA splicing 
eLife  null;4:e07938.
RBM15, an RNA binding protein, determines cell-fate specification of many tissues including blood. We demonstrate that RBM15 is methylated by protein arginine methyltransferase 1 (PRMT1) at residue R578, leading to its degradation via ubiquitylation by an E3 ligase (CNOT4). Overexpression of PRMT1 in acute megakaryocytic leukemia cell lines blocks megakaryocyte terminal differentiation by downregulation of RBM15 protein level. Restoring RBM15 protein level rescues megakaryocyte terminal differentiation blocked by PRMT1 overexpression. At the molecular level, RBM15 binds to pre-messenger RNA intronic regions of genes important for megakaryopoiesis such as GATA1, RUNX1, TAL1 and c-MPL. Furthermore, preferential binding of RBM15 to specific intronic regions recruits the splicing factor SF3B1 to the same sites for alternative splicing. Therefore, PRMT1 regulates alternative RNA splicing via reducing RBM15 protein concentration. Targeting PRMT1 may be a curative therapy to restore megakaryocyte differentiation for acute megakaryocytic leukemia.
DOI: http://dx.doi.org/10.7554/eLife.07938.001
eLife digest
The many different cell types in an adult animal all develop from a single fertilized egg. The development of cells into more specialized cell types is called ‘differentiation’. Proteins and other molecules from both inside and outside of the cells regulate the differentiation process.
RNA is a molecule that is similar to DNA, and performs several important roles inside cells. Perhaps most importantly, RNA molecules act as messengers and carry genetic instructions during gene expression. RBM15 is an RNA-binding protein that is found throughout nature, and is involved in a number of developmental processes. Previous research has linked the incorrect control of RBM15 with an increased risk of certain cancers, including megakaryocytic leukemia. However, it is not clear what role RNA-binding proteins such as RBM15 play during differentiation.
Now, Zhang, Tran, Su et al. have investigated the role of RBM15 during the development of large cells found in human bone marrow (called megakaryocytes). First, the experiments demonstrated that an enzyme called PRMT1 modifies RBM15. This enzyme adds a chemical mark called a methyl group at a specific site (an arginine amino acid) on the RNA-binding protein. Next, Zhang, Tran, Su et al. showed that the addition of this methyl group earmarks RBM15 for destruction. This means that an increase in PRMT1 levels reduces the amount of RBM15 in cells, while decreases in PRMT1 have the opposite effect.
Further experiments showed that RBM15 normally processes the RNA messengers that carry the genetic instructions needed for the differentiation of bone marrow cells. An excess of PRMT1 enzyme leads to a lack of this RNA-binding protein. This in turn interferes with the differentiation process, and can contribute to the development of cancers such as megakaryocytic leukemia. Future work will therefore explore whether targeting PRMT1 with drugs could represent an effective treatment for these kinds of cancers.
DOI: http://dx.doi.org/10.7554/eLife.07938.002
doi:10.7554/eLife.07938
PMCID: PMC4775220  PMID: 26575292
PRMT1; CNOT4; RBM15; arginine methylation; ubiquitylation; RNA metabolism; Human
17.  Generation and Expansion of highly-pure Motor Neuron Progenitors from Human Pluripotent Stem Cells 
Nature communications  2015;6:6626.
SUMMARY
Human pluripotent stem cells (hPSCs) have opened new opportunities for understanding human development, modeling disease processes and developing new therapeutics. However, these applications are hindered by low-efficiency and heterogeneity of target cell types differentiated from hPSCs, such as motor neurons (MNs), as well as our inability to maintain the potency of lineage committed progenitors. Here, by using a combination of small molecules that regulate multiple signaling pathways, we develop a method to guide human embryonic stem cells to a near-pure population (>95%) of motor neuron progenitors (MNPs) in 12 days, and an enriched population (>90%) of functionally mature MNs in an additional 16 days. More importantly, the MNPs can be expanded for at least 5 passages so that a single MNP can be amplified to 1×104. This method is reproducible in human induced pluripotent stem cells and is applied to model MNdegenerative diseases and in proof-of-principle drug screening assays.
