A DR4:tBID axis drives the p53 apoptotic response by promoting oligomerization of poised BAX

The cellular response to p53 activation varies greatly in a stimulus‐ and cell type‐specific manner. Dissecting the molecular mechanisms defining these cell fate choices will assist the development of effective p53‐based cancer therapies and also illuminate fundamental processes by which gene networks control cellular behaviour. Using an experimental system wherein stimulus‐specific p53 responses are elicited by non‐genotoxic versus genotoxic agents, we discovered a novel mechanism that determines whether cells undergo proliferation arrest or cell death. Strikingly, we observe that key mediators of cell‐cycle arrest (p21, 14‐3‐3σ) and apoptosis (PUMA, BAX) are equally activated regardless of outcome. In fact, arresting cells display strong translocation of PUMA and BAX to the mitochondria, yet fail to release cytochrome C or activate caspases. Surprisingly, the key differential events in apoptotic cells are p53‐dependent activation of the DR4 death receptor pathway, caspase 8‐mediated cleavage of BID, and BID‐dependent activation of poised BAX at the mitochondria. These results reveal a previously unappreciated role for DR4 and the extrinsic apoptotic pathway in cell fate choice following p53 activation.Fil: Henry, Ryan E. State University Of Colorado-boulder; Estados UnidosFil: Andrysik, Zdenek. State University Of Colorado-boulder; Estados UnidosFil: Paris, Ramiro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Mar del Plata. Instituto de Investigaciones Biológicas; Argentina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Biológicas; Argentina. State University Of Colorado-boulder; Estados UnidosFil: Galbraith, Matthew D.. State University Of Colorado-boulder; Estados UnidosFil: Espinosa, Joaquín M.. State University Of Colorado-boulder; Estados Unido

Long-term ocean and resource dynamics in a hotspot of climate change

Unidad de excelencia María de Maeztu CEX2019-000940-MThe abundance, distribution, and size of marine species are linked to temperature and nutrient regimes and are profoundly affected by humans through exploitation and climate change. Yet little is known about long-term historical links between ocean environmental changes and resource abundance to provide context for current and potential future trends and inform conservation and management. We synthesize >4000 years of climate and marine ecosystem dynamics in a Northwest Atlantic region currently undergoing rapid changes, the Gulf of Maine and Scotian Shelf. This period spans the late Holocene cooling and recent warming and includes both Indigenous and European influence. We compare environmental records from instrumental, sedimentary, coral, and mollusk archives with ecological records from fossils, archaeological, historical, and modern data, and integrate future model projections of environmental and ecosystem changes. This multidisciplinary synthesis provides insight into multiple reference points and shifting baselines of environmental and ecosystem conditions, and projects a near-future departure from natural climate variability in 2028 for the Scotian Shelf and 2034 for the Gulf of Maine. Our work helps advancing integrative end-to-end modeling to improve the predictive capacity of ecosystem forecasts with climate change. Our results can be used to adjust marine conservation strategies and network planning and adapt ecosystem-based management with climate change

Genomic evidence supports a clonal diaspora model for metastases of esophageal adenocarcinoma.

The poor outcomes in esophageal adenocarcinoma (EAC) prompted us to interrogate the pattern and timing of metastatic spread. Whole-genome sequencing and phylogenetic analysis of 388 samples across 18 individuals with EAC showed, in 90% of patients, that multiple subclones from the primary tumor spread very rapidly from the primary site to form multiple metastases, including lymph nodes and distant tissues-a mode of dissemination that we term 'clonal diaspora'. Metastatic subclones at autopsy were present in tissue and blood samples from earlier time points. These findings have implications for our understanding and clinical evaluation of EAC.MRC core grant (RG84369), an NIHR Research Professorship (RG67258) and Cancer Research UK (RG66287)

The environmental setting of Epipalaeolithic aggregation site Kharaneh IV

The archaeological site of Kharaneh IV in Jordan's Azraq Basin, and its relatively near neighbour Jilat 6 show evidence of sustained occupation of substantial size through the Early to Middle Epipalaeolithic (c. 24,000 - 15,000 cal BP). Here we review the geomorphological evidence for the environmental setting in which Kharaneh IV was established. The on-site stratigraphy is clearly differentiated from surrounding sediments, marked visually as well as by higher magnetic susceptibility values. Dating and analysis of off-site sediments show that a significant wetland existed at the site prior to and during early site occupation (~ 23,000 - 19,000 BP). This may explain why such a substantial site existed at this location. This wetland dating to the Last Glacial Maximum also provides important information on the palaeoenvironments and potential palaeoclimatic scenarios for today's eastern Jordanian desert, from where such evidence is scarce

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 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

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

Neuromatch Academy: Teaching Computational Neuroscience with global accessibility

Neuromatch Academy designed and ran a fully online 3-week Computational Neuroscience summer school for 1757 students with 191 teaching assistants working in virtual inverted (or flipped) classrooms and on small group projects. Fourteen languages, active community management, and low cost allowed for an unprecedented level of inclusivity and universal accessibility.Comment: 10 pages, 3 figures. Equal contribution by the executive committee members of Neuromatch Academy: Tara van Viegen, Athena Akrami, Kate Bonnen, Eric DeWitt, Alexandre Hyafil, Helena Ledmyr, Grace W. Lindsay, Patrick Mineault, John D. Murray, Xaq Pitkow, Aina Puce, Madineh Sedigh-Sarvestani, Carsen Stringer. and equal contribution by the board of directors of Neuromatch Academy: Gunnar Blohm, Konrad Kording, Paul Schrater, Brad Wyble, Sean Escola, Megan A. K. Peter