c-Cbl-Mediated Neddylation Antagonizes Ubiquitination and Degradation of the TGF-β Type II Receptor

Zuo, W.,Huang, F.,Chiang, Y.,Li, M.,Du, J.,Ding, Y.,Zhang, T.,Lee, H.,Jeong, L.,Chen, Y.,Deng, H.,Feng, X.H.,Luo, S.,Gao, C.,Chen, Y.G. Cell Press 2013 Molecular cell Vol.49 No.3

Transforming growth factor β (TGF-β) is a potent antiproliferative factor in multiple types of cells. Deregulation of TGF-β signaling is associated with the development of many cancers, including leukemia, though the molecular mechanisms are largely unclear. Here, we show that Casitas B-lineage lymphoma (c-Cbl), a known proto-oncogene encoding an ubiquitin E3 ligase, promotes TGF-β signaling by neddylating and stabilizing the type II receptor (TβRII). Knockout of c-Cbl decreases the TβRII protein level and desensitizes hematopoietic stem or progenitor cells to TGF-β stimulation, while c-Cbl overexpression stabilizes TβRII and sensitizes leukemia cells to TGF-β. c-Cbl conjugates neural precursor cell-expressed, developmentally downregulated 8 (NEDD8), a ubiquitin-like protein, to TβRII at Lys556 and Lys567. Neddylation of TβRII promotes its endocytosis to EEA1-positive early endosomes while preventing its endocytosis to caveolin-positive compartments, therefore inhibiting TβRII ubiquitination and degradation. We have also identified a neddylation-activity-defective c-Cbl mutation from leukemia patients, implying a link between aberrant TβRII neddylation and leukemia development.

비육돈에 미생물제제 급여시 분뇨 특성에 미치는 효과

곽정훈,최동윤,박치호,김재환,정광화,양창범,유용희,천현식,라창식,Kwag, J.H.,Choi, D.Y.,Park, Ch.H.,Kim, J.H.,Jeong, K.H.,Yang, Ch.B.,Yoo, Y.H.,Chen, H.S.,La, C.S. 한국축산환경학회 2007 축산시설환경학회지 Vol.13 No.3

본시험은 비육돈사료에 미생물제제를 사료에 미생물제제 A 및 B 0.1 미생물제제 C를 0.2% 혼합 급여할 경우 사료섭취량 및 돈분의 오염물질 배설농도에 미치는 영향을 분석하기 위하여 4처리$\times$반복당 5두로서 총 20두를 공시하여 실시하였는데 그 결과를 요약하면 다음과 같다. 1. 비육돈의 일일 평균사료섭취량은 대조구 3.15 kg/일.두였고 미생물A, B, C구는 각각 3.14kg/일/두, 3.31, 3.42로 미생물제제 C구에서 일일 사료섭취량이 가장 높게 조사되었으며(p<0.05), 2. 일일평균 음수량은 사료섭취량이 높았던 미생물 C구에서 3.95kg/일/두로 가장 높게 조사되었다(p<0.05). 3. 미생물제제 처리구별로 분뇨배설량은 사료섭취량이 높았던 미생물제제 C구에서 가장 많이 배설되는 것으로 조사되었으며(p<0.05), 돈뇨의 배설량도 미생물제제 C구에서 2.23kg/일/두에서 높았다(p<0.05). 4. 돈분뇨의 수분 함량은 및 비료성분인 T-N, $P_{2}O_{5}$, $K_{2}O$ 성분도 처리 간에 큰 차이를 보이지 않았다(p<0.05). 5. 돈분뇨의 평균 BOD 농도는 돈분의 경우 미생물제제 B, C제제 급여구가 유의적으로 높게 조사되었다(p<0.05). 그리고 돈뇨의 BOD의 경우에는 대조구에서 $8,657.5mg/{\ell}$로 가장 높은 것으로 조사되었다(p<0.05). 6. COD 농도는 대조구에서 가장 높게 조사되었으며(p<0.05). 돈뇨의 경우에는 미생물제제 A급여구에서 평균 $9,545mg/{\ell}$로 가장 높았다(p<0.05). 7. SS 농도는 미생물제제 B급여구에서 가장 높게 조사되었으며(p<0.05), 돈분뇨중의 T-N 농도는 처리구간에 유의적인 차이가 나타나지 않았다(p<0.05). 그리고 T-P 농도의 경우에는 미생물제제 C급여구에서 유의적인 차이가 나는 것으로 조사되었다(p<0.05). 이상의 결과를 요약해보면 비육돈에 미생물제제 혼합급여시 사료섭취량과 음수량을 증가시키는데 효과가 있는 것으로 조사되었으나, 비료성분 배설량에는 큰 차이를 보이지 않는 것으로 조사되었으나, BOD 등 오염물질농도의 경우에는 미생물제제 A급여구에서 가장 낮게 조사되어 비육돈사료에 미생물제제 급여시 오염물질 저감효과가 있는 것으로 조사되었다. Study for the effect of three different microbial feed additives(henceforth MA-A, MA-B, and MA-C) on feed coversion rate, and physical and chemical characteristics of swine finisher was conducted. MA-B had higher number of Lactobacillus spp. and yeast, compared to any other. The amylase activity of MA-B was also higher than any other. The daily feed intake rates of pigs fed control, MA-A, MA-B and MA-C were 3.15, 3.14, 3.31 and 3.42 kg, respectively. MA-C had the highest weight gain. However, there was no significant difference between treatments. The weights of feces daily excreted by pigs fed control, MA-A, MA-B, and MA-C were 2.14, 2.02, 2.18, and 2.23 kg/day, respectively. The volume of urine daily excreted by pigs fed control, MA-A, MA-B, and MA-C were 3.14, 3.26, 3.27, and $3.41\;{\ell}/day$, respectively. Water content, T-N, $P_{2}O_{5}$, and $K_{2}O$ in swine manure were not significantly different between treatments. The BOD were between 42,576 and $67,450\;mg/{\ell}$ for feces and were between 5,882.5 and $8,657.5\;mg/{\ell}$ for urine, respectively. The SS were between 138,000 and $180,000\;mg/{\ell}$ for feces and were between 875.0 and $1450.0mg/{\ell}$ for urine, respectively.

