Three-Dimensional Folding and Functional Organization Principles of the Drosophila Genome

SummaryChromosomes are the physical realization of genetic information and thus form the basis for its readout and propagation. Here we present a high-resolution chromosomal contact map derived from a modified genome-wide chromosome conformation capture approach applied to Drosophila embryonic nuclei. The data show that the entire genome is linearly partitioned into well-demarcated physical domains that overlap extensively with active and repressive epigenetic marks. Chromosomal contacts are hierarchically organized between domains. Global modeling of contact density and clustering of domains show that inactive domains are condensed and confined to their chromosomal territories, whereas active domains reach out of the territory to form remote intra- and interchromosomal contacts. Moreover, we systematically identify specific long-range intrachromosomal contacts between Polycomb-repressed domains. Together, these observations allow for quantitative prediction of the Drosophila chromosomal contact map, laying the foundation for detailed studies of chromosome structure and function in a genetically tractable system

Threat or opportunity? An analysis of perceptions of cultured meat in the UK farming sector

The environmental and social impacts of cultured meat, and its economic viability, are contingent on its implications for food production and for agriculture. However, the implications of cultured meat production for farmers have not yet been thoroughly investigated and are poorly understood. The aim of this research was to engage with the farming sector in critically assessing cultured meat as a technology which could profoundly affect future farm livelihoods, land use, rural and farming communities and agricultural value chains. Ensuring farmers' voices, and potential 'counternarratives' inform the development of cultured meat is not only inclusive, but could identify unexpected impacts of this emerging technology and contribute to the framing of the social license of the industry developing them.Six focus groups were undertaken with 75 UK farmers from a variety of farming sectors and regions. Questions focused on what the term 'cultured meat' means to farmers, the potential impacts of cultured meat, and potential business scenarios arising for farmers. All meetings were recorded, transcribed, and thematically analyzed.Farmers expressed complex and considered reflections on cultured meat, raising several perceived opportunities and risks associated with the themes of 'ethics and affective' narratives, 'environmentbased' narratives, and 'socio-economic' narratives. Aspects of foci of power, food system control and transparency associated with cultured meat emerged from the conversations, as well as cultured meat's potential impacts on the environment and on jobs, farming/rural communities and connecting with the land.Globally, meat production underpins the livelihoods of many rural communities, so a transition to cultured meat is likely to have deep-seated ethical, environmental, and socio-economic impacts. Within the discourse on cultured meat the voices of farmers are often lost. While not claiming to be representative of all UK farming, this study engaged UK farmer perspectives as a way of starting the substantive process of greater stakeholder inclusion in cultured meat innovation pathways, and which should underpin responsible technology transitions in agriculture

The equation of state for two flavor QCD at N_t=6

We calculate the two flavor equation of state for QCD on lattices with lattice spacing a=(6T)^{-1} and find that cutoff effects are substantially reduced compared to an earlier study using a=(4T)^{-1}. However, it is likely that significant cutoff effects remain. We fit the lattice data to expected forms of the free energy density for a second order phase transition at zero-quark-mass, which allows us to extrapolate the equation of state to m_q=0 and to extract the speed of sound. We find that the equation of state depends weakly on the quark mass for small quark mass.Comment: 24 pages, latex, 11 postscipt figure

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

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

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

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

Active RNA Polymerases: Mobile or Immobile Molecular Machines?

Although it is widely assumed that active RNA polymerase tracks along its template, we find that DNA, not the polymerase, moves, suggesting that polymerase works by reeling in the template