Long-term fertilization alters the relative importance of nitrate reduction pathways in salt marsh sediments

Salt marshes provide numerous valuable ecological services. In particular, nitrogen (N) removal in salt marsh sediments alleviates N loading to the coastal ocean. N removal reduces the threat of eutrophication caused by increased N inputs from anthropogenic sources. It is unclear, however, whether chronic nutrient over-enrichment alters the capacity of salt marshes to remove anthropogenic N. To assess the effect of nutrient enrichment on N cycling in salt marsh sediments, we examined important N cycle pathways in experimental fertilization plots in a New England salt marsh. We determined rates of nitrification, denitrification, and dissimilatory nitrate reduction to ammonium (DNRA) using sediment slurry incubations with 15 N labeled ammonium or nitrate tracers under oxic headspace (20% oxygen / 80% helium). Nitrification and denitrification rates were more than ten-fold higher in fertilized plots compared to control plots. By contrast, DNRA, which retains N in the system, was high in control plots but not detected in fertilized plots. The relative contribution of DNRA to total nitrate reduction largely depends on the carbon/nitrate ratio in the sediment. These results suggest that long-term fertilization shifts N cycling in salt marsh sediments from predominantly retention to removal. Long-term fertilization alters the relative importance of nitrate reduction pathways in salt marsh sediments: NO 3 - reduction in salt marsh sediments (PDF Download Available). Available from: https://www.researchgate.net/publication/305480944_Long-term_fertilization_alters_the_relative_importance_of_nitrate_reduction_pathways_in_salt_marsh_sediments_NO_3_-_reduction_in_salt_marsh_sediments [accessed Jun 6, 2017]

Determining origin in a migratory marine vertebrate: a novel method to integrate stable isotopes and satellite tracking

Stable isotope analysis is a useful tool to track animal movements in both terrestrial and marine environments. These intrinsic markers are assimilated through the diet and may exhibit spatial gradients as a result of biogeochemical processes at the base of the food web. In the marine environment, maps to predict the spatial distribution of stable isotopes are limited, and thus determining geographic origin has been reliant upon integrating satellite telemetry and stable isotope data. Migratory sea turtles regularly move between foraging and reproductive areas. Whereas most nesting populations can be easily accessed and regularly monitored, little is known about the demographic trends in foraging populations. The purpose of the present study was to examine migration patterns of loggerhead nesting aggregations in the Gulf of Mexico (GoM), where sea turtles have been historically understudied. Two methods of geographic assignment using stable isotope values in known-origin samples from satellite telemetry were compared: (1) a nominal approach through discriminant analysis and (2) a novel continuous-surface approach using bivariate carbon and nitrogen isoscapes (isotopic landscapes) developed for this study. Tissue samples for stable isotope analysis were obtained from 60 satellite-tracked individuals at five nesting beaches within the GoM. Both methodological approaches for assignment resulted in high accuracy of foraging area determination, though each has advantages and disadvantages. The nominal approach is more appropriate when defined boundaries are necessary, but up to 42% of the individuals could not be considered in this approach. All individuals can be included in the continuous-surface approach, and individual results can be aggregated to identify geographic hotspots of foraging area use, though the accuracy rate was lower than nominal assignment. The methodological validation provides a foundation for future sea turtle studies in the region to inexpensively determine geographic origin for large numbers of untracked individuals. Regular monitoring of sea turtle nesting aggregations with stable isotope sampling can be used to fill critical data gaps regarding habitat use and migration patterns. Probabilistic assignment to origin with isoscapes has not been previously used in the marine environment, but the methods presented here could also be applied to other migratory marine species

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer

The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia

Acute myeloid leukemia (AML) is a largely incurable disease, for which new treatments are urgently needed. While leukemogenesis occurs in the hypoxic bone marrow, the therapeutic tractability of the hypoxia-inducible factor (HIF) system remains undefined. Given that inactivation of HIF-1α/HIF-2α promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1α/HIF-2α degradation. Here, we reveal that genetic inactivation of Phd1/Phd2 hinders AML initiation and progression, without impacting normal hematopoiesis. We investigated clinically used PHD inhibitors and a new selective PHD inhibitor (IOX5), to stabilize HIF-α in AML cells. PHD inhibition compromises AML in a HIF-1α-dependent manner to disable pro-leukemogenic pathways, re-program metabolism and induce apoptosis, in part via upregulation of BNIP3. Notably, concurrent inhibition of BCL-2 by venetoclax potentiates the anti-leukemic effect of PHD inhibition. Thus, PHD inhibition, with consequent HIF-1α stabilization, is a promising nontoxic strategy for AML, including in combination with venetoclax

Investigating the influence of neighbouring structures on natural ventilation potential of a full-scale cubical building using time-dependent CFD

Building location and orientation with respect to incident wind angle are important parameters in determining wind-driven natural ventilation. Experimentally measured façade pressures and ventilation rates in the Silsoe cube under single-sided and cross-flow ventilation configurations are compared with CFD simulations conducted in OpenFoam and ANSYS Fluent using a typical linear workflow approach. Eight wind directions are studied with the cube in isolation and in a new staggered nine cube array format. Comparison is made using CIBSE's prescribed ventilation calculation method based on internal/external building pressure differences. Ventilation rate in the isolated cube with single-sided opening was comparatively lower than either of the cross-flow cases, and relationships between air change rate and wind angle were much weaker in the array cases. For the single opening case with the isolated cube, ventilation effectiveness decreases as the wind turns towards the opening due to increased short-circuiting of airflows. Turbulent structures close to windows improve mixing in the array case. Simulations suggest that vortex shedding from up-wind buildings provides pulsating ventilation in both window configurations, which may attenuate the negative effects of upwind flow obstruction

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment