Proceedings of the National Academy of Sciences最新文献

{"title":"Bayesian metamodeling of complex biological systems across varying representations","authors":"Barak Raveh, Liping Sun, K. White, Tanmoy Sanyal, Jeremy O. B. Tempkin, Dongqing Zheng, Kala Bharath, Jitin Singla, Chenxi Wang, Jihui Zhao, Angdi Li, N. Graham, C. Kesselman, R. Stevens, A. Sali","doi":"10.1101/2021.03.29.437574","DOIUrl":"https://doi.org/10.1101/2021.03.29.437574","url":null,"abstract":"Significance Cells are the basic units of life, yet their architecture and function remain to be fully characterized. This work describes Bayesian metamodeling, a modeling approach that divides and conquers a large problem of modeling numerous aspects of the cell into computing a number of smaller models of different types, followed by assembling these models into a complete map of the cell. Metamodeling enables a facile collaboration of multiple research groups and communities, thus maximizing the sharing of expertise, resources, data, and models. A proof of principle is provided by a model of glucose-stimulated insulin secretion produced by the Pancreatic β-Cell Consortium. Comprehensive modeling of a whole cell requires an integration of vast amounts of information on various aspects of the cell and its parts. To divide and conquer this task, we introduce Bayesian metamodeling, a general approach to modeling complex systems by integrating a collection of heterogeneous input models. Each input model can in principle be based on any type of data and can describe a different aspect of the modeled system using any mathematical representation, scale, and level of granularity. These input models are 1) converted to a standardized statistical representation relying on probabilistic graphical models, 2) coupled by modeling their mutual relations with the physical world, and 3) finally harmonized with respect to each other. To illustrate Bayesian metamodeling, we provide a proof-of-principle metamodel of glucose-stimulated insulin secretion by human pancreatic β-cells. The input models include a coarse-grained spatiotemporal simulation of insulin vesicle trafficking, docking, and exocytosis; a molecular network model of glucose-stimulated insulin secretion signaling; a network model of insulin metabolism; a structural model of glucagon-like peptide-1 receptor activation; a linear model of a pancreatic cell population; and ordinary differential equations for systemic postprandial insulin response. Metamodeling benefits from decentralized computing, while often producing a more accurate, precise, and complete model that contextualizes input models as well as resolves conflicting information. We anticipate Bayesian metamodeling will facilitate collaborative science by providing a framework for sharing expertise, resources, data, and models, as exemplified by the Pancreatic β-Cell Consortium.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"62 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86484563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Independent Markov decomposition: Toward modeling kinetics of biomolecular complexes","authors":"Tim Hempel, Mauricio J. del Razo, Christopher T. Lee, Bryn C. Taylor, Rommie E. Amaro, F. Noé","doi":"10.1101/2021.03.24.436806","DOIUrl":"https://doi.org/10.1101/2021.03.24.436806","url":null,"abstract":"Significance Molecular simulations of proteins are often interpreted using Markov state models (MSMs), in which each protein configuration is assigned to a global state. As we explore larger and more complex biological systems, the size of this global state space will face a combinatorial explosion, rendering it impossible to gather sufficient sampling data. In this work, we introduce an approach to decompose a system of interest into separable subsystems. We show that MSMs built for each subsystem can be later coupled to reproduce the behaviors of the global system. To aid in the choice of decomposition we also describe a score to quantify its goodness. This decomposition strategy has the promise to enable robust modeling of complex biomolecular systems. To advance the mission of in silico cell biology, modeling the interactions of large and complex biological systems becomes increasingly relevant. The combination of molecular dynamics (MD) simulations and Markov state models (MSMs) has enabled the construction of simplified models of molecular kinetics on long timescales. Despite its success, this approach is inherently limited by the size of the molecular system. With increasing size of macromolecular complexes, the number of independent or weakly coupled subsystems increases, and the number of global system states increases exponentially, making the sampling of all distinct global states unfeasible. In this work, we present a technique called independent Markov decomposition (IMD) that leverages weak coupling between subsystems to compute a global kinetic model without requiring the sampling of all combinatorial states of subsystems. We give a theoretical basis for IMD and propose an approach for finding and validating such a decomposition. Using empirical few-state MSMs of ion channel models that are well established in electrophysiology, we demonstrate that IMD models can reproduce experimental conductance measurements with a major reduction in sampling compared with a standard MSM approach. We further show how to find the optimal partition of all-atom protein simulations into weakly coupled subunits.