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941.
942.
Jin Zhou Xiao‐Hui Dong Feng‐Zhi Zhang Hui‐Min Zhu Tong Hao Xiao‐Xia Jiang Wei‐Bo Zheng Tao Zhang Pei‐Zhe Wang Hong Li Jie Na Chang‐Yong Wang 《Cell proliferation》2019,52(3)
Induced pluripotent stem cells (iPSCs) are reprogrammed somatic cells that gained self‐renewal and differentiation capacity similar to embryonic stem cells. Taking the precious opportunity of the TianZhou‐1 spacecraft mission, we studied the effect of space microgravity (µg) on the self‐renewal capacity of iPSCs. Murine iPSCs carrying pluripotency reporter Oct4‐GFP were used. The Oct4‐EGFP‐iPSCs clones were loaded into the bioreactor and exposed to μg in outer space for 14 days. The control experiment was performed in identical device but on the ground in earth gravity (1 g). iPSCs clones were compact and highly expressed Oct4 before launch. In μg condition, cells in iPSC clones spread out more rapidly than those in ground 1 g condition during the first 3 days after launch. However, in 1 g condition, as the cell density increases, the Oct4‐GFP signal dropped significantly during the following 3 days. Interestingly, in μg condition, iPSCs originated from the spread‐out clones during the first 3 days appeared to cluster together and reform colonies that activated strong Oct4 expression. On the other hand, iPSC clones in 1 g condition were not able to recover Oct4 expression after overgrown. Our study for the first time performed real‐time imaging on the proliferation process of iPSCs in space and found that in μg condition, cell behaviour appeared to be more dynamic than on the ground. 相似文献
943.
Birong Zhang James R. Kiefer Robert A. Blake Jae H. Chang Steven Hartman Ellen Rei Ingalla Tracy Kleinheinz Vidhi Mody Michelle Nannini Daniel F. Ortwine Yingqing Ran Amy Sambrone Deepak Sampath Maia Vinogradova Yu Zhong Jerome C. Nwachukwu Kendall W. Nettles Tommy Lai Jun Liang 《Bioorganic & medicinal chemistry letters》2019,29(7):905-911
Despite tremendous progress made in the understanding of the ERα signaling pathway and the approval of many therapeutic agents, ER+?breast cancer continues to be a leading cause of cancer death in women. We set out to discover compounds with a dual mechanism of action in which they not only compete with estradiol for binding with ERα, but also can induce the degradation of the ERα protein itself. We were attracted to the constrained chromenes containing a tetracyclic benzopyranobenzoxepine scaffold, which were reported as potent selective estrogen receptor modulators (SERMs). Incorporation of a fluoromethyl azetidine side chain yielded highly potent and efficacious selective estrogen receptor degraders (SERDs), such as 16aa and surprisingly, also its enantiomeric pair 16ab. Co-crystal structures of the enantiomeric pair 16aa and 16ab in complex with ERα revealed default (mimics the A-D rings of endogenous ligand estradiol) and core-flipped binding modes, rationalizing the equivalent potency observed for these enantiomers in the ERα degradation and MCF-7 anti-proliferation assays. 相似文献
944.
SAR inspired by aldehyde oxidase (AO) metabolism: Discovery of novel,CNS penetrant tricyclic M4 PAMs
Trevor C. Chopko Changho Han Alison R. Gregro Darren W. Engers Andrew S. Felts Mike S. Poslusney Katrina A. Bollinger Ryan D. Morrison Michael Bubser Atin Lamsal Vincent B. Luscombe Hyekyung P. Cho Nathalie C. Schnetz-Boutaud Alice L. Rodriguez Sichen Chang J. Scott Daniels Donald F. Stec Colleen M. Niswender Bruce J. Melancon 《Bioorganic & medicinal chemistry letters》2019,29(16):2224-2228
This letter describes progress towards an M4 PAM preclinical candidate inspired by an unexpected aldehyde oxidase (AO) metabolite of a novel, CNS penetrant thieno[2,3-c]pyridine core to an equipotent, non-CNS penetrant thieno[2,3-c]pyrdin-7(6H)-one core. Medicinal chemistry design efforts yielded two novel tricyclic cores that enhanced M4 PAM potency, regained CNS penetration, displayed favorable DMPK properties and afforded robust in vivo efficacy in reversing amphetamine-induced hyperlocomotion in rats. 相似文献
945.
Vicuna Requesens Deborah Gonzalez Romero Maria Elena Devaiah Shivakumar P. Chang Yeun-Kyung Flory Ashley Streatfield Stephen Ring Rebecca Phillips Cassie Hood Nathan C. Marbaniang Cyrus Dean Howard John A. Hood Elizabeth E. 《Transgenic research》2019,28(5-6):537-547
Transgenic Research - Expression of recombinant proteins in plants is a technology for producing vaccines, pharmaceuticals and industrial enzymes. For the past several years, we have produced... 相似文献
946.
Tai‐Wen Lin Chi‐Chih Chen Shu‐Mei Wu Yu‐Ching Chang Yi‐Chuan Li Yu‐Wang Su Chwan‐Deng Hsiao Hsin‐Yang Chang 《The Plant journal : for cell and molecular biology》2019,99(1):128-143
In mammals and yeast, tail‐anchored (TA) membrane proteins destined for the post‐translational pathway are safely delivered to the endoplasmic reticulum (ER) membrane by a well‐known targeting factor, TRC40/Get3. In contrast, the underlying mechanism for translocation of TA proteins in plants remains obscure. How this unique eukaryotic membrane‐trafficking system correctly distinguishes different subsets of TA proteins destined for various organelles, including mitochondria, chloroplasts and the ER, is a key question of long standing. Here, we present crystal structures of algal ArsA1 (the Get3 homolog) in a distinct nucleotide‐free open state and bound to adenylyl‐imidodiphosphate. This approximately 80‐kDa protein possesses a monomeric architecture, with two ATPase domains in a single polypeptide chain. It is capable of binding chloroplast (TOC34 and TOC159) and mitochondrial (TOM7) TA proteins based on features of its transmembrane domain as well as the regions immediately before and after the transmembrane domain. Several helices located above the TA‐binding groove comprise the interlocking hook‐like motif implicated by mutational analyses in TA substrate recognition. Our data provide insights into the molecular basis of the highly specific selectivity of interactions of algal ArsA1 with the correct sets of TA substrates before membrane targeting in plant cells. 相似文献
947.
