Endorepellin remodels the endothelial transcriptome toward a pro-autophagic and pro-mitophagic gene signature.

Regulation of autophagy by proteolytically cleaved fragments of heparan sulfate proteoglycans is a novel and current research focus in tumor biology. Endorepellin is the C-terminal angiostatic fragment of the heparan sulfate proteoglycan perlecan and induces autophagy in endothelial cells. To further investigate this property, we used NanoString, a digital PCR platform for measuring pre-defined transcripts in biological samples to analyze a custom subset of 95 autophagy-related genes in human umbilical vein endothelial cells treated with ultrapure human recombinant endorepellin. We discovered an endorepellin-evoked pro-autophagic and pro-mitophagic gene expression signatures, which included two coordinately up-regulated mitochondrial-associated genes encoding the E3 ubiquitin protein ligase Parkin and the tumor suppressor mitostatin. Induction of both proteins required the tyrosine kinase activity of vascular endothelial growth factor receptor 2 (VEGFR2). Furthermore, we discovered that endorepellin evoked mitochondrial depolarization in endothelial cells via a specific interaction between its two proximal LG1/2 domains and VEGFR2. We also found that following loss of membrane potential, mitostatin and parkin interact and that mitostatin associates with the established Parkin receptor mitofusin-2. In conclusion, we have identified a critical role for endorepellin in remodeling the autophagic transcriptome and influencing mitochondrial homeostasis

The effect of mineral and organic nutrient input on yields and nitrogen balances in western Kenya

Author Posting. © The Author(s), 2015. This is the author's version of the work. It is posted here by permission of Elsevier for personal use, not for redistribution. The definitive version was published in Agriculture, Ecosystems & Environment 214 (2015): 10-20, doi:10.1016/j.agee.2015.08.006.Soil fertility declines constrain crop productivity on smallholder farms in sub-Saharan Africa. Government and non-government organizations promote the use of mineral fertilizer and improved seed varieties to redress nutrient depletion and increase crop yields. Similarly, rotational cropping with nitrogen (N)-fixing legume cover crops or trees is promoted to improve soil fertility and crop yields. We examined maize grain yields and partial N balances on 24 smallholder maize farms in western Kenya, where interventions have increased access to agricultural inputs and rotational legume technologies. On these farms, mineral fertilizer inputs ranged from 0 to 161 kg N ha-1 (mean = 48 kg N ha-1), and maize grain yields ranged from 1-7 tons ha-1 (mean = 3.4 t ha-1). Partial N balances ranged from large losses (-112 kg N ha-1) to large gains (93 kg N ha-1)with a mean of -3 kg N ha-1. Maize grain yields increased significantly with N inputs (from fertilizer and legumes) in 2012 but not in 2013 when rainfall was lower. Nitrogen inputs of 40 kg N ha-1 were required to produce 3 tons of maize ha-1. N balances varied both among farms and between years, highlighting the importance of tracking inputs and outputs on multiple farms over multiple years before drawing conclusions about nutrient management, soil fertility outcomes and food security. The addition of N from legume rotations was a strong predictor of grain yields and positive N balances in lower-yielding farms in both years. This suggested that legume rotations may be particularly important for buffering yields from climate variability and maintaining N balances in low rainfall years.This research was funded by an Earth Institute at Columbia University Cross-Cutting Initiative Grant, a National Science Foundation PIRE grant (IIA-0968211), and by the Bill and Melinda Gates Foundation (Gates Special Initiative Grant)

Decorin protein core affects the global gene expression profile of the tumor microenvironment in a triple-negative orthotopic breast carcinoma xenograft model

Decorin, a member of the small leucine-rich proteoglycan gene family, exists and functions wholly within the tumor microenvironment to suppress tumorigenesis by directly targeting and antagonizing multiple receptor tyrosine kinases, such as the EGFR and Met. This leads to potent and sustained signal attenuation, growth arrest, and angiostasis. We thus sought to evaluate the tumoricidal benefits of systemic decorin on a triple-negative orthotopic breast carcinoma xenograft model. To this end, we employed a novel high-density mixed expression array capable of differentiating and simultaneously measuring gene signatures of both Mus musculus (stromal) and Homo sapiens (epithelial) tissue origins. We found that decorin protein core modulated the differential expression of 374 genes within the stromal compartment of the tumor xenograft. Further, our top gene ontology classes strongly suggests an unexpected and preferential role for decorin protein core to inhibit genes necessary for immunomodulatory responses while simultaneously inducing expression of those possessing cellular adhesion and tumor suppressive gene properties. Rigorous verification of the top scoring candidates led to the discovery of three genes heretofore unlinked to malignant breast cancer that were reproducibly found to be induced in several models of tumor stroma. Collectively, our data provide highly novel and unexpected stromal gene signatures as a direct function of systemic administration of decorin protein core and reveals a fundamental basis of action for decorin to modulate the tumor stroma as a biological mechanism for the ascribed anti-tumorigenic properties

Regional differences in phosphorus budgets in intensive soybean agriculture

Author Posting. © American Institute of Biological Sciences, 2013. This article is posted here by permission of University of California Press for personal use, not for redistribution. The definitive version was published in BioScience 63 (2013): 49-54, doi:10.1525/bio.2013.63.1.10.Fertilizer-intensive agriculture has been integral to increasing food production over the past half century but has been accompanied by environmental costs. We use case studies of phosphorus fertilizer use in the world’s most productive soybean-growing regions, Iowa (United States), Mato Grosso (Brazil), and Buenos Aires (Argentina), to examine influences of management and soil type on agriculture’s most prevalent phosphorusrelated environmental consequences: eutrophication and consumption of Earth’s finite phosphorus reserves. With increasing phosphorus inputs, achieving high yields on tropical soils with high phosphorus-binding capacity is becoming more common. This system has low eutrophication risks but increases demands on phosphorus supplies. In contrast, production in traditional breadbaskets, on soils with lower phosphorus-binding capacities, is being sustained with decreasing phosphorus inputs. However, in these regions, historical overuse of phosphorus may mean continued eutrophication risk even as pressures on phosphorus reserves diminish. We focus here on soybean production but illustrate how achieving sustainable agriculture involves an intricate optimization of local, regional, and global considerations.SP is supported by the Andrew Mellon Foundation, and CN and SHR’s work in Mato Grosso was funded by National Science Foundation grant no. NSF-DEB-0640661 and through collaboration with the Instituto de Pesquisa Ambiental da Amazonia