Deubiquitination and Stabilization of PD-L1 by CSN5

Lim, Seung-Oe,Li, Chia-Wei,Xia, Weiya,Cha, Jong-Ho,Chan, Li-Chuan,Wu, Yun,Chang, Shih-Shin,Lin, Wan-Chi,Hsu, Jung-Mao,Hsu, Yi-Hsin,Kim, Taewan,Chang, Wei-Chao,Hsu, Jennifer L.,Yamaguchi, Hirohito,Ding Elsevier 2016 Cancer cell Vol.30 No.6

<P><B>Summary</B></P> <P>Pro-inflammatory cytokines produced in the tumor microenvironment lead to eradication of anti-tumor immunity and enhanced tumor cell survival. In the current study, we identified tumor necrosis factor alpha (TNF-α) as a major factor triggering cancer cell immunosuppression against T cell surveillance via stabilization of programmed cell death-ligand 1 (PD-L1). We demonstrated that COP9 signalosome 5 (CSN5), induced by NF-κB p65, is required for TNF-α-mediated PD-L1 stabilization in cancer cells. CSN5 inhibits the ubiquitination and degradation of PD-L1. Inhibition of CSN5 by curcumin diminished cancer cell PD-L1 expression and sensitized cancer cells to anti-CTLA4 therapy.</P> <P><B>Highlights</B></P> <P> <UL> <LI> TNF-α stabilizes cancer cell PD-L1 in response to chronic inflammation </LI> <LI> Activation of NF-κB by TNF-α induces CSN5 expression leading to PD-L1 stabilization </LI> <LI> CSN5 enzyme activity controls T cell suppression via PD-L1 deubiquitination </LI> <LI> Destabilization of PD-L1 by CSN5 inhibitor curcumin benefits anti-CTLA4 therapy </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>

Reduction of d-lactate content in sauerkraut using starter cultures of recombinant Leuconostoc mesenteroides expressing the ldhL gene

Jin, Q.,Li, L.,Moon, J.S.,Cho, S.K.,Kim, Y.J.,Lee, S.J.,Han, N.S. Society for Bioscience and Bioengineering, Japan ; 2016 Journal of bioscience and bioengineering Vol.121 No.5

<P>The n-form of lactate, which causes metabolic stress upon excessive dietary intake, is mainly produced by Leuconostoc sp., the predominant species in sauerkraut. To shift the metabolic flux of D-lactate from pyruvate to L-lactate, we expressed the L-lactate dehydrogenase (ldhL) gene in Leuconostoc mesenteroides ATCC 8293. The IdhL gene from Lactobacillus plantarum was introduced into L. mesenteroides using the shuttle vectors pLeuCM and pLeuCM42. To elevate the expression level of IdhL in L. mesenteroides, the nucleotides for pyruvate kinase promoter were fused to IdhL and cloned into above vectors to construct pLC18pkL and pLC42pkL. As results, introduction of pLC42pkL in L. mesenteroides significantly improved both L-LDH activity and L-lactate productivity during fermentation, decreasing the D-/L-lactate ratio. When used as a starter culture for sauerkraut fermentation, recombinant L. mesenteroides harboring pLC42pkL increased L-lactate concentration and decreased D-lactate concentration compared to the wild type strain. We newly developed a recombinant L. mesenteroides which has high L-lactate dehydrogenase activity and applied this strain to minimize the harmful effect of D-lactate during the sauerkraut fermentation. To the best of our knowledge, we demonstrate for the first time the effective use of recombinant Leuconostoc sp. for quality improvement of fermented foods. (C) 2015, The Society for Biotechnology, Japan. All rights reserved.</P>

STAR FORMATION LAWS IN BOTH GALACTIC MASSIVE CLUMPS AND EXTERNAL GALAXIES: EXTENSIVE STUDY WITH DUST CONINUUM, HCN (4-3), AND CS (7-6)

Liu, Tie,Kim, Kee-Tae,Yoo, Hyunju,Liu, Sheng-yuan,Tatematsu, Ken’ichi,Qin, Sheng-Li,Zhang, Qizhou,Wu, Yuefang,Wang, Ke,Goldsmith, Paul F.,Juvela, Mika,Lee, Jeong-Eun,Tó,th, L. Viktor,Mardones, D American Astronomical Society 2016 The Astrophysical journal Vol.829 No.2

