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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   
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Probiotics and Antimicrobial Proteins - The present study investigated skimmed milk and alginate-based encapsulation for protection of a probiotic strain, Lactobacillus gastricus BTM7 during...  相似文献   
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Bioartificial liver (BAL) devices have been developed to treat patients undergoing acute liver failure. One of the most important parameters to consider in designing these devices is the oxygen consumption rate of the seeded hepatocytes which are known to have oxygen consumption rates 10 times higher than most other cell types. Hepatocytes in various culture configurations have been tested in BAL devices including those formats that involve co-culture of hepatocytes with other cell types. In this study, we investigated, for the first time, oxygen uptake rates (OUR)s of hepatocytes co-cultured with 3T3-J2 fibroblasts at various hepatocyte to fibroblast seeding ratios. OURs were determined by measuring the rate of oxygen disappearance using a ruthenium-coated optical probe after closing and sealing the culture dish. Albumin and urea production rates were measured to assess hepatocyte function. Lower hepatocyte density co-cultures demonstrated significantly higher OURs (2 to 3.5-fold) and liver- specific functions (1.6-fold for albumin and 4.5-fold for urea production) on a per cell basis than those seeded at higher densities. Increases in OUR correlated well with increased liver-specific functions. OURs (V(m)) were modeled by fitting Michaelis-Menten kinetics and the model predictions closely correlated with the experimental data. This study provides useful information for predicting BAL design parameters that will avoid oxygen limitations, as well as maximize metabolic functions.  相似文献   
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Listeria monocytogenes, the causative agent of listeriosis, has been implicated in increasing foodborne outbreaks worldwide. The disease is manifested in various forms ranging from severe sepsis in immune-compromised individuals, febrile gastroenteritis, still birth, abortions and meningoencephalitis. In India, data from studies on the detection and molecular epidemiological analysis of L. monocytogenes are only recently emerging. The presence of Listeria in different ecological niches has been recorded from India, including foods, soil, vegetables, mangrove swamps, seafood, freshwater fishes, clinical cases, and also insects. The organism has also been isolated from women with spontaneous abortions, miscarriage or recurrent obstetric history, aborted foetuses, animal clinical cases and wildlife samples. A novel species of Listeria has also been characterized. Listeria monocytogenes strains isolated from clinical, environmental, and foods showed biofilm-forming abilities. Listeria monocytogenes serotype 4b isolates of ST328, a predominant and unique ST observed in India, was repeatedly isolated from different sources, times, and geographical locations. Here, we reviewed the occurrence of Listeria in different sources in India, its resistance to biocides, and provide epidemiological analysis on its genomic landscape.  相似文献   
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Phytochemistry Reviews - Triterpenes are naturally occurring derivatives biosynthesized following the isoprene rule of Ruzicka. The triterpenes have been reported to possess a wide range of...  相似文献   
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Industrial Control Systems and Supervisory Control and Data Acquisition (ICS/SCADA) systems are profound backbones of the national critical infrastructures and are essential to the sustainability of society since they help monitoring and controlling the cyber-enable services, such as energy, transportation, healthcare, etc. Modern SCADA systems continue to use the legacy communication protocols that lack adequate security mechanisms to provide trusted device authentication and ensure data flow integrity. Furthermore, advent of state-of-the-art network-capable sensor technology exposes many unique vulnerabilities to the adversaries. Thus, integrity of the data originated from field sensors along with their identity must be managed carefully in order to enhance reliability of ICS/SCADA ecosystems. In this paper, we present a blockchain-based SRAM PUF Authentication and Integrity (BloSPAI) protocol that aims to ensure a continuous authentication of field sensors and provide a robust data flow integrity process by leveraging distributed ledger and hardware security primitives. The prototype of the protocol has been implemented in a sensor-integrated Raspberry PI testbed that is interfaced with a permissioned blockchain network. We discuss the performance and overhead aspects of the proposed BloSPAI protocol and compare with state-of-art cybersecurity solutions. Through experimental evaluation demonstrates the relationship between the size of the blockchain network impacts the throughput in terms of time to commit transactions and overall systems setup time.

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