Study of broad bandwidth vibrational energy harvesting system with optimum thickness of PET substrate

C.T. Pan,Z.H. Liu,Y.C. Chen 한국물리학회 2012 Current Applied Physics Vol.12 No.3

In this paper, we present the development of a flexible PET-based (polyethylene terephthalate; PET)vibrational energy harvesting system with broad bandwidth. This broad bandwidth harvesting system comprises of four units of individual ZnO (zinc oxide) piezoelectric harvester in the form of a cantilever structure connected in parallel, and rectifying circuit with storage module. This system has ability to convert mechanical energy into electrical energy from the varying ambient vibration. The design and simulation of a piezoelectric cantilever plate was described by using commercial software ANSYS FEA (Finite Element Analysis) to determine the optimum thickness of PET substrate, internal stress distribution,operation frequency and electric potential. With the optimum thickness predicted by developed accurate analytical formula analysis, the one-way mechanical strain that is efficient to enhance the induced electric potential can be controlled within the piezoelectric ZnO layer. In addition, the relationship among the model solution of piezoelectric cantilever plate equation, vibration-induced electric potential and electric power was realized. An individual piezoelectric harvester consists of flexible PET substrate, piezoelectric ZnO thin film with (002) c-axis preferred orientation, and selectively deposited UV-curable resin lump structure which is used to change the resonant frequency of the harvester. In combination with multi-harvesters and rectifying with storage module together, an energy harvesting system with broad bandwidth can be fabricated. One individual harvester achieves a maximum OCV (open-circuit voltage) up to 4 V with power density of 1.247 mW/cm3. So far, we succeeded in accomplishing a broad bandwidth system with operating frequency range within 100 Hze450 Hz to enhance powering efficiency. When the DC voltage (direct current voltage) across a storage module is charged up to 1.55 V after rectification, a flash LED (light emitting diode) is driven.

