Protein citrullination has been shown to regulate numerous physiological pathways (e.g., the innate immune response and gene transcription) and is, when dysregulated, known to be associated with ...numerous human diseases, including cancer, rheumatoid arthritis, and multiple sclerosis. This modification, also termed deimination, is catalyzed by a group of enzymes called the protein arginine deiminases (PADs). In mammals, there are five PAD family members (i.e., PADs 1, 2, 3, 4, and 6) that exhibit tissue-specific expression patterns and vary in their subcellular localization. The kinetic characterization of PAD4 was recently reported, and these efforts guided the development of the two most potent PAD4 inhibitors (i.e., F- and Cl-amidine) known to date. In addition to being potent PAD4 inhibitors, we show here that Cl-amidine also exhibits a strong inhibitory effect against PADs 1 and 3, thus indicating its utility as a pan PAD inhibitor. Given the increasing number of diseases in which dysregulated PAD activity has been implicated, the development of PAD-selective inhibitors is of paramount importance. To aid that goal, we characterized the catalytic mechanism and substrate specificity of PADs 1 and 3. Herein, we report the results of these studies, which suggest that, like PAD4, PADs 1 and 3 employ a reverse protonation mechanism. Additionally, the substrate specificity studies provided critical information that aided the identification of PAD3-selective inhibitors. These compounds, denoted F4- and Cl4-amidine, are the most potent PAD3 inhibitors ever described.
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Protein arginine deiminase 4 (PAD4) is a transcriptional coregulator that catalyzes the calcium-dependent conversion of specific arginine residues in proteins to citrulline. Recently, we reported the ...synthesis and characterization of F-amidine, a potent and bioavailable irreversible inactivator of PAD4. Herein, we report our efforts to identify the steric and leaving group requirements for F-amidine-induced PAD4 inactivation, the structure of the PAD4−F-amidine·calcium complex, and in vivo studies with N-α-benzoyl-N 5-(2-chloro-1-iminoethyl)-l-ornithine amide (Cl-amidine), a PAD4 inactivator with enhanced potency. The PAD4 inactivators described herein will be useful pharmacological probes in characterizing the incompletely defined physiological role(s) of this enzyme. In addition, they represent potential lead compounds for the treatment of rheumatoid arthritis because a growing body of evidence supports a role for PAD4 in the onset and progression of this chronic autoimmune disorder.
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The protein arginine deiminases (PAD), which catalyze the hydrolysis of peptidyl-arginine to form peptidyl-citrulline, play important roles in a variety of cell signaling pathways, including ...apoptosis, differentiation, and transcriptional regulation. In addition to these important cellular roles, PAD activity is dysregulated in multiple human diseases e.g., rheumatoid arthritis (RA), cancer, and colitis, and significantly, PAD inhibition with Cl-amidine has been shown to reduce disease severity in the collagen-induced arthritis model of RA. Although these enzymes play important roles in human cell signaling and disease, the mechanisms that regulate PAD activity under both physiological and pathological conditions are poorly understood. One possible mechanism for regulating PAD activity is autodeimination, to which PAD4 has been shown by us and others to be subjected in vitro and in vivo. Herein, we demonstrate that PAD4 autodeimination does not alter the activity, substrate specificity, or calcium dependence of this isozyme. However, the results of these studies indicate a novel role for autodeimination in modulating the ability of PAD4 to interact with histone deacetylase 1 (HDAC1), citrullinated histone H3 (Cit H3), and protein arginine methyltransferase 1 (PRMT1).
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Some environmentalists connect their activism to feminism, arguing that mitigating climate change will require transforming gender hierarchies. In this study, I consider two ecological intentional ...communities that attempt to meld their feminist and environmental ideals in practice. Drawing on participant observation and in-depth interviews conducted at Twin Oaks Intentional Community and Navdanya Bioconservation Farm, I examine how each group implements feminist principles and how members understand the connection between gender equality and environmental sustainability. I find that despite their different gender arrangements, both communities address the unpaid care work of women in modeling visions of environmental sustainability, suggesting an important lesson for wider society.
Protein arginine deiminase 4 (PAD4) is a Ca2+-dependent enzyme that catalyzes the posttranslational conversion of arginine to citrulline (Arg → Cit) in a number of proteins, including histones. While ...the gene encoding this enzyme has been implicated in the pathophysiology of rheumatoid arthritis (RA), little is known about its mechanism of catalysis, its in vivo role, or its role in the pathophysiology of RA; however, recent reports suggest that this enzyme can act as a transcriptional corepressor for the estrogen receptor. Herein, we report our initial kinetic and mechanistic characterization of human PAD4. Specifically, these studies confirm that PAD4 catalyzes the hydrolytic deimination of Arg residues to produce Cit and ammonia. The metal dependence of PAD4 has also been evaluated, and the results indicate that PAD4 activity is highly specific for calcium. Calcium activation of PAD4 catalysis exhibits positive cooperativity with K 0.5 values in the mid to high micromolar range. Evidence indicating that calcium binding causes a conformational change is also presented. Additionally, the steady-state kinetic parameters for a number of histone H4-based peptide substrates and benzoylated Arg derivatives have been determined. K m values for these compounds are in the high micromolar to the low millimolar range with k cat values ranging from 2.8 to 6.6 s-1. The ability of PAD4 to catalyze the deimination of methylated Arg residues has also been evaluated, and the results indicate that these compounds are poor PAD4 substrates (V/K ≤ 31.3 M-1 s-1) in comparison to other substrates. These findings suggest that the full-length enzyme does not catalyze this reaction in vitro and possibly in vivo either. Collectively, the studies described herein will provide a firm foundation for the future development of PAD4 selective inhibitors.
