Novel Phenotypes and Genotype-Phenotype Correlations in a Large Clinical Cohort of Patients With Kleefstra Syndrome.

Kleefstra syndrome (KLEFS) is a genetic neurodevelopmental disorder caused by haploinsufficiency of EHMT1. The full spectrum of clinical features and genotype-phenotype correlations is currently not fully understood. We performed a retrospective chart review of patients with KLEFS evaluated at the Boston Children's Hospital Kleefstra Clinic.

Synaptic BMAL1 phosphorylation controls circadian hippocampal plasticity.

The time of day strongly influences adaptive behaviors like long-term memory, but the correlating synaptic and molecular mechanisms remain unclear. The circadian clock comprises a canonical transcription-translation feedback loop (TTFL) strictly dependent on the BMAL1 transcription factor. We report that BMAL1 rhythmically localizes to hippocampal synapses in a manner dependent on its phosphorylation at Ser [pBMAL1(S42)].

Defining diurnal fluctuations in mouse choroid plexus and CSF at high molecular, spatial, and temporal resolution.

Transmission and secretion of signals via the choroid plexus (ChP) brain barrier can modulate brain states via regulation of cerebrospinal fluid (CSF) composition. Here, we developed a platform to analyze diurnal variations in male mouse ChP and CSF. Ribosome profiling of ChP epithelial cells revealed diurnal translatome differences in metabolic machinery, secreted proteins, and barrier components.

Keeping an eye on circadian time in clinical research and medicine.

Background: Daily rhythms are observed in humans and almost all other organisms. Most of these observed rhythms reflect both underlying endogenous circadian rhythms and evoked responses from behaviours such as sleep/wake, eating/fasting, rest/activity, posture changes and exercise. For many research and clinical purposes, it is important to understand the contribution of the endogenous circadian component to these observed rhythms.

Persistent CO reactivity deficits are associated with neurological dysfunction up to one year after repetitive mild closed head injury in adolescent mice.

Cerebrovascular reactivity (CVR) deficits in adolescents with concussion may persist after resolution of neurological symptoms. Whether or not CVR deficits predict long term neurological function is unknown. We used adolescent mice closed head injury (CHI) models (54 g, 107 cm or 117 cm drop height), followed by blood oxygenation level dependent (BOLD)-functional MRI with CO challenge to assess CVR and brain connectivity.

Modified Precordial Lead R-Wave Deflection Interval Predicts Left- and Right-Sided Idiopathic Outflow Tract Ventricular Arrhythmias.

Objectives: This study evaluated if modifying electrocardiographic (ECG) precordial leads to a higher intercostal position improved the accuracy of outflow tract ventricular arrhythmia (OTVA) localization.

Background: Precordial ECG prediction algorithms that use a standard lead configuration localize OTVA with variable accuracy.

Methods: Patients who underwent OTVA ablation were prospectively enrolled to have a standard and modified (high) precordial ECG.

Position Statement on the Management of Cardiac Electrophysiology and Cardiac Implantable Electronic Devices in Australia During the COVID-19 Pandemic: A Living Document.

The COVID-19 pandemic poses a significant stress on health resources in Australia. The Heart Rhythm Council of the Cardiac Society of Australia and New Zealand aims to provide a framework for efficient resource utilisation balanced with competing risks when appropriately treating patients with cardiac arrhythmias. This document provides practical recommendations for the electrophysiology (EP) and cardiac implantable electronic devices (CIED) services in Australia.

Adaptor protein complex 4 deficiency: a paradigm of childhood-onset hereditary spastic paraplegia caused by defective protein trafficking.

Deficiency of the adaptor protein complex 4 (AP-4) leads to childhood-onset hereditary spastic paraplegia (AP-4-HSP): SPG47 (AP4B1), SPG50 (AP4M1), SPG51 (AP4E1) and SPG52 (AP4S1). This study aims to evaluate the impact of loss-of-function variants in AP-4 subunits on intracellular protein trafficking using patient-derived cells. We investigated 15 patient-derived fibroblast lines and generated six lines of induced pluripotent stem cell (iPSC)-derived neurons covering a wide range of AP-4 variants.

Deletion of Neuronal GLT-1 in Mice Reveals Its Role in Synaptic Glutamate Homeostasis and Mitochondrial Function.

