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1.  Bacteriome and mycobiome associations in oral tongue cancer 
Oncotarget  2017;8(57):97273-97289.
Squamous cell carcinoma of the oral (mobile) tongue (OMTC), a non-human papilloma virus-associated oral cancer, is rapidly increasing without clear etiology. Poor oral hygiene has been associated with oral cancers, suggesting that oral bacteriome (bacterial community) and mycobiome (fungal community) could play a role. While the bacteriome is increasingly recognized as an active participant in health, the role of the mycobiome has not been studied in OMTC. Tissue DNA was extracted from 39 paired tumor and adjacent normal tissues from patients with OMTC. Microbiome profiling, principal coordinate, and dissimilarity index analyses showed bacterial diversity and richness, and fungal richness, were significantly reduced in tumor tissue (TT) compared to their matched non-tumor tissues (NTT, P<0.006). Firmicutes was the most abundant bacterial phylum, which was significantly increased in TT compared to NTT (48% vs. 40%, respectively; P=0.004). Abundance of Bacteroidetes and Fusobacteria were significantly decreased in TT compared to matched NTT (P≤0.003 for both). Abundance of 22 bacterial and 7 fungal genera was significantly different between the TT and NTT, including Streptococcus, which was the most abundant and significantly increased in the tumor group (34% vs. 22%, P<0.001). Abundance of fungal genus Aspergillus in TT correlated negatively with bacteria (Actinomyces, Prevotella, Streptococcus), but positively with Aggregatibacter. Patients with high T-stage disease had lower mean differences between TT and NTT compared with patients with low T-stage disease (0.07 vs. 0.21, P=0.04). Our results demonstrate differences in bacteriome and mycobiome between OMTC and their matched normal oral epithelium, and their association with T-stage.
doi:10.18632/oncotarget.21921
PMCID: PMC5722561
microbiome; metagenomics; head and neck squamous cell carcinoma; lingual carcinomas
2.  Utilization of urea and expression profiles of related genes in the dinoflagellate Prorocentrum donghaiense 
PLoS ONE  2017;12(11):e0187837.
Urea has been shown to contribute more than half of total nitrogen (N) required by phytoplankton in some estuaries and coastal waters and to provide a substantial portion of the N demand for many harmful algal blooms (HABs) of dinoflagellates. In this study, we investigated the physiological and transcriptional responses in Prorocentrum donghaiense to changes in nitrate and urea availability. We found that this species could efficiently utilize urea as sole N source and achieve comparable growth rate and photosynthesis capability as it did under nitrate. These physiological parameters were markedly lower in cultures grown under nitrate- or urea-limited conditions. P. donghaiense N content was similarly low under nitrate- or urea-limited culture condition, but was markedly higher under urea-replete condition than under nitrate-replete condition. Carbon (C) content was consistently elevated under N-limited condition. Consequently, the C:N ratio was as high as 21:1 under nitrate- or urea-limitation, but 7:1 under urea-replete condition and 9:1 to 10:1 under nitrate-replete condition. Using quantitative reverse transcription PCR, we investigated the expression pattern for four genes involved in N transport and assimilation. The results indicated that genes encoding nitrate transport, urea hydrolysis, and nickel transporter gene were sensitive to changes in general N nutrient availability whereas the urea transporter gene responded much more strongly to changes in urea concentration. Taken together, our study shows the high bioavailability of urea, its impact on C:N stoichiometry, and the sensitivity of urea transporter gene expression to urea availability.
doi:10.1371/journal.pone.0187837
PMCID: PMC5678928  PMID: 29117255
3.  Multi-modal mechanophores based on cinnamate dimers 
Nature Communications  2017;8:1147.
Mechanochemistry offers exciting opportunities for molecular-level engineering of stress-responsive properties of polymers. Reactive sites, sometimes called mechanophores, have been reported to increase the material toughness, to make the material mechanochromic or optically healable. Here we show that macrocyclic cinnamate dimers combine these productive stress-responsive modes. The highly thermally stable dimers dissociate on the sub-second timescale when subject to a stretching force of 1–2 nN (depending on isomer). Stretching a polymer of the dimers above this force more than doubles its contour length and increases the strain energy that the chain absorbs before fragmenting by at least 600 kcal per mole of monomer. The dissociation produces a chromophore and dimers are reformed upon irradiation, thus allowing optical healing of mechanically degraded parts of the material. The mechanochemical kinetics, single-chain extensibility, toughness and potentially optical properties of the dissociation products are tunable by synthetic modifications.
Mechanochemistry offers exciting opportunities for molecular engineering of stress-responsive properties of polymers. Here the authors show that macrocyclic cinnamate dimers in a polymer chain can undergo dissociation on the sub-second timescale under 1–2 nN stretching to yield a chromophore that then can be optically healed.
doi:10.1038/s41467-017-01412-8
PMCID: PMC5660084  PMID: 29079772
4.  Anaconda: AN automated pipeline for somatic COpy Number variation Detection and Annotation from tumor exome sequencing data 
BMC Bioinformatics  2017;18:436.
Background
Copy number variations (CNVs) are the main genetic structural variations in cancer genome. Detecting CNVs in genetic exome region is efficient and cost-effective in identifying cancer associated genes. Many tools had been developed accordingly and yet these tools lack of reliability because of high false negative rate, which is intrinsically caused by genome exonic bias.
Results
To provide an alternative option, here, we report Anaconda, a comprehensive pipeline that allows flexible integration of multiple CNV-calling methods and systematic annotation of CNVs in analyzing WES data. Just by one command, Anaconda can generate CNV detection result by up to four CNV detecting tools. Associated with comprehensive annotation analysis of genes involved in shared CNV regions, Anaconda is able to deliver a more reliable and useful report in assistance with CNV-associate cancer researches.
Conclusion
Anaconda package and manual can be freely accessed at http://mcg.ustc.edu.cn/bsc/ANACONDA/.
