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1.  Luminescence- and nanoparticle-mediated increase of light absorption by photoreceptor cells: Converting UV light to visible light 
Scientific Reports  2016;6:20821.
We developed new optic devices – singly-doped luminescence glasses and nanoparticle-coated lenses that convert UV light to visible light – for improvement of visual system functions. Tb3+ or Eu3+ singly-doped borate glasses or CdS-quantum dot (CdS-QD) coated lenses efficiently convert UV light to 542 nm or 613 nm wavelength narrow-band green or red light, or wide-spectrum white light, and thereby provide extra visible light to the eye. In zebrafish (wild-type larvae and adult control animals, retinal degeneration mutants, and light-induced photoreceptor cell degeneration models), the use of Tb3+ or Eu3+ doped luminescence glass or CdS-QD coated glass lenses provide additional visible light to the rod and cone photoreceptor cells, and thereby improve the visual system functions. The data provide proof-of-concept for the future development of optic devices for improvement of visual system functions in patients who suffer from photoreceptor cell degeneration or related retinal diseases.
doi:10.1038/srep20821
PMCID: PMC4748410  PMID: 26860393
2.  UHRF1 Contributes to DNA Damage Repair as a Lesion Recognition Factor and Nuclease Scaffold 
Cell reports  2015;10(12):1957-1966.
Summary
We identified UHRF1 as a binding factor for DNA interstrand crosslink (ICL) lesions through affinity purification of ICL-recognition activities. UHRF1 is recruited to DNA lesions in vivo and binds directly to ICL-containing DNA. UHRF1-deficient cells display increased sensitivity to a variety of DNA damages. We found that loss of UHRF1 led to retarded lesion processing and reduced recruitment of ICL repair nucleases to the site of DNA damage. UHRF1 interacts physically with both ERCC1 and MUS81, two nucleases involved in the repair of ICL lesions. Depletion of both UHRF1 and components of the Fanconi anemia pathway resulted in increased DNA damage sensitivity compared to defect of each mechanism alone. These results suggest that UHRF1 promotes recruitment of lesion-processing activities via its DNA damage recognition affinity and functions as a nuclease recruitment scaffold in parallel to the Fanconi anemia pathway.
doi:10.1016/j.celrep.2015.03.038
PMCID: PMC4748712  PMID: 25818288
3.  Co-activation of AKT and c-Met triggers rapid hepatocellular carcinoma development via the mTORC1/FASN pathway in mice 
Scientific Reports  2016;6:20484.
Activation of the AKT/mTOR cascade and overexpression of c-Met have been implicated in the development of human hepatocellular carcinoma (HCC). To elucidate the functional crosstalk between the two pathways, we generated a model characterized by the combined expression of activated AKT and c-Met in the mouse liver. Co-expression of AKT and c-Met triggered rapid liver tumor development and mice required to be euthanized within 8 weeks after hydrodynamic injection. At the molecular level, liver tumors induced by AKT/c-Met display activation of AKT/mTOR and Ras/MAPK cascades as well as increased lipogenesis and glycolysis. Since a remarkable lipogenic phenotype characterizes liver lesions from AKT/c-Met mice, we determined the requirement of lipogenesis in AKT/c-Met driven hepatocarcinogenesis using conditional Fatty Acid Synthase (FASN) knockout mice. Of note, hepatocarcinogenesis induced by AKT/c-Met was fully inhibited by FASN ablation. In human HCC samples, coordinated expression of FASN, activated AKT, and c-Met proteins was detected in a subgroup of biologically aggressive tumors. Altogether, our study demonstrates that co-activation of AKT and c-Met induces HCC development that depends on the mTORC1/FASN pathway. Suppression of mTORC1 and/or FASN might be highly detrimental for the growth of human HCC subsets characterized by concomitant induction of the AKT and c-Met cascades.
doi:10.1038/srep20484
PMCID: PMC4746674  PMID: 26857837
4.  Randomized trial of acupoints herbal patching in Sanfu Days for asthma in clinical remission stage 
Background
Although China has a long history of using acupoints herbal patching (acupoints herbal patching means applying herbal patch on special acupoints to stimulate skin to form blisters, hyperemia, and even suppuration) in Sanfu Days (Sanfu Days are supposed to be the three hottest days in a year which is calculated by the ancient calendar) for the treatment of asthma, there is insufficient evidence to support its effectiveness and safety issues. This study investigated the efficacy and safety of acupoints herbal patching compared with placebo in participants with asthma in clinical remission stage.
Methods
We enrolled participants with asthma in clinical remission stage, above 13 years old and both genders in a randomized, double-blind and placebo-control trial at clinical center, School of Chinese Medicine, The University of Hong Kong to assess the effectiveness and safety of acupoints herbal patching, as compared with placebo, when added to guidelines-based therapy. The trial was conducted for three times (these three times were 19 July, 29 July and 8 August 2010), and the primary outcome was pulmonary function test. Secondary outcome was self-made questionnaire which were designed based on Traditional Chinese Medicine theory and clinical experience summary.
