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1.  The development of non-coding RNA ontology 
Identification of non-coding RNAs (ncRNAs) has been significantly improved over the past decade. On the other hand, semantic annotation of ncRNA data is facing critical challenges due to the lack of a comprehensive ontology to serve as common data elements and data exchange standards in the field. We developed the Non-Coding RNA Ontology (NCRO) to handle this situation. By providing a formally defined ncRNA controlled vocabulary, the NCRO aims to fill a specific and highly needed niche in semantic annotation of large amounts of ncRNA biological and clinical data.
PMCID: PMC5156483  PMID: 27990175
non-coding RNA; bio-ontologies; domain ontology; reference ontology; ontology development; semantic data annotation
2.  The Radical Extent of lymphadenectomy — D2 dissection versus complete mesocolic excision of LAparoscopic Right Colectomy for right-sided colon cancer (RELARC) trial: study protocol for a randomized controlled trial 
Trials  2016;17:582.
The extent of lymphadenectomy during laparoscopic right colectomy can affect the oncological outcome and the safety of surgery. The principle of complete mesocolic excision (CME) has been gradually accepted and increasingly applied by colorectal surgeons. The aim of this study is to investigate whether extended lymphadenectomy (CME) in laparoscopic colectomy could improve the oncological outcomes of patients with right-sided colon cancers, compared with D2 lymphadenectomy.
The Radical Extent of lympadenectomy: D2 dissection versus complete mesocolic excision of LAparoscopic Right Colectomy for right-sided colon cancer (RELARC) study is a prospective, multicenter, randomized controlled trial in which 1072 eligible patients with right-sided colon cancers will be randomly assigned to the CME group or the D2 dissection group during laparoscopic right colectomy. Inclusion criteria are locally advanced colon cancers situated from the cecum to the right third of the transverse colon and clinically staged as T2-4aN0M0 or TanyN + M0. The primary endpoint of this trial is 3-year disease-free survival. Secondary endpoints include 3-year overall survival, postoperative complication rates, perioperative mortality rates, and rates of positive central lymph nodes (the station 3 nodes).
The RELARC trial is a prospective, multicenter, randomized controlled trial that will provide evidence on the optimal extent of lymphadenectomy during laparoscopic right colectomy in terms of better oncological outcome and operation safety.
Trial registration NCT02619942. Registered on 29 November 2015.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-016-1710-9) contains supplementary material, which is available to authorized users.
PMCID: PMC5146822  PMID: 27931247
Colon cancer; Laparoscopic right colectomy; Complete mesocolic excision; Oncological outcome
3.  Cigarette smoke extract induces placental growth factor release from human bronchial epithelial cells via ROS/MAPK (ERK-1/2)/Egr-1 axis 
Etiological evidence demonstrates that there is a significant association between cigarette smoking and chronic airway inflammatory disease. Abnormal expression of placental growth factor (PlGF) has been reported in COPD, and its downstream signaling molecules have been reported to contribute to the pathogenesis of airway epithelial cell apoptosis and emphysema. However, the signaling mechanisms underlying cigarette smoke extract (CSE)-induced PlGF expression in airway microenvironment remain unclear. Herein, we investigated the effects of reactive oxygen species (ROS)-dependent activation of the mitogen-activated protein kinase (MAPK) (extracellular signal-regulated kinase1/2 [ERK-1/2])/early growth response-1 (Egr-1) pathway on CSE-induced PlGF upregulation in human bronchial epithelium (HBE). The data obtained with quantitative reverse transcription polymerase chain reaction, Western blot, enzyme-linked immunosorbent assay (ELISA) and immunofluorescence staining analyses showed that CSE-induced Egr-1 activation was mainly mediated through production of ROS and activation of the MAPK (ERK-1/2) cascade. The binding of Egr-1 to the PlGF promoter was corroborated by an ELISA-based DNA binding activity assay. These results demonstrate that ROS activation of the MAPK (ERK-1/2)/Egr-1 pathway is a main player in the regulatory mechanism for CSE-induced PlGF production and that the use of an antioxidant could partly abolish these effects. Understanding the mechanisms of PlGF upregulation by CSE in the airway microenvironment may provide rational therapeutic interventions for cigarette smoking-related airway inflammatory diseases.
PMCID: PMC5144910  PMID: 27980400
cigarette smoke; reactive oxygen species; airway epithelium; placental growth factor; extracellular signal-regulated kinase1/2; early growth response-1
4.  Cancer Therapy: Anti‐Metastatic and Anti‐Angiogenic Activities of Core–Shell SiO2@LDH Loaded with Etoposide in Non‐Small Cell Lung Cancer (Adv. Sci. 11/2016) 
Advanced Science  2016;3(11):n/a.
