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A Genetically Defined Compartmentalized Striatal Direct Pathway for Negative Reinforcement
No full textThe striosome compartment within the dorsal striatum has been implicated in reinforcement learning and regulation of motivation, but how striosomal neurons contribute to these functions remains elusive. Here, we show that a genetically identified striosomal population, which expresses the Teashirt family zinc finger 1 (Tshz1) and belongs to the direct pathway, drives negative reinforcement and is essential for aversive learning in mice. Contrasting a "conventional" striosomal direct pathway, the Tshz1 neurons cause aversion, movement suppression, and negative reinforcement once activated, and they receive a distinct set of synaptic inputs. These neurons are predominantly excited by punishment rather than reward and represent the anticipation of punishment or the motivation for avoidance. Furthermore, inhibiting these neurons impairs punishment-based learning without affecting reward learning or movement. These results establish a major role of striosomal neurons in behaviors reinforced by punishment and moreover uncover functions of the direct pathway unaccounted for in classic models
Sensory Experience Engages Microglia to Shape Neural Connectivity through a Non-Phagocytic Mechanism.
No full textSensory experience remodels neural circuits in the early postnatal brain through mechanisms that remain to be elucidated. Applying a new method of ultrastructural analysis to the retinogeniculate circuit, we find that visual experience alters the number and structure of synapses between the retina and the thalamus. These changes require vision-dependent transcription of the receptor Fn14 in thalamic relay neurons and the induction of its ligand TWEAK in microglia. Fn14 functions to increase the number of bulbous spine-associated synapses at retinogeniculate connections, likely contributing to the strengthening of the circuit that occurs in response to visual experience. However, at retinogeniculate connections near TWEAK-expressing microglia, TWEAK signals via Fn14 to restrict the number of bulbous spines on relay neurons, leading to the elimination of a subset of connections. Thus, TWEAK and Fn14 represent an intercellular signaling axis through which microglia shape retinogeniculate connectivity in response to sensory experience
Current status of the multinational Arabidopsis community
Get PDFThe multinational Arabidopsis research community is highly collaborative and over the past thirty years these activities have been documented by the Multinational Arabidopsis Steering Committee (MASC). Here, we (a) highlight recent research advances made with the reference plant Arabidopsis thaliana; (b) provide summaries from recent reports submitted by MASC subcommittees, projects and resources associated with MASC and from MASC country representatives; and (c) initiate a call for ideas and foci for the “fourth decadal roadmap,” which will advise and coordinate the global activities of the Arabidopsis research community
Unraveling molecular mechanisms of immunity and cancer-resistance using the genomes of the Neotropical bats Artibeus jamaicensis and Pteronotus mesoamericanus
Get PDFBats are exceptional among mammals for harbouring diverse pathogens and for their robust immune systems. In addition, bats are unusually long-lived and show low rates of cancer. Contiguous and complete reference genomes are needed to determine the genetic basis of these adaptations and establish bats as models for research into mammalian health. Here we sequenced and analysed the genomes of the Jamaican fruit bat ( Artibeus jamaicensis ) and the Mesoamerican mustached bat ( Pteronotus mesoamericanus ). We sequenced these two species using a mix of Illumina and Oxford Nanopore Technologies (ONT), assembling draft genomes with some of the highest contig N50s (28-29Mb) of bat genomes to date. Work is in progress to increase the base-level accuracies of these genomes. We conducted gene annotation and identified a set of 10,928 orthologs from bats and mammalian outgroups including humans, rodents, horses, pigs, and dogs. To detect positively selected genes as well as lineage-specific gene gains and losses, we carried out comprehensive branch-site likelihood ratio tests and gene family size analyses. Our analysis found signatures of rapid evolution in the innate immune response genes of bats, and evidence of past infections with diverse viral clades in Artibeus jamaicensis and Pteronotus mesoamericanus . We additionally found evidence of positive selection of tumor suppressors, which may play a role in the low cancer rates, in the most recent common ancestor of bats. These new genomic resources enable insights into the extraordinary adaptations of bats, with implications for mammalian evolutionary studies and public health
Heterogeneity and chimerism of endothelial cells revealed by single-cell transcriptome in orthotopic liver tumors.
