Biology subjects

Sherwood, J.

Publications and source records attributed to Sherwood, J..

4 recordsLinked to original sources

bioRxiv2021

The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

To study how the 22q11.2 deletion predisposes to psychiatric disease, we generated induced pluripotent stem cells from deletion carriers and controls, as well as utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Upon differentiation into neural progenitor cells, we found the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including Autism Spectrum Disorder. In more differentiated excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common (per-SNP heritability p ({tau}c)= 4.2 x 10-6) and rare, loss of function variants (p = 1.29x10-12). These findings suggest a potential relationship between cellular states, developmental windows and susceptibility to psychiatric conditions with different ages of onset. To understand how the deletion contributed to these observed changes in gene expression, we developed and applied PPItools, which identifies the minimal protein-protein interaction network that best explains an observed set of gene expression alterations. We found that many of the genes in the 22q11.2 interval interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways that underlie the broader alterations in psychiatric risk gene expression we identified. Our findings suggest that the 22q11.2 deletion impacts genes and pathways that may converge with risk loci implicated by psychiatric genetic studies to influence disease manifestation in each deletion carrier.

neuroscience↗

bioRxiv2020

A Novel Performance Metric for Multiclass Subject Invariant Brain Computer Interfaces with Imbalanced Classes

[Finding suitable common feature sets for use in multiclass subject independent brain-computer interface (BCI) classifiers is problematic due to characteristically large inter-subject variation of electroencephalographic signatures. We propose a wrapper search method using a one versus the rest discrete output classifier. Obtaining and evaluating the quality of feature sets requires the development of appropriate classifier metrics. A one versus the rest classifier must be evaluated by a scalar performance metric that provides feedback for the feature search algorithm. However, the one versus the rest discrete classifier is prone to settling into degenerate states for difficult discrimination problems. The chance of occurrence of degeneracy increases with the number of classes, number of subjects and imbalance between the number of samples in the majority and minority classes. This paper proposes a scalar Quality (Q)-factor to compensate for classifier degeneracy and to improve the convergence of the wrapper search. The Q-factor, calculated from the ratio of sensitivity to specificity of the confusion matrix, is applied as a penalty to the accuracy (1-error rate). This method is successfully applied to a multiclass subject independent BCI using 10 untrained subjects performing 4 motor tasks in conjunction with the Sequential Floating Forward Selection feature search algorithm and Support Vector Machine classifiers.]

neuroscience↗

bioRxiv2019

Localized delivery and uncaging of glutamate from MRI-visible albumin nanoclusters in the rat hippocampus using focused ultrasound

There is an ongoing need for noninvasive tools to manipulate brain activity with molecular, spatial and temporal specificity. Here we have investigated the use of MRI-visible, albumin-based nanoclusters for noninvasive, localized and temporally specific drug delivery to the rat brain. We demonstrated that IV injected nanoclusters could be deposited into target brain regions via focused ultrasound facilitated blood brain barrier opening. We showed that nanocluster location could be confirmed in vivo with MRI. Additionally, following confirmation of nanocluster delivery, release of the nanocluster payload into brain tissue can be triggered by a second focused ultrasound treatment performed without circulating microbubbles. Release of glutamate from nanoclusters in vivo caused enhanced c-Fos expression, indicating that the loading capacity of the nanoclusters is sufficient to induce neuronal activation. This novel technique for noninvasive stereotactic drug delivery to the brain with temporal specificity could provide a new way to study brain circuits in vivo preclinically with high relevance for clinical translation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=36 SRC="FIGDIR/small/696237v4_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@b528f9org.highwire.dtl.DTLVardef@1950228org.highwire.dtl.DTLVardef@1c0ada0org.highwire.dtl.DTLVardef@c71790_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2019

Pervasive head-to-tail insertions of DNA templates mask desired CRISPR/Cas9-mediated genome editing events

CRISPR/Cas9 mediated homology-directed DNA repair is the method of choice for precise gene editing in a wide range of model organisms, including mouse and human. Broad use by the biomedical community refined the method, making it more efficient and sequence specific. Nevertheless, the rapidly evolving technique still contains pitfalls. During the generation of six different conditional knock-out mouse models, we discovered that frequently (sometimes solely) homology-directed repair and/or non-homologous end-joining mechanisms caused multiple unwanted head-to-tail insertions of donor DNA templates. Disturbingly, conventionally applied PCR analysis--in most cases--failed to identify such multiple integration events, which led to a high rate of falsely claimed precisely edited alleles. We caution that comprehensive analysis of modified alleles is essential, and offer practical solutions to correctly identify precisely edited chromosomes.

genetics↗