Results
Three hundred and twenty three eligible participants were enrolled, they were randomly assigned to acupoints herbal patching group (n = 165), placebo control group (n = 158). There was no significant difference in primary and secondary outcome as compared with placebo group at the end of 3rd treatment and four times follow ups. But sub-analysis of secondary outcome in four times follow ups showed that acupoints herbal patching significantly reduced the proportion of participants who didn’t need medical treatment when they had a small rise in asthma-related symptoms increased from 6–15 % at 1st follow up and 0–7 % at 3rd follow up (P < 0.05). It indicated that the proportion of participants who can spontaneous resolution of an asthma attack increased through acupoints herbal patching. In addition, acupoints herbal patching was significantly superior to placebo in reducing the percentage of participants who were susceptibly waken up by asthma symptoms from 27–14 %, and the percentage of participants who had the symptom of running nose and sneezing before onset from 18–8 % at 2nd follow up (P < 0.05). Improvements also occurred with treatment group, it reduced the proportion of participants who were spontaneous sweating at 3rd follow up (P < 0.05).
Conclusions
There was no significant difference between acupoints herbal patching and placebo in pulmonary function test in this study. Self-made questionnaire showed that the lasting effect of acupoints herbal patching was significantly better than placebo in reducing the need for medications to control asthma and the proportion of susceptible symptoms in participants with asthma in clinical remission stage. It showed that the low quality of life caused by asthma-related symptoms was significantly improved through acupoints herbal patching in Sanfu Days. Besides, acupoints herbal patching was as safe as placebo for chronic stable asthma.
Trial registration number: HKUCTR-1128, Registration date 22 Jul 2010
doi:10.1186/s40169-016-0084-7
PMCID: PMC4742458  PMID: 26846122
Asthma; Randomized trial; Acupoints herbal patching; Sanfu days
5.  Mitochondrial genomes and exceptional longevity in a Chinese population: the Rugao longevity study 
Age  2015;37(1):14.
Genetic variants of whole mitochondrial DNA (mtDNA) that predispose to exceptional longevity need to be systematically identified and appraised. Here, we conducted a case-control study with 237 exceptional longevity subjects (aged 95–107) and 444 control subjects (aged 40–69) randomly recruited from a “longevity town”—the city of Rugao in China—to investigate the effects of mtDNA variants on exceptional longevity. We sequenced the entire mtDNA genomes of the 681 subjects using a next-generation platform and employed a complete mtDNA phylogenetic analytical strategy. We identified T3394C as a candidate that counteracts longevity, and we observed a higher load of private nonsynonymous mutations in the COX1 gene predisposing to female longevity. Additionally, for the first time, we identified several variants and new subhaplogroups related to exceptional longevity. Our results provide new clues for genetic mechanisms of longevity and shed light on strategies for evaluating rare mitochondrial variants that underlie complex traits.
Electronic supplementary material
The online version of this article (doi:10.1007/s11357-015-9750-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s11357-015-9750-8
PMCID: PMC4322039  PMID: 25666573
Mitochondrial genome; Exceptional longevity; mtDNA variations; Private mutations; Subhaplogroups
6.  The cell cycle regulator 14-3-3σ opposes and reverses cancer metabolic reprogramming 
Nature communications  2015;6:7530.
Summary
Extensive reprogramming of cellular energy metabolism is a hallmark of cancer. Despite its importance, the molecular mechanism controlling this tumour metabolic shift remains not fully understood. Here we show that 14-3-3σ regulates cancer metabolic reprogramming and protects cells from tumourigenic transformation. 14-3-3σ opposes tumour-promoting metabolic programs by enhancing c-Myc poly-ubiquitination and subsequent degradation. 14-3-3σ demonstrates the suppressive impact on cancer glycolysis, glutaminolysis, mitochondrial biogenesis and other major metabolic processes of tumours. Importantly, 14-3-3σ expression levels predict overall and recurrence-free survival rates, tumour glucose uptake and metabolic gene expression in breast cancer patients. Thus, these results highlight that 14-3-3σ is an important regulator of tumour metabolism, and loss of 14-3-3σ expression is critical for cancer metabolic reprogramming. We anticipate that pharmacologically elevating the function of 14-3-3σ in tumours could be a promising direction for targeted anti-cancer metabolism therapy development in future.
doi:10.1038/ncomms8530
PMCID: PMC4507299  PMID: 26179207
7.  p38 MAP kinase–dependent phosphorylation of the Gp78 E3 ubiquitin ligase controls ER–mitochondria association and mitochondria motility 
Molecular Biology of the Cell  2015;26(21):3828-3840.
Epitope mapping of the 3F3A mAb identified p38 MAPK phosphorylation of Ser-538 of the E3 ubiquitin ligase Gp78. p38 MAPK phosphorylation of Ser-538 prevents Gp78-dependent mitofusin degradation, mitochondrial fission, and ER–mitochondria association, defining a novel regulatory mechanism of Gp78 activity at the ER–mitochondria interface.