<P>We observed 146 Galactic clumps in HCN (4-3) and CS (7-6) with the Atacama Submillimeter Telescope Experiment 10 m telescope. A tight linear relationship between star formation rate and gas mass traced by dust continuum emission was found for both Galactic clumps and the high redshift (z > 1) star forming galaxies (SFGs), indicating a constant gas depletion time of similar to 100 Myr for molecular gas in both Galactic clumps and high z SFGs. However, low z galaxies do not follow this relation and seem to have a longer global gas depletion time. The correlations between total infrared luminosities (L-TIR) and molecular line luminosities (L-mol') of HCN (4-3) and CS (7-6) are tight and sublinear extending down to clumps with L-TIR similar to 10(3) L-circle dot. These correlations become linear when extended to external galaxies. A bimodal behavior in the L-TIR-L-mol' correlations was found for clumps with different dust temperature, luminosity-to-mass ratio, and sigma(line)/sigma(vir). Such bimodal behavior may be due to evolutionary effects. The slopes of L-TIR-L-mol' correlations become more shallow as clumps evolve. We compared our results with lower J transition lines in Wu et al. (2010). The correlations between clump masses and line luminosities are close to linear for low effective excitation density tracers but become sublinear for high effective excitation density tracers for clumps with L-TIR larger than L-TIR similar to 10(4.5) L-circle dot. High effective excitation density tracers cannot linearly trace the total clump masses, leading to a sublinear correlations for both M-clump-L-mol' and L-TIR-L-mol' relations.</P>

A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples

Chen, Han,Li, Chunyan,Peng, Xinxin,Zhou, Zhicheng,Weinstein, John N.,Caesar-Johnson, Samantha J.,Demchok, John A.,Felau, Ina,Kasapi, Melpomeni,Ferguson, Martin L.,Hutter, Carolyn M.,Sofia, Heidi J.,Ta Elsevier 2018 Cell Vol.173 No.2

<P><B>Summary</B></P> <P>The role of enhancers, a key class of non-coding regulatory DNA elements, in cancer development has increasingly been appreciated. Here, we present the detection and characterization of a large number of expressed enhancers in a genome-wide analysis of 8928 tumor samples across 33 cancer types using TCGA RNA-seq data. Compared with matched normal tissues, global enhancer activation was observed in most cancers. Across cancer types, global enhancer activity was positively associated with aneuploidy, but not mutation load, suggesting a hypothesis centered on “chromatin-state” to explain their interplay. Integrating eQTL, mRNA co-expression, and Hi-C data analysis, we developed a computational method to infer causal enhancer-gene interactions, revealing enhancers of clinically actionable genes. Having identified an enhancer ∼140 kb downstream of PD-L1, a major immunotherapy target, we validated it experimentally. This study provides a systematic view of enhancer activity in diverse tumor contexts and suggests the clinical implications of enhancers.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Systematic analysis of enhancer expression across ∼9,000 samples of 33 cancer types </LI> <LI> Global enhancer activation positively correlates with aneuploidy but not mutations </LI> <LI> A computational method that infers causal enhancer-target-gene relationships </LI> <LI> Enhancers as key regulators of therapeutic targets, including PD-L1 </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>

Effect of dietary lactulose supplementation on growth performance, nutrient digestibility, meat quality, relative organ weight, and excreta microflora in broilers

Zhao, P.Y.,Li, H.L.,Mohammadi, M.,Kim, I.H. Elsevier 2016 Poultry science Vol.95 No.1

<P>A 35 d trial was conducted to evaluate the effects of dietary lactulose on growth performance, nutrient digestibility, meat quality, relative organ weight, and excreta microflora in broilers. A total of 816 1-day-old male Ross broilers (40.2 +/- 0.4 g) were allotted to 4 dietary treatments using 12 cages with 17 chicks per cage. Treatments were: 1) CON, basal diet; 2) L05, CON + 0.05% lactulose; 3) L10, CON + 0.10% lactulose; and 4) L15, CON + 0.15% lactulose. Higher (P < 0.05) body weight gain (BWG) and lower (P < 0.05) feed conversion ratio (FCR) were observed in broilers fed the L15 diet compared with those fed the CON diet during d 22 to 35. During d 0 to 35, BWG was higher (P < 0.05) and FCR was lower (P < 0.05) in broilers fed lactulose diets than those fed the CON diet. Additionally, broilers fed L15 diets had the highest BWG (P < 0.05) and lowest FCR (P < 0.05). The apparent total tract digestibility (ATTD) of DM and nitrogen (N) was increased (P < 0.05) in broilers fed the L15 diet compared with those fed the CON diet. Drip loss was decreased (P < 0.05) in L10 and L15 treatments compared with CON treatment on d 1, d 3, and d 5. On d 3, lowest (P < 0.05) drip loss was observed in the L15 treatment. Excreta E. coli counts in the L15 treatment were decreased (P < 0.05) on d 14, but Lactobacillus counts in the L15 treatment were increased (P < 0.05) on d 14 and d 35 compared with the CON diet. A linear effect (P < 0.05) was observed on BWG (d 22 to 35), FCR (d 0 to 35), the ATTD of DM and N, drip loss, E. coli (d 14), and Lactobacillus (d 14 and d 35) counts. In conclusion, dietary supplementation of 0.15% lactulose can improve growth performance and nutrient digestibility; as well as increase the proliferation of Lactobacillus and decrease E. coli counts in excreta.</P>