doi:10.1038/ncomms7626
PMCID: PMC4375778  PMID: 25806427
18.  Serum thymidine kinase 1 levels correlate with clinical characteristics of esophageal squamous cell carcinoma 
Patients with esophageal cancer are often diagnosed at advanced stages, leading to poor prognosis. Biomarkers are needed to enable earlier detection as well as to aid in the prediction of prognosis, but to date these tools remain scarce. Thymidine kinase (TK1) has been shown to exhibit altered expression levels in esophageal tumor cells, therefore this study sought to determine whether serum TK1 levels are also altered and, if so, to assess the utility of TK1 as a biomarker in esophageal squamous cell carcinoma. Eighty patients with esophageal squamous cell carcinoma were included as the case group and 80 healthy persons were selected as the control group. Serum TK1 levels, postoperatively for cancer patients, were detected by chemiluminescence. Follow-up was performed for cancer patients to determine the progression free survival (PFS) and overall survival (OS). Serum TK1 levels were significantly higher in cases of esophageal cancer than in healthy control individuals (t=7.235, P<0.05). When cancer cases were sub-divided into lower and higher serum TK1 levels, based on the mean level of 3.38 pmol/L, statistically significant differences in TNM stage, tumor differentiation, and lymph node metastasis were observed between patients with ≥3.38 pmol/L and <3.38 pmol/L (χ2=28.134, 3.187, 7.234, P<0.05). The average OS of all esophageal cancer patients was 30.13 months, and the average PFS was 24.73 months. However, when the cases were divided by serum TK1 level, average OS of those with higher serum TK1 (≥3.38 pmol/L) was significantly lower (23.98 mo) than those with lower serum TK1 (32.96 mo) (χ2=5.439, P<0.05). Similarly, average PFS was significantly lower in patients with higher serum TK1 (17.65 mo versus 27.62) (χ2=4.640, P<0.05). OS was correlated with TNM stage (hazard ratio, HR=3.116), degree of tumor differentiation (HR=0.427), lymph node metastasis (HR=0.535), and serum TK1 level (HR=1.913) (Wald χ2=6.782, 6.228, 4.562, 5.681, P<0.05). Similarly, PFS was correlated with TMN stage (HR=2.153), degree of tumor differentiation (HR=0.627), and serum TK1 level (HR=1.632) (Wald χ2=7.035, 5.335, 4.887, P<0.05). Thus, patients with esophageal squamous cell carcinoma exhibit higher circulating TK1 levels, consistent with findings of increased TK1 expression in tumor cells. Further, the correlation of serum TK1 levels with clinical features of esophageal cancer and with patient survival suggest that serum TK1 may serve as a valuable biomarker for predicting patient prognosis.
PMCID: PMC4612885  PMID: 26550200
Thymidine kinase 1; esophageal squamous cell carcinoma; prognosis; survival analysis; serological detection
19.  TLR4-HMGB1-, MyD88- and TRIF-dependent signaling in mouse intestinal ischemia/reperfusion injury 
AIM: To characterize high-mobility group protein 1-toll-like receptor 4 (HMGB1-TLR4) and downstream signaling pathways in intestinal ischemia/reperfusion (I/R) injury.
METHODS: Forty specific-pathogen-free male C57BL/6 mice were randomly divided into five groups (n = 8 per group): sham, control, anti-HMGB1, anti-myeloid differentiation gene 88 (MyD88), and anti-translocating-chain-associating membrane protein (TRIF) antibody groups. Vehicle with the control IgG antibody, anti-HMGB1, anti-MyD88, or anti-TRIF antibodies (all 1 mg/kg, 0.025%) were injected via the caudal vein 30 min prior to ischemia. After anesthetization, the abdominal wall was opened and the superior mesenteric artery was exposed, followed by 60 min mesenteric ischemia and then 60 min reperfusion. For the sham group, the abdominal wall was opened for 120 min without I/R. Levels of serum nuclear factor (NF)-κB p65, interleukin (IL)-6, and tumor necrosis factor (TNF)-α were measured, along with myeloperoxidase activity in the lung and liver. In addition,morphologic changes that occurred in the lung and intestinal tissues were evaluated. Levels of mRNA transcripts encoding HMGB1 and NF-κB were measured by real-time quantitative PCR, and levels of HMGB1 and NF-κB protein were measured by Western blot. Results were analyzed using one-way analysis of variance.
