CIAO1 and MMS19 deficiency: A lethal neurodegenerative phenotype caused by cytosolic Fe-S cluster protein assembly disorders.

Purpose: The functionality of many cellular proteins depends on cofactors; yet, they have only been implicated in a minority of Mendelian diseases. Here, we describe the first 2 inherited disorders of the cytosolic iron-sulfur protein assembly system.

Methods: Genetic testing via genome sequencing was applied to identify the underlying disease cause in 3 patients with microcephaly, congenital brain malformations, progressive developmental and neurologic impairments, recurrent infections, and a fatal outcome.

The Physiological and Molecular Links Between Physical Activity and Brain Health: A Review.

There is currently an epidemic of sedentary behavior throughout the world, leading to negative impacts on physical health and contributing to both mortality and burden of disease. The consequences of this also impact the brain, where increased levels of cognitive decline are observed in individuals who are more sedentary. This review explores the physiological and molecular responses to our sedentary propensity, its contribution to several medical conditions and cognitive deficits, and the benefits of moderate levels of physical activity and exercise.

Separating the Wheat from the Chaff: The Use of Upstream Regulator Analysis to Identify True Differential Expression of Single Genes within Transcriptomic Datasets.

The development of DNA microarray and RNA-sequencing technology has led to an explosion in the generation of transcriptomic differential expression data under a wide range of biologic systems including those recapitulating the monogenic muscular dystrophies. Data generation has increased exponentially due in large part to new platforms, improved cost-effectiveness, and processing speed. However, reproducibility and thus reliability of data remain a central issue, particularly when resource constraints limit experiments to single replicates.

Compounded topographical and physicochemical cueing by micro-engineered chitosan substrates on rat dorsal root ganglion neurons and human mesenchymal stem cells.

Given the intertwined physicochemical effects exerted in vivo by both natural and synthetic (e.g., biomaterial) interfaces on adhering cells, the evaluation of structure-function relationships governing cellular response to micro-engineered surfaces for applications in neuronal tissue engineering requires the use of in vitro testing platforms which consist of a clinically translatable material with tunable physiochemical properties.

[C]meta-hydroxyephedrine PET evaluation in experimental pulmonary arterial hypertension: Effects of carvedilol of right ventricular sympathetic function.

Background: Little is known about the sequelae of chronic sympathetic nervous system (SNS) activation in patients with pulmonary arterial hypertension (PAH) and right heart failure (RHF). We aimed to, (1) validate the use of [11C]-meta-hydroxyephedrine (HED) for assessing right ventricular (RV) SNS integrity, and (2) determine the effects of β-receptor blockade on ventricular function and myocardial SNS activity in a PAH rat model.

Methods: PAH was induced in male Sprague-Dawley rats (N = 36) using the Sugen+chronic hypoxia model.

Educational Research Report Correlation between Student Self-Assessment and Proctor Evaluation in a Veterinary Surgical Laboratory.

Self-assessment has been shown to facilitate learning, goal setting, and professional development. We sought to evaluate whether veterinary students in a surgical curriculum would have self-assessments that differed from proctor evaluations and whether high-performing students would differ from low-performing students in self-assessment characteristics. Student and proctor assessments were compared for 8 weeks of a spay/neuter surgical laboratory taking place in the second year of the curriculum.

Electrophysiological Alterations of Pyramidal Cells and Interneurons of the CA1 Region of the Hippocampus in a Novel Mouse Model of Dravet Syndrome.

Dravet syndrome is a developmental epileptic encephalopathy caused by pathogenic variation in To characterize the pathogenic substitution (p.H939R) of a local individual with Dravet syndrome, fibroblast cells from the individual were reprogrammed to pluripotent stem cells and differentiated into neurons. Sodium currents of these neurons were compared with healthy control induced neurons.

Transcriptomic RNAseq drug screen in cerebrocortical cultures: toward novel neurogenetic disease therapies.