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"170 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74881157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tradeoffs for a viral mutant with enhanced replication speed","authors":"Matthew R. Lanahan, R. Maples, J. Pfeiffer","doi":"10.1101/2021.03.24.436823","DOIUrl":"https://doi.org/10.1101/2021.03.24.436823","url":null,"abstract":"Significance Viruses have characteristic replication speeds within a given cell type. Many factors can slow the rate of viral replication, including attenuating mutations and host antiviral responses. However, it has been unclear whether it would be possible to “speed up” a virus that already replicates efficiently in a specific cell type. Here, we selected for a mutant coxsackievirus with enhanced replication speed by sequentially harvesting the very earliest progeny in multiple rounds of selection. A single mutation conferred the fast-replication phenotype. While this mutant virus has enhanced replication in cultured cells due to faster genome uncoating, it was attenuated in mice. These results highlight selective pressures that shape viral populations in different environments. RNA viruses exist as genetically heterogeneous populations due to high mutation rates, and many of these mutations reduce fitness and/or replication speed. However, it is unknown whether mutations can increase replication speed of a virus already well adapted to replication in cultured cells. By sequentially passaging coxsackievirus B3 in cultured cells and collecting the very earliest progeny, we selected for increased replication speed. We found that a single mutation in a viral capsid protein, VP1-F106L, was sufficient for the fast-replication phenotype. Characterization of this mutant revealed quicker genome release during entry compared to wild-type virus, highlighting a previously unappreciated infection barrier. However, this mutation also reduced capsid stability in vitro and reduced replication and pathogenesis in mice. These results reveal a tradeoff between overall replication speed and fitness. Importantly, this approach—selecting for the earliest viral progeny—could be applied to a variety of viral systems and has the potential to reveal unanticipated inefficiencies in viral replication cycles.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86886070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The radish Ogura fertility restorer impedes translation elongation along its cognate CMS-causing mRNA","authors":"Chuande Wang, L. Lezhneva, N. Arnal, Martine Quadrado, H. Mireau","doi":"10.1101/2021.03.17.435859","DOIUrl":"https://doi.org/10.1101/2021.03.17.435859","url":null,"abstract":"Significance Nucleo-cytoplasmic male sterilities (CMS) are two-component genetic systems in which mitochondria-encoded male sterility transcripts are controlled through the action of nuclear-encoded restorer-of-fertility proteins. Fertility restorers most often impact the accumulation of CMS transcripts. In this analysis, we demonstrate that fertility restoration in the Ogura system from radish operates through a specific blockade of ribosome progression along the orf138 CMS transcript. Our analysis reveals that CMS transcripts can be controlled at the translational level, a discovery that will be instrumental to produce custom synthetic fertility restorers. The control of messenger RNA (mRNA) translation has been increasingly recognized as a key regulatory step for gene control, but clear examples in eukaryotes are still scarce. Nucleo-cytoplasmic male sterilities (CMS) represent ideal genetic models to dissect genetic interactions between the mitochondria and the nucleus in plants. This trait is determined by specific mitochondrial genes and is associated with a pollen sterility phenotype that can be suppressed by nuclear genes known as restorer-of-fertility (Rf). In this study, we focused on the Ogura CMS system in rapeseed and showed that reversion to male sterility by the PPR-B fertility restorer (also called Rfo) occurs through a specific translation inhibition of the mitochondria-encoded CMS-causing mRNA orf138. We also demonstrate that PPR-B binds within the coding sequence of orf138 and acts as a ribosome blocker to specifically impede translation elongation along the orf138 mRNA. Rfo is the first recognized fertility restorer shown to act this way. These observations will certainly facilitate the development of synthetic fertility restorers for CMS systems in which efficient natural Rfs are lacking.