Electronic supplementary material
The online version of this article (10.1186/s12859-017-1833-3) contains supplementary material, which is available to authorized users.
doi:10.1186/s12859-017-1833-3
PMCID: PMC5627484  PMID: 28974218
Copy number variation; Exome sequencing; Functional analysis; Cancer
5.  Effects of In Utero Exposure to Di-n-Butyl Phthalate on Testicular Development in Rat 
Humans are inevitably exposed to ubiquitous phthalate esters (PAEs). In utero exposure to di-n-butyl phthalate (DBP) induces abnormal development of the testis and reproductive tract in male offspring, which correspond closely with the human condition of testicular dysgenesis syndrome (TDS)-like syndrome. However, the underlying mechanisms have not been elucidated in detail. In this study, pregnant rats were orally exposed to either corn oil (controls) or DBP at three different doses by gavage during Gestational Days 12.5–21.5. Pathological examinations were performed for toxicity evaluation. Proliferation and apoptosis related proteins (ras related dexamethasone induced 1 (Rasd1), mitogen-activated protein kinase kinases1/2 (MEK1/2), Bcl-2, and Bax) were measured for mechanisms exploration. The results showed that different doses of DBP caused male developmental and reproductive toxicity in rats, including the decrease of anogenital distance (AGD), the histological damage of testis, and apoptosis of seminiferous tubule cells. Our data suggested that DBP played chronic and continuous toxic roles on male reproductive system by disrupting expression of Rasd1 and MEK1/2 as well as Bcl-2/Bax ratio. Further research is warranted.
doi:10.3390/ijerph14101284
PMCID: PMC5664784  PMID: 29064414
prenatal DBP exposure; testicular cells; ras related dexamethasone induced 1 (Rasd1); MEK1/2; Bcl-2; Bax; cell proliferation; apoptosis
6.  Mean platelet volume, platelet distribution width and carcinoembryonic antigen to discriminate gastric cancer from gastric ulcer 
Oncotarget  2017;8(37):62600-62605.
Activated platelets are involved in cancer development and progression. Mean platelet volume (MPV) and platelet distribution width (PDW) are early indexes of platelet activation. The objectives of this study were to investigate the ability of MPV, PDW and carcinoembryonic antigen (CEA) individually or in combination, to distinguish between gastric cancer and gastric ulcer. The study involved 194 patients with gastric cancer, 191 patients with gastric ulcer, and 185 control subjects. Subjects’ characteristics and hematologic tests data at initial diagnosis were collected. We found that MPV levels are significantly increased and PDW levels are significantly reduced in patients with gastric ulcer and in control subjects compared with those in gastric cancer. When the area under the curve (AUC) was used to analyze control subjects versus gastric cancer, the combination of PDW and CEA exhibited a significantly larger AUC of 0.939 (0.910-0.961) compared with the combination of MPV and CEA (p = 0.0045). When AUC was used to analyze gastric ulcer versus gastric cancer, PDW alone had the high specificity (98.5%) and high sensitivity (97.4%). In conclusion, combined use of MPV, PDW and CEA can accurately distinguish gastric cancer from gastric ulcer and controls. Further studies in larger samples are warranted.
doi:10.18632/oncotarget.15898
PMCID: PMC5617532
gastric cancer; mean platelet volume; platelet distribution width; diagnosis
7.  The Effect of Item Similarity and Response Competition Manipulations on Collaborative Inhibition in Group Recall 
Scientific Reports  2017;7:11946.
Collaborative inhibition refers to when people working together remember less than their predicted potential. The most common explanation for this effect is the retrieval-disruption hypothesis during collaborative recall. However, several recent studies have obtained conflicting results concerning this hypothesis. In the current study, item similarity was manipulated in Experiment 1 by requiring participants to study overlapping or non-overlapping unrelated wordlists. The unstructured instructions were then manipulated during a turn-taking recall task between conditions. The results showed that collaborative inhibition occurred for both overlapping and non-overlapping conditions. Subsequently, response competition during collaborative recall, in addition to item similarity, was manipulated in Experiment 2, and the results showed that when collaborative group members were instructed to recall in turn and monitor their partner’s recall (the medium- and high-response-competition conditions), collaborative inhibition occurred. However, no such effect was shown when collaborative group members were instructed not to communicate with each other, but to simply recall in turn while in a group (low-response-competition condition). Together, these results suggest that the conflicts between the findings of the aforementioned studies were probably caused by differing instructions, which induced response competition in collaborative settings. Aside from retrieval-disruption, other possible mechanisms underlying collaborative inhibition were also discussed.
doi:10.1038/s41598-017-12177-x
PMCID: PMC5607282  PMID: 28931904
8.  Recyclable Polydimethylsiloxane Network Crosslinked by Dynamic Transesterification Reaction 
Scientific Reports  2017;7:11833.
This article reports preparation of a crosslinked polydimethylsiloxane (PDMS) network via dynamic transesterification reaction between PDMS-diglycidyl ether and pripol 1017 with Zn(OAc)2 as the catalyst. The thermal dynamic nature of the network was investigated by the creep-recovery and stress-relaxation tests. The synthesized PDMS elastomer showed excellent solvent resistance even under high temperature, and could be reprocessed by hot pressing at 180 °C with the mechanical properties maintained after 10 cycles. Application of the PDMS elastomer in constructing micro-patterned stamps repeatedly has been demonstrated. The high plastic temperature and good solvent resistance distinguish the research from other reported thermoplastic PDMS elastomers and broaden the practical application areas.
doi:10.1038/s41598-017-11485-6
PMCID: PMC5605709  PMID: 28928370
9.  Meta-analysis of the association between three microRNA polymorphisms and breast cancer susceptibility 
Oncotarget  2017;8(40):68809-68824.
