What do the JAMA editors say when they discuss manuscripts that they are considering for publication? Developing a schema for classifying the content of editorial discussion

<p>Abstract</p> <p>Background</p> <p>In an effort to identify previously unrecognized aspects of editorial decision-making, we explored the words and phrases that one group of editors used during their meetings.</p> <p>Methods</p> <p>We performed an observational study of discussions at manuscript meetings at <it>JAMA</it>, a major US general medical journal. One of us (KD) attended 12 editorial meetings in 2003 as a visitor and took notes recording phrases from discussion surrounding 102 manuscripts. In addition, editors attending the meetings completed a form for each manuscript considered, listing the reasons they were inclined to proceed to the next step in publication and reasons they were not (DR attended 4/12 meetings). We entered the spoken and written phrases into NVivo 2.0. We then developed a schema for classifying the editors' phrases, using an iterative approach.</p> <p>Results</p> <p>Our classification schema has three main themes: science, journalism, and writing. We considered 2,463 phrases, of which 87 related mainly to the manuscript topic and were not classified (total 2,376 classified). Phrases related to science predominated (1,274 or 54%). The editors, most of whom were physicians, also placed major weight on goals important to JAMA's mission (journalism goals) such as importance to medicine, strategic emphasis for the journal, interest to the readership, and results (729 or 31% of phrases). About 16% (n = 373) of the phrases used related to writing issues, such as clarity and responses to the referees' comments.</p> <p>Conclusion</p> <p>Classification of editorial discourse provides insight into editorial decision making and concepts that need exploration in future studies.</p

From Transactional to Transformative: The Case for Equity in Gateway City Transit-Oriented Development

We as a society have made choices that have led to deep inequities. Whether intentional or not, these inequities divide places, races, classes, and cultures across the Commonwealth. To bridge these divisions, policymakers, leaders, and practitioners must reframe decisions and actions with equity as an intentional outcome and part of the process. We write this paper to present a framework of how transit-oriented development (TOD) can help cities, specifically Gateway Cities, embed equity into market-based and other policy tools and practices, thereby transforming their regions through equitable growth and development.This report expands on our 2018 recommendations and lays the groundwork for a series of future policy briefs that will explore the issues covered here in more depth. We call for infusing equity into TOD policies and practices for four specific reasons:Over the past 50 years, demographic change has divided people and communities socially and economically in Gateway City metropolitan regions.Gentrification fears have surged in Gateway Cities' weak real estate markets, where increasing property values threaten to destabilize households and neighborhoods, strip cities of their cultural vibrancy, and put vulnerable residents at risk of displacement and homelessness.Local and nationwide histories of socioeconomic exclusion—particularly along racial and cultural lines—persist today. These histories have exacerbated wealth gaps and income inequality and require both acknowledgement and correction.Finally, a false policy dichotomy that supports either large "urban" or small "nonurban" communities ignores the vital role Gateway Cities play as regional hubs for surrounding towns and cities, thus deepening geographic disparities across the Commonwealth

A selective jumonji H3K27 demethylase inhibitor modulates the proinflammatory macrophage response

The jumonji (JMJ) family of histone demethylases are Fe2+- and α-ketoglutarate-dependent oxygenases that are essential components of regulatory transcriptional chromatin complexes. These enzymes demethylate lysine residues in histones in a methylation-state and sequence-specific context. Considerable effort has been devoted to gaining a mechanistic understanding of the roles of histone lysine demethylases in eukaryotic transcription, genome integrity and epigenetic inheritance, as well as in development, physiology and disease. However, because of the absence of any selective inhibitors, the relevance of the demethylase activity of JMJ enzymes in regulating cellular responses remains poorly understood. Here we present a structure-guided small-molecule and chemoproteomics approach to elucidating the functional role of the H3K27me3-specific demethylase subfamily (KDM6 subfamily members JMJD3 and UTX). The liganded structures of human and mouse JMJD3 provide novel insight into the specificity determinants for cofactor, substrate and inhibitor recognition by the KDM6 subfamily of demethylases. We exploited these structural features to generate the first small-molecule catalytic site inhibitor that is selective for the H3K27me3-specific JMJ subfamily. We demonstrate that this inhibitor binds in a novel manner and reduces lipopolysaccharide-induced proinflammatory cytokine production by human primary macrophages, a process that depends on both JMJD3 and UTX. Our results resolve the ambiguity associated with the catalytic function of H3K27-specific JMJs in regulating disease-relevant inflammatory responses and provide encouragement for designing small-molecule inhibitors to allow selective pharmacological intervention across the JMJ family

Discovery and Optimization of Small-Molecule Ligands for the CBP/p300 Bromodomains

Small-molecule inhibitors that target bromo­domains outside of the bromo­domain and extra-terminal (BET) sub-family are lacking. Here, we describe highly potent and selective ligands for the bromo­domain module of the human lysine acetyl transferase CBP/p300, developed from a series of 5-isoxazolyl-benz­imid­azoles. Our starting point was a fragment hit, which was optimized into a more potent and selective lead using parallel synthesis employing Suzuki couplings, benz­imid­azole-forming reactions, and reductive aminations. The selectivity of the lead compound against other bromo­domain family members was investigated using a thermal stability assay, which revealed some inhibition of the structurally related BET family members. To address the BET selectivity issue, X-ray crystal structures of the lead compound bound to the CREB binding protein (CBP) and the first bromo­domain of BRD4 (BRD4(1)) were used to guide the design of more selective compounds. The crystal structures obtained revealed two distinct binding modes. By varying the aryl substitution pattern and developing conformationally constrained analogues, selectivity for CBP over BRD4(1) was increased. The optimized compound is highly potent (<i>K</i>_d = 21 nM) and selective, displaying 40-fold selectivity over BRD4(1). Cellular activity was demonstrated using fluorescence recovery after photo-bleaching (FRAP) and a p53 reporter assay. The optimized compounds are cell-active and have nano­molar affinity for CBP/p300; therefore, they should be useful in studies investigating the biological roles of CBP and p300 and to validate the CBP and p300 bromo­domains as therapeutic targets