In article 1600229, Shilong Wang, Rongrong Zhu, Yechang Qian, and co‐workers investigate the anti‐metastatic and anti‐angiogenic effects of SiO2@LDH (LDH: layered double hydroxide) loaded with etoposide (VP16). SiO2@LDH has very suitable qualities as drug delivery agent and enhances the anti‐metastatic action of VP16 both in vitro and in vivo. Enhanced anti‐angiogenic efficacy is also proven which might contribute to the anti‐cancer action. The cover image represents the 3D structure of core‐shell SiO2@LDH‐VP16, which silicon dioxide sphere flexibly enclosed by double‐layered hydroxide.
PMCID: PMC5115527
anti‐angiogenic; anti‐metastasis; etoposide; lung cancer; SiO2@LDH
5.  Anti‐Metastatic and Anti‐Angiogenic Activities of Core–Shell SiO2@LDH Loaded with Etoposide in Non‐Small Cell Lung Cancer 
Advanced Science  2016;3(11):1600229.
Currently, nanoparticles have gained a great attention in the anti‐tumor research area. However, to date, studies on the anti‐metastasis action of core–shell SiO2@LDH (LDH: layered double hydroxide) nanoparticles remain untouched. Two emerging aspects considered are establishing research on the controlling delivery effect of SiO2@LDH combined with anti‐cancer medicine from a new perspective. The fine properties synthetic SiO2@LDH‐VP16 (VP16: etoposide) are practiced to exhibit the nanoparticle's suppression on migration and invasion of non‐small cell lung cancer (NSCLC). Both in vitro and in vivo inspection shows that SiO2@LDH can help VP16 better function as an anti‐metastasis agent. On the other hand, anti‐angiogenic efficiency, co‐localization, as well as western blot are investigated to explain the possible mechanism. A clear mergence of SiO2@LDH‐VP16 and cytomembrane/microtubule may be observed from co‐location images. Results offer evidence that SiO2@LDH‐VP16 plays positions on cytomembrane and microtubules. It efficiently inhibits metastasis on NSCLC by reducing vascularization, and eliciting depression of the PI3K‐AKT and FAK‐Paxillin signaling pathways. SiO2@LDH‐VP16, the overall particle morphology, and function on anti‐metastasis and anti‐angiogenic may be tuned to give new opportunities for novel strategies for cancer therapy.
PMCID: PMC5102674  PMID: 27980999
anti‐angiogenic; anti‐metastasis; etoposide; lung cancer; SiO2@LDH
6.  Biscogniauxone, a New Isopyrrolonaphthoquinone Compound from the Fungus Biscogniauxia mediterranea Isolated from Deep-Sea Sediments † 
Marine Drugs  2016;14(11):204.
The properties and the production of new metabolites from the fungal strain LF657 isolated from the Herodotes Deep (2800 m depth) in the Mediterranean Sea are reported in this study. The new isolate was identified as Biscogniauxia mediterranea based on ITS1-5.8S-ITS2 and 28S rRNA gene sequences. A new isopyrrolonaphthoquinone with inhibitory activity against glycogen synthase kinase (GSK-3β) was isolated from this fungus. This is the first report of this class of compounds from a fungus isolated from a deep-sea sediment, as well as from a Biscogniauxia species.
PMCID: PMC5128747  PMID: 27827848
marine fungi; glycogen synthase kinase; acetylcholinesterase; Biscogniauxia mediterranea; deep sea
7.  Anti‐Metastatic and Anti‐Angiogenic Activities of Core–Shell SiO2@LDH Loaded with Etoposide in Non‐Small Cell Lung Cancer 
Advanced Science  2016;3(11):1600229.
Currently, nanoparticles have gained a great attention in the anti‐tumor research area. However, to date, studies on the anti‐metastasis action of core–shell SiO2@LDH (LDH: layered double hydroxide) nanoparticles remain untouched. Two emerging aspects considered are establishing research on the controlling delivery effect of SiO2@LDH combined with anti‐cancer medicine from a new perspective. The fine properties synthetic SiO2@LDH‐VP16 (VP16: etoposide) are practiced to exhibit the nanoparticle's suppression on migration and invasion of non‐small cell lung cancer (NSCLC). Both in vitro and in vivo inspection shows that SiO2@LDH can help VP16 better function as an anti‐metastasis agent. On the other hand, anti‐angiogenic efficiency, co‐localization, as well as western blot are investigated to explain the possible mechanism. A clear mergence of SiO2@LDH‐VP16 and cytomembrane/microtubule may be observed from co‐location images. Results offer evidence that SiO2@LDH‐VP16 plays positions on cytomembrane and microtubules. It efficiently inhibits metastasis on NSCLC by reducing vascularization, and eliciting depression of the PI3K‐AKT and FAK‐Paxillin signaling pathways. SiO2@LDH‐VP16, the overall particle morphology, and function on anti‐metastasis and anti‐angiogenic may be tuned to give new opportunities for novel strategies for cancer therapy.
