M Ryan Corces, Jeffrey M Granja, Shadi Shams, Bryan H Louie, Jose A Seoane, Wanding Zhou, Tiago C Silva, Clarice Groeneveld, Christopher K Wong, Seung Woo Cho, Ansuman T Satpathy, Maxwell R Mumbach, Katherine A Hoadley, A Gordon Robertson, Nathan C Sheffield, Ina Felau, Mauro A A Castro, Benjamin P Berman, Louis M Staudt, Jean C Zenklusen, Peter W Laird, Christina Curtis, Cancer Genome Atlas Analysis Network, William J Greenleaf, Howard Y Chang <<<

We present the genome-wide chromatin accessibility profiles of 410 tumor samples spanning 23 cancer types from The Cancer Genome Atlas (TCGA). We identify 562,709 transposase-accessible DNA elements that substantially extend the compendium of known cis-regulatory elements. Integration of ATAC-seq (the assay for transposase-accessible chromatin using sequencing) with TCGA multi-omic data identifies a large number of putative distal enhancers that distinguish molecular subtypes of cancers, uncovers specific driving transcription factors via protein-DNA footprints, and nominates long-range gene-regulatory interactions in cancer. These data reveal genetic risk loci of cancer predisposition as active DNA regulatory elements in cancer, identify gene-regulatory interactions underlying cancer immune evasion, and pinpoint noncoding mutations that drive enhancer activation and may affect patient survival. These results suggest a systematic approach to understanding the noncoding genome in cancer to advance diagnosis and therapy. <<<

C Domínguez Conde, C Xu, L B Jarvis, D B Rainbow, S B Wells, T Gomes, S K Howlett, O Suchanek, K Polanski, H W King, L Mamanova, N Huang, P A Szabo, L Richardson, L Bolt, E S Fasouli, K T Mahbubani, M Prete, L Tuck, N Richoz, Z K Tuong, L Campos, H S Mousa, E J Needham, S Pritchard, T Li, R Elmentaite, J Park, E Rahmani, D Chen, D K Menon, O A Bayraktar, L K James, K B Meyer, N Yosef, M R Clatworthy, P A Sims, D L Farber, K Saeb-Parsy, J L Jones, S A Teichmann <<<

Despite their crucial role in health and disease, our knowledge of immune cells within human tissues remains limited. We surveyed the immune compartment of 16 tissues from 12 adult donors by single-cell RNA sequencing and VDJ sequencing generating a dataset of ~360,000 cells. To systematically resolve immune cell heterogeneity across tissues, we developed CellTypist, a machine learning tool for rapid and precise cell type annotation. Using this approach, combined with detailed curation, we determined the tissue distribution of finely phenotyped immune cell types, revealing hitherto unappreciated tissue-specific features and clonal architecture of T and B cells. Our multitissue approach lays the foundation for identifying highly resolved immune cell types by leveraging a common reference dataset, tissue-integrated expression analysis, and antigen receptor sequencing. <<<

In coming to understand the world-in learning concepts, acquiring language, and grasping causal relations-our minds make inferences that appear to go far beyond the data available. How do we do it? This review describes recent approaches to reverse-engineering human learning and cognitive development and, in parallel, engineering more humanlike machine learning systems. Computational models that perform probabilistic inference over hierarchies of flexibly structured representations can address some of the deepest questions about the nature and origins of human thought: How does abstract knowledge guide learning and reasoning from sparse data? What forms does our knowledge take, across different domains and tasks? And how is that abstract knowledge itself acquired? <<<

V Gopalakrishnan, C N Spencer, L Nezi, A Reuben, M C Andrews, T V Karpinets, P A Prieto, D Vicente, K Hoffman, S C Wei, A P Cogdill, L Zhao, C W Hudgens, D S Hutchinson, T Manzo, M Petaccia de Macedo, T Cotechini, T Kumar, W S Chen, S M Reddy, R Szczepaniak Sloane, J Galloway-Pena, H Jiang, P L Chen, E J Shpall, K Rezvani, A M Alousi, R F Chemaly, S Shelburne, L M Vence, P C Okhuysen, V B Jensen, A G Swennes, F McAllister, E Marcelo Riquelme Sanchez, Y Zhang, E Le Chatelier, L Zitvogel, N Pons, J L Austin-Breneman, L E Haydu, E M Burton, J M Gardner, E Sirmans, J Hu, A J Lazar, T Tsujikawa, A Diab, H Tawbi, I C Glitza, W J Hwu, S P Patel, S E Woodman, R N Amaria, M A Davies, J E Gershenwald, P Hwu, J E Lee, J Zhang, L M Coussens, Z A Cooper, P A Futreal, C R Daniel, N J Ajami, J F Petrosino, M T Tetzlaff, P Sharma, J P Allison, R R Jenq, J A Wargo <<<

Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti-programmed cell death 1 protein (PD-1) immunotherapy ( = 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patient fecal microbiome samples ( = 43, 30 responders, 13 nonresponders) showed significantly higher alpha diversity ( < 0.01) and relative abundance of bacteria of the Ruminococcaceae family ( < 0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors. <<<

Senjie Lin, Shifeng Cheng, Bo Song, Xiao Zhong, Xin Lin, Wujiao Li, Ling Li, Yaqun Zhang, Huan Zhang, Zhiliang Ji, Meichun Cai, Yunyun Zhuang, Xinguo Shi, Lingxiao Lin, Lu Wang, Zhaobao Wang, Xin Liu, Sheng Yu, Peng Zeng, Han Hao, Quan Zou, Chengxuan Chen, Yanjun Li, Ying Wang, Chunyan Xu, Shanshan Meng, Xun Xu, Jun Wang, Huanming Yang, David A Campbell, Nancy R Sturm, Steve Dagenais-Bellefeuille, David Morse <<<

Dinoflagellates are important components of marine ecosystems and essential coral symbionts, yet little is known about their genomes. We report here on the analysis of a high-quality assembly from the 1180-megabase genome of Symbiodinium kawagutii. We annotated protein-coding genes and identified Symbiodinium-specific gene families. No whole-genome duplication was observed, but instead we found active (retro)transposition and gene family expansion, especially in processes important for successful symbiosis with corals. We also documented genes potentially governing sexual reproduction and cyst formation, novel promoter elements, and a microRNA system potentially regulating gene expression in both symbiont and coral. We found biochemical complementarity between genomes of S. kawagutii and the anthozoan Acropora, indicative of host-symbiont coevolution, providing a resource for studying the molecular basis and evolution of coral symbiosis. <<<

Leore T Geller, Michal Barzily-Rokni, Tal Danino, Oliver H Jonas, Noam Shental, Deborah Nejman, Nancy Gavert, Yaara Zwang, Zachary A Cooper, Kevin Shee, Christoph A Thaiss, Alexandre Reuben, Jonathan Livny, Roi Avraham, Dennie T Frederick, Matteo Ligorio, Kelly Chatman, Stephen E Johnston, Carrie M Mosher, Alexander Brandis, Garold Fuks, Candice Gurbatri, Vancheswaran Gopalakrishnan, Michael Kim, Mark W Hurd, Matthew Katz, Jason Fleming, Anirban Maitra, David A Smith, Matt Skalak, Jeffrey Bu, Monia Michaud, Sunia A Trauger, Iris Barshack, Talia Golan, Judith Sandbank, Keith T Flaherty, Anna Mandinova, Wendy S Garrett, Sarah P Thayer, Cristina R Ferrone, Curtis Huttenhower, Sangeeta N Bhatia, Dirk Gevers, Jennifer A Wargo, Todd R Golub, Ravid Straussman <<<

Growing evidence suggests that microbes can influence the efficacy of cancer therapies. By studying colon cancer models, we found that bacteria can metabolize the chemotherapeutic drug gemcitabine (2',2'-difluorodeoxycytidine) into its inactive form, 2',2'-difluorodeoxyuridine. Metabolism was dependent on the expression of a long isoform of the bacterial enzyme cytidine deaminase (CDD), seen primarily in Gammaproteobacteria. In a colon cancer mouse model, gemcitabine resistance was induced by intratumor Gammaproteobacteria, dependent on bacterial CDD expression, and abrogated by cotreatment with the antibiotic ciprofloxacin. Gemcitabine is commonly used to treat pancreatic ductal adenocarcinoma (PDAC), and we hypothesized that intratumor bacteria might contribute to drug resistance of these tumors. Consistent with this possibility, we found that of the 113 human PDACs that were tested, 86 (76%) were positive for bacteria, mainly Gammaproteobacteria. <<<

Longlong Si, Huan Xu, Xueying Zhou, Ziwei Zhang, Zhenyu Tian, Yan Wang, Yiming Wu, Bo Zhang, Zhenlan Niu, Chuanling Zhang, Ge Fu, Sulong Xiao, Qing Xia, Lihe Zhang, Demin Zhou <<<

The conversion of life-threatening viruses into live but avirulent vaccines represents a revolution in vaccinology. In a proof-of-principle study, we expanded the genetic code of the genome of influenza A virus via a transgenic cell line containing orthogonal translation machinery. This generated premature termination codon (PTC)-harboring viruses that exerted full infectivity but were replication-incompetent in conventional cells. Genome-wide optimization of the sites for incorporation of multiple PTCs resulted in highly reproductive and genetically stable progeny viruses in transgenic cells. In mouse, ferret, and guinea pig models, vaccination with PTC viruses elicited robust humoral, mucosal, and T cell-mediated immunity against antigenically distinct influenza viruses and even neutralized existing infecting strains. The methods presented here may become a general approach for generating live virus vaccines that can be adapted to almost any virus. <<<