Randomized phase II study of axitinib versus placebo plus best supportive care in second-line treatment of advanced hepatocellular carcinoma

Kang, Y.-K.,Yau, T.,Park, J.-W.,Lim, H. Y.,Lee, T.-Y.,Obi, S.,Chan, S. L.,Qin, SK.,Kim, R. D.,Casey, M.,Chen, C.,Bhattacharyya, H.,Williams, J. A.,Valota, O.,Chakrabarti, D.,Kudo, M. Oxford University Press 2015 Annals of oncology Vol.26 No.12

<P>Axitinib plus best supportive care failed to meet the primary end point of overall survival in second-line treatment of advanced hepatocellular carcinoma in a randomized phase II study. However, the axitinib arm showed substantially improved progression-free survival, time to tumour progression, and clinical benefit rate compared with the placebo arm, with acceptable safety profile. Background: The efficacy and safety of axitinib, a potent and selective vascular endothelial growth factor receptors 1-3 inhibitor, combined with best supportive care (BSC) was evaluated in a global, randomized, placebo-controlled phase II trial in patients with locally advanced or metastatic hepatocellular carcinoma (HCC). Patients and methods: Patients with HCC and Child-Pugh Class A who progressed on or were intolerant to one prior antiangiogenic therapy were stratified by tumour invasion (presence/absence of extrahepatic spread and/or vascular invasion) and region (Asian/non-Asian) and randomized (2:1) to axitinib/BSC (starting dose 5 mg twice-daily) or placebo/BSC. The primary end point was overall survival (OS). Results: The estimated hazard ratio for OS was 0.907 [95% confidence interval (CI) 0.646-1.274; one-sided stratified P = 0.287] for axitinib/BSC (n = 134) versus placebo/BSC (n = 68), with the median (95% CI) of 12.7 (10.2-14.9) versus 9.7 (5.9-11.8) months, respectively. Results of prespecified subgroup analyses in Asian versus non-Asian patients or presence versus absence of tumour invasion were consistent with the overall population. Improvements favouring axitinib/BSC (P < 0.01) were observed in secondary efficacy end point analyses [progression-free survival (PFS), time to tumour progression (TTP), and clinical benefit rate (CBR)], and were retained among Asian patients in the prespecified subgroup analyses. Overall response rate did not differ significantly between treatments and patient-reported outcomes favoured placebo/BSC. Most common all-causality adverse events with axitinib/BSC were diarrhoea (54%), hypertension (54%), and decreased appetite (47%). Baseline serum analyses identified potential new prognostic (interleukin-6, E-selectin, interleukin-8, angiopoietin-2, migration inhibitory factor, and c-MET) or predictive (E-selectin and stromal-derived factor-1) factors for survival. Conclusions: Axitinib/BSC did not improve OS over placebo/BSC in the overall population or in stratification subgroups. However, axitinib/BSC resulted in significantly longer PFS and TTP and higher CBR, with acceptable toxicity in patients with advanced HCC. Trial Registration: ClinicalTrials.gov, NCT01210495.</P>

PEG-transferrin conjugated TRAIL (TNF-related apoptosis-inducing ligand) for therapeutic tumor targeting

Kim, T.H.,Jo, Y.G.,Jiang, H.H.,Lim, S.M.,Youn, Y.S.,Lee, S.,Chen, X.,Byun, Y.,Lee, K.C. Elsevier Science Publishers 2012 Journal of controlled release Vol.162 No.2

Transferrin (Tf) is considered an effective tumor-targeting agent, and PEGylation effectively prolongs in vivo pharmacokinetics by delaying excretion via the renal route. The authors describe the active tumor targeting of long-acting Tf-PEG-TNF-related apoptosis-inducing ligand conjugate (Tf-PEG-TRAIL) for effective cancer therapy. Tf-PEG-TRAIL was prepared using a two-step N-terminal specific PEGylation procedure using different PEGs (Mw: 3.4, 5, 10kDa). Eventually, only 10kDa PEG was linked to Tf and TRAIL because TRAIL (66kDa) and Tf (81kDa) were too large to link to 3.4 and 5kDa PEG. The final conjugate Tf-PEG<SUB>10K</SUB>-TRAIL was successfully purified and characterized by SDS-PAGE, western blotting. To determine the specific binding of Tf-PEG<SUB>10K</SUB>-TRAIL to Tf receptor, competitive receptor binding assays were performed on K 562 cells. The results obtained demonstrate that the affinity of Tf-PEG<SUB>10K</SUB>-TRAIL for Tf receptor is similar to that of native Tf. In contrast, PEG<SUB>10K</SUB>-TRAIL demonstrated no specificity. Biodistribution patterns and antitumor effects were investigated in C57BL6 mice bearing B16F10 murine melanomas and BALB/c athymic mice bearing HCT116. Tumor accumulation of Tf-PEG<SUB>10K</SUB>-TRAIL was 5.2 fold higher (at 2h) than TRAIL, because Tf-PEG<SUB>10K</SUB>-TRAIL has both passive and active tumor targeting ability. Furthermore, the suppression of tumors by Tf-PEG<SUB>10K</SUB>-TRAIL was 3.6 and 1.5 fold those of TRAIL and PEG<SUB>10K</SUB>-TRAIL, respectively. These results suggest that Tf-PEG<SUB>10K</SUB>-TRAIL is a superior pharmacokinetic conjugate that potently targets tumors and that it should be viewed as a potential cancer therapy.