RESULTS: Blocking HMGB1, MyD88, and TRIF expression by injecting anti-HMGB1, anti-MyD88, or anti-TRIF antibodies prior to ischemia reduced the levels of inflammatory cytokines in serum; NF-κB p65: 104.64 ± 11.89, 228.53 ± 24.85, 145.00 ± 33.63, 191.12 ± 13.22, and 183.73 ± 10.81 (P < 0.05); IL-6: 50.02 ± 6.33, 104.91 ± 31.18, 62.28 ± 6.73, 85.90 ± 17.37, and 78.14 ± 7.38 (P < 0.05); TNF-α, 43.79 ± 4.18, 70.81 ± 6.97, 52.76 ± 5.71, 63.19 ± 5.47, and 59.70 ± 4.63 (P < 0.05) for the sham, control, anti-HMGB1, anti-MyD88, and anti-TRIF groups, respectively (all in pg/mL).Antibodies also alleviated tissue injury in the lung and small intestine compared with the control group in the mouse intestinal I/R model. The administration of anti-HMGB1, anti-MyD88, and anti-TRIF antibodies markedly reduced damage caused by I/R, for which anti-HMGB1 antibody had the most obvious effect.
CONCLUSION: HMGB1 and its downstream signaling pathway play important roles in the mouse intestinal I/R injury, and the effect of the TRIF-dependent pathway is slightly greater.
doi:10.3748/wjg.v21.i27.8314
PMCID: PMC4507101  PMID: 26217083
C57BL/6 mouse; High-mobility group protein 1; Intestinal ischemia-reperfusion injury; Myeloid differentiation gene 88; Nuclear factor-κB translocating-chain-associating membrane protein
20.  Thioredoxin reductase: A novel, independent prognostic marker in patients with hepatocellular carcinoma 
Oncotarget  2015;6(19):17792-17804.
Here we found that hepatocellular carcinoma (HCC) patients with recurrence outcome and nonsurvivors had significantly increased thioredoxin reductase (TrxR) serum levels on reoperation (P < 0.0001 and P < 0.0001). Multivariate regression analysis adjusted for common risk factors showed that TrxR was an independent predictor of recurrence (hazard ratios [HR] = 4.19; 95% confidence intervals [CI]: 3.21–7.08) and overall survival (HR = 5.56; 95% CI: 3.42–10.21). The area under the receiver operating characteristic curve of TrxR was 0.837 (95% CI, 0.794–0.881) for recurrence outcome and 0.901 (95% CI, 0.869–0.933) for mortality, which was superior to high-sensitivity-C-reactive protein and a-fetoprotein (P < 0.001). The preoperative serum TrxR level is an independent and significant indicator predictive of poor prognosis and early recurrence in patients with HCC, which offering reliable information for predicting survival.
PMCID: PMC4627346  PMID: 25970775
hepatocellular carcinoma; thioredoxin reductase; prognosis; recurrence; chinese
21.  Biodegradable double nanocapsule as a novel multifunctional carrier for drug delivery and cell imaging 
Highly-efficient delivery of macromolecules into cells for both imaging and therapy (theranostics) remains a challenge for the design of a delivery system. Here, we suggested a novel hybrid protein–lipid polymer nanocapsule as an effective and nontoxic drug delivery and imaging carrier. The biodegradable nanocapsules showed the typical double emulsion features, including fluorescently labeled bovine serum albumin shell, oil phase containing poly(lactic-co-glycolic acid) and linoleic acid, and inner aqueous phase. The nanocapsules were spherical in shape, with an average size of about 180 nm. Proteins packed into the inner aqueous phase of the nanocapsules could be delivered into cells with high efficiency, and the fluorescence of the fluorescently labeled bovine serum albumin could be used for tracing the protein migration and cellular location. Further studies suggested that the co-delivery of transcription factor p53 and lipophilic drug paclitaxel with the nanocapsules acted synergistically to induce Hela cell apoptosis, and the fluorescence of apoptotic cells was clearly observed under a fluorescence microscope. Such multifunctional delivery system would have great potential applications in drug delivery and theranostic fields.
doi:10.2147/IJN.S83731
PMCID: PMC4487237  PMID: 26203242
emulsion; protein transport; fluorescence labeling; theranostics; cell apoptosis
22.  Network-based survival-associated module biomarker and its crosstalk with cell death genes in ovarian cancer 
Scientific Reports  2015;5:11566.
