Synovial sarcoma (SS) is defined by the hallmark SS18-SSX fusion oncoprotein, which renders BAF complexes aberrant in two manners: gain of SSX to the SS18 subunit and concomitant loss of BAF47 subunit assembly. Here we demonstrate that SS18-SSX globally hijacks BAF complexes on chromatin to activate an SS transcriptional signature that we define using primary tumors and cell lines. Specifically, SS18-SSX retargets BAF complexes from enhancers to broad polycomb domains to oppose PRC2-mediated repression and activate bivalent genes. Upon suppression of SS18-SSX, reassembly of BAF47 restores enhancer activation, but is not required for proliferative arrest. These results establish a global hijacking mechanism for SS18-SSX on chromatin, and define the distinct contributions of two concurrent BAF complex perturbations.

Introduction: Malignant pleural mesothelioma is a disease primarily associated with exposure to the carcinogen asbestos. Whereas other carcinogen-related tumors are associated with a high tumor mutation burden, mesothelioma is not. We sought to resolve this discrepancy. Methods: We used mate-pair (n ¼ 22), RNA (n ¼ 28), and T cell receptor sequencing along with in silico predictions and immunologic assays to understand how structural variants of chromosomes affect the transcriptome. Results: We observed that inter-or intrachromosomal rearrangements were present in every specimen and were frequently in a pattern of chromoanagenesis such as chromoplexy or chromothripsis. Transcription of rearrangementrelated junctions was predicted to result in many potential neoantigens, some of which were proven to bind patient-specific major histocompatibility complex molecules and to expand intratumoral T cell clones. T cells responsive to these predicted neoantigens were also present in a patient's circulating T cell repertoire. Analysis of genomic array data from the mesothelioma cohort in The Cancer Genome Atlas suggested that multiple chromothriptic-like events negatively impact survival. Conclusions: Our findings represent the discovery of potential neoantigen expression driven by structural chromosomal rearrangements. These results may have implications for the development of novel immunotherapeutic strategies and the selection of patients to receive immunotherapies.

The COVID-19 pandemic demands assimilation of all biomedical knowledge to decode mechanisms of pathogenesis. Despite the recent renaissance in neural networks, a platform for the real-time synthesis of the exponentially growing biomedical literature and deep omics insights is unavailable. Here, we present the nferX platform for dynamic inference from over 45 quadrillion possible conceptual associations from unstructured text, and triangulation with insights from single-cell RNA-sequencing, bulk RNA-seq and proteomics from diverse tissue types. A hypothesis-free profiling of ACE2 suggests tongue keratinocytes, olfactory epithelial cells, airway club cells and respiratory ciliated cells as potential reservoirs of the SARS-CoV-2 receptor. We find the gut as the putative hotspot of COVID-19, where a maturation correlated transcriptional signature is shared in small intestine enterocytes among coronavirus receptors (ACE2, DPP4, ANPEP). A holistic data science platform triangulating insights from structured and unstructured data holds potential for accelerating the generation of impactful biological insights and hypotheses.

SUMMARYA long-standing concept in vision science has held that a single photoreceptor expresses a single type of opsin, the protein component of visual pigment. However, the number of examples in the literature of photoreceptors from vertebrates and invertebrates that break this rule is increasing. Here, we describe a newly discovered Limulus opsin, Limulus opsin5, which is significantly different from previously characterized Limulus opsins, opsins1 and 2. We show that opsin5 is co-expressed with opsins1 and 2 in Limulus lateral and ventral eye photoreceptors and provide the first evidence that the expression of coexpressed opsins can be differentially regulated. We show that the relative levels of opsin5 and opsin1 and 2 in the rhabdom change with a diurnal rhythm and that their relative levels are also influenced by the animal's central circadian clock. An analysis of the sequence of opsin5 suggests it is sensitive to visible light (400-700nm) but that its spectral properties may be different from that of opsins1 and 2. Changes in the relative levels of these opsins may underlie some of the dramatic day-night changes in Limulus photoreceptor function and may produce a diurnal change in their spectral sensitivity. Supplementary material available online at

When faced with proteotoxic stress, cells mount adaptive responses to eliminate aberrant proteins. Adaptive responses increase the expression of protein folding and degradation factors to enhance the cellular quality control machinery. However, it is unclear whether and how this augmented machinery acquires new activities during stress. Here, we uncover a regulatory cascade in budding yeast that consists of the hydrophilin protein Roq1/Yjl144w, the HtrA-type protease Ynm3/Nma111, and the ubiquitin ligase Ubr1. Various stresses stimulate ROQ1 transcription. The Roq1 protein is cleaved by Ynm3. Cleaved Roq1 interacts with Ubr1, transforming its substrate specificity. Altered substrate recognition by Ubr1 accelerates proteasomal degradation of misfolded as well as native proteins at the endoplasmic reticulum membrane and in the cytosol. We term this pathway stress-induced homeostatically regulated protein degradation (SHRED) and propose that it promotes physiological adaptation by reprogramming a key component of the quality control machinery.