THE TAOS PROJECT: RESULTS FROM SEVEN YEARS OF SURVEY DATA

Zhang, Z.-W.,Lehner, M. J.,Wang, J.-H.,Wen, C.-Y.,Wang, S.-Y.,King, S.-K.,Granados, Á,. P.,Alcock, C.,Axelrod, T.,Bianco, F. B.,Byun, Y.-I.,Chen, W. P.,Coehlo, N. K.,Cook, K. H.,de Pater, I.,Kim American Institute of Physics 2013 The Astronomical journal Vol.146 No.1

<P>The Taiwanese-American Occultation Survey (TAOS) aims to detect serendipitous occultations of stars by small (~1 km diameter) objects in the Kuiper Belt and beyond. Such events are very rare (<10<SUP>–3</SUP> events per star per year) and short in duration (~200 ms), so many stars must be monitored at a high readout cadence. TAOS monitors typically ~500 stars simultaneously at a 5 Hz readout cadence with four telescopes located at Lulin Observatory in central Taiwan. In this paper, we report the results of the search for small Kuiper Belt objects (KBOs) in seven years of data. No occultation events were found, resulting in a 95% c.l. upper limit on the slope of the faint end of the KBO size distribution of q = 3.34-3.82, depending on the surface density at the break in the size distribution at a diameter of about 90 km.</P>

Polymorphisms in the Promoter Region of the Chinese Bovine PPARGC1A Gene

Li, M.J.,Liu, M.,Liu, D.,Lan, X.Y.,Lei, C.Z.,Yang, D.Y.,Chen, H. Asian Australasian Association of Animal Productio 2013 Animal Bioscience Vol.26 No.4

The peroxisome proliferator-activated receptor gamma coactivator-1 alpha protein, encoded by the PPARGC1A gene, plays an important role in energy homeostasis. The genetic variations within the PPARGC1A gene promoter region were scanned in 808 Chinese native bovines belonging to three cattle breeds and yaks. A total of 6 SNPs and one 4 bp insertion variation in the promoter region of the bovine PPARGC1A gene were identified: SNP -259 T>A, -301_-298insCTTT, -915 A>G, -1175 T>G, -1590 C>T, -1665 C>T and -1690 G>A, which are in the binding sites of some important transcription factors: sex-determining region Y (SRY), myeloid-specific zinc finger-1 (MZF-1) and octamer factor 1(Oct-1). It is expected that these polymorphisms may regulate PPARGC1A gene transcription and might have consequences at a regulatory level.

Integrated cladding-pumped multicore few-mode erbium-doped fibre amplifier for space-division-multiplexed communications

Chen, H.,Jin, C.,Huang, B.,Fontaine, N. K.,Ryf, R.,Shang, K.,Gré,goire, N.,Morency, S.,Essiambre, R.-J.,Li, G.,Messaddeq, Y.,LaRochelle, S. Nature Publishing Group 2016 Nature photonics Vol.10 No.8

Space-division multiplexing (SDM), whereby multiple spatial channels in multimode and multicore optical fibres are used to increase the total transmission capacity per fibre, is being investigated to avert a data capacity crunch and reduce the cost per transmitted bit. With the number of channels employed in SDM transmission experiments continuing to rise, there is a requirement for integrated SDM components that are scalable. Here, we demonstrate a cladding-pumped SDM erbium-doped fibre amplifier (EDFA) that consists of six uncoupled multimode erbium-doped cores. Each core supports three spatial modes, which enables the EDFA to amplify a total of 18 spatial channels (six cores × three modes) simultaneously with a single pump diode and a complexity similar to a single-mode EDFA. The amplifier delivers >20 dBm total output power per core and <7 dB noise figure over the C-band. This cladding-pumped EDFA enables combined space-division and wavelength-division multiplexed transmission over multiple multimode fibre spans.