Ovarian cancer remains a dismal disease with diagnosing in the late, metastatic stages, therefore, there is a growing realization of the critical need to develop effective biomarkers for understanding underlying mechanisms. Although existing evidences demonstrate the important role of the single genetic abnormality in pathogenesis, the perturbations of interactors in the complex network are often ignored. Moreover, ovarian cancer diagnosis and treatment still exist a large gap that need to be bridged. In this work, we adopted a network-based survival-associated approach to capture a 12-gene network module based on differential co-expression PPI network in the advanced-stage, high-grade ovarian serous cystadenocarcinoma. Then, regulatory genes (protein-coding genes and non-coding genes) direct interacting with the module were found to be significantly overlapped with cell death genes. More importantly, these overlapping genes tightly clustered together pointing to the module, deciphering the crosstalk between network-based survival-associated module and cell death in ovarian cancer.
doi:10.1038/srep11566
PMCID: PMC4477367  PMID: 26099452
23.  Human-derived neural progenitors functionally replace astrocytes in adult mice 
The Journal of Clinical Investigation  2015;125(3):1033-1042.
Astrocytes are integral components of the homeostatic neural network as well as active participants in pathogenesis of and recovery from nearly all neurological conditions. Evolutionarily, compared with lower vertebrates and nonhuman primates, humans have an increased astrocyte-to-neuron ratio; however, a lack of effective models has hindered the study of the complex roles of human astrocytes in intact adult animals. Here, we demonstrated that after transplantation into the cervical spinal cords of adult mice with severe combined immunodeficiency (SCID), human pluripotent stem cell–derived (PSC-derived) neural progenitors migrate a long distance and differentiate to astrocytes that nearly replace their mouse counterparts over a 9-month period. The human PSC-derived astrocytes formed networks through their processes, encircled endogenous neurons, and extended end feet that wrapped around blood vessels without altering locomotion behaviors, suggesting structural, and potentially functional, integration into the adult mouse spinal cord. Furthermore, in SCID mice transplanted with neural progenitors derived from induced PSCs from patients with ALS, astrocytes were generated and distributed to a similar degree as that seen in mice transplanted with healthy progenitors; however, these mice exhibited motor deficit, highlighting functional integration of the human-derived astrocytes. Together, these results indicate that this chimeric animal model has potential for further investigating the roles of human astrocytes in disease pathogenesis and repair.
doi:10.1172/JCI69097
PMCID: PMC4362241  PMID: 25642771
24.  Transcriptional Profiling of Host Gene Expression in Chicken Embryo Fibroblasts Infected with Reticuloendotheliosis Virus Strain HA1101 
PLoS ONE  2015;10(5):e0126992.
Reticuloendotheliosis virus (REV), a member of the Gammaretrovirus genus in the Retroviridae family, causes an immunosuppressive, oncogenic and runting-stunting syndrome in multiple avian hosts. To better understand the host interactions at the transcriptional level, microarray data analysis was performed in chicken embryo fibroblast cells at 1, 3, 5, and 7 days after infection with REV. This study identified 1,785 differentially expressed genes that were classified into several functional groups including signal transduction, immune response, biological adhesion and endocytosis. Significant differences were mainly observed in the expression of genes involved in the immune response, especially during the later post-infection time points. These results revealed that differentially expressed genes IL6, STAT1, MyD88, TLRs, NF-κB, IRF-7, and ISGs play important roles in the pathogenicity of REV infection. Our study is the first to use microarray analysis to investigate REV, and these findings provide insights into the underlying mechanisms of the host antiviral response and the molecular basis of viral pathogenesis.
doi:10.1371/journal.pone.0126992
PMCID: PMC4431687  PMID: 25973612
25.  Both MicroRNA-155 and Virus-Encoded MiR-155 Ortholog Regulate TLR3 Expression 
PLoS ONE  2015;10(5):e0126012.
MicroRNA-155 (miR-155) has been as an important controller of TLR3 signalling. However, the interactions between miR-155 and TLR3 are poorly understood. Here, we focused on the regulation of the relationship between miR-155 and TLR3. Sequence analyses and firefly luciferase reporter assay revealed that miR-155 target were present in the coding sequences (CDS) of TLR3. And the expression of the TLR3 protein could be inhibited by a miR-155 mimic or by a virally encoded orthologue in chick embryo fibroblast cells. Notably, endogenous miR-155 induction emerged a negative regulation on TLR3 expression in TLR2, 4 and 7 ligands stimulated HD11 cells, an avian macrophage cell line. Moreover, treatment with the miR-155 antagomir increased TLR3 levels while significantly decreased the abundance of TLR3 with miR-155 agomir. In addition, our data showed that miR-155 could inhibit IFN-β production possibly though TLR3 signal pathway. All these findings might reveal a new mechanism by which miR-155 can regulate the TLR3 immune response.
doi:10.1371/journal.pone.0126012
PMCID: PMC4418834  PMID: 25938551

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