Re-programing chromatin with a bifunctional LSD1/HDAC inhibitor induces therapeutic differentiation in DIPG

H3K27M mutations resulting in epigenetic dysfunction are frequently observed in diffuse intrinsic pontine glioma (DIPGs), an incurable pediatric cancer. We conduct a CRISPR screen revealing that knockout of KDM1A encoding lysine-specific demethylase 1 (LSD1) sensitizes DIPG cells to histone deacetylase (HDAC) inhibitors. Consistently, Corin, a bifunctional inhibitor of HDACs and LSD1, potently inhibits DIPG growth in vitro and in xenografts. Mechanistically, Corin increases H3K27me3 levels suppressed by H3K27M histones, and simultaneously increases HDAC-targeted H3K27ac and LSD1-targeted H3K4me1 at differentiation-associated genes. Corin treatment induces cell death, cell-cycle arrest, and a cellular differentiation phenotype and drives transcriptional changes correlating with increased survival time in DIPG patients. These data suggest a strategy for treating DIPG by simultaneously inhibiting LSD1 and HDACs

Forming the Future of Agrohydrology

Agricultural water management is increasingly prioritized throughout the world as producers are tasked with meeting growing crop demand while also managing environmental resources more sustainably. Likewise, agriculture is increasingly modifying the terrestrial water cycle. In response to these dynamics, the informal research discipline of agrohydrology continues to grow, fueled by a new era of rapidly evolving research tools and big data availability. While many researchers are actively invested in agrohydrology as a research topic, there remains a gap in formalizing this valuable discipline. This article aims to: (a) identify key research themes in agrohydrology, (b) conceptualize future research topics within each theme, and (c) estimate a timeframe before topics become pressing (i.e., before a topic becomes a limiting factor in advancing water management in an agricultural context). This commentary is meant to guide the trajectory of an evolving discipline of agrohydrology, the practice of agricultural water management at multiple nested scales, and the conversation of the invested public

When Veblen meets Krugman: social network and city dynamics

The present paper explores the role of the social structure of suburban areas on city dynamics. We focus on relative concerns in the form of conspicuous consumption and introduce them into a standard economic geography model a la Krugman. We show that the level of social integration within the suburban areas of cities and the level of economic integration across cities are crucial in determining the city sizes. An interesting case arises with moderate trade costs when relatively small shares of income are devoted to the consumption of the differentiated good: if classes of workers are segregated (as in homogenous suburban areas), relative concerns tend to generate dispersed, medium-size cities; when workers of different classes socially interact, relative concerns contribute to foster socially integrated megalopolises. This result shows that keeping-up-with-the-Joneses motives may generate counterintuitive results when agents are able to choose their location