Gp78 is an ERAD-associated E3 ubiquitin ligase that induces degradation of the mitofusin mitochondrial fusion proteins and mitochondrial fission. Gp78 is localized throughout the ER; however, the anti-Gp78 3F3A monoclonal antibody (mAb) recognizes Gp78 selectively in mitochondria-associated ER domains. Epitope mapping localized the epitope of 3F3A and a commercial anti-Gp78 mAb to an 8–amino acid motif (533–541) in mouse Gp78 isoform 2 that forms part of a highly conserved 41–amino acid region containing 14-3-3– and WW-binding domains and a p38 MAP kinase (p38 MAPK) consensus site on Ser-538 (S538). 3F3A binds selectively to nonphosphorylated S538 Gp78. Using 3F3A as a reporter, we induced Gp78 S538 phosphorylation by serum starvation and showed it to be mediated by p38 MAPK. Mass spectroscopy analysis of Gp78 phosphopeptides confirmed S538 as a major p38 MAPK phosphorylation site on Gp78. Gp78 S538 phosphorylation limited its ability to induce mitochondrial fission and degrade MFN1 and MFN2 but did not affect in vitro Gp78 ubiquitin E3 ligase activity. Phosphomimetic Gp78 S538D mutation prevented Gp78 promotion of ER–mitochondria interaction, and SB203580 inhibition of p38 MAPK increased ER–mitochondria association. p38 MAPK phosphorylation of Gp78 S538 therefore regulates Gp78-dependent ER–mitochondria association and mitochondria motility.
doi:10.1091/mbc.E15-02-0120
PMCID: PMC4626067  PMID: 26337390
8.  Adipose triglyceride lipase (Atgl) mediates the antibiotic jinggangmycin-stimulated reproduction in the brown planthopper, Nilaparvata lugens Stål 
Scientific Reports  2016;6:18984.
The antibiotic jinggangmycin (JGM) is an agrochemical product widely used in China for controlling rice sheath blight, Rhizoctonia solani. Unexpectedly, it stimulates reproduction in the brown planthopper (BPH), Nilaparvata lugens (Stål). However, the underlying molecular mechanisms of the stimulation are unclear. The present investigation demonstrates that adipose triglyceride lipase (Atgl) is one of the enzymes involved in the JGM-stimulated reproduction in BPH. Silence of Atgl in JGM-treated (JGM + dsAtgl) females eliminated JGM-stimulated fecundity of BPH females. In addition, Atgl knockdown significantly reduced the protein and glycerin contents in the ovaries and fat bodies of JGM + dsAtgl females required for reproduction. We conclude that Atgl is one of the key enzymes responsible for JGM-stimulated reproduction in BPH.
doi:10.1038/srep18984
PMCID: PMC4704046  PMID: 26739506
9.  Association of Genetic Polymorphisms on Vascular Endothelial Growth Factor and its Receptor Genes with Susceptibility to Coronary Heart Disease 
Background
Coronary heart disease (CHD) is a cardiovascular disease characterized by high morbidity and mortality. Vascular endothelial growth factor (VEGF) and its receptor, named kinase insert domain-containing receptor (KDR, or VEGFR2), which are involved with angiogenesis and vascular repair, could partly contribute to the development of CHD. The aim of this study, therefore, was to investigate the potential correlations between genetic polymorphisms on VEGF and KDR and susceptibility to CHD, and the integrative role of SNPs combined on susceptibility to CHD were also studied.
Material/Methods
Venous blood samples gathered from 533 DCM patients and 533 healthy controls were used to genotype tag-SNPs of VEGF (rs699947, rs2010963, and rs3025010) and KDR (rs2071559, rs2305948, and rs1870377) by polymerase chain reaction (PCR) and SNaPshot assay. Investigations of potential haplotypes were conducted on the basis of SHEsis software. The odds ratio (ORs) and relevant 95% confidence intervals (95% CI) were used to estimate associations of SNPs/haplotypes with risk of CHD. Multivariate logistic regression was also performed, taking certain clinical characteristics (e.g., BMI, smoking, alcohol consumption, diabetes, and hypertension) into consideration. All statistical analyses were done with STATA Version 12.0 software.
Results
Our results suggest that rs699947 (T>C) on KDR are associated with susceptibility to CHD under the dominant model before (OR=1.35, 95% CI: 1.05–1.73, P=0.019) and after (OR=1.33, 95% CI: 1.01–1.76, P=0.044), allowing for clinical characteristics (e.g., BMI, smoking, alcohol consumption, diabetes, and hypertension). rs2305948 (G>A) and rs1870377 (A>T) on VEGF were also found to be associated with risk of CHD under the recessive model after adjustment with multivariate regression analyses (OR=1.21, 95% CI: 1.02–1.43, P=0.029; OR=2.54, 95% CI: 1.13–5.75, P=0.025); OR=2.83, 95% CI: 1.47–5.46, P=0.002, respectively). Additionally, haplotype analyses revealed that integration of 5 SNPs would either raise (e.g. C-C-T-G-T and T-G-T-G-T) or reduce (e.g. C-C-C-G-T, T-C-T-G-A, T-C-T-G-T, and T-G-T-G-A) risk of CHD.
Conclusions
Genetic polymorphisms on VEGF (rs699947) and KDR (rs2305948and rs1870377), as well as relevant haplotypes, may serve as genetic markers that might be useful in future investigations on the pathogenesis of CHD.
doi:10.12659/MSM.895163
PMCID: PMC4706102  PMID: 26726843
Coronary Disease; Disease Susceptibility; Polymorphism, Genetic; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factor, Endocrine-Gland-Derived
10.  Perhexiline activates KLF14 and reduces atherosclerosis by modulating ApoA-I production 
The Journal of Clinical Investigation  2015;125(10):3819-3830.
Recent genome-wide association studies have revealed that variations near the gene locus encoding the transcription factor Krüppel-like factor 14 (KLF14) are strongly associated with HDL cholesterol (HDL-C) levels, metabolic syndrome, and coronary heart disease. However, the precise mechanisms by which KLF14 regulates lipid metabolism and affects atherosclerosis remain largely unexplored. Here, we report that KLF14 is dysregulated in the liver of 2 dyslipidemia mouse models. We evaluated the effects of both KLF14 overexpression and genetic inactivation and determined that KLF14 regulates plasma HDL-C levels and cholesterol efflux capacity by modulating hepatic ApoA-I production. Hepatic-specific Klf14 deletion in mice resulted in decreased circulating HDL-C levels. In an attempt to pharmacologically target KLF14 as an experimental therapeutic approach, we identified perhexiline, an approved therapeutic small molecule presently in clinical use to treat angina and heart failure, as a KLF14 activator. Indeed, in WT mice, treatment with perhexiline increased HDL-C levels and cholesterol efflux capacity via KLF14-mediated upregulation of ApoA-I expression. Moreover, perhexiline administration reduced atherosclerotic lesion development in apolipoprotein E–deficient mice. Together, these results provide comprehensive insight into the KLF14-dependent regulation of HDL-C and subsequent atherosclerosis and indicate that interventions that target the KLF14 pathway should be further explored for the treatment of atherosclerosis.
doi:10.1172/JCI79048
PMCID: PMC4607137  PMID: 26368306
11.  Infiltrating T cells promote prostate cancer metastasis via modulation of FGF11→miRNA-541→androgen receptor (AR)→MMP9 signaling 
Molecular oncology  2014;9(1):44-57.
Early clinical studies suggested infiltrating T cells might be associated with poor outcomes in prostate cancer (PCa) patients. The detailed mechanisms how T cells contribute to PCa progression, however, remained unclear. Here, we found PCa cells have a better capacity to recruit more CD4(+) T cells than the surrounding normal prostate cells via secreting more chemokines-CXCL9. The consequences of more recruited CD4(+) T cells to PCa might then lead to enhance PCa cell invasion. Mechanism dissection revealed that infiltrating CD4(+) T cells might function through the modulation of FGF11→miRNA-541 signals to suppress PCa androgen receptor (AR) signals. The suppressed AR signals might then alter the MMP9 signals to promote the PCa cell invasion. Importantly, suppressed AR signals via AR-siRNA or anti-androgen Enzalutamidein PCa cells also enhanced the recruitment of T cells and the consequences of this positive feed back regulation could then enhance the PCa cell invasion. Targeting these newly identified signals viaFGF11-siRNA, miRNA-541 inhibitor or MMP9 inhibitor all led to partially reverse the enhanced PCa cell invasion. Results from in vivo mouse models also confirmed the in vitro cell lines in co-culture studies. Together, these results concluded that infiltrating CD4(+) T cells could promote PCa metastasis via modulation of FGF11→miRNA-541→AR→MMP9 signaling. Targeting these newly identified signals may provide us a new potential therapeutic approach to better battle PCa metastasis.
doi:10.1016/j.molonc.2014.07.013
PMCID: PMC4277919  PMID: 25135278
Prostate cancer; T cells; Androgen Receptor; Tumor metastasis; Tumor microenvironment
12.  A TAK1 Signaling Pathway Critically Regulates Myocardial Survival and Remodeling 
Circulation  2014;130(24):2162-2172.
Background
Programmed necrosis (necroptosis) plays an important role in development, tissue homeostasis, and disease pathogenesis. The molecular mechanisms that regulate necroptosis in the heart and its physiological relevance in myocardial remodeling and heart failure remain largely unknown.
Methods and Results
Here we identified an obligate function for TAK1 (TGFβ-activated kinase 1, gene name Map3k7) in regulating necroptotic myocyte death, myocardial remodeling, and heart failure propensity. Cardiac-specific ablation of Map3k7 induced spontaneous apoptosis and necroptosis that led to adverse remodeling and heart failure, and these effects were abolished by ablation of tumor necrosis factor receptor 1 (TNFR1). Mechanistically, TAK1 functions as a “molecular switch” in TNFR1 signaling by regulating the formation of two cell death complexes, RIP1-FADD-caspase 8 and RIP1-RIP3, a process that is dependent on FADD and caspase 8 as scaffolding molecules. Importantly, ablation of RIP1 or RIP3 largely blocked necroptotic cell death, adverse remodeling, and heart failure in TAK1-deficient mice.
Conclusions
These results indicate that TAK1 functions as a key survival factor in the heart by directly antagonizing necroptosis, which is critical for the maintenance of myocardial homeostasis and the prevention of adverse myocardial remodeling.
doi:10.1161/CIRCULATIONAHA.114.011195
PMCID: PMC4302054  PMID: 25278099
signal transduction; myocyte apoptosis and necrosis; remodeling; heart failure
13.  Metagenomic sequencing of bile from gallstone patients to identify different microbial community patterns and novel biliary bacteria 
Scientific Reports  2015;5:17450.