PMCID: PMC5102674  PMID: 27980999
anti‐angiogenic; anti‐metastasis; etoposide; lung cancer; SiO2@LDH
8.  Microstructural changes in compressed nerve roots treated by percutaneous transforaminal endoscopic discectomy in patients with lumbar disc herniation 
Medicine  2016;95(40):e5106.
To investigate the microstructural changes in compressed nerves using diffusion tensor imaging (DTI) of herniated disc treated with percutaneous transforaminal endoscopic discectomy.
Diffusion tensor imaging has been widely used to visualize peripheral nerves, and the microstructure of compressed nerve roots can be assessed using DTI. However, the microstructural changes after surgery are not well-understood in patients with lumbar disc herniation.
Thirty-four consecutive patients with foraminal disc herniation affecting unilateral sacral 1 (S1) nerve roots were enrolled in this study. DTI with tractography was performed on S1 nerve roots before and after surgery. The mean fractional anisotropy (FA) and apparent diffusion coefficient values were calculated from tractography images.
In compressed nerve roots, the FA value before surgery was significantly lower than that after surgery (P = 0.000). A significant difference in FA values was found between the compressed and normal sides before surgery (P = 0.000). However, no significant difference was found between the compressed and normal sides after surgery (P = 0.057). A significant difference in apparent diffusion coefficient values was found before and after surgery at the compressed side (P = 0.023). However, no significant difference was found between the compressed and normal sides after surgery (P = 0.203).
We show that the diffusion parameters of compressed nerve roots were not significantly different before and after percutaneous transforaminal endoscopic discectomy, indicating that the microstructure of the nerve root recovered after surgery.
PMCID: PMC5059094  PMID: 27749591
diffusion tensor imaging; herniated disc; microstructural properties of nerve roots; percutaneous transforaminal endoscopic discectomy
9.  Effectiveness of Omega-3 Polyunsaturated Fatty Acids in Non-Alcoholic Fatty Liver Disease: A Meta-Analysis of Randomized Controlled Trials 
PLoS ONE  2016;11(10):e0162368.
Non-alcoholic fatty liver disease (NAFLD) is a clinical syndrome with the main characteristic of diffuse liver cells with fatty changes. The clinical evolution of NAFLD includes simple non-alcoholic fatty liver, non-alcoholic steatohepatitis (NASH), liver fibrosis and cirrhosis, and even hepatocellular carcinoma.
Methods and Findings
We conducted this review to identify the effectiveness of omega-3 polyunsaturated fatty acids (ω-3 PUFA) in NAFLD. We searched PubMed, Cochrane Library and Embase. All randomized controlled trials (RCTs) of ω-3 PUFA treatment for NAFLD were considered. Two reviewers assessed the quality of each study and collected data independently. Disagreements were resolved by discussion among the reviewers and any of the other authors of the paper. We performed a meta-analysis and reported summary estimates of outcomes as inverse variance (IV), fixed or random, with 95% confidence intervals (CIs). We included seven RCTs involving 442 patients (227 for the experimental group and 215 for the control group). All the patients were divided into two groups: one treated with ω-3 PUFA and the other was the control group (generally placebo). The demographics of the ω-3 PUFA and control groups were comparable. Beneficial changes in alanine aminotransferase (ALT) (IV 95% CI: −7.61 [−12.83 to −2.39], p = 0.004), total cholesterol (TC) (IV 95% CI: −13.41 [−21.44 to −5.38], p = 0.001), triglyceride (TG) (IV 95% CI: −43.96 [−51.21 to −36.71], p<0.00001) and high-density lipoprotein cholesterol (HDL-C) (IV 95% CI: 6.97 [2.05 to 11.90], p = 0.006) favored ω-3 PUFA treatment. Omega-3 PUFA tended towards a beneficial effect on aspartate aminotransferase (AST) (IV 95% CI: −6.89 [−17.71 to 3.92], p = 0.21), γ-glutamyl transferase (GGT) (IV 95% CI: −8.28 [−18.38 to 1.83], p = 0.11) and low-density lipoprotein cholesterol (LDL-C) (IV 95% CI: −7.13 [−14.26 to 0.0], p = 0.05).
Supplementation with ω-3 PUFA is a practical and effective treatment for NAFLD to decrease ALT, TC and increase HDL-C, especially to decrease TG. Omega-3 PUFA also has a tendency toward a beneficial effect on AST, GGT and LDL-C. More high-quality, large RCTs are needed to validate our findings.
PMCID: PMC5053538  PMID: 27711128
10.  Structural characterization of a flexible two-domain protein in solution using Small Angle X-ray Scattering and NMR spectroscopy 
Structure (London, England : 1993)  2014;22(12):1862-1874.
