Cdh1 and Pik3ca Mutations Cooperate to Induce Immune-Related Invasive Lobular Carcinoma of the Breast.

CDH1 and PIK3CA are the two most frequently mutated genes in invasive lobular carcinoma (ILC) of the breast. Transcription profiling has identified molecular subtypes for ILC, one of which, immune-related (IR), is associated with gene expression linked to lymphocyte and macrophage infiltration. Here, we report that deletion of Cdh1, together with activation of Pik3ca in mammary epithelium of genetically modified mice, leads to formation of IR-ILC-like tumors with immune cell infiltration, as well as gene expression linked to T-regulatory (Treg) cell signaling and activation of targetable immune checkpoint pathways. Interestingly, these tumors show enhanced Rac1- and Yap-dependent transcription and signaling, as well as sensitivity to PI3K, Rac1, and Yap inhibitors in culture. Finally, high-dimensional immunophenotyping in control mouse mammary gland and IR-ILC tumors by mass cytometry shows dramatic alterations in myeloid and lymphoid populations associated with immune suppression and exhaustion, highlighting the potential for therapeutic intervention via immune checkpoint regulators.

Chelator-Free and Biocompatible Melanin Nanoplatform with Facile-Loading Gadolinium and Copper-64 for Bioimaging.

Development of a chelator-free and biocompatible platform for the facile construction of gadolinium3+ (Gd3+)-loaded nanoparticle based probes for in vivo magentic resonance imaging (MRI) is still challenging. Herein, biocompatible Gd3+-loading melanin dots (Gd-M-dots) have been easily prepared and have exhibited good loading efficiency for Gd3+, high stability, and higher T1 relaxivity compared to the commercial Gd-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) agent. Furthermore, Gd-M-dots showed unique photoacoustic (PA) properties, and a high PA imaging signal could be observed in vivo 1 h after injection. Compared to the traditional Gd3+-loaded nanoparticles for single-modal MRI, Gd-M-dots can also be radiolabeled with 64Cu2+ for positron emission tomography. Overall, these attractive properties of Gd-M-dots render them a promising imaging agent for various biomedical applications.

Urban forests sustain diverse carrion beetle assemblages in the New York City metropolitan area.

Urbanization is an increasingly pervasive form of land transformation that reduces biodiversity of many taxonomic groups. Beetles exhibit a broad range of responses to urbanization, likely due to the high functional diversity in this order. Carrion beetles (Order: Coleoptera, Family: Silphidae) provide an important ecosystem service by promoting decomposition of small-bodied carcasses, and have previously been found to decline due to forest fragmentation caused by urbanization. However, New York City (NYC) and many other cities have fairly large continuous forest patches that support dense populations of small mammals, and thus may harbor relatively robust carrion beetle communities in city parks. In this study, we investigated carrion beetle community composition, abundance and diversity in forest patches along an urban-to-rural gradient spanning the urban core (Central Park, NYC) to outlying rural areas. We conducted an additional study comparing the current carrion beetle community at a single suburban site in Westchester County, NY that was intensively surveyed in the early 1970's. We collected a total of 2,170 carrion beetles from eight species at 13 sites along this gradient. We report little to no effect of urbanization on carrion beetle diversity, although two species were not detected in any urban parks. Nicrophorus tomentosus was the most abundant species at all sites and seemed to dominate the urban communities, potentially due to its generalist habits and shallower burying depth compared to the other beetles surveyed. Variation between species body size, habitat specialization, and % forest area surrounding the surveyed sites also did not influence carrion beetle communities. Lastly, we found few significant differences in relative abundance of 10 different carrion beetle species between 1974 and 2015 at a single site in Westchester County, NY, although two of the rare species in the early 1970's were not detected in 2015. These results indicate that NYC's forested parks have the potential to sustain carrion beetle communities and the ecosystem services they provide.

Crystal structure of DPF3b in complex with an acetylated histone peptide.

Histone acetylation plays an important role in chromatin dynamics and is associated with active gene transcription. This modification is written by acetyltransferases, erased by histone deacetylases and read out by bromodomain containing proteins, and others such as tandem PHD fingers of DPF3b. Here we report the high resolution crystal structure of the tandem PHD fingers of DPF3b in complex with an H3K14ac peptide. In the complex structure, the histone peptide adopts an α-helical conformation, unlike previously observed by NMR, but similar to a previously reported MOZ-H3K14ac complex structure. Our crystal structure adds to existing evidence that points to the α-helix as a natural conformation of histone tails as they interact with histone-associated proteins.

PhyloPro2.0: a database for the dynamic exploration of phylogenetically conserved proteins and their domain architectures across the Eukarya.

PhyloPro is a database and accompanying web-based application for the construction and exploration of phylogenetic profiles across the Eukarya. In this update article, we present six major new developments in PhyloPro: (i) integration of Pfam-A domain predictions for all proteins; (ii) new summary heatmaps and detailed level views of domain conservation; (iii) an interactive, network-based visualization tool for exploration of domain architectures and their conservation; (iv) ability to browse based on protein functional categories (GOSlim); (v) improvements to the web interface to enhance drill down capability from the heatmap view; and (vi) improved coverage including 164 eukaryotes and 12 reference species. In addition, we provide improved support for downloading data and images in a variety of formats. Among the existing tools available for phylogenetic profiles, PhyloPro provides several innovative domain-based features including a novel domain adjacency visualization tool. These are designed to allow the user to identify and compare proteins with similar domain architectures across species and thus develop hypotheses about the evolution of lineage-specific trajectories. Database URL: http://www.compsysbio.org/phylopro/.

Hyperscape: visualization for complex biological networks.

MOTIVATION: Network biology has emerged as a powerful tool to uncover the organizational properties of living systems through the application of graph theoretic approaches. However, due to limitations in underlying data models and visualization software, knowledge relating to large molecular assemblies and biologically active fragments is poorly represented. RESULTS: Here, we demonstrate a novel hypergraph implementation that better captures hierarchical structures, using components of elastic fibers and chromatin modification as models. These reveal unprecedented views of the biology of these systems, demonstrating the unique capacity of hypergraphs to resolve overlaps and uncover new insights into the subfunctionalization of variant complexes. AVAILABILITY AND IMPLEMENTATION: Hyperscape is available as a web application at http://www.compsysbio.org/hyperscape. Source code, examples and a tutorial are freely available under a GNU license. CONTACTS: john.parkinson@utoronto.ca or graham.cromar@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.