Despite the high worldwide prevalence of gallstone disease, the role of the biliary microbiota in gallstone pathogenesis remains obscure. Next-generation sequencing offers advantages for systematically understanding the human microbiota; however, there have been few such investigations of the biliary microbiome. Here, we performed whole-metagenome shotgun (WMS) sequencing and 16S rRNA sequencing on bile samples from 15 Chinese patients with gallstone disease. Microbial communities of most individuals were clustered into two types, according to the relative enrichment of different intestinal bacterial species. In the bile samples, oral cavity/respiratory tract inhabitants were more prevalent than intestinal inhabitants and existed in both community types. Unexpectedly, the two types were not associated with fever status or surgical history, and many bacteria were patient-specific. We identified 13 novel biliary bacteria based on WMS sequencing, as well as genes encoding putative proteins related to gallstone formation and bile resistance (e.g., β-glucuronidase and multidrug efflux pumps). Bile samples from gallstone patients had reduced microbial diversity compared to healthy faecal samples. Patient samples were enriched in pathways related to oxidative stress and flagellar assembly, whereas carbohydrate metabolic pathways showed varying behaviours. As the first biliary WMS survey, our study reveals the complexity and specificity of biliary microecology.
doi:10.1038/srep17450
PMCID: PMC4667190  PMID: 26625708
14.  Analysis of the miRNA–mRNA–lncRNA networks in ER+ and ER− breast cancer cell lines 
Abstract
Recently, rapid advances in bioinformatics analysis have expanded our understanding of the transcriptome to a genome‐wide level. miRNA–mRNA–lncRNA interactions have been shown to play critical regulatory role in cancer biology. In this study, we discussed the use of an integrated systematic approach to explore new facets of the oestrogen receptor (ER)‐regulated transcriptome. The identification of RNAs that are related to the expression status of the ER may be useful in clinical therapy and prognosis. We used a network modelling strategy. First, microarray expression profiling of mRNA, lncRNA and miRNA was performed in MCF‐7 (ER‐positive) and MDA‐MB‐231 cells (ER‐ negative). A co‐expression network was then built using co‐expression relationships of the differentially expressed mRNAs and lncRNAs. Finally, the selected miRNA–mRNA network was added to the network. The key miRNA–mRNA–lncRNA interaction can be inferred from the network. The mRNA and non‐coding RNA expression profiles of the cells with different ER phenotypes were distinct. Among the aberrantly expressed miRNAs, the expression levels of miR‐19a‐3p, miR‐19b‐3p and miR‐130a‐3p were much lower in the MCF‐7 cells, whereas that of miR‐148b‐3p was much higher. In a cluster of miR‐17‐92, the expression levels of six of seven miRNAs were lower in the MCF‐7 cells, in addition to miR‐20b in the miR‐106a‐363 cluster. However, the levels of all the miRNAs in the miR‐106a‐25 cluster were higher in the MCF‐7 cells. In the co‐expression networking, CD74 and FMNL2 gene which is involved in the immune response and metastasis, respectively, had a stronger correlation with ER. Among the aberrantly expressed lncRNAs, lncRNA‐DLEU1 was highly expressed in the MCF‐7 cells. A statistical analysis revealed that there was a co‐expression relationship between ESR1 and lncRNA‐DLEU1. In addition, miR‐19a and lncRNA‐DLEU1 are both located on the human chromosome 13q. We speculate that miR‐19a might be co‐expressed with lncRNA‐DLEU1 to co‐regulate the expression of ESR1, which influences the occurrence and development of breast cancer cells with different levels of ER expression. Our findings reveal that the status of ER is mainly due to the differences in the mRNA and ncRNA profile between the breast cancer cell lines, and highlight the importance of studying the miRNA–mRNA–lncRNA interactions to completely illustrate the intricate transcriptome.
doi:10.1111/jcmm.12681
PMCID: PMC4687702  PMID: 26416600
oestrogen receptor; mRNA; miRNA; lncRNA; networks
15.  Phylloseptin-PBa—A Novel Broad-Spectrum Antimicrobial Peptide from the Skin Secretion of the Peruvian Purple-Sided Leaf Frog (Phyllomedusa Baltea) Which Exhibits Cancer Cell Cytotoxicity 
Toxins  2015;7(12):5182-5193.
Antimicrobial peptides from amphibian skin secretion display remarkable broad-spectrum antimicrobial activity and are thus promising for the discovery of new antibiotics. In this study, we report a novel peptide belonging to the phylloseptin family of antimicrobial peptides, from the skin secretion of the purple-sided leaf frog, Phyllomedusa baltea, which was named Phylloseptin-PBa. Degenerate primers complementary to putative signal peptide sites of frog skin peptide precursor-encoding cDNAs were designed to interrogate a skin secretion-derived cDNA library from this frog. Subsequently, the peptide was isolated and identified using reverse phase HPLC and MS/MS fragmentation. The synthetic replicate was demonstrated to have activity against S. aureus, E. coli and C. albicans at concentrations of 8, 128 and 8 mg/L, respectively. In addition, it exhibited anti-proliferative activity against the human cancer cell lines, H460, PC3 and U251MG, but was less active against a normal human cell line (HMEC). Furthermore, a haemolysis assay was performed to assess mammalian cell cytotoxicity of Phylloseptin-PBa. This peptide contained a large proportion of α-helical domain, which may explain its antimicrobial and anticancer activities.
doi:10.3390/toxins7124878
PMCID: PMC4690128  PMID: 26633506
amphibian; antimicrobial; anticancer; peptides; molecular cloning; mass spectrometry
16.  Androgen receptor and immune inflammation in benign prostatic hyperplasia and prostate cancer 
Clinical investigation  2014;4(10):935-950.