Multidomain proteins in which individual domains are connected by linkers often possess inherent inter-domain flexibility that significantly complicates their structural characterization in solution using either NMR spectroscopy or small-angle X-ray scatting (SAXS) alone. Here we report a novel protocol for joint refinement of flexible multidomain protein structures against NMR distance and angular restraints, residual dipolar couplings and SAXS data. The protocol is based on the EOM principle (Bernardo et al., 2007) and is compared with different refinement strategies for the structural characterization of the flexible two-domain protein sf3636 from Shigella flexneri 2a. The results of our refinement suggest the existence of a dominant population of configurational states in solution possessing an overall elongated shape and restricted relative twisting of the two domains.
PMCID: PMC5046226  PMID: 25456817
11.  Inactivation of NF-κB p65 (RelA) in Liver Improves Insulin Sensitivity and Inhibits cAMP/PKA Pathway 
Diabetes  2015;64(10):3355-3362.
The transcription factor nuclear factor-κB (NF-κB) mediates inflammation and stress signals in cells. To test NF-κB in the control of hepatic insulin sensitivity, we inactivated NF-κB in the livers of C57BL/6 mice through deletion of the p65 gene, which was achieved by crossing floxed-p65 and Alb-cre mice to generate L-p65-knockout (KO) mice. KO mice did not exhibit any alterations in growth, reproduction, and body weight while on a chow diet. However, the mice on a high-fat diet (HFD) exhibited an improvement in systemic insulin sensitivity. Hepatic insulin sensitivity was enhanced as indicated by increased pyruvate tolerance, Akt phosphorylation, and decreased gene expression in hepatic gluconeogenesis. In the liver, a decrease in intracellular cAMP was observed with decreased CREB phosphorylation. Cyclic nucleotide phosphodiesterase-3B (PDE3B), a cAMP-degrading enzyme, was increased in mRNA and protein as a result of the absence of NF-κB activity. NF-κB was found to inhibit PDE3B transcription through three DNA-binding sites in the gene promoter in response to tumor necrosis factor-α. Body composition, food intake, energy expenditure, and systemic and hepatic inflammation were not significantly altered in KO mice on HFD. These data suggest that NF-κB inhibits hepatic insulin sensitivity by upregulating cAMP through suppression of PDE3B gene transcription.
PMCID: PMC4587638  PMID: 26038580
12.  TRIM29 Overexpression Promotes Proliferation and Survival of Bladder Cancer Cells through NF-κB Signaling 
TRIM29 overexpression has been reported in several human malignancies and showed correlation with cancer cell malignancy. The aim of the current study is to examine its clinical significance and biological roles in human bladder cancer tissues and cell lines.
Materials and Methods
A total of 102 cases of bladder cancer tissues were examined for TRIM29 expression by immunohistochemistry. siRNA and plasmid transfection were performed in 5637 and BIU-87 cell lines. Cell Counting Kit-8, flow cytometry, western blot, and real-time polymerase chain reaction were performed to examine its biological roles and mechanism in bladder cancer cells.
We found that TRIM29 overexpression showed correlation with invading depth (p=0.0087). Knockdown of TRIM29 expression in bladder cancer cell line 5637 inhibited cell growth rate and cell cycle transition while its overexpression in BIU-87 cells accelerated cell proliferation and cell cycle progression. TRIM29 overexpression also inhibited cell apoptosis induced by cisplatin. In addition, we demonstrated that TRIM29 depletion decreased while its overexpression led to upregulated expression of cyclin D1, cyclin E, and Bcl-2. We also showed that TRIM29 knockdown inhibited protein kinase C (PKC) and nuclear factor κB (NF-κB) signaling while its overexpression stimulated the PKC and NF-κB pathways. BAY 11-7082 (NF-κB inhibitor) partly attenuated the effect of TRIM29 on expression of cyclin and Bcl-2. Treatment with PKC inhibitor staurosporine resulted in ameliorated TRIM29 induced activation of NF-κB.
The current study demonstrated that TRIM29 upregulates cyclin and Bcl family proteins level to facilitate malignant cell growth and inhibit drug-induced apoptosis in bladder cancer, possibly through PKC–NF-κB signaling pathways.
PMCID: PMC5080803  PMID: 26987391
TRIM29; NF-κB; Urinary bladder neoplasms; PKC
13.  BmP02 Atypically Delays Kv4.2 Inactivation: Implication for a Unique Interaction between Scorpion Toxin and Potassium Channel 
Toxins  2016;8(10):280.
