Polygenic Risk in Families With Spontaneous Coronary Artery Dissection.

Importance: Spontaneous coronary artery dissection (SCAD) is a poorly understood cause of acute coronary syndrome that predominantly affects women. Evidence to date suggests a complex genetic architecture, while a family history is reported for a minority of cases.

Objective: To determine the contribution of rare and common genetic variants to SCAD risk in familial cases, the latter via the comparison of a polygenic risk score (PRS) with those with sporadic SCAD and healthy controls.

Neural Ensemble Fragmentation in the Anesthetized Brain.

General anesthetics cause a profound loss of behavioral responsiveness in all animals. In mammals, general anesthesia is induced in part by the potentiation of endogenous sleep-promoting circuits, although "deep" anesthesia is understood to be more similar to coma (Brown et al., 2011).

Insights into the genetic architecture underlying complex, critical congenital heart disease.

Congenital heart disease (CHD) has a multifactorial aetiology, raising the possibility of an underlying genetic burden, predisposing to disease but also variable expression, including variation in disease severity, and incomplete penetrance. Using whole genome sequencing (WGS), the findings of this study, indicate that complex, critical CHD is distinct from other types of disease due to increased genetic burden in common variation, specifically among established CHD genes. Additionally, these findings highlight associations with regulatory genes and environmental "stressors" in the final presentation of disease.

Exploring the Genetic Architecture of Spontaneous Coronary Artery Dissection Using Whole-Genome Sequencing.

Background: Spontaneous coronary artery dissection (SCAD) is a cause of acute coronary syndrome that predominantly affects women. Its pathophysiology remains unclear but connective tissue disorders (CTD) and other vasculopathies have been observed in many SCAD patients. A genetic component for SCAD is increasingly appreciated, although few genes have been robustly implicated.

Scavenger: A pipeline for recovery of unaligned reads utilising similarity with aligned reads.

Read alignment is an important step in RNA-seq analysis as the result of alignment forms the basis for downstream analyses. However, recent studies have shown that published alignment tools have variable mapping sensitivity and do not necessarily align all the reads which should have been aligned, a problem we termed as the false-negative non-alignment problem. Here we present Scavenger, a python-based bioinformatics pipeline for recovering unaligned reads using a novel mechanism in which a putative alignment location is discovered based on sequence similarity between aligned and unaligned reads.

Syntaxin1A Neomorphic Mutations Promote Rapid Recovery from Isoflurane Anesthesia in Drosophila melanogaster.

Background: Mutations in the presynaptic protein syntaxin1A modulate general anesthetic effects in vitro and in vivo. Coexpression of a truncated syntaxin1A protein confers resistance to volatile and intravenous anesthetics, suggesting a target mechanism distinct from postsynaptic inhibitory receptor processes. Hypothesizing that recovery from anesthesia may involve a presynaptic component, the authors tested whether syntaxin1A mutations facilitated recovery from isoflurane anesthesia in Drosophila melanogaster.

Spliceogen: an integrative, scalable tool for the discovery of splice-altering variants.

Motivation: In silico prediction tools are essential for identifying variants which create or disrupt cis-splicing motifs. However, there are limited options for genome-scale discovery of splice-altering variants.

Results: We have developed Spliceogen, a highly scalable pipeline integrating predictions from some of the individually best performing models for splice motif prediction: MaxEntScan, GeneSplicer, ESRseq and Branchpointer.

Identification of clinically actionable variants from genome sequencing of families with congenital heart disease.

Purpose: Congenital heart disease (CHD) affects up to 1% of live births. However, a genetic diagnosis is not made in most cases. The purpose of this study was to assess the outcomes of genome sequencing (GS) of a heterogeneous cohort of CHD patients.

Acute control of the sleep switch in reveals a role for gap junctions in regulating behavioral responsiveness.

Sleep is a dynamic process in most animals, involving distinct stages that probably perform multiple functions for the brain. Before sleep functions can be initiated, it is likely that behavioral responsiveness to the outside world needs to be reduced, even while the animal is still awake. Recent work in has uncovered a sleep switch in the dorsal fan-shaped body (dFB) of the fly's central brain, but it is not known whether these sleep-promoting neurons also govern the acute need to ignore salient stimuli in the environment during sleep transitions.

