Zebrafish behavioural profiling identifies GABA and serotonin receptor ligands related to sedation and paradoxical excitation.

Anesthetics are generally associated with sedation, but some anesthetics can also increase brain and motor activity-a phenomenon known as paradoxical excitation. Previous studies have identified GABAA receptors as the primary targets of most anesthetic drugs, but how these compounds produce paradoxical excitation is poorly understood. To identify and understand such compounds, we applied a behavior-based drug profiling approach. Here, we show that a subset of central nervous system depressants cause paradoxical excitation in zebrafish. Using this behavior as a readout, we screened thousands of compounds and identified dozens of hits that caused paradoxical excitation. Many hit compounds modulated human GABAA receptors, while others appeared to modulate different neuronal targets, including the human serotonin-6 receptor. Ligands at these receptors generally decreased neuronal activity, but paradoxically increased activity in the caudal hindbrain. Together, these studies identify ligands, targets, and neurons affecting sedation and paradoxical excitation in vivo in zebrafish

What works with men? A systematic review of health promoting interventions targeting men

Peer reviewedPublisher PD

2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease

The recommendations listed in this document are, whenever possible, evidence based. An extensive evidence review was conducted as the document was compiled through December 2008. Repeated literature searches were performed by the guideline development staff and writing committee members as new issues were considered. New clinical trials published in peer-reviewed journals and articles through December 2011 were also reviewed and incorporated when relevant. Furthermore, because of the extended development time period for this guideline, peer review comments indicated that the sections focused on imaging technologies required additional updating, which occurred during 2011. Therefore, the evidence review for the imaging sections includes published literature through December 2011

Neuroactive compound discovery by high-content screens in zebrafish

Neuroactive compounds are crucial tools in drug discovery and neuroscience. However, discovering mechanistically novel drugs has proven challenging. Behavioral screens in larval zebrafish have helped researchers discover compounds with novel mechanisms.In Chapter 2, we introduce and evaluate an open platform for behavioral screening, SauronX. This instrument records movement behaviors in multiwell plates, capturing high-resolution video data at high framerate (100 Hz) under complex photic and acoustic stimuli. To test, we trained machine learning models to resolve phenotypes caused by compounds with diverse mechanisms in fully randomized screens. First, we benchmarked the system with 14 quality--control (QC) compounds and found that all 14 could be distinguished from each other and from vehicle controls. We then extended to a set of reference phenotypic readouts from 648 neuroactive compounds.The hardware and software system has been used in studies by several research groups, so far limited to direct collaborations. In this work, we have sought to document the platform fully, providing 3D diagrams, component information, and source code. We have also deposited 7 years of phenotypic data for 3.2 million animals and 34,000 compounds. The data are curated, structured, tied to extensive metadata, and available under a permissive Creative Commons (CC-BY) license

Supplements

Extended supplemental data and procedures for relevant publication

Documentation

Hardware components, CAD diagrams, and software overvie

Datasets

Large datasets as flat Feather-format files

Zebrafish behavioral profiling using SauronX

Data for SauronX, a platform for phenotypic neuroactive compound discovery (doi:10.1101/2020.01.01.891432)

Systematic detection of internal symmetry in proteins using CE-Symm.

Symmetry is an important feature of protein tertiary and quaternary structures that has been associated with protein folding, function, evolution, and stability. Its emergence and ensuing prevalence has been attributed to gene duplications, fusion events, and subsequent evolutionary drift in sequence. This process maintains structural similarity and is further supported by this study. To further investigate the question of how internal symmetry evolved, how symmetry and function are related, and the overall frequency of internal symmetry, we developed an algorithm, CE-Symm, to detect pseudo-symmetry within the tertiary structure of protein chains. Using a large manually curated benchmark of 1007 protein domains, we show that CE-Symm performs significantly better than previous approaches. We use CE-Symm to build a census of symmetry among domain superfamilies in SCOP and note that 18% of all superfamilies are pseudo-symmetric. Our results indicate that more domains are pseudo-symmetric than previously estimated. We establish a number of recurring types of symmetry-function relationships and describe several characteristic cases in detail. With the use of the Enzyme Commission classification, symmetry was found to be enriched in some enzyme classes but depleted in others. CE-Symm thus provides a methodology for a more complete and detailed study of the role of symmetry in tertiary protein structure [availability: CE-Symm can be run from the Web at http://source.rcsb.org/jfatcatserver/symmetry.jsp. Source code and software binaries are also available under the GNU Lesser General Public License (version 2.1) at https://github.com/rcsb/symmetry. An interactive census of domains identified as symmetric by CE-Symm is available from http://source.rcsb.org/jfatcatserver/scopResults.jsp]