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Highlights • Maintenance of CLABSI prevention strategies. • Significant decrease in S. epidermidis blood stream infection. • Significant decrease in Gram negative blood stream infections. • ...Susceptibility to Cefipime and Piperacillin-tazobactam has remained stable in the past decade.
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•Presents concepts of renewable energy trading market.•Explain possible trading market in India, China, USA, France and Germany.•Identify application of blockchain in renewable energy trading.•The ...significance of this paper are the assessment of renewable energy trading through the Ethereum and R3 Corda based blockchain technique.
Renewable energy trading could be considered the next step in power trading's development. It is probable that individuals currently involved in power trading will need to upgrade their data collection, processing, and reporting systems. This article provides a comprehensive evaluation of renewable energy trading utilizing Blockchain technology. Initially, the paper examines country-specific renewable energy trading with a focus on India, China, the US, France, and Germany's renewable energy policies. Moreover, the paper presents potential renewable energy trading markets such as peer-to-peer, over the grid, and partially or fully independent microgrid's. This paper shows the appraisal of bond, commodity, derivative, and algorithm-based renewable energy trading using different Blockchain methods, including Ethereum and R3 Corda. It is find out during the renewable energy trading, proposers of bid, also include capital cost of the renewable energy power plant, salvage value after useful life of different component of renewable energy power plant. It is also find out proper trading is to be done with offering subsidies of up to 70 % of the capital cost, and with a 30 % viability gap finance (VGF) at this cost.
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A growing body of literature suggests that creating a just sustainable society will require reorganizing economic arrangements and, in particular, rethinking work. Previous studies have recognized ...alternative organizations, such as cooperatives and intentional communities, as sites for building more democratic, sustainable models of work. This study contributes a description and analysis of work and sustainability at Twin Oaks Intentional Community, an 80-person income- and resource-sharing commune in Louisa, Virginia. Some measures show that Twin Oaks members live more sustainably in terms of energy consumption than the average US resident. In this article, I investigate the relationship between sustainability and work at Twin Oaks. I find that sustainable work is linked to the following key principles: broadening definitions of work, prioritizing community well-being, and democratizing decision making. In doing so, I contribute to previous literature on work, sustainability, and alternative organizations by suggesting that (1) sustainability in intentional communities is deeply intertwined with systems of work; (2) broadening definitions of work to include social reproductive labour contributes to sustainability; and (3) the democratization of work can further goals of sustainability.
Protein arginine deiminase 4 (PAD4), which catalyzes the post-translational conversion of peptidyl arginine to peptidyl citrulline, is widely regarded as one of the best new targets for the ...development of a novel rheumatoid arthritis therapeutic. In addition to its presumed role in this disease, PAD4 is also a calcium-dependent histone deiminase that acts as a transcriptional co-repressor. Herein we describe the design, synthesis, and in vitro evaluation of two fluorescently labeled activity-based protein profiling (ABPP) reagents that specifically and irreversibly modify the active, that is, calcium-bound, form PAD4 with equal affinity to previously described small molecule chemical probes of PAD4 function. These fluorescently tagged ABPPs will be useful for identifying the conditions under which this enzyme is activated in vivo and may prove to be useful RA diagnostics.
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Background Few studies have described preventive strategies for central line–associated bloodstream infections (CLABSIs) in pediatric hematopoietic stem cell transplantation (HSCT) recipients. ...Methods We performed a pilot intervention study in our pediatric HSCT population in 2006-2008 and compared CLABSI rates before and after implementation of preventive strategies (ie, training staff and caregivers in procedures for dressing changes and drawing blood) in the inpatient, outpatient, and non–health care (ie, home) settings. We also studied the pathogens associated with hospital-onset versus community-onset CLABSIs. Results During the study period, 90 children (median age, 10 years) underwent HSCT. Fifty-nine children (66%) developed a CLABSI; 18 in the hospital, 27 in the community, and 14 in both settings. After implementation of central line (CL) maintenance care strategies, the overall CLABSI rate declined from 10.03 to 3.00 CLABSIs per 1,000 CL-days (rate ratio, 0.3; 95% confidence interval, 0.2-0.5, P < .0001) and rates declined for both hospital- and community-onset CLABSIs. Gram negative pathogens caused more community-onset (45/65, 69%) than hospital-onset (22/46, 48%) CLABSIs (odds ratio, 2.5; 95% confidence interval, 1.1-5.4; P = .02). Conclusions Standardization of care practices for CL maintenance was associated with a reduction of CLABSIs in our pediatric HSCT population. A multicenter study is needed to confirm these observations.
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