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74908554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome-wide screen identifies curli amyloid fibril as a bacterial component promoting host neurodegeneration","authors":"Chenyin Wang, C. Lau, Fuqiang Ma, C. Zheng","doi":"10.1101/2021.03.22.436366","DOIUrl":"https://doi.org/10.1101/2021.03.22.436366","url":null,"abstract":"Significance We investigate microbe–host interaction in the context of neurodegeneration by screening for Escherichia coli genes whose deletion alleviates Parkinson’s disease symptoms in the nematode Caenorhabditis elegans overexpressing human α-synuclein (α-syn, A53T). The screen yields 38 E. coli genes that promote neurodegeneration. Two of these genes, csgA and csgB, code for proteins that form curli, one type of bacterial amyloid fibers. Curli cross-seeds and colocalizes with α-syn both in C. elegans neurons and human neuroblastoma cells. Curli-induced α-syn aggregations down-regulate mitochondrial genes, causing energy failure in neurons. Moreover, we found that curli may have general effects in promoting neuropathologies induced by different aggregation-prone proteins, such as A-β in Alzheimer’s disease, Huntingtin in Huntington’s disease, and SOD1 in amyotrophic lateral sclerosis. Growing evidence indicates that gut microbiota play a critical role in regulating the progression of neurodegenerative diseases such as Parkinson’s disease. The molecular mechanism underlying such microbe–host interaction is unclear. In this study, by feeding Caenorhabditis elegans expressing human α-syn with Escherichia coli knockout mutants, we conducted a genome-wide screen to identify bacterial genes that promote host neurodegeneration. The screen yielded 38 genes that fall into several genetic pathways including curli formation, lipopolysaccharide assembly, and adenosylcobalamin synthesis among others. We then focused on the curli amyloid fibril and found that genetically deleting or pharmacologically inhibiting the curli major subunit CsgA in E. coli reduced α-syn–induced neuronal death, restored mitochondrial health, and improved neuronal functions. CsgA secreted by the bacteria colocalized with α-syn inside neurons and promoted α-syn aggregation through cross-seeding. Similarly, curli also promoted neurodegeneration in C. elegans models of Alzheimer’s disease, amyotrophic lateral sclerosis, and Huntington’s disease and in human neuroblastoma cells.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77899756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tardigrades exhibit robust interlimb coordination across walking speeds and terrains","authors":"Jasmine A. Nirody, Lisset A. Duran, D. Johnston, D. Cohen","doi":"10.1101/2021.03.19.436228","DOIUrl":"https://doi.org/10.1101/2021.03.19.436228","url":null,"abstract":"Significance As perhaps the smallest legged animal and one of the only known soft-bodied walkers, tardigrades possess a uniquely versatile set of locomotor tools. Tardigrades have evolved to move through a vast array of environments—freshwater, marine, and terrestrial—using a strongly conserved body plan. We characterize tardigrade interleg coordination patterns using high-speed video of animals walking on gel substrates. Tardigrades utilize a tetrapod-like stepping pattern remarkably similar to that observed in insects, despite significant disparities in size and skeletal structure between the two groups. We find that tardigrades adapt their locomotion to a “galloping” coordination pattern when walking on softer substrates. This strategy has also been observed in arthropods to move efficiently on flowing or granular substrates. Tardigrades must negotiate heterogeneous, fluctuating environments and accordingly utilize locomotive strategies capable of dealing with variable terrain. We analyze the kinematics and interleg coordination of freely walking tardigrades (species: Hypsibius exemplaris). We find that tardigrade walking replicates several key features of walking in insects despite disparities in size, skeleton, and habitat. To test the effect of environmental changes on tardigrade locomotor control circuits we measure kinematics and interleg coordination during walking on two substrates of different stiffnesses. We find that the phase offset between contralateral leg pairs is flexible, while ipsilateral coordination is preserved across environmental conditions. This mirrors similar results in insects and crustaceans. We propose that these functional similarities in walking coordination between tardigrades and arthropods is either due to a generalized locomotor control circuit common to panarthropods or to independent convergence onto an optimal strategy for robust multilegged control in small animals with simple circuitry. Our results highlight the value of tardigrades as a comparative system toward understanding the mechanisms—neural and/or mechanical—underlying coordination in panarthropod locomotion.