A Fast and Flexible Algorithm for Solving the Lasso in Large-scale and Ultrahigh-dimensional Problems, bioRxiv, 2019-05-07
AbstractSince its first proposal in statistics (Tibshirani, 1996), the lasso has been an effective method for simultaneous variable selection and estimation. A number of packages have been developed to solve the lasso efficiently. However as large datasets become more prevalent, many algorithms are constrained by efficiency or memory bounds. In this paper, we propose a meta algorithm batch screening iterative lasso (BASIL) that can take advantage of any existing lasso solver and build a scalable lasso solution for large datasets. We also introduce snpnet, an R package that implements the proposed algorithm on top of glmnet (Friedman et al., 2010a) for large-scale single nucleotide polymorphism (SNP) datasets that are widely studied in genetics. We demonstrate results on a large genotype-phenotype dataset from the UK Biobank, where we achieve state-of-the-art heritability estimation on quantitative and qualitative traits including height, body mass index, asthma and high cholesterol.
biorxiv bioinformatics 0-100-users 2019Defined cell types in superior colliculus make distinct contributions to prey capture behavior in the mouse, bioRxiv, 2019-05-04
SummaryThe superior colliculus (SC) mediates rapid orienting to visual stimuli across species. To determine the specific circuits within the SC that drive orienting and approach behavior toward appetitive stimuli, we explored the role of three genetically defined cell types in mediating prey capture in mice. Chemogenetic inactivation of two classically defined cell types, the wide-field (WF) and narrow-field (NF) vertical neurons, revealed that they are involved in distinct aspects of prey capture. WF neurons were required for rapid prey detection and distant approach initiation, whereas NF neurons were required for continuous and accurate orienting during pursuit. In contrast, prey capture did not require parvalbumin-expressing (PV) neurons that have previously been implicated in fear responses. The visual coding of WF and NF cells in the awake mouse and their projection targets were consistent with their roles in prey detection versus pursuit. Thus, our studies link specific neural circuit connectivity and function with stimulus detection and orienting behavior, providing insight into visuomotor and attentional mechanisms mediated by superior colliculus.Highlights<jatslist list-type=bullet><jatslist-item>This study provides the first demonstration of the role of specific cell populations in the superior colliculus in orienting and approach behavior.<jatslist-item><jatslist-item>A genetically targeted population of wide-field vertical neurons in the superior colliculus is required for rapid prey detection and initiation of long-distance approaches.<jatslist-item><jatslist-item>A genetically targeted population of narrow-field vertical neurons is required for approach initiation, accurate targeting, and approach continuity.<jatslist-item><jatslist-item>Visual response properties and projection targets of these cells are consistent with their role in prey capture, linking neural circuit connectivity and function with behavior.<jatslist-item>
biorxiv neuroscience 0-100-users 2019The Increasing Importance of Fellowships and Career Development Awards in the Careers of Early-Stage Biomedical Academic Researchers, bioRxiv, 2019-05-03
AbstractExcessive competition for biomedical faculty positions has ratcheted up the need to accumulate some mix of high-quality publications and prestigious grants to move from a training position to university faculty. How universities value each of these attributes when considering faculty candidates is critical for understanding what is needed to succeed as academic faculty. In this study, I analyzed publicly available NIH grant information to determine the grants first-time R01 (FTR01) awardees held during their training period. Increases in the percentage of the FTR01 population that held a training award demonstrate these awards are becoming a more common component of a faculty candidate’s resume. The increase was largely due to an expansion of NIH K-series career development awards between 2000 and 2017. FTR01 awardees with a K01, K08, K23, or K99 award were overrepresented in a subset of institutions, whereas FTR01 awardees with F32 fellowships and those with no training award were evenly distributed across institutions. Finally, training awardees from top institutions were overrepresented in the faculty of the majority of institutions, echoing data from other fields where a select few institutions supply an overwhelming majority of the faculty for the rest of the field. These data give important insight into how trainees compete for NIH funding and faculty positions and how institutions prefer those with or without training awards.