Kinetics of Enzymatic Synthesis of L-ascorbyl Acetate by Lipozyme TLIM and Novozym 435

Dong-Hao Zhang,Ya-Qiong Li,Chao Li,Yv-Qin Lv,Yang-L 한국생물공학회 2012 Biotechnology and Bioprocess Engineering Vol.17 No.1

L-ascorbyl acetate was synthesized through lipase-catalyzed esterification using Lipozyme TLIM and Novozym 435. Four solvents, including methanol, ethanol,acetonitrile, and acetone were investigated for the reaction,and acetone and acetonitrile were found to be suitable reaction media. The influences of several parameters such as water activity (aw), substrate molar ratio, enzyme loading,and reaction temperature on esterification of Lascorbic acid were systematically and quantitatively analyzed. Through optimizing the reaction, lipase-catalyzed esterification of L-ascorbic acid gave a maximum conversion of 99%. The results from using Lipozyme TLIM and Novozym 435 as biocatalysts both showed that aw was an important factor for the conversion of L-ascorbic acid. The effect of pH value on lipase-catalyzed L-ascorbic acid esterification in acetone was also investigated. Furthermore,results from a kinetic characterization of Lipozyme TLIM were compared with those for Novozym 435, and suggested that the maximum reaction rate for Lipozyme TLIM was greater than that for Novozym 435, while the enzyme affinity for substrate was greater for Novozym 436.

Silk apatite composites from electrospun fibers

Li, Chunmei,Jin, Hyoung-Joon,Botsaris, Gregory D.,Kaplan, David L. Cambridge University Press (Materials Research Soc 2005 Journal of materials research Vol.20 No.12

<P>Human bone is a three-dimensional composite structure consisting of inorganic apatite crystals and organic collagen fibers. An attractive strategy for fabricating mimics of these types of composite biomaterials is to selectively grow apatite on polymers with control of structure, mechanical properties, and function. In the present study, silk/apatite composites were prepared by growing apatite on functionalized nanodiameter silk fibroin fibers prepared by electrospinning. The functionalized fibers were spun from an aqueous solution of silk/polyethylene oxide (PEO) (78/22 wt/wt) containing poly(L-aspartate) (poly-Asp), which was introduced as an analogue of noncollageous proteins normally found in bone. Silk fibroin associated with the acidic poly-Asp and acted as template for mineralization. Apatite mineral growth occurred preferentially along the longitudinal direction of the fibers, a feature that was not present in the absence of the combination of components at appropriate concentrations. Energy dispersive spectroscopy and x-ray diffraction confirmed that the mineral deposits were apatite. The results suggest that this approach can be used to form structures with potential utility for bone-related biomaterials based on the ability to control the interface wherein nucleation and crystal growth occur on the silk fibroin. With this level of inorganic-organic control, coupled with the unique mechanical properties, slow rates of biodegradation, and polymorphic features of this type of proteins, new opportunities emerge for utility of biomaterials.</P>

The anti-diabetic drug dapagliflozin induces vasodilation via activation of PKG and Kv channels

Li, Hongliang,Shin, Sung Eun,Seo, Mi Seon,An, Jin Ryeol,Choi, Il-Whan,Jung, Won-Kyo,Firth, Amy L.,Lee, Dae-Sung,Yim, Mi-Jin,Choi, Grace,Lee, Jeong Min,Na, Sung Hun,Park, Won Sun Elsevier 2018 Life sciences Vol.197 No.-