Genetic polymorphism in pvmdr1 and pvcrt-o genes in relation to in vitro drug susceptibility of Plasmodium vivax isolates from malaria-endemic countries

Lu, F.,Lim, C.S.,Nam, D.H.,Kim, K.,Lin, K.,Kim, T.S.,Lee, H.W.,Chen, J.H.,Wang, Y.,Sattabongkot, J.,Han, E.T. Verlag für Recht und Gesellschaft ; Elsevier 2011 Acta Tropica Vol.117 No.2

Treatment failure of chloroquine for Plasmodium vivax infection has increased in endemic countries. However, the molecular mechanisms for resistance and in vitro susceptibility of P. vivax to chloroquine remain elusive. We investigated the prevalence of mutations in the pvmdr1 and pvcrt-o genes, and the copy number of the pvmdr1 gene in isolates from the Republic of Korea (ROK), Thailand, the Union of Myanmar (Myanmar), and Papua New Guinea (PNG). We also measured in vitro susceptibility of Korean isolates to antimalarial drugs. The pvmdr1 analysis showed that mutations at amino acid position Y976F of pvmdr1 were found in isolates from Thailand (17.9%), Myanmar (13.3%), and PNG (100%), but none from the ROK, and mutation at position F1076L was present in isolates from the ROK (100%), Thailand (60.7%), and Myanmar (46.7%). One copy of the pvmdr1 gene was observed in most isolates and double copy numbers of the gene were observed in two Thai isolates. In the exons of the pvcrt-o gene that were sequenced, a K10 insertion was present in isolates from Thailand (56.0%) and Myanmar (46.2%), and the wild type was found in all Korean isolates. The results suggest that gene polymorphisms and copy number variation was observed in isolates of P. vivax from Southeast Asian countries. In Korean isolates polymorphism as limited to the F1076L variant, and no isolates with high level of resistance were found by in vitro susceptibility determinations. Moreover, our results provide a baseline for future prospective drug studies in malaria-endemic areas.

Differential Cross Section and Photon-Beam Asymmetry for the γ→p → π−Δ++(1232) Reaction at Forward π− Angles for Eγ=1.5-2.95 GeV

Kohri, H.,Shiu, S. H.,Chang, W. C.,Yanai, Y.,Ahn, D. S.,Ahn, J. K.,Chen, J. Y.,Daté,, S.,Ejiri, H.,Fujimura, H.,Fujiwara, M.,Fukui, S.,Gohn, W.,Hicks, K.,Hosaka, A.,Hotta, T.,Hwang, S. H.,Imai, American Physical Society 2018 Physical Review Letters Vol.120 No.20

<P>Differential cross sections and photon-beam asymmetries for the gamma(->)p -> Pi(-)Delta(++)(1232) reaction have been measured for 0.7 < cos Theta(c.m.)(Pi) < 1 and E-gamma= 1.5-2.95 GeV at SPring-8/LEPS. The first-ever high statistics cross-section data are obtained in this kinematical region, and the asymmetry data for 1.5 < E-gamma(GeV) < 2.8 are obtained for the first time. This reaction has a unique feature for studying the production mechanisms of a pure uu quark pair in the final state from the proton. Although there is no distinct peak structure in the cross sections, a non-negligible excess over the theoretical predictions is observed at E-gamma= 1.5-1.8 GeV. The asymmetries are found to be negative in most of the present kinematical regions, suggesting the dominance of n exchange in the t channel. The negative asymmetries at forward meson production angles are different from the asymmetries previously measured for the photoproduction reactions producing a dd(-) or an ss quark pair in the final state. Advanced theoretical models introducing nucleon resonances and additional unnatural-parity exchanges are needed to reproduce the present data.</P>