Biology subjects

Lee, J. J.

Publications and source records attributed to Lee, J. J..

7 recordsLinked to original sources

bioRxiv2018

Open channel droplet-based microfluidics

Droplet-based microfluidics enables compartmentalization and controlled manipulation of small volumes. Open microfluidics provides increased accessibility, adaptability, and ease of manufacturing compared to closed microfluidic platforms. Here, we begin to build a toolbox for the emerging field of open channel droplet-based microfluidics, combining the ease of use associated with open microfluidic platforms with the benefits of compartmentalization afforded by droplet-based microfluidics. We develop fundamental microfluidic features to control droplets flowing in an immiscible carrier fluid within open microfluidic systems. Our systems use capillary flow to move droplets and carrier fluid through open channels and are easily fabricated through 3D printing, micromilling, or injection molding; further, droplet generation can be accomplished by simply pipetting into the open channel. We demonstrate droplet incubation and transport for downstream experimentation and tunable droplet splitting in open channels driven by capillary flow. Potential applications of our toolbox for droplet manipulation in open channels include cell culture and analysis, on-chip microscale reactions, and reagent delivery.

bioengineering↗

bioRxiv2018

Persistent activity in primate auditory cortex evoked by sensory stimulation

Persistent activity, the elevated firing of a neuron after the termination of a stimulus, is hypothesized to play a critical role in working memory. This form of activity is therefore typically studied within the context of a behavioural task that includes a working memory component. Here we investigated whether persistent activity is observed in sensory cortex and thalamus in the absence of any explicit behavioural task. We recorded spiking activity from single units in the auditory cortex (fields A1, R and RT) and thalamus of awake, passively-listening marmosets. We observed persistent activity that lasted for hundreds of milliseconds following the termination of the acoustic stimulus, in the absence of a task. Persistent activity was observed following both adapting and sustained responses during the stimulus and showed similar stimulus tuning to these evoked responses. Persistent activity was also observed following suppression in firing during the stimulus. These response types were observed across all cortical fields tested, but were largely absent from thalamus. As well as being of shorter duration, thalamic persistent activity emerged following a longer latency than in cortex, indicating that persistent activity may be generated within auditory cortex during passive listening. Given that these responses were observed in the absence of a explicit behavioural task, persistent activity in sensory cortex may have functional importance beyond storing task-relevant information in working memory.

neuroscience↗

bioRxiv2018

Childhood cerebellar tumors mirror conserved fetal transcriptional programs

The study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. We used single-cell transcriptomics to study >60,000 cells from the developing murine cerebellum, and show that different molecular subgroups of childhood cerebellar tumors mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. Sonic Hedgehog medulloblastoma transcriptionally mirrors the granule cell hierarchy as expected, whereas Group 3 medulloblastoma resemble Nestin+ve stem cells, Group 4 medulloblastomas resemble unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the prenatal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumors demonstrates that many bulk tumors contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumors as a disorder of early brain development, and provide a proximate explanation for the peak incidence of cerebellar tumors in early childhood.

cancer biology↗

bioRxiv2018

Exploring the genetic correlations of antisocial behavior and life history traits

Prior evolutionary theory provided reason to suspect that measures of development and reproduction would be correlated with antisocial behaviors in human and non-human species. Behavioral genetics has revealed that most quantitative traits are heritable, suggesting that these phenotypic correlations may share genetic etiologies. We use GWAS data to estimate the genetic correlations between various measures of reproductive development (N= 52,776 - 318,863) and antisocial behavior (N= 31,968). Our genetic correlation analyses demonstrate that alleles associated with higher reproductive output (number of children ever born, rg=0.50, p=.0065) were positively correlated with alleles associated with antisocial behavior, whereas alleles associated with more delayed reproductive onset (age of first birth, rg=-.64, p=.0008) were negatively associated with alleles linked to antisocial behavior. Ultimately, these findings coalesce with evolutionary theories suggesting that increased antisocial behaviors may partly represent a faster life history approach, which may be significantly calibrated by genes.

genomics↗

bioRxiv2018

Basal mitophagy is widespread in Drosophila but minimally affected by loss of Pink1 or parkin

Parkinsons disease factors, PINK1 and parkin, are strongly implicated in stress-induced mitophagy in vitro, but little is known about their impact on basal mitophagy in vivo. We generated transgenic Drosophila expressing fluorescent mitophagy reporters to evaluate the impact of Pink1/parkin mutations on basal mitophagy under physiological conditions. We find that mitophagy is readily detectable and abundant in many tissues including Parkinsons disease relevant dopaminergic neurons. However, we did not detect mitolysosomes in flight muscle. Surprisingly, in Pink1 or parkin null flies we did not observe any substantial impact on basal mitophagy. As these flies exhibit locomotor defects and dopaminergic neuron loss, our findings raise questions about current assumptions of the pathogenic mechanism associated with the PINK1/Parkin pathway. Our findings provide evidence that Pink1 and parkin are not essential for bulk basal mitophagy in Drosophila. They also emphasize that mechanisms underpinning basal mitophagy remain largely obscure.\n\nSummaryPINK1/parkin are key mediators of stress-induced mitophagy in vitro but their impact on basal mitophagy in vivo is unclear. Novel Drosophila reporters lines reveal abundant mitophagy in many tissues including dopaminergic neurons but is unaffected by loss of PINK1/parkin.

cell biology↗

bioRxiv2017

LD Score regression as an estimator of confounding and genetic correlations in genome-wide association studies

In order to infer that a single-nucleotide polymorphism (SNP) either affects a phenotype or is linkage disequilibrium with a causal site, we must have some assurance that any SNP-phenotype correlation is not the result of confounding with environmental variables that also affect the trait. In this work we study the properties of LD Score regression, a recently developed method for using summary statistics from genome-wide association studies (GWAS) to ensure that confounding does not inflate the number of false positives. We do not treat the effects of genetic variation as a random variable and thus are able to obtain results about the unbiasedness of this method. We demonstrate that LD Score regression can produce estimates of confounding at null SNPs that are unbiased or conservative under fairly general conditions. This robustness holds in the case of the parent genotype affecting the offspring phenotype through some environmental mechanism, despite the resulting correlation over SNPs between LD Scores and the degree of confounding. Additionally, we demonstrate that LD Score regression can produce reasonably robust estimates of the genetic correlation, even when its estimates of the genetic covariance and the two univariate heritabilities are substantially biased.

genetics↗

bioRxiv2017

MTAG: Multi-Trait Analysis of GWAS

We introduce Multi-Trait Analysis of GWAS (MTAG), a method for joint analysis of summary statistics from GWASs of different traits, possibly from overlapping samples. We apply MTAG to summary statistics for depressive symptoms (Neff = 354,862), neuroticism (N = 168,105), and subjective well-being (N = 388,538). Compared to 32, 9, and 13 genome-wide significant loci in the single-trait GWASs (most of which are themselves novel), MTAG increases the number of loci to 64, 37, and 49, respectively. Moreover, association statistics from MTAG yield more informative bioinformatics analyses and increase variance explained by polygenic scores by approximately 25%, matching theoretical expectations.

genomics↗