Single nucleotide polymorphisms (SNPs) in three microRNAs (miRNAs), rs2910164 in miR-146a, rs11614913 in miR-196a2, and rs3746444 in miR-499, have been associated with breast cancer (BC) susceptibility, but the evidence is conflicting. To obtain a more robust assessment of the association between these miRNA variants and BC risk, we carried out a meta-analysis through systematic literature retrieval from the PubMed and Embase databases. A total of 9 case-control studies on rs2910164, 12 on rs11614913, and 7 on rs3746444 were included. Pooled odds ratios and 95% confidence intervals were used to evaluate associations with BC risk. Overall analysis showed that rs2910164 was not associated with BC susceptibility in any genetic model, whereas rs11614913 was associated with a decreased risk in both the allelic contrast and recessive models, and rs3746444 imparted an increased risk in all genetic models. Stratified analyses showed that rs11614913 may decrease the risk of BC in the heterozygote model in Asians, and in all genetic models, except the heterozygote model, when the sample size is ≥ 500. Subgroup analysis indicated that rs3746444 was associated with increased risk of BC in Asians, but not Caucasians, at all sample sizes. This meta-analysis suggests that rs11614913 in miR-196a2 may decrease the risk of BC, while rs3746444 in miR-499 may increase it, especially in Asians when the sample size is large. We propose that rs11614913(C > T) and rs3746444 (A > G) may be useful biomarkers predictive of BC risk.
doi:10.18632/oncotarget.18516
PMCID: PMC5620298
breast cancer; meta-analysis; miRNA; polymorphisms
10.  Proceedings of the 14th annual conference of INEBRIA 
Holloway, Aisha S. | Ferguson, Jennifer | Landale, Sarah | Cariola, Laura | Newbury-Birch, Dorothy | Flynn, Amy | Knight, John R. | Sherritt, Lon | Harris, Sion K. | O’Donnell, Amy J. | Kaner, Eileen | Hanratty, Barbara | Loree, Amy M. | Yonkers, Kimberly A. | Ondersma, Steven J. | Gilstead-Hayden, Kate | Martino, Steve | Adam, Angeline | Schwartz, Robert P. | Wu, Li-Tzy | Subramaniam, Geetha | Sharma, Gaurav | McNeely, Jennifer | Berman, Anne H. | Kolaas, Karoline | Petersén, Elisabeth | Bendtsen, Preben | Hedman, Erik | Linderoth, Catharina | Müssener, Ulrika | Sinadinovic, Kristina | Spak, Fredrik | Gremyr, Ida | Thurang, Anna | Mitchell, Ann M. | Finnell, Deborah | Savage, Christine L. | Mahmoud, Khadejah F. | Riordan, Benjamin C. | Conner, Tamlin S. | Flett, Jayde A. M. | Scarf, Damian | McRee, Bonnie | Vendetti, Janice | Gallucci, Karen Steinberg | Robaina, Kate | Clark, Brendan J. | Jones, Jacqueline | Reed, Kathryne D. | Hodapp, Rachel M. | Douglas, Ivor | Burnham, Ellen L. | Aagaard, Laura | Cook, Paul F. | Harris, Brett R. | Yu, Jiang | Wolff, Margaret | Rogers, Meighan | Barbosa, Carolina | Wedehase, Brendan J. | Dunlap, Laura J. | Mitchell, Shannon G. | Dusek, Kristi A. | Gryczynski, Jan | Kirk, Arethusa S. | Oros, Marla T. | Hosler, Colleen | O’Grady, Kevin E. | Brown, Barry S. | Angus, Colin | Sherborne, Sidney | Gillespie, Duncan | Meier, Petra | Brennan, Alan | de Vargas, Divane | Soares, Janaina | Castelblanco, Donna | Doran, Kelly M. | Wittman, Ian | Shelley, Donna | Rotrosen, John | Gelberg, Lillian | Edelman, E. Jennifer | Maisto, Stephen A. | Hansen, Nathan B. | Cutter, Christopher J. | Deng, Yanhong | Dziura, James | Fiellin, Lynn E. | O’Connor, Patrick G. | Bedimo, Roger | Gibert, Cynthia | Marconi, Vincent C. | Rimland, David | Rodriguez-Barradas, Maria C. | Simberkoff, Michael S. | Justice, Amy C. | Bryant, Kendall J. | Fiellin, David A. | Giles, Emma L. | Coulton, Simon | Deluca, Paolo | Drummond, Colin | Howel, Denise | McColl, Elaine | McGovern, Ruth | Scott, Stephanie | Stamp, Elaine | Sumnall, Harry | Vale, Luke | Alabani, Viviana | Atkinson, Amanda | Boniface, Sadie | Frankham, Jo | Gilvarry, Eilish | Hendrie, Nadine | Howe, Nicola | McGeechan, Grant J. | Ramsey, Amy | Stanley, Grant | Clephane, Justine | Gardiner, David | Holmes, John | Martin, Neil | Shevills, Colin | Soutar, Melanie | Chi, Felicia W. | Weisner, Constance | Ross, Thekla B. | Mertens, Jennifer | Sterling, Stacy A. | Shorter, Gillian W. | Heather, Nick | Bray, Jeremy | Cohen, Hildie A. | McPherson, Tracy L. | Adam, Cyrille | López-Pelayo, Hugo | Gual, Antoni | Segura-Garcia, Lidia | Colom, Joan | Ornelas, India J. | Doyle, Suzanne | Donovan, Dennis | Duran, Bonnie | Torres, Vanessa | Gaume, Jacques | Grazioli, Véronique | Fortini, Cristiana | Paroz, Sophie | Bertholet, Nicolas | Daeppen, Jean-Bernard | Satterfield, Jason M. | Gregorich, Steven | Alvarado, Nicholas J. | Muñoz, Ricardo | Kulieva, Gozel | Vijayaraghavan, Maya | Adam, Angéline | Cunningham, John A. | Díaz, Estela | Palacio-Vieira, Jorge | Godinho, Alexandra | Kushir, Vladyslav | O’Brien, Kimberly H. M. | Aguinaldo, Laika D. | Sellers, Christina M. | Spirito, Anthony | Chang, Grace | Blake-Lamb, Tiffany | LaFave, Lea R. Ayers | Thies, Kathleen M. | Pepin, Amy L. | Sprangers, Kara E. | Bradley, Martha | Jorgensen, Shasta | Catano, Nico A. | Murray, Adelaide R. | Schachter, Deborah | Andersen, Ronald M. | Rey, Guillermina Natera | Vahidi, Mani | Rico, Melvin W. | Baumeister, Sebastian E. | Johansson, Magnus | Sinadinovic, Christina | Hermansson, Ulric | Andreasson, Sven | O’Grady, Megan A. | Kapoor, Sandeep | Akkari, Cherine | Bernal, Camila | Pappacena, Kristen | Morley, Jeanne | Auerbach, Mark | Neighbors, Charles J. | Kwon, Nancy | Conigliaro, Joseph | Morgenstern, Jon | Magill, Molly | Apodaca, Timothy R. | Borsari, Brian | Hoadley, Ariel | Scott Tonigan, J. | Moyers, Theresa | Fitzgerald, Niamh M. | Schölin, Lisa | Barticevic, Nicolas | Zuzulich, Soledad | Poblete, Fernando | Norambuena, Pablo | Sacco, Paul | Ting, Laura | Beaulieu, Michele | Wallace, Paul George | Andrews, Matthew | Daley, Kate | Shenker, Don | Gallagher, Louise | Watson, Rod | Weaver, Tim | Bruguera, Pol | Oliveras, Clara | Gavotti, Carolina | Barrio, Pablo | Braddick, Fleur | Miquel, Laia | Suárez, Montse | Bruguera, Carla | Brown, Richard L. | Capell, Julie Whelan | Paul Moberg, D. | Maslowsky, Julie | Saunders, Laura A. | McCormack, Ryan P. | Scheidell, Joy | Gonzalez, Mirelis | Bauroth, Sabrina | Liu, Weiwei | Lindsay, Dawn L. | Lincoln, Piper | Hagle, Holly | Wallhed Finn, Sara | Hammarberg, Anders | Andréasson, Sven | King, Sarah E. | Vargo, Rachael | Kameg, Brayden N. | Acquavita, Shauna P. | Van Loon, Ruth Anne | Smith, Rachel | Brehm, Bonnie J. | Diers, Tiffiny | Kim, Karissa | Barker, Andrea | Jones, Ashley L. | Skinner, Asheley C. | Hinman, Agatha | Svikis, Dace S. | Thacker, Casey L. | Resnicow, Ken | Beatty, Jessica R. | Janisse, James | Puder, Karoline | Bakshi, Ann-Sofie | Milward, Joanna M. | Kimergard, Andreas | Garnett, Claire V. | Crane, David | Brown, Jamie | West, Robert | Michie, Susan | Rosendahl, Ingvar | Andersson, Claes | Gajecki, Mikael | Blankers, Matthijs | Donoghue, Kim | Lynch, Ellen | Maconochie, Ian | Phillips, Ceri | Pockett, Rhys | Phillips, Tom | Patton, R. | Russell, Ian | Strang, John | Stewart, Maureen T. | Quinn, Amity E. | Brolin, Mary | Evans, Brooke | Horgan, Constance M. | Liu, Junqing | McCree, Fern | Kanovsky, Doug | Oberlander, Tyler | Zhang, Huan | Hamlin, Ben | Saunders, Robert | Barton, Mary B. | Scholle, Sarah H. | Santora, Patricia | Bhatt, Chirag | Ahmed, Kazi | Hodgkin, Dominic | Gao, Wenwu | Merrick, Elizabeth L. | Drebing, Charles E. | Larson, Mary Jo | Sharma, Monica | Petry, Nancy M. | Saitz, Richard | Weisner, Constance M. | Young-Wolff, Kelly C. | Lu, Wendy Y. | Blosnich, John R. | Lehavot, Keren | Glass, Joseph E. | Williams, Emily C. | Bensley, Kara M. | Chan, Gary | Dombrowski, Julie | Fortney, John | Rubinsky, Anna D. | Lapham, Gwen T. | Forray, Ariadna | Olmstead, Todd A. | Gilstad-Hayden, Kathryn | Kershaw, Trace | Dillon, Pamela | Weaver, Michael F. | Grekin, Emily R. | Ellis, Jennifer D. | McGoron, Lucy | McGoron, Lucy
doi:10.1186/s13722-017-0087-8
PMCID: PMC5606215
11.  Bi-directional plasticity: Rotifer prey adjust spine length to different predator regimes 
Scientific Reports  2017;7:10254.
Numerous prey organisms, including many rotifers, exhibit inducible defensive plasticity, such as spines, in response to predators. Here, we test the hypothesis that prey modify their defence response to different predator sizes with a bi-directional adjustment in spine length. First, we show experimentally, that large-sized predators induce a reduction in prey spine length. Second, we conducted a complementary field monitoring study showing that the spine length of the prey rotifer Keratella cochlearis changed in opposite directions, in response to the shift in dominance between small-sized and large-sized predators. Third, in order to test the generality of our novel findings, we conducted a meta-analysis covering a wide array of rotifer prey taxa, strengthening the conclusions from our experimental and field studies. Hence, by combining evidence from experiments and studies in the field with a meta-analysis, we, for the first time, demonstrate that rotifer prey distinguish between predators and adjust their protective spine length accordingly, i.e. rapidly adjust spine length to escape either below or above the dominant predator’s gape size window. In a broader perspective, our conclusions advance our knowledge on observed spatial and temporal variations in protective morphologies among prey organisms.
doi:10.1038/s41598-017-08772-7
PMCID: PMC5579284  PMID: 28860451
12.  T-cell immunoglobulin mucin-3 expression in invasive ductal breast carcinoma: Clinicopathological correlations and association with tumor infiltration by cytotoxic lymphocytes 
Molecular and Clinical Oncology  2017;7(4):557-563.