The glutamate transporter GLT-1 is highly expressed in astrocytes but also in neurons, primarily in axon terminals. We generated a conditional neuronal GLT-1 KO using synapsin 1-Cre (synGLT-1 KO) to elucidate the metabolic functions of GLT-1 expressed in neurons, here focusing on the cerebral cortex. Both synaptosomal uptake studies and electron microscopic immunocytochemistry demonstrated knockdown of GLT-1 in the cerebral cortex in the synGLT-1 KO mice.

Assessment of ablation catheter contact on valve annulus: Implications on accessory pathway ablation.

Background: Catheter-tissue contact force is an important factor influencing lesion size and efficacy and thereby potential for arrhythmia recurrence following accessory pathway (AP) radiofrequency ablation. We aim to evaluate adequacy and perception of catheter contact on the tricuspid and mitral annuli.

Methods: Data were collected from 42 patients undergoing catheter ablation.

Mechanisms of sleep and circadian ontogeny through the lens of neurodevelopmental disorders.

Sleep is a mysterious, developmentally regulated behavior fundamental for cognition in both adults and developing animals. A large number of studies offer a substantive body of evidence that demonstrates that the ontogeny of sleep architecture parallels brain development. Sleep deprivation impairs the consolidation of learned tasks into long-term memories and likely links sleep to the neural mechanisms underlying memory and its physiological roots in brain plasticity.

Proteomics, Post-translational Modifications, and Integrative Analyses Reveal Molecular Heterogeneity within Medulloblastoma Subgroups.

There is a pressing need to identify therapeutic targets in tumors with low mutation rates such as the malignant pediatric brain tumor medulloblastoma. To address this challenge, we quantitatively profiled global proteomes and phospho-proteomes of 45 medulloblastoma samples. Integrated analyses revealed that tumors with similar RNA expression vary extensively at the post-transcriptional and post-translational levels.

New Insights Into an Old Arrhythmia: High-Resolution Mapping Demonstrates Conduction and Substrate Variability in Right Atrial Macro-Re-Entrant Tachycardia.

Objectives: Using high-resolution 3-dimensional (3D) mapping, the aim of this study was to further characterize right atrial macro-re-entrant tachycardias and answer unresolved questions in the understanding of this arrhythmia.

Background: Despite advances in understanding of the mechanisms of right atrial macro-re-entrant tachycardias, many questions lack definitive answers. The advent of high-resolution 3D mapping provides an opportunity to gain further insights into the nature of these common circuits.

mGluR5 Modulation of Behavioral and Epileptic Phenotypes in a Mouse Model of Tuberous Sclerosis Complex.

Drugs targeting metabotropic glutamate receptor 5 (mGluR5) have therapeutic potential in autism spectrum disorders (ASD), including tuberous sclerosis complex (TSC). The question whether inhibition or potentiation of mGluR5 could be beneficial depends, among other factors, on the specific indication. To facilitate the development of mGluR5 treatment strategies, we tested the therapeutic utility of mGluR5 negative and positive allosteric modulators (an mGluR5 NAM and PAM) for TSC, using a mutant mouse model with neuronal loss of Tsc2 that demonstrates disease-related phenotypes, including behavioral symptoms of ASD and epilepsy.

Neural Circuitry of Wakefulness and Sleep.

Sleep remains one of the most mysterious yet ubiquitous animal behaviors. We review current perspectives on the neural systems that regulate sleep/wake states in mammals and the circadian mechanisms that control their timing. We also outline key models for the regulation of rapid eye movement (REM) sleep and non-REM sleep, how mutual inhibition between specific pathways gives rise to these distinct states, and how dysfunction in these circuits can give rise to sleep disorders.

Impaired Mitochondrial Dynamics and Mitophagy in Neuronal Models of Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is a neurodevelopmental disease caused by TSC1 or TSC2 mutations and subsequent activation of the mTORC1 kinase. Upon mTORC1 activation, anabolic metabolism, which requires mitochondria, is induced, yet at the same time the principal pathway for mitochondrial turnover, autophagy, is compromised. How mTORC1 activation impacts mitochondrial turnover in neurons remains unknown.

The Circadian Protein BMAL1 Regulates Translation in Response to S6K1-Mediated Phosphorylation.

The circadian timing system synchronizes cellular function by coordinating rhythmic transcription via a transcription-translational feedback loop. How the circadian system regulates gene expression at the translational level remains a mystery. Here, we show that the key circadian transcription factor BMAL1 associates with the translational machinery in the cytosol and promotes protein synthesis.