A Multimodal, In Vivo Approach for Assessing Structurally and Phenotypically Related Neuroactive Molecules.

A recently reported behavioral screen in larval zebrafish for phenocopiers of known anesthetics and associated drugs yielded an isoflavone. Related isoflavones have also been reported as GABA potentiators. From this, we synthesized a small library of isoflavones and incorporated an in vivo phenotypic approach to perform structure-behavior relationship studies of the screening hit and related analogs via behavioral profiling, patch-clamp experiments, and whole brain imaging.

Structural switch in acetylcholine receptors in developing muscle.

During development, motor neurons originating in the brainstem and spinal cord form elaborate synapses with skeletal muscle fibres. These neurons release acetylcholine (ACh), which binds to nicotinic ACh receptors (AChRs) on the muscle, initiating contraction. Two types of AChR are present in developing muscle cells, and their differential expression serves as a hallmark of neuromuscular synapse maturation.

Structural insights into GABA receptor potentiation by Quaalude.

Methaqualone, a quinazolinone marketed commercially as Quaalude, is a central nervous system depressant that was used clinically as a sedative-hypnotic, then became a notorious recreational drug in the 1960s-80s. Due to its high abuse potential, medical use of methaqualone was eventually prohibited, yet it persists as a globally abused substance. Methaqualone principally targets GABA receptors, which are the major inhibitory neurotransmitter-gated ion channels in the brain.

Structural bases for stoichiometry-selective calcium potentiation of a neuronal nicotinic receptor.

Background And Purpose: α4β2 nicotinic acetylcholine (nACh) receptors assemble in two stoichiometric forms, one of which is potentiated by calcium. The sites of calcium binding that underpin potentiation are not known.

Experimental Approach: To identify calcium binding sites, we applied cryo-electron microscopy (cryo-EM) and molecular dynamics (MD) simulations to each stoichiometric form of the α4β2 nACh receptor in the presence of calcium ions.

Structural mechanisms of α7 nicotinic receptor allosteric modulation and activation.

The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that plays an important role in cholinergic signaling throughout the nervous system. Its unique physiological characteristics and implications in neurological disorders and inflammation make it a promising but challenging therapeutic target. Positive allosteric modulators overcome limitations of traditional α7 agonists, but their potentiation mechanisms remain unclear.

Benchmarks for dialectical behavioural therapy intervention in adults and adolescents with borderline personality symptoms.

Background: Dialectical Behaviour Therapy (DBT) is a multi-component cognitive behavioural intervention with proven efficacy in treating people with borderline personality disorder symptoms. Establishing benchmarks for DBT intervention with both adults and adolescents is essential for bridging the gap between research and clinical practice, improving teams' performance and procedures.

Aim: This study aimed to establish benchmarks for DBT using the EQ-5D, Borderline Symptoms List (BSL) and Difficulties in Emotion Regulation Scale (DERS) for adults and adolescents.

Structural insights into opposing actions of neurosteroids on GABA receptors.

γ-Aminobutyric acid type A (GABA) receptors mediate fast inhibitory signaling in the brain and are targets of numerous drugs and endogenous neurosteroids. A subset of neurosteroids are GABA receptor positive allosteric modulators; one of these, allopregnanolone, is the only drug approved specifically for treating postpartum depression. There is a consensus emerging from structural, physiological and photolabeling studies as to where positive modulators bind, but how they potentiate GABA activation remains unclear.

Structural interplay of anesthetics and paralytics on muscle nicotinic receptors.

General anesthetics and neuromuscular blockers are used together during surgery to stabilize patients in an unconscious state. Anesthetics act mainly by potentiating inhibitory ion channels and inhibiting excitatory ion channels, with the net effect of dampening nervous system excitability. Neuromuscular blockers act by antagonizing nicotinic acetylcholine receptors at the motor endplate; these excitatory ligand-gated ion channels are also inhibited by general anesthetics.

Structural basis of sensory receptor evolution in octopus.

Chemotactile receptors (CRs) are a cephalopod-specific innovation that allow octopuses to explore the seafloor via 'taste by touch'. CRs diverged from nicotinic acetylcholine receptors to mediate contact-dependent chemosensation of insoluble molecules that do not readily diffuse in marine environments. Here we exploit octopus CRs to probe the structural basis of sensory receptor evolution.

Sensory specializations drive octopus and squid behaviour.

The evolution of new traits enables expansion into new ecological and behavioural niches. Nonetheless, demonstrated connections between divergence in protein structure, function and lineage-specific behaviours remain rare. Here we show that both octopus and squid use cephalopod-specific chemotactile receptors (CRs) to sense their respective marine environments, but structural adaptations in these receptors support the sensation of specific molecules suited to distinct physiological roles.

A simple flash and freeze system for cryogenic time-resolved electron microscopy.

As the resolution revolution in CryoEM expands to encompass all manner of macromolecular complexes, an important new frontier is the implementation of cryogenic time resolved EM (cryoTREM). Biological macromolecular complexes are dynamic systems that undergo conformational changes on timescales from microseconds to minutes. Understanding the dynamic nature of biological changes is critical to understanding function.

Differential interactions of resting, activated, and desensitized states of the α7 nicotinic acetylcholine receptor with lipidic modulators.

The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel that modulates neuronal excitability, largely by allowing Ca permeation. Agonist binding promotes transition from a resting state to an activated state, and then rapidly to a desensitized state. Recently, cryogenic electron microscopy (cryo-EM) structures of the human α7 receptor in nanodiscs were reported in multiple conformations.