As a negative regulatory molecule, T-cell immunoglobulin and mucin domain-3 (Tim-3) is closely associated with tumor immunological tolerance. The aim of this study was to investigate Tim-3 expression in invasive ductal breast cancer (IDC), its effect on clinicopathological parameters and its association with cytotoxic lymphocyte infiltration. Tim-3 protein expression was measured in 150 paraffin-embedded IDC specimens and 100 paired normal breast tissue specimens by immunohistochemistry. It was demonstrated that the infiltration of the tumor by CD8+ T cells was significantly higher compared with that of normal tissue, and the Tim-3 expression on CD8+ T cells was higher in IDC tissue compared with that in normal tissue; the differences were statistically significant (both P-values=0.000). The median expression level of Tim-3 on tumor cells was significantly associated with clinicopathological parameters such as age, axillary lymph node metastasis and TNM stage (P=0.015, 0.001 and 0.027, respectively). The expression of Tim-3 on CD8+ T cells was correlated with lymph node metastasis, World Health Organization (WHO) grade and molecular classification (P=0.000, 0.004 and 0.000, respectively). Additionally, the number of tumor-infiltrating CD8+ T cells was associated with primary tumor size, lymph node metastasis, WHO grade, Ki-67 and molecular classification (P=0.017, 0.002, 0.007, 0.003 and 0.000, respectively). Thus, Tim-3 may promote the development and progression of breast cancer and affect the tumor microenvironment; thus, it may be used as an independent prognostic factor for IDC patients.
doi:10.3892/mco.2017.1360
PMCID: PMC5574202  PMID: 28855989
invasive ductal breast cancer; T-cell immunoglobulin and mucin domain-3; tumor-infiltrating cytotoxic lymphocyte; immune regulation; tumor invasion and metastasis; immunohistochemical
13.  Chemical Analysis of Astragali Complanati Semen and Its Hypocholesterolemic Effect Using Serum Metabolomics Based on Gas Chromatography-Mass Spectrometry 
Antioxidants  2017;6(3):57.
The hypocholesterolemic protective effect of the dried seed of Astragalus complanatus (ACS) was investigated in rats fed with normal diet, high cholesterol diet (HCD), and HCD plus 70% ethanol extract of ACS (600 mg/kg/day) by oral gavage for four weeks. ACS extract was tested to be rich in antioxidants, which may be contributed to its high content of phenolic compounds. Consumption of ACS remarkably suppressed the elevated total cholesterol (p < 0.01) and LDL-C (p < 0.001) induced by HCD. Chemical constituents of ACS extract were analyzed by ultra-performance liquid chromatography coupled with electrospray ionization orbitrap mass spectrometry and the results showed that the ACS extract mainly consisted of phenolic compounds including flavonoids and flavonoid glycosides. In addition, based on the serum fatty acid profiles, elucidated using gas chromatography-mass spectrometry, free and esterified fatty acids including docosapentaenoic acid, adrenic acid, dihomo-γ-linolenic acid and arachidonic acid were regulated in ACS treatment group. Western blot results further indicated the protein expression of peroxisome proliferator-activated receptor alpha (PPARα) (p < 0.05) in liver was upregulated in ACS treatment group. To conclude, our results clearly demonstrated that ACS provides beneficial effect on lowering HCD associated detrimental change.
doi:10.3390/antiox6030057
PMCID: PMC5618085  PMID: 28753987
Astragali Complanati Semen; serum metabolomics; hypercholesterolemia; mass spectrometry
14.  Higher platelet distribution width predicts poor prognosis in laryngeal cancer 
Oncotarget  2017;8(29):48138-48144.
Background
Activated platelets promote cancer progression and metastasis. However, the prognostic value of platelet indices in laryngeal cancer remains poorly understood. The purpose of this study was to investigate the predictive significance of platelet indices in laryngeal cancer.
Results
Of the 241 patients, high platelet distribution width (PDW) levels were observed in 116 (48.1 %) patients. In the Kaplan-Meier analysis, increased PDW was significantly associated with a poorer overall survival (p < 0.001). In the multivariate Cox model, PDW was an independent prognostic index for overall survival (HR=4.381, 95% CI=2.313-8.298, P < 0.001).
Method
The retrospective study included 241 consecutive patients with laryngeal cancer between January 2009 and December 2009. The relationships between PDW and clinicopathological characteristics were analyzed. Kaplan-Meier method and Cox regression were used to evaluate the prognostic impact of PDW.
Conclusions
Elevated PDW might be a novel prognostic marker in laryngeal cancer.
doi:10.18632/oncotarget.18306
PMCID: PMC5564632  PMID: 28624815
laryngeal cancer; platelet distribution width; prognosis; survival
15.  OsCNGC13 promotes seed-setting rate by facilitating pollen tube growth in stylar tissues 
PLoS Genetics  2017;13(7):e1006906.
Seed-setting rate is a critical determinant of grain yield in rice (Oryza sativa L.). Rapid and healthy pollen tube growth in the style is required for high seed-setting rate. The molecular mechanisms governing this process remain largely unknown. In this study, we isolate a dominant low seed-setting rate rice mutant, sss1-D. Cellular examination results show that pollen tube growth is blocked in about half of the mutant styles. Molecular cloning and functional assays reveals that SSS1-D encodes OsCNGC13, a member of the cyclic nucleotide-gated channel family. OsCNGC13 is preferentially expressed in the pistils and its expression is dramatically reduced in the heterozygous plant, suggesting a haploinsufficiency nature for the dominant mutant phenotype. We show that OsCNGC13 is permeable to Ca2+. Consistent with this, accumulation of cytoplasmic calcium concentration ([Ca2+]cyt) is defective in the sss1-D mutant style after pollination. Further, the sss1-D mutant has altered extracellular matrix (ECM) components and delayed cell death in the style transmission tract (STT). Based on these results, we propose that OsCNGC13 acts as a novel maternal sporophytic factor required for stylar [Ca2+]cyt accumulation, ECM components modification and STT cell death, thus facilitating the penetration of pollen tube in the style for successful double fertilization and seed-setting in rice.