Both benign prostatic hyperplasia (BPH) and prostate cancer (PCa) are frequent diseases in middle-aged to elderly men worldwide. While both diseases are linked to abnormal growth of the prostate, the epidemiological and pathological features of these two prostate diseases are different. BPH nodules typically arise from the transitional zone, and, in contrast, PCa arises from the peripheral zone. Androgen deprivation therapy alone may not be sufficient to cure these two prostatic diseases due to its undesirable side effects. The alteration of androgen receptor-mediated inflammatory signals from infiltrating immune cells and prostate stromal/epithelial cells may play key roles in those unwanted events. Herein, this review will focus on the roles of androgen/androgen receptor signals in the inflammation-induced progression of BPH and PCa.
doi:10.4155/cli.14.77
PMCID: PMC4652646  PMID: 26594314
androgen receptor; benign prostate hyperplasia; immune inflammation; metastasis; prostate cancer
17.  Genome-wide identification and evolutionary analyses of bZIP transcription factors in wheat and its relatives and expression profiles of anther development related TabZIP genes 
BMC Genomics  2015;16:976.
Background
Among the largest and most diverse transcription factor families in plants, basic leucine zipper (bZIP) family participate in regulating various processes, including floral induction and development, stress and hormone signaling, photomorphogenesis, seed maturation and germination, and pathogen defense. Although common wheat (Triticum aestivum L.) is one of the most widely cultivated and consumed food crops in the world, there is no comprehensive analysis of bZIPs in wheat, especially those involved in anther development. Previous studies have demonstrated wheat, T. urartu, Ae. tauschii, barley and Brachypodium are evolutionarily close in Gramineae family, however, the real evolutionary relationship still remains mysterious.
Results
In this study, 187 bZIP family genes were comprehensively identified from current wheat genome. 98, 96 and 107 members of bZIP family were also identified from the genomes of T.urartu, Ae.tauschii and barley, respectively. Orthology analyses suggested 69.4 % of TubZIPs were orthologous to 68.8 % of AetbZIPs and wheat had many more in-paralogs in the bZIP family than its relatives. It was deduced wheat had a closer phylogenetic relationship with barley and Brachypodium than T.urartu and Ae.tauschii. bZIP proteins in wheat, T.urartu and Ae.tauschii were divided into 14 subgroups based on phylogenetic analyses. Using Affymetrix microarray data, 48 differentially expressed TabZIP genes were identified to be related to anther development from comparison between the male sterility line and the restorer line. Genes with close evolutionary relationship tended to share similar gene structures. 15 of 23 selected TabZIP genes contained LTR elements in their promoter regions. Expression of 21 among these 23 TabZIP genes were obviously responsive to low temperature. These 23 TabZIP genes all exhibited distinct tissue-specific expression pattern. Among them, 11 TabZIP genes were predominantly expressed in anther and most of them showed over-dominance expression mode in the cross combination TY806 × BS366.
Conclusions
The genome-wide identification provided an overall insight of bZIP gene family in wheat and its relatives. The evolutionary relationship of wheat and its relatives was proposed based on orthology analyses. Microarray and expression analyses suggested the potential involvement of bZIP genes in anther development and facilitated selection of anther development related gene for further functional characterization.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-2196-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-015-2196-7
PMCID: PMC4652339  PMID: 26581444
Basic leucine zipper (bZIP); Common wheat; Orthology analyses; Gene expression; Anther development; Over-dominance
18.  Focused Role of an Organic Small-Molecule PBD on Performance of the Bistable Resistive Switching 
An undoped organic small-molecule 2-(4-tert-butylphenyl)-5-(4-biphenylyl)-1,3,4-oxadiazole (PBD) and a kind of nanocomposite blending poly(methyl methacrylate) (PMMA) into PBD are employed to implement bistable resistive switching. For the bistable resistive switching indium tin oxide (ITO)/PBD/Al, its ON/OFF current ratio can touch 6. What is more, the ON/OFF current ratio, approaching to 104, is available due to the storage layer PBD:PMMA with the chemical composition 1:1 in the bistable resistive switching ITO/PBD:PMMA/Al. The capacity, data retention of more than 1 year and endurance performance (>104 cycles) of ITO/PBD:PMMA(1:1)/Al, exhibits better stability and reliability of the samples, which underpins the technique and application of organic nonvolatile memory.
doi:10.1186/s11671-015-1148-0
PMCID: PMC4646886  PMID: 26573933
ITO/PBD/Al; Small molecule; PBD:PMMA nanocomposite film; Nonvolatile bistable resistive switching
19.  TAK1 Regulates Myocardial Response to Pathological Stress via NFAT, NFκB, and Bnip3 Pathways 
Scientific Reports  2015;5:16626.