Rare monogenic diseases affect millions worldwide; although over 4500 rare disease genotypes are known, disease-modifying drugs are available for only 5% of them. The sheer number of these conditions combined with their rarity precludes traditional costly drug discovery programs. An economically viable alternative is to repurpose established drugs for rare diseases.

Anisomycin Activates Utrophin Upregulation Through a p38 Signaling Pathway.

Duchenne muscular dystrophy is a recessive X-linked disease characterized by progressive muscle wasting; cardiac or respiratory failure causes death in most patients by the third decade.  The disease is caused by mutations in the dystrophin gene that lead to a loss of functional dystrophin protein. Although there are currently few treatments for Duchenne muscular dystrophy, previous reports have shown that upregulating the dystrophin paralog utrophin in Duchenne muscular dystrophy mouse models is a promising therapeutic strategy.

CRHR1 exacerbates the glial inflammatory response and alters BDNF/TrkB/pCREB signaling in a rat model of global cerebral ischemia: implications for neuroprotection and cognitive recovery.

This study examined the impact of corticotropin-releasing hormone type 1 receptor (CRHR1) blockade using Antalarmin (ANT) on the expression of markers of neuroplasticity and inflammation, as well as neuroprotection and behavioral recovery following global cerebral ischemia. Male Wistar rats (N=50) were treated with ANT (2μg/2μl; icv) or a vehicle solution prior to a sham or four vessel (4VO) occlusion. Seven days post ischemia, anxiety was assessed in the Elevated Plus Maze and Open Field tests, and fear and spatial learning in a Y-Maze Passive Avoidance Task and the Barnes Maze.

Activation of CRHR1 receptors regulates social and depressive-like behaviors and expression of BDNF and TrkB in mesocorticolimbic regions following global cerebral ischemia.

Increased HPA axis activation and CRH release characterize the brain's response to global cerebral ischemia. Recently, CRH via activation of CRH type 1 receptors (CRHR1) has been shown to regulate Brain Derived Neurotrophic Factor (BDNF) secretion and emotional behavior. The current study investigates the impact of CRHR1 blockade on BDNF/TrkB signaling expression in the mesolimbic circuitry, and social and depressive-like behavior following global ischemia.

Cilostazol reduces blood brain barrier dysfunction, white matter lesion formation and motor deficits following chronic cerebral hypoperfusion.

Cerebral small vessel disease (CSVD) is a pathological process leading to lacunar infarcts, leukoaraiosis and cerebral microbleeds. Dysfunction of the blood brain barrier (BBB) has been proposed as a mechanism in the progression cerebral small vessel disease. A rodent model commonly used to study some aspects of CSVD is bilateral common carotid artery occlusion (BCCAO) in the rat.

Evaluation of the direct effects of poly(dopamine) on the in vitro response of human osteoblastic cells.

Functional polymeric coatings have rapidly become one of the most efficient strategies to endow biomaterials with enhanced bioactive properties. Among the bio-inspired polymers used for biomedical applications, mussel-derived poly(dopamine) (PDA) has increasingly attracted considerable interest because of its unique characteristics. In this work, we carried out detailed physicochemical characterization of a PDA film deposited on nanoporous titanium.

Microparticles generated during chronic cerebral ischemia increase the permeability of microvascular endothelial barriers in vitro.

Numbers of circulating microparticles (MPs) are elevated in a variety of cardiovascular disorders, and recent studies indicate that they are involved in inflammatory intercellular signaling. In the present study the signaling properties of MPs were assessed in an in vitro model of the blood brain barrier. MPs isolated from the plasma of rats exposed to chronic cerebral ischemia caused a significant reduction in the transendothelial electrical resistance (TEER) when applied to in vitro endothelial barriers, while MPs isolated from an equal volume of plasma from unoperated or sham operated rats did not.

A rapid and efficient method for dissociated cultures of mouse myenteric neurons.