Author summary
Rice is not only the staple food for more than half of the world’s population, but also a model species for plant developmental and genetic studies. After pollination, rice pollen grains adhere and hydrate at the surface of stigmatic papilla cells. Then, the germinated pollen tubes invade the stigma and navigate through the style transmission tract to reach the micropyle of the embryo sac for fertilization. During this long and arduous process, pollen tube requires abundant communication with the surrounding sporophytic maternal tissues. However, how the growth of pollen tube is regulated by maternal tissue remains largely elusive. This work identifies a typical cyclic nucleotide-gated channel protein in rice, OsCNGC13, which can mediate Ca2+ inward current. Our results suggest that OsCNGC13 acts as a novel maternal sporophytic factor required for stylar [Ca2+]cyt accumulation, extracellular matrix components modification and style cell death, thus facilitating the penetration of pollen tube in the style for successful double fertilization and seed-setting in rice. These findings provide new insights into the molecular genetic control mechanisms of seed-setting rate/grain yield in rice and expand our knowledge on the cyclic nucleotide-gated channel proteins in plant sexual reproduction.
doi:10.1371/journal.pgen.1006906
PMCID: PMC5533464  PMID: 28708858
16.  Identification of TBK1 and IKKε, the non-canonical IκB kinases, as crucial pro-survival factors in HTLV-1-transformed T lymphocytes 
Leukemia research  2016;46:37-44.
Persistent activation of NF-κB is a prerequisite for development of adult T cell leukemia-lymphoma (ATL) caused by human T cell leukemia virus type 1 (HTLV-1). HTLV-1 genome encodes a viral transforming protein named Tax, which constitutively activates the canonical IκB kinases (IKK), the central regulator of NF-κB signaling. However, the role of the non-canonical IκB kinases, TBK1 and IKKε, in the pathogenesis of HTLV-1-associated leukemia has not been evaluated. We here show that TBK1/IKKε are crucial pro-survival molecules by maintaining persistent activity of Stat3. Consistent with this finding, silencing Stat3 by the specific shRNA or by the chemical inhibitor ruxolitinib results in drastic impediment of leukemia cell growth. We further find that in HTLV-1-transformed T cells expressing Tax, TBK1 co-localizes with the canonical IκB kinases and Tax in the lipid raft microdomains. The wild type Tax, but not the Tax mutant defective in activating the canonical IKK, promotes the lipid raft translocation of TBK1. This phenomenon correlates with Tax activation of both NF-κB and Stat3. Tax does not interact directly with TBK1/IKKε, and it rather engages a molecular crosstalk between the canonical IKKs and TBK1/IKKε. Our data, therefore, demonstrate a key role of TBK1/IKKε in the survival and proliferation of HTLV-1-transformed T cells and implicate a potential therapy targeting TBK1/IKKε and Stat3 in controlling HTLV-1-mediated oncogenesis.
doi:10.1016/j.leukres.2016.04.012
PMCID: PMC4899189  PMID: 27123832
TBK1/IKKε; IKK; NF-κB; Stat3; HTLV-1 Tax; T lymphocyte transformation
18.  Meiotic defects and decreased expression of genes located around the chromosomal breakpoint in the testis of a patient with a novel 46,X,t(Y;1)(p11.3;p31) translocation 
Balanced translocations are known to be associated with infertility, spontaneous abortions and birth defects in mammals. Spermatocyte spreading and immunostaining were applied to detect meiotic prophase I progression, homologous chromosome pairing, synapsis and recombination in an azoospermic reciprocal translocation 46,X,t(Y;1)(p11.3;p31) carrier. Histological examination of testicular sections revealed a severely reduced number of germ cells with no spermatids or sperm in the carrier. A significant reduction in XY recombination was observed in the patient. The number of MLH1 foci on autosomes that are not involved in the translocation per cell was also significantly decreased in our patient as compared to the controls, which indicates an inter-chromosomal effect (ICE) of the translocation on recombination. An increase in leptotene (P<0.001) and zygotene (P<0.001) and a decrease in pachytene spermatocytes (P<0.001) were observed in the carrier when compared with the controls, indicating disturbed meiotic progression in the patient. Increased RAD51 foci during pachytene (P=0.02) in the spermatocytes of the patient were noted. A decreased expression of the genes (USP1, INSL5, LEPR and MSH4) critical for meiosis/spermatogenesis and located around the breakpoint region of chromosome 1 was observed in the 46,X,t(Y;1) carrier, which may further exacerbate the meiotic failure such as reduced recombination on autosomes and ultimately cause spermatogenesis arrest. In summary, we report a series of events that may have caused infertility in our 46,X,t(Y;1) carrier. To the best of our knowledge, this is the first report shedding light on how, possibly, a reciprocal translocation affects meiosis at the molecular level in azoospermia patients.
doi:10.3892/ijmm.2017.3029
PMCID: PMC5504999  PMID: 28627638
chromosomal translocation; synaptonemal complex; recombination; transcriptional inactivation; infertility
19.  LASSIM—A network inference toolbox for genome-wide mechanistic modeling 
PLoS Computational Biology  2017;13(6):e1005608.
Recent technological advancements have made time-resolved, quantitative, multi-omics data available for many model systems, which could be integrated for systems pharmacokinetic use. Here, we present large-scale simulation modeling (LASSIM), which is a novel mathematical tool for performing large-scale inference using mechanistically defined ordinary differential equations (ODE) for gene regulatory networks (GRNs). LASSIM integrates structural knowledge about regulatory interactions and non-linear equations with multiple steady state and dynamic response expression datasets. The rationale behind LASSIM is that biological GRNs can be simplified using a limited subset of core genes that are assumed to regulate all other gene transcription events in the network. The LASSIM method is implemented as a general-purpose toolbox using the PyGMO Python package to make the most of multicore computers and high performance clusters, and is available at https://gitlab.com/Gustafsson-lab/lassim. As a method, LASSIM works in two steps, where it first infers a non-linear ODE system of the pre-specified core gene expression. Second, LASSIM in parallel optimizes the parameters that model the regulation of peripheral genes by core system genes. We showed the usefulness of this method by applying LASSIM to infer a large-scale non-linear model of naïve Th2 cell differentiation, made possible by integrating Th2 specific bindings, time-series together with six public and six novel siRNA-mediated knock-down experiments. ChIP-seq showed significant overlap for all tested transcription factors. Next, we performed novel time-series measurements of total T-cells during differentiation towards Th2 and verified that our LASSIM model could monitor those data significantly better than comparable models that used the same Th2 bindings. In summary, the LASSIM toolbox opens the door to a new type of model-based data analysis that combines the strengths of reliable mechanistic models with truly systems-level data. We demonstrate the power of this approach by inferring a mechanistically motivated, genome-wide model of the Th2 transcription regulatory system, which plays an important role in several immune related diseases.