BmP02, a short-chain peptide with 28 residues from the venom of Chinese scorpion Buthus martensi Karsch, has been reported to inhibit the transient outward potassium currents (Ito) in rat ventricular muscle cells. However, it remains unclear whether BmP02 modulates the Kv4.2 channel, one of the main contributors to Ito. The present study investigated the effects of BmP02 on Kv4.2 kinetics and its underlying molecular mechanism. The electrophysiological recordings showed that the inactivation of Kv4.2 expressed in HEK293T cells was significantly delayed by BmP02 in a dose-response manner with EC50 of ~850 nM while the peak current, activation and voltage-dependent inactivation of Kv4.2 were not affected. Meanwhile, the recovery from inactivation of Kv4.2 was accelerated and the deactivation was slowed after the application of BmP02. The site-directed mutagenesis combined with computational modelling identified that K347 and K353, located in the turret motif of the Kv4.2, and E4/E5, D20/D21 in BmP02 are key residues to interact with BmP02 through electrostatic force. These findings not only reveal a novel interaction between Kv4.2 channel and its peptidyl modulator, but also provide valuable information for design of highly-selective Kv4.2 modulators.
PMCID: PMC5086640  PMID: 27690098
scorpion toxin; voltage-gated potassium channels; electrophysiology; interaction mode
14.  Mst1 inhibits CMECs autophagy and participates in the development of diabetic coronary microvascular dysfunction 
Scientific Reports  2016;6:34199.
Cardiovascular complications account for a substantial proportion of morbidity and mortality in diabetic patients. Abnormalities of cardiac microvascular endothelial cells (CMECs) lead to impaired cardiac microvascular vessel integrity and subsequent cardiac dysfunction, underlining the importance of coronary microvascular dysfunction. In this study, experimental diabetes models were constructed using Mst1 transgenic, Mst1 knockout and sirt1 knockout mice. Diabetic Mst1 transgenic mice exhibited impaired cardiac microvessel integrity and decreased cardiac function. Mst1 overexpression deceased CMECs autophagy as evidenced by decreased LC3 expression and enhanced protein aggregation when subjected to high glucose culture. Mst1 knockout improved cardiac microvessel integrity and enhanced cardiac functions in diabetic mice. Mst1 knockdown up-regulated autophagy as indicated by more typical autophagosomes and increased LC3 expression in CMECs subjected to high glucose cultures. Mst1 knockdown also promoted autophagic flux in the presence of bafilomycin A1. Mst1 overexpression increased CMECs apoptosis, whereas Mst1 knockout decreased CMECs apoptosis. Sirt1 knockout abolished the effects of Mst1 overexpression in cardiac microvascular injury and cardiac dysfunction. In conclusion, Mst1 knockout preserved cardiac microvessel integrity and improved cardiac functions in diabetic mice. Mst1 decreased sirt1 activity, inhibited autophagy and enhanced apoptosis in CMECs, thus participating in the pathogenesis of diabetic coronary microvascular dysfunction.
PMCID: PMC5040958  PMID: 27680548
15.  Brain natriuretic peptide suppresses pain induced by BmK I, a sodium channel-specific modulator, in rats 
A previous study found that brain natriuretic peptide (BNP) inhibited inflammatory pain via activating its receptor natriuretic peptide receptor A (NPRA) in nociceptive sensory neurons. A recent study found that functional NPRA is expressed in almost all the trigeminal ganglion (TG) neurons at membrane level suggesting a potentially important role for BNP in migraine pathophysiology.
An inflammatory pain model was produced by subcutaneous injection of BmK I, a sodium channel-specific modulator from venom of Chinese scorpion Buthus martensi Karsch. Quantitative PCR, Western Blot, and immunohistochemistry were used to detect mRNA and protein expression of BNP and NPRA in dorsal root ganglion (DRG) and dorsal horn of spinal cord. Whole-cell patch clamping experiments were conducted to record large-conductance Ca2+-activated K+ (BKCa) currents of membrane excitability of DRG neurons. Spontaneous and evoked pain behaviors were examined.
The mRNA and protein expression of BNP and NPRA was up-regulated in DRG and dorsal horn of spinal cord after BmK I injection. The BNP and NPRA was preferentially expressed in small-sized DRG neurons among which BNP was expressed in both CGRP-positive and IB4-positive neurons while NPRA was preferentially expressed in CGRP-positive neurons. BNP increased the open probability of BKCa channels and suppressed the membrane excitability of small-sized DRG neurons. Intrathecal injection of BNP significantly inhibited BmK-induced pain behaviors including both spontaneous and evoked pain behaviors.
These results suggested that BNP might play an important role as an endogenous pain reliever in BmK I-induced inflammatory pain condition. It is also suggested that BNP might play a similar role in other pathophysiological pain conditions including migraine.
PMCID: PMC5042912  PMID: 27687165
16.  Mechanical Stimulation Increases Knee Meniscus Gene RNA-level Expression in Adipose-derived Stromal Cells 
Supplemental Digital Content is available in the text.
Efforts have been made to engineer knee meniscus tissue for injury repair, yet most attempts have been unsuccessful. Creating a cell source that resembles the complex, heterogeneous phenotype of the meniscus cell remains difficult. Stem cell differentiation has been investigated, mainly using bone marrow mesenchymal cells and biochemical means for differentiation, resulting in no solution. Mechanical stimulation has been investigated to an extent with no conclusion. Here, we explore the potential for and effectiveness of mechanical stimulation to induce the meniscal phenotype in adipose-derived stromal cells.