Songtao Li Hongling Zhao Xiaomin Chang Jianping Wang Enhong Zhao Zhifeng Yin Xiaoxia Mao Shuhua Deng Ting Hao Huina Wang Yaqi Yang 《Journal of peptide science》2019,25(1)
Overexpression of gonadotropin‐releasing hormone (GnRH) receptor in many tumors but not in normal tissues makes it possible to use GnRH analogs as targeting peptides for selective delivery of cytotoxic agents, which may help to enhance the uptake of anticancer drugs by cancer cells and reduce toxicity to normal cells. The GnRH analogs [d ‐Cys6, desGly10, Pro9‐NH2]‐GnRH, [d ‐Cys6, desGly10, Pro9‐NHEt]‐GnRH, and [d ‐Cys6, α‐aza‐Gly10‐NH2]‐GnRH were conjugated with doxorubicin (Dox), respectively, through N‐succinimidyl‐3‐maleimidopropionate as a linker to afford three new GnRH‐Dox conjugates. The metabolic stability of these conjugates in human serum was determined by RP‐HPLC. The antiproliferative activity of the conjugates was examined in GnRH receptor‐positive MCF‐7 human breast cancer cell line by MTT assay. The three GnRH‐Dox conjugates showed improved metabolic stability in human serum in comparison with AN‐152. The antiproliferative effect of conjugate II ([d ‐Cys6, desGly10, Pro9‐NHEt]‐GnRH‐Dox) on MCF‐7 cells was higher than that of conjugate I ([d ‐Cys6, desGly10, Pro9‐NH2]‐GnRH‐Dox) and conjugate III ([d ‐Cys6, α‐aza‐Gly10‐NH2]‐GnRH‐Dox), and the cytotoxicity of conjugate II against GnRH receptor‐negative 3T3 mouse embryo fibroblast cells was decreased in comparison with free Dox. GnRH receptor inhibition test suggested that the antiproliferative activity of conjugate II might be due to the cellular uptake mediated by the targeting binding of [d ‐Cys6‐des‐Gly10‐Pro9‐NHEt]‐GnRH to GnRH receptors. Our study indicates that targeting delivery of conjugate II mediated by [d ‐Cys6‐des‐Gly10‐Pro9‐NHEt]‐GnRH is a promising strategy for chemotherapy of tumors that overexpress GnRH receptors. 相似文献
948.
949.
Shih‐Fan Chan Wei‐Kai Shih An‐Yu Chang Sheng‐Feng Shen I‐Ching Chen 《Ecology letters》2019,22(10):1668-1679
How abiotic and biotic factors constrain distribution limits at the harsh and benign edges of species ranges is hotly debated, partly because macroecological experiments testing the proximate causes of distribution limits are scarce. It has long been recognized – at least since Darwin’s On the Origin of Species – that a harsh climate strengthens competition and thus sets species range limits. Using thorough field manipulations along a large elevation gradient, we show the mechanisms by which temperature determines competition type, resulting in a transition from interference to exploitative competition from the lower to the upper elevation limits in burying beetles (Nicrophorus nepalensis). This transition is an example of Darwin’s classic hypothesis that benign climates favor direct competition for highly accessible resources while harsh climates result in competition through resources of high rivalry. We propose that identifying the properties of these key resources will provide a more predictive framework to understand the interplay between biotic and abiotic factors in determining geographic range limits. 相似文献
950.
Qiang Zheng Qi Chen Ruanhong Cai Chen He Weidong Guo Yu Wang Quan Shi Chang Chen Nianzhi Jiao 《Environmental microbiology》2019,21(7):2533-2543
In this study, we investigated the microbially mediated transformation of labile Synechococcus-derived DOM to RDOM using a 60-day experimental incubation system. Three phases of TOC degradation activity (I, II and III) were observed following the addition of Synechococcus-derived DOM. The phases were characterized by organic carbon consumption rates of 8.77, 1.26 and 0.16 μmol L−1 day−1, respectively. Excitation emission matrix analysis revealed the presence of three FDOM components including tyrosine-like, fulvic acid-like, and humic-like molecules. The three components also exhibited differing biological availabilities that could be considered as labile DOM (LDOM), semi-labile DOM (SLDOM) and RDOM, respectively. DOM molecular composition was also evaluated using FT-ICR MS. Based on differing biological turnover rates and normalized intensity values, a total of 1704 formulas were identified as candidate LDOM, SLDOM and RDOM molecules. Microbial transformation of LDOM to RDOM tended to proceed from high to low molecular weight, as well as from molecules with high to low double bond equivalent (DBE) values. Relatively higher aromaticity was observed in the formulas of RDOM molecules relative to those of LDOM molecules. FDOM components provide valuable proxy information to investigate variation in the bioavailability of DOM. These results suggest that coordinating fluorescence spectroscopy and FT-ICR MS of DOM, as conducted here, is an effective strategy to identify and characterize LDOM, SLDOM and RDOM molecules in incubation experiments emulating natural systems. The results described here provide greater insight into the metabolism of phytoplankton photosynthate by heterotrophic bacteria in marine environments. 相似文献