Author summary
There are excellent methods to mathematically model time-resolved biological data on a small scale using accurate mechanistic models. Despite the rapidly increasing availability of such data, mechanistic models have not been applied on a genome-wide level due to excessive runtimes and the non-identifiability of model parameters. However, genome-wide, mechanistic models could potentially answer key clinical questions, such as finding the best drug combinations to induce an expression change from a disease to a healthy state. We present LASSIM, which is a toolbox built to infer parameters within mechanistic models on a genomic scale. This is made possible due to a property shared across biological systems, namely the existence of a subset of master regulators, here denoted the core system. The introduction of a core system of genes simplifies the network inference into small solvable sub-problems, and implies that all main regulatory actions on peripheral genes come from a small set of regulator genes. This separation allows substantial parts of computations to be solved in parallel, i.e. permitting the use of a computer cluster, which substantially reduces computation time.
doi:10.1371/journal.pcbi.1005608
PMCID: PMC5501685  PMID: 28640810
20.  A soluble starch synthase I gene, IbSSI, alters the content, composition, granule size and structure of starch in transgenic sweet potato 
Scientific Reports  2017;7:2315.
Soluble starch synthase I (SSI) is a key enzyme in the biosynthesis of plant amylopectin. In this study, the gene named IbSSI, was cloned from sweet potato, an important starch crop. A high expression level of IbSSI was detected in the leaves and storage roots of the sweet potato. Its overexpression significantly increased the content and granule size of starch and the proportion of amylopectin by up-regulating starch biosynthetic genes in the transgenic plants compared with wild-type plants (WT) and RNA interference plants. The frequency of chains with degree of polymerization (DP) 5–8 decreased in the amylopectin fraction of starch, whereas the proportion of chains with DP 9–25 increased in the IbSSI-overexpressing plants compared with WT plants. Further analysis demonstrated that IbSSI was responsible for the synthesis of chains with DP ranging from 9 to 17, which represents a different chain length spectrum in vivo from its counterparts in rice and wheat. These findings suggest that the IbSSI gene plays important roles in determining the content, composition, granule size and structure of starch in sweet potato. This gene may be utilized to improve the content and quality of starch in sweet potato and other plants.
doi:10.1038/s41598-017-02481-x
PMCID: PMC5443758  PMID: 28539660
21.  NID1, a new regulator of EMT required for metastasis and chemoresistance of ovarian cancer cells 
Oncotarget  2017;8(20):33110-33121.
Nidogen-1 (NID1) has been identified as a novel candidate diagnostic biomarker of ovarian cancer in our previous study. Nevertheless, the role of NID1 in the pathogenesis of ovarian cancer is unclear. In the present study, we demonstrated that NID1 was a mesenchymal associated gene and its high expression was significantly correlated with shorter overall survival of ovarian cancer patients. The ectopic expression of NID1 in OVCAR-3 cells revealed a epithelial-mesenchymal transition (EMT) phenotype accompanied by enhancement of motility, invasiveness and cisplatin resistance, whereas the knockdown of NID1 was sufficient to convert HEY cells into epithelial phenotype with decreased capability of motility, invasiveness and cisplatin resistance. Mechanistic studies disclosed that NID1 activated ERK/MAPK signaling pathway to promote EMT. Collectively, our findings have uncovered the molecular mechanisms of NID1 in promoting ovarian cancer metastasis and chemoresistance, and provide a rationale for the therapeutic potential of NID1 suppression in ovarian cancer.
doi:10.18632/oncotarget.16145
PMCID: PMC5464854  PMID: 28416770
ovarian cancer; NID1; EMT; metastasis; chemoresistance
22.  The E3 ubiquitin ligase CHIP mediates ubiquitination and proteasomal degradation of PRMT5 
Biochimica et biophysica acta  2015;1863(2):335-346.
Protein arginine methyltransferase 5 (PRMT5) is an important member of the protein arginine methyltransferase family that regulates many cellular processes through epigenetic control of target gene expression. Because of its overexpression in a number of human cancers and its essential role in cell proliferation, transformation, and cell cycle progression, PRMT5 has been recently proposed to function as an oncoprotein in cancer cells. However, how its expression is regulated in cancer cells remains largely unknown. We have previously demonstrated that the transcription of PRMT5 can be negatively regulated by the PKC/c-Fos signaling pathway through modulating the transcription factor NF-Y in prostate cancer cells. In the present study, we demonstrated that PRMT5 undergoes polyubiquitination, possibly through multiple lysine residues. We also identified carboxyl terminus of heat shock cognate 70-interacting protein (CHIP), an important chaperone-dependent E3 ubiquitin ligase that couples protein folding/refolding to protein degradation, as an interacting protein of PRMT5 via mass spectrometry. Their interaction was further verified by co-immuoprecipitation, GST pull-down, and bimolecular fluorescence complementation (BiFC) assay. In addition, we provided evidence that the CHIP/chaperone system is essential for the negative regulation of PRMT5 expression via K48-linked ubiquitin-dependent proteasomal degradation. Given that down-regulation of CHIP and overexpression of PRMT5 have been observed in several human cancers, our finding suggests that down-regulation of CHIP may be one of the mechanisms underlying PRMT5 overexpression in these cancers.