Background: The enteric nervous system controls gastrointestinal functions such as secretion and smooth muscle contraction/relaxation. Neuronal enteric dysfunction is a feature of many direct gastrointestinal disorders and can be secondary to central nervous system disorders. Research in this field has been limited and there are few published methods on dissociated enteric cultures.

Microparticles generated during chronic cerebral ischemia deliver proapoptotic signals to cultured endothelial cells.

Circulating microparticles (MPs) are involved in many physiological processes and numbers are increased in a variety of cardiovascular disorders. The present aims were to characterize levels of MPs in a rodent model of chronic cerebral hypoperfusion (CCH) and to determine their signaling properties. MPs were isolated from the plasma of rats exposed to CCH and quantified by flow cytometry.

Microparticles: biomarkers and beyond.

Membrane microparticles are submicron fragments of membrane shed into extracellular space from cells under conditions of stress/injury. They may be distinguished from other classes of extracellular vesicles (i.e.

Development of dissociated cryopreserved rat cortical neurons in vitro.

Dissociated neuronal cultures of various brain regions are commonly used to study physiological and pathophysiological processes in vitro. The data derived from these studies are often viewed to have relevance to processes taking place in the mature brain. However, due to the practical challenges associated with lengthy neuronal culture, neurons are often kept for 14 days in vitro (DIV), or less, before being subject to experimentation.

The corticostriatal system in dissociated cell culture.

The sparse connectivity within the striatum in vivo makes the investigation of individual corticostriatal synapses very difficult. Most studies of the corticostriatal input have been done using electrical stimulation under conditions where it is hard to identify the precise origin of the cortical input. We have employed an in vitro dissociated cell culture system that allows the identification of individual corticostriatal pairs and have been developing methods to study individual neuron inputs to striatal neurons.

LIM domain only 4 protein promotes granulocyte colony-stimulating factor-induced signaling in neurons.

Granulocyte colony-stimulating factor (GCSF) is currently in clinical trials to treat neurodegenerative diseases and stroke. Here, we tested whether LIM domain only 4 protein (LMO4), a hypoxia-inducible gene that protects neurons from ischemic injury, could modulate the neuroprotective effect of GCSF. We showed that GCSF treatment acetylates and phosphorylates Stat3, activates expression of a Stat3-dependent anti-apoptotic gene, p27, and increases neuron survival from ischemic injury.

Protection conferred by Corticotropin-releasing hormone in rat primary cortical neurons against chemical ischemia involves opioid receptor activation.

Different studies have supported neuroprotective effects of Corticotropin-releasing hormone (CRH) against various excitotoxic and oxidative insults in vitro. However, the physiological mechanisms involved in this protection remain largely unknown. The present study was undertaken to determine the impact of CRH administration (at concentrations ranging from 200 fmol to 2 nmol) before and at delayed time intervals following potassium cyanide (KCN)-induced insult in rat primary cortical neurons.

Rescue of neurons from ischemic injury by peroxisome proliferator-activated receptor-gamma requires a novel essential cofactor LMO4.

Activation of peroxisome proliferator-activated receptor-gamma (PPARgamma) signaling after stroke may reduce brain injury, but this effect will depend on the levels of receptor and cofactors. Here, we showed that the direct effect of PPARgamma signaling to protect neurons from ischemic injury requires a novel cofactor LMO4, because this effect was lost in LMO4-null cortical neurons. PPARgamma agonist also failed to reduce cerebral infarction after transient focal ischemia in CaMKIIalphaCre/LMO4loxP mice with LMO4 ablated in neurons of the forebrain.

ATP release by way of connexin 36 hemichannels mediates ischemic tolerance in vitro.

Spreading depression (SD) is a self-propagating wave of neuronal and glial depolarization that may occur in virtually any gray matter region in the brain. One consequence of SD is an increased tolerance to ischemia. It has been shown that during cortical SD ATP is released into the extracellular space and activation of purinergic receptors leads to the induction of ischemic tolerance.