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1.
Dr. Dae-Shik Kim Dr. Atsushi Endo Dr. Francis G. Fang Dr. Kuan-Chun Huang Dr. Xingfeng Bao Dr. Hyeong-wook Choi Dr. Utpal Majumder Dr. Young Y. Shen Steven Mathieu Xiaojie Zhu Kristen Sanders Dr. Thomas Noland Dr. Ming-Hong Hao Dr. Yu Chen Dr. John Y. Wang So Yasui Karen TenDyke Jiayi Wu Christy Ingersoll Kara A. Loiacono Dr. Janna E. Hutz Dr. Nadeem Sarwar 《ChemMedChem》2021,16(11):1741-1744
A strategy for creating potent and pan-genotypic stimulator of interferon genes (STING) agonists is described. Locking a bioactive U-shaped conformation of cyclic dinucleotides by introducing a transannular macrocyclic bridge between the nucleic acid bases leads to a topologically novel macrocycle-bridged STING agonist (MBSA). In addition to substantially enhanced potency, the newly designed MBSAs, exemplified by clinical candidate E7766 , exhibit broad pan-genotypic activity in all major human STING variants. E7766 is shown to have potent antitumor activity with long lasting immune memory response in a mouse liver metastatic tumor model. Two complementary stereoselective synthetic routes to E7766 are also described. 相似文献
2.
Jacky Lu Kathryn P. Haley Jamisha D. Francis Miriam A. Guevara Ryan S. Doster Kelly M. Craft Rebecca E. Moore Schuyler A. Chambers Alberto G. Delgado Maria Blanca Piazuelo Steven M. Damo Dr. Steven D. Townsend Dr. Jennifer A. Gaddy 《Chembiochem : a European journal of chemical biology》2021,22(18):2783-2790
Chronic infection with Helicobacter pylori increases risk of gastric diseases including gastric cancer. Despite development of a robust immune response, H. pylori persists in the gastric niche. Progression of gastric inflammation to serious disease outcomes is associated with infection with H. pylori strains which encode the cag Type IV Secretion System (cag T4SS). The cag T4SS is responsible for translocating the oncogenic protein CagA into host cells and inducing pro-inflammatory and carcinogenic signaling cascades. Our previous work demonstrated that nutrient iron modulates the activity of the T4SS and biogenesis of T4SS pili. In response to H. pylori infection, the host produces a variety of antimicrobial molecules, including the iron-binding glycoprotein, lactoferrin. Our work shows that apo-lactoferrin exerts antimicrobial activity against H. pylori under iron-limited conditions, while holo-lactoferrin enhances bacterial growth. Culturing H. pylori in the presence of holo-lactoferrin prior to co-culture with gastric epithelial cells, results in repression of the cag T4SS activity. Concomitantly, a decrease in biogenesis of cag T4SS pili at the host-pathogen interface was observed under these culture conditions by high-resolution electron microscopy analyses. Taken together, these results indicate that acquisition of alternate sources of nutrient iron plays a role in regulating the pro-inflammatory activity of a bacterial secretion system and present novel therapeutic targets for the treatment of H. pylori-related disease. 相似文献
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Shunqing Zhang Dr. Ravindra R. Cheruku Dr. Mykhaylo Dukh Walter Tabaczynski Dr. Nayan J. Patel Dr. William H. White III Joseph R. Missert Dr. Joseph A. Spernyak Dr. Ravindra K. Pandey 《ChemMedChem》2020,15(21):2058-2070
3-(1’-Hexyloxyethyl)-3-devinyl-pyropheophorbide-a (HPPH or Photochlor), a tumor-avid chlorophyll-a derivative currently undergoing human clinical trials, was conjugated at various peripheral positions (position-17 or 20) of HPPH with either Gd(III)-aminobenzyl-DTPA (Gd(III) DTPA) or Gd(III)-aminoethylamido-DOTA (Gd(III) DOTA). The corresponding conjugates were evaluated for in vitro PDT efficacy, T1, T2 relaxivities, in vivo fluorescence, and MR imaging under similar treatment parameters. Among these analogs, the water-soluble Gd(III)-aminoethylamido-DOTA linked at position-17 of HPPH, i. e., HPPH-17-Gd(III) DOTA, demonstrated strong potential for tumor imaging by both MR and fluorescence, while maintaining the PDT efficacy in BALB/c mice bearing Colon-26 tumors (7/10 mice were tumor free on day 60). In contrast to Gd(III) DTPA (Magnevist) and Gd(III) DOTA (Dotarem), the HPPH-Gd(III) DOTA retains in the tumor for a long period of time (24 to 48 h) and provides an option of fluorescence-guided cancer therapy. Thus, a single agent can be used for cancer-imaging and therapy. However, further detailed pharmacokinetic, pharmacodynamic, and toxicological studies of the conjugate are required before initiating Phase I human clinical trials. 相似文献
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Steven März 《Energy Efficiency》2018,11(7):1721-1743