Graphical abstract
doi:10.1016/j.bbamcr.2015.12.001
PMCID: PMC5397900  PMID: 26658161
CHIP; E3 ubiquitin ligase; PRMT5; ubiquitination; chaperone; prostate cancer
23.  Chemical constituents and anti-inflammatory activities of Maqian (Zanthoxylum myriacanthum var. pubescens) bark extracts 
Scientific Reports  2017;7:45805.
In this study, 44 compounds in the petroleum ether extract of Maqian (Zanthoxylum myriacanthum var. pubescens) bark, a traditional Dai herbal medicine, were identified by GC-MS. Major components included 3(2H)-benzofuranone, asarinin and (dimethoxymethyl)-3-methoxy-benzene. A total of 18 compounds were isolated from the ethyl acetate extracts of Maqian bark by column chromatography and identified by chemical and spectral analyses. Rhoifoline B, zanthoxyline dimethoxy derivative, N-nortidine, nitidine, decarine are the major alkaloids. Both the petroleum ether and ethyl acetate extracts showed significant inhibition on NO production, which imply anti-inflammatory activity, in lipopolysaccharide-induced RAW 264.7 cells without cell toxicity. Decarine is the major anti-inflammatory constituent with NO IC50 values of 48.43 μM on RAW264.7 cells. The petroleum ether extract, the ethyl acetate extract and decarine showed anti-inflammatory activities through inhibiting TNF-α and IL-1β production in lipopolysaccharide-stimulated THP-1 cells without cell toxicity too. Decarine showed anti-inflammatory activity on human colon cells by reducing IL-6 and IL-8 production in TNF-α+IL-1β-induced Caco-2 cells. These results support the use of Maqian bark as a remedy for enteritis and colitis recorded by Dai medicine in China, and elucidate the major pharmacological compounds in Maqian bark.
doi:10.1038/srep45805
PMCID: PMC5382921  PMID: 28383530
24.  Fatty acid DSF binds and allosterically activates histidine kinase RpfC of phytopathogenic bacterium Xanthomonas campestris pv. campestris to regulate quorum-sensing and virulence 
PLoS Pathogens  2017;13(4):e1006304.
As well as their importance to nutrition, fatty acids (FA) represent a unique group of quorum sensing chemicals that modulate the behavior of bacterial population in virulence. However, the way in which full-length, membrane-bound receptors biochemically detect FA remains unclear. Here, we provide genetic, enzymological and biophysical evidences to demonstrate that in the phytopathogenic bacterium Xanthomonas campestris pv. campestris, a medium-chain FA diffusible signal factor (DSF) binds directly to the N-terminal, 22 amino acid-length sensor region of a receptor histidine kinase (HK), RpfC. The binding event remarkably activates RpfC autokinase activity by causing an allosteric change associated with the dimerization and histidine phosphotransfer (DHp) and catalytic ATP-binding (CA) domains. Six residues were found essential for sensing DSF, especially those located in the region adjoining to the inner membrane of cells. Disrupting direct DSF-RpfC interaction caused deficiency in bacterial virulence and biofilm development. In addition, two amino acids within the juxtamembrane domain of RpfC, Leu172 and Ala178, are involved in the autoinhibition of the RpfC kinase activity. Replacements of them caused constitutive activation of RpfC-mediated signaling regardless of DSF stimulation. Therefore, our results revealed a biochemical mechanism whereby FA activates bacterial HK in an allosteric manner, which will assist in future studies on the specificity of FA-HK recognition during bacterial virulence regulation and cell-cell communication.
Author summary
Besides roles in nutrition, lipids also function as important signals in the regulation of prokaryotic and eukaryotic cells. In bacteria, fatty acids are part of the language of cell-cell communication known as quorum sensing for a decade. However, how bacteria detect these signals and regulate virulence remains elusive. Here, we provide multiple evidences to show that a full-length receptor histidine kinase, RpfC, directly binds to a fatty acid-based signal factor using a short sensor region. This binding event stimulates RpfC autokinase activity by triggering conformational change in its catalytic region, which is critical in regulating bacterial quorum sensing and virulence. Our results confirm a long-outstanding assumption in cell signaling of phytobacteria, and provide a technical pipeline to analyze fatty acid-receptor interactions.
doi:10.1371/journal.ppat.1006304
PMCID: PMC5391125  PMID: 28369120
25.  Enhancement of Non-photochemical Quenching as an Adaptive Strategy under Phosphorus Deprivation in the Dinoflagellate Karlodinium veneficum 
Intensified water column stratification due to global warming has the potential to decrease nutrient availability while increasing excess light for the photosynthesis of phytoplankton in the euphotic zone, which together will increase the need for photoprotective strategies such as non-photochemical quenching (NPQ). We investigated whether NPQ is enhanced and how it is regulated molecularly under phosphorus (P) deprivation in the dinoflagellate Karlodinium veneficum. We grew K. veneficum under P-replete and P-depleted conditions, monitored their growth rates and chlorophyll fluorescence, and conducted gene expression and comparative proteomic analyses. The results were used to characterize NPQ modulation and associated gene expression dynamics under P deprivation. We found that NPQ in K. veneficum was elevated significantly under P deprivation. Accordingly, the abundances of three light-harvesting complex stress-related proteins increased under P-depleted condition. Besides, many proteins related to genetic information flow were down-regulated while many proteins related to energy production and conversion were up-regulated under P deprivation. Taken together, our results indicate that K. veneficum cells respond to P deprivation by reconfiguring the metabolic landscape and up-tuning NPQ to increase the capacity to dissipate excess light energy and maintain the fluency of energy flow, which provides a new perspective about what adaptive strategy dinoflagellates have evolved to cope with P deprivation.
doi:10.3389/fmicb.2017.00404
PMCID: PMC5350143  PMID: 28360892
non-photochemical quenching; dinoflagellates; phosphorus deprivation; metabolic machinery reconfiguration; energy flow

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