Get PDFThe liver is a common host organ for cancer, either through lesions that arise in liver epithelial cells [e.g., hepatocellular carcinoma (HCC)] or as a site of metastasis by tumors arising in other organs (e.g., colorectal cancer). However, the changes that occur in liver stromal cells in response to cancer have not been fully characterized, nor has it been determined whether the different sources of liver cancer induce distinct stromal changes. Here, we performed single-cell profiling of liver stromal cells from mouse models of induced spontaneous liver cancer or implanted colorectal liver metastases, with a focus on tumor endothelial cells (ECs). While ECs in liver tissue adjacent to cancerous lesions (so-called adjacent normal) corresponded to liver zonation phenotypes, their transcriptomes were also clearly altered by the presence of a tumor. In comparison, tumor EC transcriptomes show stronger similarities to venous than sinusoidal ECs. Further, tumor ECs, independent of tumor origin, formed distinct clusters displaying conserved "tip-like" or "stalk-like" characteristics, similar to ECs from subcutaneous tumors. However, they also carried liver-specific signatures found in normal liver ECs, suggesting an influence of the host organ on tumor ECs. Our results document gene expression signatures in ECs in liver cancer and show that the host organ, and not the site of tumor origin (liver versus colorectal), is a primary determinant of EC phenotype. In addition, primarily in tumors, we further defined a cluster of chimeric cells that expressed both myeloid and endothelial cell markers and might play a role in tumor angiogenesis
Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies.
No full textAntibodies targeting the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) present a promising approach to combat the coronavirus disease 2019 (COVID-19) pandemic; however, concerns remain that mutations can yield antibody resistance. We investigated the development of resistance against four antibodies to the spike protein that potently neutralize SARS-CoV-2, individually as well as when combined into cocktails. These antibodies remain effective against spike variants that have arisen in the human population. However, novel spike mutants rapidly appeared after in vitro passaging in the presence of individual antibodies, resulting in loss of neutralization; such escape also occurred with combinations of antibodies binding diverse but overlapping regions of the spike protein. Escape mutants were not generated after treatment with a noncompeting antibody cocktail
Absence of central tolerance in Aire-deficient mice synergizes with immune-checkpoint inhibition to enhance antitumor responses.
Get PDFThe endogenous anti-tumor responses are limited in part by the absence of tumor-reactive T cells, an inevitable consequence of thymic central tolerance mechanisms ensuring prevention of autoimmunity. Here we show that tumor rejection induced by immune checkpoint blockade is significantly enhanced in Aire-deficient mice, the epitome of central tolerance breakdown. The observed synergy in tumor rejection extended to different tumor models, was accompanied by increased numbers of activated T cells expressing high levels of Gzma, Gzmb, Perforin, Cxcr3, and increased intratumoural levels of Cxcl9 and Cxcl10 compared to wild-type mice. Consistent with Aire's central role in T cell repertoire selection, single cell TCR sequencing unveiled expansion of several clones with high tumor reactivity. The data suggest that breakdown in central tolerance synergizes with immune checkpoint blockade in enhancing anti-tumor immunity and may serve as a model to unmask novel anti-tumor therapies including anti-tumor TCRs, normally purged during central tolerance
Deep learning for inferring transcription factor binding sites
Get PDFDeep learning is a powerful tool for predicting transcription factor binding sites from DNA sequence. Despite their high predictive accuracy, there are no guarantees that a high-performing deep learning model will learn causal sequence-function relationships. Thus, a move beyond performance comparisons on benchmark data sets is needed. Interpreting model predictions is a powerful approach to identify which features drive performance gains and ideally provide insight into the underlying biological mechanisms. Here, we highlight timely advances in deep learning for genomics, with a focus on inferring transcription factor binding sites. We describe recent applications, model architectures, and advances in ‘local’ and ‘global’ model interpretability methods and then conclude with a discussion on future research directions
WASP family proteins regulate the mobility of the B cell receptor during signaling activation.
Get PDFRegulation of membrane receptor mobility tunes cellular response to external signals, such as in binding of B cell receptors (BCR) to antigen, which initiates signaling. However, whether BCR signaling is regulated by BCR mobility, and what factors mediate this regulation, are not well understood. Here we use single molecule imaging to examine BCR movement during signaling activation and a novel machine learning method to classify BCR trajectories into distinct diffusive states. Inhibition of actin dynamics downstream of the actin nucleating factors, Arp2/3 and formin, decreases BCR mobility. Constitutive loss or acute inhibition of the Arp2/3 regulator, N-WASP, which is associated with enhanced signaling, increases the proportion of BCR trajectories with lower diffusivity. Furthermore, loss of N-WASP reduces the diffusivity of CD19, a stimulatory co-receptor, but not that of FcγRIIB, an inhibitory co-receptor. Our results implicate a dynamic actin network in fine-tuning receptor mobility and receptor-ligand interactions for modulating B cell signaling