The German government aims to achieve virtually climate-neutral building stock by 2050 to tackle climate change. To realise this goal, comprehensive policy packages based on neoclassical economic theory are in place to foster energy efficiency investment. However, in the building sector, there is increasingly a gap between this aspiration and the reality. It is claimed that one of the main reasons for this is that the existing policy framework fails to address the specific characteristics and needs of different groups of building owners. This is a particular challenge in Germany, where 80% of all dwellings are owned privately and 37% are rented out by small private landlords (SPL). Despite the significant numbers of SPL, they often follow black box decision-making processes when considering energy renovations. In this study, the author uses an explanatory model to understand the decision-making processes of SPL, combining theoretical aspects from different research disciplines. This model was applied to a low-demand housing market in a neighbourhood in the Ruhr area. Eighteen semi-structured interviews (each lasting between 37 and 115 min) were conducted, demonstrating that in addition to economic factors, the values, beliefs, norms and routines of SPL—as well as their personal capabilities and contextual factors—play an important role in their decision-making. Based on the findings, recommendations are made for enhancing the effectiveness of existing energy efficiency policies and other supporting instruments (e.g. tenancy law and social legislation), tailored to the specific needs of SPL. 相似文献
8.
Zishan Ding Xiaohui Jiang Miaoxian Guo Steven Y. Liang 《The International Journal of Advanced Manufacturing Technology》2018,97(5-8):1767-1778
In this study, the distribution of temperature and energy under the process parameter conditions and thermal physical parameters are investigated using a physics-based model via the finite element modeling (FEM) simulation and experimental validation during cylindrical grinding. A cylindrical grinding model is modeled to simulate the chip removal behavior in the grinding process and to measure the workpiece and chip temperatures by refining the temperature field. Workpiece speed affects the energy partition into chip more obviously than other grinding parameters. Reasonable selection of grinding parameters greatly reduces the energy partition into the workpiece from 80% to 50–30% or even lower. This study offers a comprehensive understanding of heating mechanisms during grinding and thus is very beneficial for process optimization. 相似文献
9.
Steven Brady Kuzyk Kaitlyn Wiens Xiao Ma Vladimir Yurkov 《Journal of Great Lakes research》2021,47(3):567-582
While nutrient loading has affected all levels of Lake Winnipeg’s ecology, its greatest influence has likely been on the microbial community. In addition to eutrophication, zebra mussels (Dreissena polymorpha) have recently invaded the ecosystem and threaten food web dynamics. Their filter-feeding predation and association with bacteria, specifically phototrophs, was investigated. A sampling trip to Lake Winnipeg in October 2017, focused on the isolation, enumeration, and identification of aerobic anoxygenic phototrophs in littoral water, sediment, and tissues of mussels. Gimli, Patricia, and Grand beaches, separated by >15 km across the South Basin, had similar bacterial counts when cultivated on rich organic, BG-11, purple non-sulphur, and K2TeO3-supplemented media. Culture-based enumeration on rich organic medium revealed 1.74% of heterotrophs from littoral waters were aerobic anoxygenic phototrophs, and represented 13.98% within sediments. In contrast, 0.48, 1.15, and 0.16% of cultured heterotrophs were aerobic anoxygenic phototrophs within zebra mussel gill, gut, and gonadal tissues, respectively. High-throughput sequencing of bacterial 16S V4 rDNA maintained similar trends in respective bivalve organs, where 0.22, 1.13, and 0.20% of total 16S genes belonged to these phototrophs. Several Sphingomonadaceae isolates were recovered from gut tissues, all with filamentous morphology large enough for predation. Bioaccumulation of metals was also studied in D. polymorpha. All tested associated aerobic anoxygenic phototrophs were capable of resisting the metalloid oxide tellurite. The consistent distribution of aerobic anoxygenic phototrophs within microbial communities across Lake Winnipeg, and their predominance in the gut tissues of zebra mussels suggested bacterial consumption by this invasive species. 相似文献
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