TAK1 (TGFβ-activated kinase-1) signaling is essential in regulating a number of important biological functions, including innate immunity, inflammatory response, cell growth and differentiation, and myocardial homeostasis. The precise role of TAK1 in the adult heart under pathological conditions remains largely unknown. Importantly, we observed that TAK1 is upregulated during compensatory hypertrophy but downregulated in end-stage heart failure. Here we generated transgenic mice with inducible expression of an active TAK1 mutant (TAK1ΔN) in the adult heart. TAK1ΔN transgenic mice developed greater cardiac hypertrophy compared with control mice after transverse aortic constriction (TAC), which was largely blocked by ablation of calcineurin Aβ. Expression of TAK1ΔN also promoted NFAT (nuclear factor of activated T-cells) transcriptional activity in luciferase reporter mice at baseline, which was further enhanced after TAC. Our results revealed that activation of TAK1 promoted adaptive cardiac hypertrophy through a cross-talk between calcineurin-NFAT and IKK-NFκB pathways. More significantly, adult-onset inducible expression of TAK1ΔN protected the myocardium from adverse remodeling and heart failure after myocardial infarction or long-term pressure overload, by preventing cardiac cell death and fibrosis. Mechanistically, TAK1 exerts its cardioprotective effect through activation of NFAT/NFκB, downregulation of Bnip3, and inhibition of cardiac cell death.
doi:10.1038/srep16626
PMCID: PMC4643217  PMID: 26564789
20.  A novel function of the human oncogene Stil: Regulation of PC12 cell toxic susceptibility through the Shh pathway 
Scientific Reports  2015;5:16513.
The human oncogene SCL/TAL1 interrupting locus (Stil) is highly conserved in vertebrate species. Here, we report new findings of Stil in the regulation of toxic susceptibility in mammalian dopaminergic (DA)-like PC12 cells. RNAi-mediated knockdown of Stil expression did not affect the survival of proliferating PC12 cells but caused a significant amount of cell death in differentiated neurons after toxic drug treatment. In contrast, overexpression of Stil increased toxic susceptibility only in proliferating cells but produced no effect in mature neurons. Exogenetic inactivation or activation of the Sonic hedgehog (Shh) signaling transduction mimicked the effect of Stil knockdown or overexpression in regulation of PC12 cell toxic susceptibility, suggesting that Stil exerts its role through the Shh pathway. Together, the data provide evidence for novel functions of the human oncogene Stil in neural toxic susceptibility.
doi:10.1038/srep16513
PMCID: PMC4637888  PMID: 26549353
21.  Between-Hospital Variation in Treatment and Outcomes in Extremely Preterm Infants 
The New England journal of medicine  2015;372(19):1801-1811.
BACKGROUND
Between-hospital variation in outcomes among extremely preterm infants is largely unexplained and may reflect differences in hospital practices regarding the initiation of active lifesaving treatment as compared with comfort care after birth.
METHODS
We studied infants born between April 2006 and March 2011 at 24 hospitals included in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Data were collected for 4987 infants born before 27 weeks of gestation without congenital anomalies. Active treatment was defined as any potentially lifesaving intervention administered after birth. Survival and neurodevelopmental impairment at 18 to 22 months of corrected age were assessed in 4704 children (94.3%).
RESULTS
Overall rates of active treatment ranged from 22.1% (interquartile range [IQR], 7.7 to 100) among infants born at 22 weeks of gestation to 99.8% (IQR, 100 to 100) among those born at 26 weeks of gestation. Overall rates of survival and survival without severe impairment ranged from 5.1% (IQR, 0 to 10.6) and 3.4% (IQR, 0 to 6.9), respectively, among children born at 22 weeks of gestation to 81.4% (IQR, 78.2 to 84.0) and 75.6% (IQR, 69.5 to 80.0), respectively, among those born at 26 weeks of gestation. Hospital rates of active treatment accounted for 78% and 75% of the between-hospital variation in survival and survival without severe impairment, respectively, among children born at 22 or 23 weeks of gestation, and accounted for 22% and 16%, respectively, among those born at 24 weeks of gestation, but the rates did not account for any of the variation in outcomes among those born at 25 or 26 weeks of gestation.
CONCLUSIONS
Differences in hospital practices regarding the initiation of active treatment in infants born at 22, 23, or 24 weeks of gestation explain some of the between-hospital variation in survival and survival without impairment among such patients. (Funded by the National Institutes of Health.)
doi:10.1056/NEJMoa1410689
PMCID: PMC4465092  PMID: 25946279
22.  dRNA-Seq Reveals Genomewide TSSs and Noncoding RNAs of Plant Beneficial Rhizobacterium Bacillus amyloliquefaciens FZB42 
PLoS ONE  2015;10(11):e0142002.
Bacillus amyloliquefaciens subsp. plantarum FZB42 is a representative of Gram-positive plant-growth-promoting rhizobacteria (PGPR) that inhabit plant root environments. In order to better understand the molecular mechanisms of bacteria-plant symbiosis, we have systematically analyzed the primary transcriptome of strain FZB42 grown under rhizosphere-mimicking conditions using differential RNA sequencing (dRNA-seq). Our analysis revealed 4,877 transcription start sites for protein-coding genes, identified genes differentially expressed under different growth conditions, and corrected many previously mis-annotated genes. We also identified a large number of riboswitches and cis-encoded antisense RNAs, as well as trans-encoded small noncoding RNAs that may play important roles in the gene regulation of Bacillus. Overall, our analyses provided a landscape of Bacillus primary transcriptome and improved the knowledge of rhizobacteria-host interactions.
doi:10.1371/journal.pone.0142002
PMCID: PMC4634765  PMID: 26540162
23.  Transcriptomic Analysis of Myocardial Ischemia Using the Blood of Rat 
PLoS ONE  2015;10(11):e0141915.