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74029609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Representation learning of RNA velocity reveals robust cell transitions","authors":"Chen Qiao, Yuanhua Huang","doi":"10.1101/2021.03.19.436127","DOIUrl":"https://doi.org/10.1101/2021.03.19.436127","url":null,"abstract":"Significance The recently introduced RNA velocity methods, by leveraging the intrinsic RNA splicing process, have shown their unique capability of identifying the directionality of the cell differentiation trajectory. However, due to the minimal amount of unspliced RNA contents, the estimation of RNA velocity suffers from high noise and may result in less reliable trajectories. Here, we present Velocity Autoencoder (VeloAE), a tailored autoencoder to denoise RNA velocity for more accurate quantification of cell transitions. Through various biological systems, we demonstrate its effectiveness for correcting the inferred trajectory and its interpretability for linking the learned dimensions to underlying biological processes. RNA velocity is a promising technique for quantifying cellular transitions from single-cell transcriptome experiments and revealing transient cellular dynamics among a heterogeneous cell population. However, the cell transitions estimated from high-dimensional RNA velocity are often unstable or inaccurate, partly due to the high technical noise and less informative projection. Here, we present Velocity Autoencoder (VeloAE), a tailored representation learning method, to learn a low-dimensional representation of RNA velocity on which cellular transitions can be robustly estimated. On various experimental datasets, we show that VeloAE can both accurately identify stimulation dynamics in time-series designs and effectively capture expected cellular differentiation in different biological systems. VeloAE, therefore, enhances the usefulness of RNA velocity for studying a wide range of biological processes.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78158748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electrochemical borylation of carboxylic acids","authors":"Lisa M Barton, Longrui Chen, D. Blackmond, P. Baran","doi":"10.26434/CHEMRXIV.14210963.V1","DOIUrl":"https://doi.org/10.26434/CHEMRXIV.14210963.V1","url":null,"abstract":"Significance Boronic acids are one of the most useful functional groups in organic chemistry and can be used as intermediates in synthesis or as key motifs in medicines. This work describes an extremely simple and economical way to use electrochemistry to convert carboxylic acids, through the intermediacy of redox-active esters, to boronic acids. The scope of this reaction is broad, the mechanism has been thoroughly studied, and it can be easily scaled up. Finally, application to the synthesis of a complex polycyclopropane natural product is demonstrated. A simple electrochemically mediated method for the conversion of alkyl carboxylic acids to their borylated congeners is presented. This protocol features an undivided cell setup with inexpensive carbon-based electrodes and exhibits a broad substrate scope and scalability in both flow and batch reactors. The use of this method in challenging contexts is exemplified with a modular formal synthesis of jawsamycin, a natural product harboring five cyclopropane rings.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81697369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An integrative transcriptional logic model of hepatic insulin resistance","authors":"T. Kitamoto, T. Kuo, A. Okabe, Atsushi Kaneda, D. Accili","doi":"10.1101/2021.03.15.435438","DOIUrl":"https://doi.org/10.1101/2021.03.15.435438","url":null,"abstract":"Significance The liver is a source of excess lipid, atherogenic lipoproteins, and glucose in patients with type 2 diabetes. These factors predispose to micro- and macrovascular complications. The underlying pathophysiology is not well understood, and mechanistic insight into it may provide better tools to prevent, treat, and reverse the disease. Here, we propose an alternative explanation for this pathophysiologic conundrum by illustrating a transcriptional “logic” underlying the regulation of different classes of genes. These findings can be interpreted to provide an integrated stepwise model for the coexistence of lipid and glucose abnormalities in hepatic insulin resistance. Abnormalities of lipid/lipoprotein and glucose metabolism are hallmarks of hepatic insulin resistance in type 2 diabetes. The former antedate the latter, but the latter become progressively refractory to treatment and contribute to therapeutic failures. It’s unclear whether the two processes share a common pathogenesis and what underlies their progressive