biorxiv scientific-communication-and-education 0-100-users 2019Xenotransplanted human cortical neurons reveal species-specific development and functional integration into mouse visual circuits, bioRxiv, 2019-05-03
SummaryHow neural circuits develop in the human brain has remained almost impossible to study at the neuronal level. Here we investigate human cortical neuron development, plasticity and function, using a mousehuman chimera model in which xenotransplanted human cortical pyramidal neurons integrate as single cells into the mouse cortex. Combined neuronal tracing, electrophysiology, and in vivo structural and functional imaging revealed that the human neurons develop morphologically and functionally following a prolonged developmental timeline, revealing the cell-intrinsic retention of juvenile properties of cortical neurons as an important mechanism underlying human brain neoteny. Following maturation, human neurons transplanted in the visual cortex display tuned responses to visual stimuli that are similar to those of mouse neurons, indicating capacity for physiological synaptic integration of human neurons in mouse cortical circuits. These findings provide new insights into human neuronal development, and open novel experimental avenues for the study of human neuronal function and diseases.Highlights<jatslist list-type=bullet><jatslist-item>Coordinated morphological and functional maturation of ESC-derived human cortical neurons transplanted in the mouse cortex.<jatslist-item><jatslist-item>Transplanted neurons display prolonged juvenile features indicative of intrinsic species-specific neoteny.<jatslist-item><jatslist-item>Transplanted neurons develop elaborate dendritic arbors, stable spine patterns and long-term synaptic plasticity.<jatslist-item><jatslist-item>In the visual cortex transplanted neurons display tuned visual responses that resemble those of the host cortical neurons.<jatslist-item>
biorxiv neuroscience 0-100-users 2019A Spatiomolecular Map of the Striatum, bioRxiv, 2019-05-02
SUMMARYThe striatum is organized into two major outputs formed by striatal projection neuron (SPN) subtypes with distinct molecular identities. In addition, the histochemical division into patch and matrix compartments represents an additional spatial organization, proposed to mirror a functional specialization in a motor-motivation dimension. To map the molecular diversity of SPNs in the context of the patch and matrix division, we genetically labeled mu-opioid receptor (Oprm1) expressing striatal neurons and performed single-nucleus RNA sequencing (snRNA-seq). This allowed us to establish new molecular definitions of the patch-matrix compartments, resulting in a molecular code for mapping patch SPNs at the cellular level. In addition, Oprm1 expression labeled exopatch SPNs, which we found to be molecularly distinct from both patch as well as neighboring matrix SPNs, thereby forming a separate molecular entity. At the cell-type level, we found an unexpected SPN diversity, leading to the identification of a new Col11a1+ striatonigral SPN type. At the tissue level, we found that mapping the spatial expression of a number of markers revealed new definitions of spatial domains in the striatum, which were conserved in the non-human primate brain. Interestingly, the spatial markers were cell-type independent and instead represented a spatial code that was found across all SPNs within a spatially restricted domain. This spatiomolecular map establishes a formal system for targeting and studying the striatal subregions and SPNs subtypes, beyond the classical striatonigral and striatopallidal division.
biorxiv neuroscience 0-100-users 2019Functional integration of “undead” neurons in the olfactory system, bioRxiv, 2019-05-02
AbstractProgrammed cell death (PCD) is widespread during neurodevelopment, typically countering the surpluses of neuronal production. We examined, in the Drosophila olfactory system, the potential of cells fated to die to contribute to circuit evolution. Inhibition of PCD is sufficient to generate many new cells that express neural markers and exhibit odor-evoked activity. These “undead” neurons express a subset of olfactory receptors, enriched for recent receptor duplicates, and including those normally found in other chemosensory organs and life-stages. Moreover, undead neuron axons integrate into the olfactory circuitry in the brain. Comparison of homologous olfactory lineages across drosophilids reveals natural examples of fate changes from death to a functional neuron. These results reveal the remarkable potential of alterations in patterns of PCD to evolve novel neural pathways.
biorxiv neuroscience 0-100-users 2019