Human adipose-derived stromal cells were chosen for their fibrogenic nature and conduciveness for chondrogenesis. Biochemical and mechanical stimulation were investigated. Biochemical stimulation included fibrogenic and chondrogenic media. For mechanical stimulation, a custom-built device was used to apply constant, cyclical, uniaxial strain for up to 6 hours. Strain and frequency varied.
Under biochemical stimulation, both fibrogenic (collagen I, versican) and chondrogenic (collagen II, Sox9, aggrecan) genes were expressed by cells exposed to either fibrogenic or chondrogenic biochemical factors. Mechanical strain was found to preferentially promote fibrogenesis over chondrogenesis, confirming that tensile strain is an effective fibrogenic cue. Three hours at 10% strain and 1 Hz in chondrogenic media resulted in the highest expression of fibrochondrogenic genes. Although mechanical stimulation did not seem to affect protein level expression, biochemical means did affect protein level presence of collagen fibers.
Mechanical stimulation can be a useful differentiation tool for mechanoresponsive cell types as long as biochemical factors are also integrated.
PMCID: PMC5054995  PMID: 27757329
17.  Dysfunctional cerebellar Purkinje cells contribute to autism-like behaviour in Shank2-deficient mice 
Nature Communications  2016;7:12627.
Loss-of-function mutations in the gene encoding the postsynaptic scaffolding protein SHANK2 are a highly penetrant cause of autism spectrum disorders (ASD) involving cerebellum-related motor problems. Recent studies have implicated cerebellar pathology in the aetiology of ASD. Here we evaluate the possibility that cerebellar Purkinje cells (PCs) represent a critical locus of ASD-like pathophysiology in mice lacking Shank2. Absence of Shank2 impairs both PC intrinsic plasticity and induction of long-term potentiation at the parallel fibre to PC synapse. Moreover, inhibitory input onto PCs is significantly enhanced, most prominently in the posterior lobe where simple spike (SS) regularity is most affected. Using PC-specific Shank2 knockouts, we replicate alterations of SS regularity in vivo and establish cerebellar dependence of ASD-like behavioural phenotypes in motor learning and social interaction. These data highlight the importance of Shank2 for PC function, and support a model by which cerebellar pathology is prominent in certain forms of ASD.
Mutations in SHANK2 are associated with autism spectrum disorders (ASD). Here, Peter et al. show that selective loss of Shank2 in Purkinje cells of the mouse cerebellum leads to deficits in plasticity, motor behaviour, and a social behaviour phenotype similar to that seen in ASD.
PMCID: PMC5025785  PMID: 27581745
18.  Surgical treatment of double primary liver cancer 
Medicine  2016;95(32):e4412.
Double primary liver cancer (DPLC) is a special type of clinical situation. As such, a detailed analysis of the surgical management and prognosis of patients with DPLC is lacking. The objective of the current study was to define the management and outcome of patients undergoing surgery for DPLC at a major hepatobiliary center.
A total of 87 patients treated by surgical resection at the Eastern Hepatobiliary Surgery Hospital from January 1st, 2007 to October 31st, 2013 who had DPLC demonstrated by final pathological diagnosis were identified. Among these, 50 patients had complete clinical and prognostic data. Demographic and tumor characteristics as well as the prognosis were analyzed.
The proportion of hepatitis B surface antigen (HBsAg) (+) and hepatitis B virus e antigen (HBeAg) (+), HBsAg (+), and HBeAg (−) hepatocirrhosis in all patients was 21.84%, 67.82%, and 63.22%, respectively. Incidental findings accounted for 58.62% of patients; among those who had symptoms, the main symptom was abdominal pain (31.03%). Nonanatomic wedge resection was the main operative approach (62.07%). Postoperatively, the main complications included seroperitoneum (11.49%), hypoproteinemia (10.34%), and pleural effusion (8.05%). Factors associated with disease-free survival (DFS) included intrahepatic cholangiocarcinoma (ICC) tumor size (P = 0.002) and use of postoperative prophylactic transcatheter arterial chemoembolization (TACE) treatment (P = 0.015). Meanwhile, hepatocellular carcinoma (HCC) size (P = 0.045), ICC size (P < 0.001), and liver function (including aspartate aminotransferase [P = 0.001] and r-glutamyl transferase [P < 0.001]) were associated with overall survival (OS).
Hepatitis B virus (HBV)-related hepatitis or cirrhosis is also an important factor in the pathogenesis of DPLC and surgical treatment is safe for it with low complication rates. In addition, it is effective to prolong DFS that DPLC patients undergo postoperative prophylactic TACE treatment.
