The 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 2019Insights about variation in meiosis from 31,228 human sperm genomes, bioRxiv, 2019-05-02
AbstractMeiosis, while critical for reproduction, is also highly variable and error prone crossover rates vary among humans and individual gametes, and chromosome nondisjunction leads to aneuploidy, a leading cause of miscarriage. To study variation in meiotic outcomes within and across individuals, we developed a way to sequence many individual sperm genomes at once. We used this method to sequence the genomes of 31,228 gametes from 20 sperm donors, identifying 813,122 crossovers, 787 aneuploid chromosomes, and unexpected genomic anomalies. Different sperm donors varied four-fold in the frequency of aneuploid sperm, and aneuploid chromosomes gained in meiosis I had 36% fewer crossovers than corresponding non-aneuploid chromosomes. Diverse recombination phenotypes were surprisingly coordinated donors with high average crossover rates also made a larger fraction of their crossovers in centromere-proximal regions and placed their crossovers closer together. These same relationships were also evident in the variation among individual gametes from the same donor sperm with more crossovers tended to have made crossovers closer together and in centromere-proximal regions. Variation in the physical compaction of chromosomes could help explain this coordination of meiotic variation across chromosomes, gametes, and individuals.
biorxiv genomics 100-200-users 2019Tmem119-EGFP and Tmem119-CreERT2 transgenic mice for labeling and manipulating microglia, bioRxiv, 2019-05-02
AbstractMicroglia are specialized brain-resident macrophages with important functions in health and disease. To improve our understanding of these cells, the research community needs genetic tools to identify and control them in a manner that distinguishes them from closely related cell-types. We have targeted the recently discovered microglia-specific Tmem119 gene to generate knock-in mice expressing EGFP (JAX#031823) or CreERT2 (JAX#031820) for the identification and manipulation of microglia, respectively. Genetic characterization of the locus and qPCR-based analysis demonstrate correct positioning of the transgenes and intact expression of endogenous Tmem119 in the knock-in mouse models. Immunofluorescence analysis further shows that parenchymal microglia, but not other brain macrophages, are completely and faithfully labeled in the EGFP-line at different time points of development. Flow cytometry indicates highly selective expression of EGFP in CD11b+CD45lo microglia. Similarly, immunofluorescence and flow cytometry analyses using a Cre-dependent reporter mouse line demonstrate activity of CreERT2 primarily in microglia upon tamoxifen administration with the caveat of activity in leptomeningeal cells. Finally, flow cytometric analyses reveal absence of EGFP expression and minimal activity of CreERT2 in blood monocytes of the Tmem119-EGFP and Tmem119-CreERT2 lines, respectively. These new transgenic lines extend the microglia toolbox by providing the currently most specific genetic labeling and control over these cells in the myeloid compartment of mice.Visual abstract<jatsfig id=ufig1 position=float orientation=portrait fig-type=figure><jatsgraphic xmlnsxlink=httpwww.w3.org1999xlink xlinkhref=624825v2_ufig1 position=float orientation=portrait >Significance statementTools that specifically label and manipulate only microglia are currently unavailable, but are critically needed to further our understanding of this cell type. Complementing and significantly extending recently introduced microglia-specific immunostaining methods that have quickly become a new standard in the field, we generated two mouse lines that label and control gene expression in microglia with high specificity and made them publicly available. Using these readily accessible mice, the research community will be able to study microglia biology with improved specificity.
biorxiv neuroscience 0-100-users 2019