<P><B>Abstract</B></P> <P><B>Aim</B></P> <P>Considering the clinical efficacy of dapagliflozin in patients with type 2 DM and the pathophysiological relevance of Kv channels for vascular reactivity. We investigate the vasodilatory effect of dapagliflozin and related mechanisms using phenylephrine (Phe)-induced contracted aortic rings.</P> <P><B>Material and methods</B></P> <P>Arterial tone measurement was performed in aortic smooth muscle.</P> <P><B>Key findings</B></P> <P>Application of dapagliflozin induced vasodilation in a concentration-dependent manner. Pre-treatment with the BK<SUB>Ca</SUB> channel inhibitor paxilline, the K<SUB>ATP</SUB> channel inhibitor glibenclamide, and the Kir channel inhibitor Ba<SUP>2+</SUP> did not change dapagliflozin-induced vasodilation. However, application of the Kv channels inhibitor 4-AP effectively inhibited dapagliflozin-induced vasodilation. Application of the Ca<SUP>2+</SUP> channel inhibitor nifedipine and the sarcoplasmic/endoplasmic reticulum Ca<SUP>2+</SUP>-ATPase (SERCA) pump inhibitor thapsigargin did not alter the vasodilatory effect of dapagliflozin. Moreover, the adenylyl cyclase inhibitor SQ 22536 and the protein kinase A (PKA) inhibitor KT 5720 had no effect on dapagliflozin-induced vasodilation. Although guanylyl cyclase inhibitors, NS 2028 and ODQ, did not reduce the vasodilatory effect of dapagliflozin, the protein kinase G (PKG) inhibitor KT 5823 effectively inhibited dapagliflozin-induced vasodilation. The vasodilatory effect of dapagliflozin was not affected by elimination of the endothelium. Furthermore, pretreatment with the nitric oxide synthase inhibitor L-NAME or the small-conductance Ca<SUP>2+</SUP>-activated K (SKCa) channel inhibitor apamin did not change the vasodilatory effect of dapagliflozin.</P> <P><B>Significance</B></P> <P>We concluded that dapagliflozin induced vasodilation via the activation of Kv channels and PKG, and was independent of other K<SUP>+</SUP> channels, Ca<SUP>2+</SUP> channels, intracellular Ca<SUP>2+</SUP>, and the endothelium.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Effects of Nitrogen Application Rate on the Yields, Nutritive Value and Silage Fermentation Quality of Whole-crop Wheat

Li, C.J.,Xu, Z.H.,Dong, Z.X.,Shi, S.L.,Zhang, J.G. Asian Australasian Association of Animal Productio 2016 Animal Bioscience Vol.29 No.8

Whole-crop wheat (Triticum aestivum L.) as forage has been extensively used in the world. In this study, the effects of N application rates on the yields, nutritive value and silage quality were investigated. The N application rates were 0, 75, 150, 225, and 300 kg/ha. The research results indicated that the dry matter yield of whole-crop wheat increased significantly with increasing N rate up to 150 kg/ha, and then leveled off. The crude protein content and in vitro dry matter digestibility of whole-crop wheat increased significantly with increasing N up to 225 kg/ha, while they no longer increased at N 300 kg/ha. On the contrary, the content of various fibers tended to decrease with the increase of N application. The content of lactic acid, acetic acid and propionic acid in silages increased with the increase of N rate (p<0.05). The ammonia-N content of silages with higher N application rates (${\geq}225kg/ha$) was significantly higher than that with lower N application rates (${\leq}150kg/ha$). Whole-crop wheat applied with high levels of N accumulated more nitrate-N. In conclusion, taking account of yields, nutritive value, silage quality and safety, the optimum N application to whole-crop wheat should be about 150 kg/ha at the present experiment conditions.

Numerical studies on the effects of the lateral boundary on soil-structure interaction in homogeneous soil foundations

Li, Z.N.,Li, Q.S.,Lou, M.L. Techno-Press 2005 Structural Engineering and Mechanics, An Int'l Jou Vol.20 No.4

In this paper, the finite element method is applied to investigate the effect of the lateral boundary in homogenous soil on the seismic response of a superstructure. Some influencing factors are presented and discussed, and several parameters are identified to be important for conducting soil-structure interaction experiments on shaking tables. Numerical results show that the cross-section width L, thickness H, wave propagation velocity and lateral boundaries of soil layer have certain influences on the computational accuracy. The dimensionless parameter L/H is the most significant one among the influencing factors. In other words, a greater depth of soil layer near the foundation should be considered in shaking table tests as the thickness of the soil layer increases, which can be regarded as a linear relationship approximately. It is also found that the wave propagation velocity in soil layer affects the numerical accuracy and it is suggested to consider a greater depth of the soil layer as the wave propagation velocity increases. A numerical study on a soil-structure experimental model with a rubber ring surrounding the soil on a shaking table is also conducted. It is found the rubber ring has great effect on the soil-structure interaction experiments on shaking table. The experimental precision can be improved by reasonably choosing the elastic parameter and width of the rubber ring.