Myocardial ischemia is a pathological state of heart with reduced blood flow to heart and abnormal myocardial energy metabolism. This disease occurs commonly in middle aged and elderly people. Several studies have indicated that the rat was an appropriate animal model used to study myocardial ischemia. In this study, in order to gain insights into the pathogenesis of myocardial ischemia, we sequenced the transcriptomes of three normal rats as control and the same number of myocardial ischemia rats. We sequenced the genomes of 6 rats, including 3 cases (myocardial ischemia) and 3 controls using Illumina HiSeq 2000. Then we calculated the gene expression values and identified differentially expressed genes based on reads per kilobase transcriptome per million (RPKM). Meanwhile we performed a GO enrichment analysis and predicted novel transcripts. In our study, we found that 707 genes were up-regulated and 21 genes were down-regulated in myocardial ischemia rats by at least 2-fold compared with controls. By the distribution of reads and the annotation of reference genes, we found 1,703 and 1,552 novel transcripts in cases and controls, respectively. At the same time, we refined the structure of 9,587 genes in controls and 10,301 in cases. According to the results of GO term and pathway analysis of differentially expressed genes, we found that the immune response, stimulus response, response to stress and some diseases may be associated with myocardial ischemia. Since many diseases, especially immune diseases, are associated with myocardial ischemia, we should pay more attention to the complications which might result from myocardial ischemia.
doi:10.1371/journal.pone.0141915
PMCID: PMC4634849  PMID: 26540270
24.  Transcriptome Profiling of CTLs Regulated by Rapamycin Using RNA-Seq 
Immunogenetics  2014;66(11):625-633.
Memory programming of CTLs by inflammatory cytokines can be regulated by mTOR. We have shown that inhibition of mTOR during CTL activation leads to the enhancement of memory, but the molecular mechanisms remain largely unknown. Using high-throughput RNA-Seq, we identified genes and functions in mouse CTLs affected by mTOR inhibition through rapamycin. Of the 43,221 identified transcripts, 184 transcripts were differentially expressed after rapamycin treatment, corresponding to 128 annotated genes. Of these genes, 114 were downregulated and only 14 were upregulated. Most importantly, 50 of them are directly related to cell death and survival. In addition, several genes such as CD62L are related to migration. Furthermore, we predicted downregulation of transcriptional regulators based on the total differentially expressed genes, as well as the subset of apoptosis related genes. Quantitative PCR confirmed the differential expressions detected in RNA-Seq. We conclude that the regulatory function of rapamycin may work through inhibition of multiple genes related to apoptosis and migration, which enhance CTL survival into memory.
doi:10.1007/s00251-014-0790-5
PMCID: PMC4198470  PMID: 25113844
CTLs; memory; mTOR; rapamycin; RNA-Seq
25.  Identification of cytochrome P450 enzymes critical for lung tumorigenesis by the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK): insights from a novel Cyp2abfgs-null mouse 
Carcinogenesis  2014;35(11):2584-2591.
Summary
This study describes the generation of a novel Cyp2abfgs-null mouse model and evidence obtained with this mouse model that supports the critical role of P450 enzymes of the Cyp2abfgs gene subfamilies in NNK-induced lung tumorigenesis.
Cytochrome P450 (P450) enzymes encoded by the mouse Cyp2abfgs gene cluster are preferentially expressed in the respiratory tract. Previous studies have demonstrated that pulmonary P450-mediated bioactivation is necessary for lung tumorigenesis induced by the tobacco-specific lung procarcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and that CYP2A5 mediates a noteworthy fraction, but not all, of NNK bioactivation in the lung. The aim of this study was to determine whether other P450s encoded by the Cyp2abfgs gene cluster also play significant roles in NNK lung tumorigenesis. A novel Cyp2abfgs-null mouse was generated, in which all Cyp2a, 2b, 2g, 2f and 2s genes are deleted. The Cyp2abfgs-null mouse was viable, fertile and without discernible physiological abnormalities or compensatory increases in the expression of other P450s. NNK bioactivation in vitro and NNK-induced DNA adduction and lung tumorigenesis in vivo were determined for wild-type (WT) and Cyp2abfgs-null mice; the results were compared with previous findings from Cyp2a5-null mice. The Cyp2abfgs-null mice exhibited significantly lower rates of NNK bioactivation in lung and liver microsomes, compared with either WT or Cyp2a5-null mice. The levels of lung O6-methyl guanine DNA adduct were also substantially reduced in Cyp2abfgs-null mice, compared with either WT or Cyp2a5-null mice. Moreover, the Cyp2abfgs-null mice were largely resistant to NNK-induced lung tumorigenesis at both low (50mg/kg) and high (200mg/kg) NNK doses, in contrast to the WT or Cyp2a5-null mice. These results indicate for the first time that, collectively, the CYP2A, 2B, 2F, 2G, and 2S enzymes are indispensable for NNK-induced lung tumorigenesis.
doi:10.1093/carcin/bgu182
PMCID: PMC4216058  PMID: 25173884

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