The COVID-19 pandemic demands assimilation of all available biomedical knowledge to decode its mechanisms of pathogenicity and transmission. Despite the recent renaissance in unsupervised neural networks for decoding unstructured natural languages, a platform for the real-time synthesis of the exponentially growing biomedical literature and its comprehensive triangulation with deep omic insights is not available. Here, we present the nferX platform for dynamic inference from over 45 quadrillion possible conceptual associations extracted from unstructured biomedical text, and their triangulation with Single Cell RNA-sequencing based insights from over 25 tissues. Using this platform, we identify intersections between the pathologic manifestations of COVID-19 and the comprehensive expression profile of the SARS-CoV-2 receptor ACE2. We find that tongue keratinocytes, airway club cells, and ciliated cells are likely underappreciated targets of SARS-CoV-2 infection, in addition to type II pneumocytes and olfactory epithelial cells. We further identify mature small intestinal enterocytes as a possible hotspot of COVID-19 fecal-oral transmission, where an intriguing maturation-correlated transcriptional signature is shared between ACE2 and the other coronavirus receptors DPP4 (MERS-CoV) and ANPEP (ɑ-coronavirus). This study demonstrates how a holistic data science platform can leverage unprecedented quantities of structured and unstructured publicly available data to accelerate the generation of impactful biological insights and hypotheses.The nferX Platform Single-cell resource -https://academia.nferx.com/

actual: 152 words)The recent explosion of biomedical knowledge presents both a major opportunity and challenge for scientists tackling complex problems in healthcare. Here we present an approach for synthesizing biomedical knowledge based on a combination of word-embeddings and select cooccurrences. We evaluated our ability to recapitulate and retrospectively predict disease-gene associations from the Online Mendelian Inheritance in Man (OMIM) resource. Our metrics achieved an area under the curve (AUC) value of 0.981 at the recapitulation task for 2,400 disease-gene associations. At the most stringent cutoff, our metrics predicted 13.89% of these associations before their first cooccurrence in the literature, with a median time of 4 years between prediction and first cooccurrence. Finally, our literature metrics can be combined with human genetics data to retrospectively predict disease-gene associations, IL-6 and Giant Cell Arteritis provided as an example. We believe this framework can provide robust biomedical hypotheses at a much faster pace than current standard practices.

Members of the calbindin subfamily serve as markers of subpopulations of neurons within the vertebrate nervous system. Although markers of these proteins are widely available and used, their application to invertebrate nervous systems has been very limited. In this study we investigated the presence and distribution of members of the calbindin subfamily in the sea cucumber Holothuria glaberrima (Selenka, 1867). Immunohistological experiments with antibodies made against rat calbindin 1, parvalbumin, and calbindin 2, showed that these antibodies labeled cells and fibers within the nervous system of H. glaberrima. Most of the cells and fibers were co-labeled with the neural-specific marker RN1, showing their neural specificity. These were distributed throughout all of the nervous structures, including the connective tissue plexi of the body wall and podia. Bioinformatics analyses of the possible antigen recognized by these markers showed that a calbindin 2-like protein present in the sea urchin Strongylocentrotus purpuratus, corresponded to the calbindin-D32k previously identified in other invertebrates. Western blots with anti-calbindin 1 and anti-parvalbumin showed that these markers recognized an antigen of approximately 32 kDa in homogenates of radial nerve cords of H. glaberrima and Lytechinus variegatus. Furthermore, immunoreactivity with anti-calbindin 1 and anti-parvalbumin was obtained to a fragment of calbindin-D32k of H. glaberrima. Our findings suggest that calbindin-D32k is present in invertebrates and its sequence is more similar to the vertebrate calbindin 2 than to calbindin 1. Thus, characterization of calbindin-D32k in echinoderms provides an important view of the evolution of this protein family and represents a valuable marker to study the nervous system of invertebrates.