Using Drosophila to Understand General Anesthesia: From Synapses to Behavior.

Investigating mechanisms of general anesthesia requires access to multiple levels of neuronal function, from effects at individual synapses to responses in behaving animals. Drosophila melanogaster provides an excellent model to test different theories for general anesthesia because it offers robust methods for testing local as well as global target processes, in an animal that is similarly impacted by these diverse drugs as humans. Here, we outline methods to quantify two such endpoints, neurotransmission and behavioral responsiveness, focusing on the intravenous drug propofol.

Oscillatory brain activity in spontaneous and induced sleep stages in flies.

Sleep is a dynamic process comprising multiple stages, each associated with distinct electrophysiological properties and potentially serving different functions. While these phenomena are well described in vertebrates, it is unclear if invertebrates have distinct sleep stages. We perform local field potential (LFP) recordings on flies spontaneously sleeping, and compare their brain activity to flies induced to sleep using either genetic activation of sleep-promoting circuitry or the GABA agonist Gaboxadol.

Scalability and Validation of Big Data Bioinformatics Software.

This review examines two important aspects that are central to modern big data bioinformatics analysis - software scalability and validity. We argue that not only are the issues of scalability and validation common to all big data bioinformatics analyses, they can be tackled by conceptually related methodological approaches, namely divide-and-conquer (scalability) and multiple executions (validation). Scalability is defined as the ability for a program to scale based on workload.

CIDR: Ultrafast and accurate clustering through imputation for single-cell RNA-seq data.

Most existing dimensionality reduction and clustering packages for single-cell RNA-seq (scRNA-seq) data deal with dropouts by heavy modeling and computational machinery. Here, we introduce CIDR (Clustering through Imputation and Dimensionality Reduction), an ultrafast algorithm that uses a novel yet very simple implicit imputation approach to alleviate the impact of dropouts in scRNA-seq data in a principled manner. Using a range of simulated and real data, we show that CIDR improves the standard principal component analysis and outperforms the state-of-the-art methods, namely t-SNE, ZIFA, and RaceID, in terms of clustering accuracy.

Transient Dysregulation of Dopamine Signaling in a Developing Arousal Circuit Permanently Impairs Behavioral Responsiveness in Adults.

The dopamine ontogeny hypothesis for schizophrenia proposes that transient dysregulation of the dopaminergic system during brain development increases the likelihood of this disorder in adulthood. To test this hypothesis in a high-throughput animal model, we have transiently manipulated dopamine signaling in the developing fruit fly and examined behavioral responsiveness in adult flies. We found that either a transient increase of dopamine neuron activity or a transient decrease of dopamine receptor expression during fly brain development permanently impairs behavioral responsiveness in adults.

Long Noncoding RNA-Directed Epigenetic Regulation of Gene Expression Is Associated With Anxiety-like Behavior in Mice.

Background: RNA-directed regulation of epigenetic processes has recently emerged as an important feature of mammalian differentiation and development. Perturbation of this regulatory system in the brain may contribute to the development of neuropsychiatric disorders.

Methods: RNA sequencing was used to identify changes in the experience-dependent expression of long noncoding RNAs (lncRNAs) within the medial prefrontal cortex of adult mice.

A sleep/wake circuit controls isoflurane sensitivity in Drosophila.

General anesthesia remains a mysterious phenomenon, even though a number of compelling target proteins and processes have been proposed [1]. General anesthetics such as isoflurane abolish behavioral responsiveness in all animals, and in the mammalian brain, these diverse compounds probably achieve this in part by targeting endogenous sleep mechanisms [2, 3]. However, most animals sleep [4], and they are therefore likely to have conserved sleep processes.

Fin-tail coordination during escape and predatory behavior in larval zebrafish.

Larval zebrafish innately perform a suite of behaviors that are tightly linked to their evolutionary past, notably escape from threatening stimuli and pursuit and capture of prey. These behaviors have been carefully examined in the past, but mostly with regard to the movements of the trunk and tail of the larvae. Here, we employ kinematics analyses to describe the movements of the pectoral fins during escape and predatory behavior.