PMCID: PMC4985310  PMID: 27512855
clinical characteristics; double primary liver cancer; prognosis; surgical treatment
19.  Evolutionary Games of Multiplayer Cooperation on Graphs 
PLoS Computational Biology  2016;12(8):e1005059.
There has been much interest in studying evolutionary games in structured populations, often modeled as graphs. However, most analytical results so far have only been obtained for two-player or linear games, while the study of more complex multiplayer games has been usually tackled by computer simulations. Here we investigate evolutionary multiplayer games on graphs updated with a Moran death-Birth process. For cycles, we obtain an exact analytical condition for cooperation to be favored by natural selection, given in terms of the payoffs of the game and a set of structure coefficients. For regular graphs of degree three and larger, we estimate this condition using a combination of pair approximation and diffusion approximation. For a large class of cooperation games, our approximations suggest that graph-structured populations are stronger promoters of cooperation than populations lacking spatial structure. Computer simulations validate our analytical approximations for random regular graphs and cycles, but show systematic differences for graphs with many loops such as lattices. In particular, our simulation results show that these kinds of graphs can even lead to more stringent conditions for the evolution of cooperation than well-mixed populations. Overall, we provide evidence suggesting that the complexity arising from many-player interactions and spatial structure can be captured by pair approximation in the case of random graphs, but that it need to be handled with care for graphs with high clustering.
Author Summary
Cooperation can be defined as the act of providing fitness benefits to other individuals, often at a personal cost. When interactions occur mainly with neighbors, assortment of strategies can favor cooperation but local competition can undermine it. Previous research has shown that a single coefficient can capture this trade-off when cooperative interactions take place between two players. More complicated, but also more realistic, models of cooperative interactions involving multiple players instead require several such coefficients, making it difficult to assess the effects of population structure. Here, we obtain analytical approximations for the coefficients of multiplayer games in graph-structured populations. Computer simulations show that, for particular instances of multiplayer games, these approximate coefficients predict the condition for cooperation to be promoted in random graphs well, but fail to do so in graphs with more structure, such as lattices. Our work extends and generalizes established results on the evolution of cooperation on graphs, but also highlights the importance of explicitly taking into account higher-order statistical associations in order to assess the evolutionary dynamics of cooperation in spatially structured populations.
PMCID: PMC4981334  PMID: 27513946
20.  An Unusual Conformational Isomer of Verrucosidin Backbone from a Hydrothermal Vent Fungus, Penicillium sp. Y-50-10 
Marine Drugs  2016;14(8):156.
A new verrucosidin derivative, methyl isoverrucosidinol (1), was isolated from the marine fungus Penicillium sp. Y-50-10, dwelling in sulfur rich sediment in the Kueishantao hydrothermal vents off Taiwan. The structure was established by spectroscopic means including HRMS and 2D-NMR spectroscopic analysis. The absolute configuration was defined mainly by comparison of quantum chemical TDDFT calculated and experimental ECD spectra. Among hitherto known compounds with a verrucosidine backbone isolated from natural resource, compound 1 represents the first example of a new conformational isomer of its skeleton, exhibiting antibiotic activity against Bacillus subtilis with MIC value 32 μg/mL.
PMCID: PMC4999917  PMID: 27548192
marine fungus; Penicillium sp.; verrucosidin; conformational isomer; antibiotic
21.  Theophylline-Based KMUP-1 Improves Steatohepatitis via MMP-9/IL-10 and Lipolysis via HSL/p-HSL in Obese Mice 
KMUP-1 (7-[2-[4-(2-chlorobenzene)piperazinyl]ethyl]-1,3-dimethylxanthine) has been reported to cause hepatic fat loss. However, the action mechanisms of KMUP-1 in obesity-induced steatohepatitis remains unclear. This study elucidated the steatohepatitis via matrix metallopeptidase 9 (MMP-9) and tumor necrosis factor α (TNFα), and related lipolysis via hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL) by KMUP-1. KMUP-1 on steatohepatitis-associated HSL/p-HSL/ATGL/MMP-9/TNFα/interleukin-10 (IL-10) and infiltration of M1/M2 macrophages in obese mice were examined. KMUP-1 was administered by oral gavage from weeks 1–14 in high-fat diet (HFD)-supplemented C57BL/6J male mice (protection group) and from weeks 8–14, for 6 weeks, in HFD-induced obese mice (treatment group). Immunohistochemistry (IHC) and hematoxylin and eosin (H&E) staining of tissues, oil globules number and size, infiltration and switching of M1/M2 macrophages were measured to determine the effects on livers. IL-10 and MMP-9 proteins were explored to determine the effects of KMUP-1 on M1/M2 macrophage polarization in HFD-induced steatohepatitis. Long-term administration of KMUP-1 reversed HFD-fed mice increased in body weight, sGOT/sGPT, triglyceride (TG) and glucose. Additionally, KMUP-1 decreased MMP-9 and reactive oxygen species (ROS), and increased HSL/p-HSL and IL-10 in HFD mice livers. In conclusion, KMUP-1, a phosphodiesterase inhibitor (PDEI), was shown to reduce lipid accumulation in liver tissues, suggesting that it could be able to prevent or treat steatohepatitis induced by HFD.
