Nested oscillatory dynamics in cortical organoids model early human brain network development, bioRxiv, 2018-06-29

SUMMARYStructural and transcriptional changes during early brain maturation follow fixed developmental programs defined by genetics. However, whether this is true for functional network activity remains unknown, primarily due to experimental inaccessibility of the initial stages of the living human brain. Here, we developed cortical organoids that spontaneously display periodic and regular oscillatory network events that are dependent on glutamatergic and GABAergic signaling. These nested oscillations exhibit cross-frequency coupling, proposed to coordinate neuronal computation and communication. As evidence of potential network maturation, oscillatory activity subsequently transitioned to more spatiotemporally irregular patterns, capturing features observed in preterm human electroencephalography (EEG). These results show that the development of structured network activity in the human neocortex may follow stable genetic programming, even in the absence of external or subcortical inputs. Our approach provides novel opportunities for investigating and manipulating the role of network activity in the developing human cortex.HIGHLIGHTS<jatslist list-type=bullet><jatslist-item>Early development of human functional neural networks and oscillatory activity can be modeled in vitro.<jatslist-item><jatslist-item>Cortical organoids exhibit phase-amplitude coupling between delta oscillation (2 Hz) and high-frequency activity (100-400 Hz) during network-synchronous events.<jatslist-item><jatslist-item>Differential role of glutamate and GABA in initiating and maintaining oscillatory network activity.<jatslist-item><jatslist-item>Developmental impairment of MECP2-KO cortical organoids impacts the emergence of oscillatory activity.<jatslist-item><jatslist-item>Cortical organoid network electrophysiological signatures correlate with human preterm neonatal EEG features.<jatslist-item>eTOCBrain oscillations are a candidate mechanism for how neural populations are temporally organized to instantiate cognition and behavior. Cortical organoids initially exhibit periodic and highly regular nested oscillatory network events that eventually transition to more spatiotemporally complex activity, capturing features of late-stage preterm infant electroencephalography. Functional neural circuitry in cortical organoids exhibits emergence and development of oscillatory network dynamics similar to those found in the developing human brain.

biorxiv neuroscience 0-100-users 2018

Up, down, and out optimized libraries for CRISPRa, CRISPRi, and CRISPR-knockout genetic screens, bioRxiv, 2018-06-27

ABSTRACTAdvances in CRISPR-Cas9 technology have enabled the flexible modulation of gene expression at large scale. In particular, the creation of genome-wide libraries for CRISPR knockout (CRISPRko), CRISPR interference (CRISPRi), and CRISPR activation (CRISPRa) has allowed gene function to be systematically interrogated. Here, we evaluate numerous CRISPRko libraries and show that our recently-described CRISPRko library (Brunello) is more effective than previously published libraries at distinguishing essential and non-essential genes, providing approximately the same perturbation-level performance improvement over GeCKO libraries as GeCKO provided over RNAi. Additionally, we developed genome-wide libraries for CRISPRi (Dolcetto) and CRISPRa (Calabrese). Negative selection screens showed that Dolcetto substantially outperforms existing CRISPRi libraries with fewer sgRNAs per gene and achieves comparable performance to CRISPRko in the detection of gold-standard essential genes. We also conducted positive selection CRISPRa screens and show that Calabrese outperforms the SAM library approach at detecting vemurafenib resistance genes. We further compare CRISPRa to genome-scale libraries of open reading frames (ORFs). Together, these libraries represent a suite of genome-wide tools to efficiently interrogate gene function with multiple modalities.tracr

biorxiv genomics 0-100-users 2018

Career Choice, Gender, and Mentor Impact Results of the U.S. National Postdoc Survey, bioRxiv, 2018-06-26

AbstractThe postdoctoral community is an essential component of the academic and scientific workforce. As economic and political pressures impacting these enterprises continue to change, the postdoc experience has evolved from short, focused periods of training into often multidisciplinary, extended positions with less clear outcomes. As efforts are underway to amend U.S. federally funded research policies, the paucity of postdoc data has made evaluating the impact of policy recommendations challenging. Here we present comprehensive survey results from over 7,600 postdocs based at 351 academic and non-academic U.S. institutions in 2016. In addition to demographic and salary information, we present multivariate analyses on the factors that influence postdoc career plans and mentorship satisfaction in this population. We further analyze gender dynamics and expose wage disparities and career choice differences. Academic research positions remain the predominant career choice of postdocs in the U.S., although unequally between postdocs based on gender and residency status. Receiving mentorship training during the postdoctoral period has a large, positive effect on postdoc mentorship satisfaction. Strikingly, the quality of and satisfaction with postdoc mentorship appears to also heavily influence career choice. The data presented here are the most comprehensive data on the U.S. postdoc population to date. These results provide an evidence basis for informing government and institutional policies, and establish a critical cornerstone for quantifying the effects of future legislation aimed at the academic and scientific workforce.

biorxiv scientific-communication-and-education 200-500-users 2018

 

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