nature. In this study, we investigated the hypothesis that genes in the lipid/lipoprotein pathway and those in the glucose metabolic pathway are governed by different transcriptional regulatory logics that affect their response to physiologic (fasting/refeeding) as well as pathophysiologic cues (insulin resistance and hyperglycemia). To this end, we obtained genomic and transcriptomic maps of the key insulin-regulated transcription factor, FoxO1, and integrated them with those of CREB, PPAR-α, and glucocorticoid receptor. We found that glucose metabolic genes are primarily regulated by promoter and intergenic enhancers in a fasting-dependent manner, while lipid genes are regulated through fasting-dependent intron enhancers and fasting-independent enhancerless introns. Glucose genes also showed a remarkable transcriptional resiliency (i.e., the ability to compensate following constitutive FoxO1 ablation through an enrichment of active marks at shared PPAR-α/FoxO1 regulatory elements). Unexpectedly, insulin resistance and hyperglycemia were associated with a “spreading” of FoxO1 binding to enhancers and the emergence of unique target sites. We surmise that this unusual pattern correlates with the progressively intractable nature of hepatic insulin resistance. This transcriptional logic provides an integrated model to interpret the combined lipid and glucose abnormalities of type 2 diabetes.","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85609694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leslie Ungerleider, 1946–2020: Who, what, and where","authors":"D. V. Van Essen, S. Kastner, P. Bandettini","doi":"10.1073/pnas.2102784118","DOIUrl":"https://doi.org/10.1073/pnas.2102784118","url":null,"abstract":"Leslie Ungerleider, a pioneering neuroscientist who profoundly shaped our understanding of the visual system, died unexpectedly but peacefully at her home on December 11, 2020, at the age of 74. She was the Chief of the Laboratory of Brain and Cognition at the National Institute of Mental Health and an NIH Distinguished Investigator. Despite struggling with health issues in recent years, she remained vibrant and fully engaged in science until her abrupt passing, leaving many colleagues, collaborators, and mentees in shock. Leslie’s intellectual legacy runs both deep and broad, as she made major contributions to our understanding of the functional organization of the visual cortex in humans and nonhuman primates using a combination of neuroanatomical, neurophysiological, neuroimaging, and behavioral methods. Leslie is best known for demonstrating that the primate visual cortex contains separate neural systems for perceiving “what” things are and “where” they are located. Leslie was an ardent supporter of women in neuroscience and was a highly inspirational role model, starting at a time when there were far fewer female senior neuroscientists than in the present day. In her many leadership positions across multiple scientific organizations, she was a passionate advocate for women. More broadly, the depth to which she influenced those she mentored, collaborated, or interacted closely with revealed itself in the outpouring of sentiment in the days immediately following her passing (1). Leslie was not only a brilliant and influential scientist, but equally notably, she deeply cared about all of her laboratory members as well as the community, and was gifted in communicating at all levels. She fully engaged with whomever she was talking with and suffered the details to get all aspects of doing science right, from the experimental design to the final write-up. While kind, Leslie was also blunt, direct, and honest. Under her mentorship, her laboratory members thrived. Leslie received her undergraduate degree in psychology from Harper College (later renamed the State University of New York) in Binghamton, New York. Intrigued by animal behavior, she entered graduate school at New York University and in 1970 received a doctorate in experimental psychology by studying hypothalamic stimulation effects on rat behavior; her first peer-reviewed publication was in Science (2). After a brief period at the University of Oklahoma, Leslie joined the laboratory of Karl Pribram at Stanford in order to study the effects of brain lesions on visual perception in macaque monkeys. Mortimer Mishkin, a leading neuroscientist at the NIH, having heard Leslie talk about her work at the 1974 Society for Neuroscience meeting, initiated a conversation with her to discuss seemingly conflicting findings from his own laboratory, then invited her to the NIH to “sort things Leslie Ungerleider. Image credit: Michael Beauchamp (Perelman School of Medicine at the University of Pennsylvania","PeriodicalId":20595,"journal":{"name":"Proceedings of the National Academy of Sciences","volume":"56 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84697526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}