PMCID: PMC5000741  PMID: 27548140
adipose triglyceride lipase; fatty liver; hormone sensitive lipase; M1/M2 macrophage; matrix metallopeptidase 9; tumor necrosis factor α
22.  Translation dynamics of single mRNAs in live cells and neurons 
Science (New York, N.Y.)  2016;352(6292):1430-1435.
Translation is the fundamental biological process converting mRNA information into proteins. Single-molecule imaging in live cells has illuminated the dynamics of RNA transcription; however, it is not yet applicable to translation. Here, we report single-molecule imaging of nascent peptides (SINAPS) to assess translation in live cells. The approach provides direct readout of initiation, elongation, and location of translation. We show that mRNAs coding for endoplasmic reticulum (ER) proteins are translated when they encounter the ER membrane. Single-molecule fluorescence recovery after photobleaching provides direct measurement of elongation speed (5 amino acids per second). In primary neurons, mRNAs are translated in proximal dendrites but repressed in distal dendrites and display “bursting” translation. This technology provides a tool with which to address the spatiotemporal translation mechanism of single mRNAs in living cells.
PMCID: PMC4939616  PMID: 27313041
23.  Quantifying protein-mRNA interactions in single live cells 
Cell  2015;162(1):211-220.
Specific binding proteins are crucial for the correct spatiotemporal expression of mRNA. To understand this process, a method is required to characterize RNA-protein interactions in single living cells with subcellular resolution. We combined endogenous single RNA and protein detection with two-photon fluorescence fluctuation analysis to measure the average number of proteins bound to mRNA at specific locations within live cells. We applied this to quantify the known binding of zipcode binding protein 1 (ZBP1) and ribosomes, to β-actin mRNA within subcellular compartments of primary fibroblasts and neurons. ZBP1-mRNA binding did not occur in nuclei, contrary to previous conclusions. ZBP1 interaction with β-actin mRNA was enhanced perinuclearly in neurons compared to fibroblasts. Cytoplasmic ZBP1 and ribosome binding to the mRNA were anti-correlated depending on their location in the cell. These measurements support a mechanism whereby ZBP1 inhibits translation of localizing mRNA until its release from the mRNA peripherally, allowing ribosome binding.
PMCID: PMC4491145  PMID: 26140598
beta-actin mRNA; ZBP1; ribosomes; fluorescence fluctuation spectroscopy; translational regulation
24.  Evolving synergetic interactions 
Journal of the Royal Society Interface  2016;13(120):20160282.
Cooperators forgo their own interests to benefit others. This reduces their fitness and thus cooperators are not likely to spread based on natural selection. Nonetheless, cooperation is widespread on every level of biological organization ranging from bacterial communities to human society. Mathematical models can help to explain under which circumstances cooperation evolves. Evolutionary game theory is a powerful mathematical tool to depict the interactions between cooperators and defectors. Classical models typically involve either pairwise interactions between individuals or a linear superposition of these interactions. For interactions within groups, however, synergetic effects may arise: their outcome is not just the sum of its parts. This is because the payoffs via a single group interaction can be different from the sum of any collection of two-player interactions. Assuming that all interactions start from pairs, how can such synergetic multiplayer games emerge from simpler pairwise interactions? Here, we present a mathematical model that captures the transition from pairwise interactions to synergetic multiplayer ones. We assume that different social groups have different breaking rates. We show that non-uniform breaking rates do foster the emergence of synergy, even though individuals always interact in pairs. Our work sheds new light on the mechanisms underlying such synergetic interactions.
PMCID: PMC4971219  PMID: 27466437
synergetic interactions; multiplayer games; cooperation
25.  Homeobox protein VentX induces p53-independent apoptosis in cancer cells 
Oncotarget  2016;7(26):39719-39729.
Identifying novel tumor suppressors holds promise for improving cancer treatment. Our recent studies identified VentX, a homeobox transcriptional factor, as a putative tumor suppressor. Here we demonstrate that VentX exerts strong inhibitory effects on the proliferation and survival of cancer cells, but not primary transformed cells, such as 293T cells. Mechanistically, both in vitro and in vivo data showed that VentX induces apoptosis of cancer cells in a p53-independent manner. We found that VentX expression can be induced by chemotherapeutic agents. Taken together, our findings suggest that VentX may function as a novel therapeutic target in cancer treatment.
PMCID: PMC5129965  PMID: 27175592
ventX; apoptosis; p53; caspase-3; PARP

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