Service delivery for complex rehabilitation technology: a scoping review.

Purpose: Complex rehabilitation technologies (CRT) support independence for individuals with disabilities by enabling mobility for function, employment, education, and independent living. CRT service delivery is evolving, with changes to funding, provider qualifications, consumer needs, and technological advances. This scoping review investigated service delivery processes for individuals with disabilities who have a mobility impairment, while specifically identifying best practices, barriers, and unique features of health delivery policies and practices.

Structural and dynamic mechanisms of GABA receptor modulators with opposing activities.

γ-Aminobutyric acid type A (GABA) receptors are pentameric ligand-gated ion channels abundant in the central nervous system and are prolific drug targets for treating anxiety, sleep disorders and epilepsy. Diverse small molecules exert a spectrum of effects on γ-aminobutyric acid type A (GABA) receptors by acting at the classical benzodiazepine site. They can potentiate the response to GABA, attenuate channel activity, or counteract modulation by other ligands.

Structural mechanisms of GABA receptor autoimmune encephalitis.

Autoantibodies targeting neuronal membrane proteins can cause encephalitis, seizures, and severe behavioral abnormalities. While antibodies for several neuronal targets have been identified, structural details on how they regulate function are unknown. Here we determined cryo-electron microscopy structures of antibodies derived from an encephalitis patient bound to the γ-aminobutyric acid type A (GABA) receptor.

Exploring the impact of excessive daytime sleepiness caused by obstructive sleep apnea on patient and partner quality of life: a time trade-off utility study in the UK general public.

Study Objectives: This study aimed to quantify the impact of excessive daytime sleepiness (EDS) on patient and patient's partner health-related quality of life in the form of utility values typically used in health economic evaluations.

Methods: A time trade-off study was conducted in a UK general population sample (representing a societal perspective) to elicit utility values, measured on a 0 to 1 scale, for health states with varying obstructive sleep apnea-associated EDS severity. In a time trade-off study, health states are described, and participants "trade off" time in a specific higher severity state for a shorter amount of time in full health.

Structural mechanism of muscle nicotinic receptor desensitization and block by curare.

Binding of the neurotransmitter acetylcholine to its receptors on muscle fibers depolarizes the membrane and thereby triggers muscle contraction. We sought to understand at the level of three-dimensional structure how agonists and antagonists alter nicotinic acetylcholine receptor conformation. We used the muscle-type receptor from the Torpedo ray to first define the structure of the receptor in a resting, activatable state.

Neonatal digital chest radiography- should we be using additional copper filtration?

Objectives: Copper filtration removes lower energy X-ray photons, which do not enhance image quality but would otherwise contribute to patient radiation dose. This study explores the use of additional copper filtration for neonatal mobile chest imaging.

Methods: A controlled factorial-designed experiment was used to determine the effect of independent variables on image quality and radiation dose.

Face validity of standardized assessments for wheeled mobility & seating evaluations.

A problem in the Complex Rehabilitation Technology industry is the lack of standardization in the assessment for wheeled mobility and seating (WMS). The aim of this paper was to identify assessment tools commonly used by clinicians during WMS evaluations. After the tools were identified by a panel of 12 subject matter experts, a presentation at the 2018 International Seating Symposium in Vancouver, Canada and the 2018 European Seating Symposium in Dublin, Ireland polled attendees via the Sli.

Purification of a native nicotinic receptor.

Nicotinic acetylcholine receptors are members of the Cys-loop superfamily of pentameric ligand-gated ion channels. The electric organ of the Torpedo ray is extraordinarily rich in an acetylcholine receptor that is homologous to the human nicotinic receptor found at the neuromuscular junction. Due to this abundant natural source in the fish and the relatively accessible preparation of the neuromuscular junction (compared to a central synapse), this muscle-type receptor and specifically the fish receptors have long been used as the prototype for study of nicotinic receptors.

Effectiveness of a Web-Based Direct-to-User Transfer Training Program: A Randomized Controlled Trial.

Objective: To determine the effectiveness of a web-based, direct-to-user transfer training program in improving transfer quality and maintaining improvements for up to 1 month after training as compared with a control group.

Design: Randomized controlled trial with participants randomized to an immediate intervention group (IIG) or waitlist control group (WLCG) that received the training after a 6-month delay.

Setting: Wherever the participants accessed the web-based training, likely the home environment.

Toward Improving the Prediction of Functional Ambulation After Spinal Cord Injury Through the Inclusion of Limb Accelerations During Sleep and Personal Factors.

Objective: To determine if functional measures of ambulation can be accurately classified using clinical measures; demographics; personal, psychosocial, and environmental factors; and limb accelerations (LAs) obtained during sleep among individuals with chronic, motor incomplete spinal cord injury (SCI) in an effort to guide future, longitudinal predictions models.

Design: Cross-sectional, 1-5 days of data collection.

Setting: Community-based data collection.

Structure and gating mechanism of the α7 nicotinic acetylcholine receptor.

The α7 nicotinic acetylcholine receptor plays critical roles in the central nervous system and in the cholinergic inflammatory pathway. This ligand-gated ion channel assembles as a homopentamer, is exceptionally permeable to Ca, and desensitizes faster than any other Cys-loop receptor. The α7 receptor has served as a prototype for the Cys-loop superfamily yet has proven refractory to structural analysis.