Semaphorin4D Induces Inhibitory Synapse Formation by Rapid Stabilization of Presynaptic Boutons via MET Coactivation.

Changes in inhibitory connections are essential for experience-dependent circuit adaptations. Defects in inhibitory synapses are linked to neurodevelopmental disorders, but the molecular processes underlying inhibitory synapse formation are not well understood. Here we use high-resolution two-photon microscopy in organotypic hippocampal slices from GAD65-GFP mice of both sexes to examine the signaling pathways induced by the postsynaptic signaling molecule Semaphorin4D (Sema4D) during inhibitory synapse formation.

A BDNF-Mediated Push-Pull Plasticity Mechanism for Synaptic Clustering.

During development, activity-dependent synaptic plasticity refines neuronal networks with high precision. For example, spontaneous activity helps sorting synaptic inputs with similar activity patterns into clusters to enhance neuronal computations in the mature brain. Here, we show that TrkB activation and postsynaptic brain-derived neurotrophic factor (BDNF) are required for synaptic clustering in developing hippocampal neurons.

Scientists' views about attribution of global warming.

Results are presented from a survey held among 1868 scientists studying various aspects of climate change, including physical climate, climate impacts, and mitigation. The survey was unique in its size, broadness and level of detail. Consistent with other research, we found that, as the level of expertise in climate science grew, so too did the level of agreement on anthropogenic causation.

CNS-targeted glucocorticoid reduces pathology in mouse model of amyotrophic lateral sclerosis.

Background: Hallmarks of CNS inflammation, including microglial and astrocyte activation, are prominent features in post-mortem tissue from amyotrophic lateral sclerosis (ALS) patients and in mice overexpressing mutant superoxide dismutase-1 (SOD1G93A). Administration of non-targeted glucocorticoids does not significantly alter disease progression, but this may reflect poor CNS delivery. Here, we sought to discover whether CNS-targeted, liposomal encapsulated glucocorticoid would inhibit the CNS inflammatory response and reduce motor neuron loss.

Glutathione pegylated liposomal methylprednisolone administration after the early phase of status epilepticus did not modify epileptogenesis in the rat.

It has been reported that glucocorticoids (GCs) can effectively control seizures in pediatric epilepsy syndromes, possibly by inhibition of inflammation. Since inflammation is supposed to be involved in epileptogenesis, we hypothesized that treatment with GCs would reduce brain inflammation and thereby modify epileptogenesis in a rat model for temporal lobe epilepsy, in which epilepsy gradually develops after electrically induced status epilepticus (SE). To prevent the severe adverse effects that are inevitable with long-term GC treatment, we used liposome nanotechnology (G-Technology(®)) to enhance the sustained delivery to the brain.

Pharmacokinetics, brain delivery, and efficacy in brain tumor-bearing mice of glutathione pegylated liposomal doxorubicin (2B3-101).

Brain cancer is a devastating disease affecting many people worldwide. Effective treatment with chemotherapeutics is limited due to the presence of the blood-brain barrier (BBB) that tightly regulates the diffusion of endogenous molecules but also xenobiotics. Glutathione pegylated liposomal doxorubicin (2B3-101) is being developed as a new treatment option for patients with brain cancer.

Enhanced brain delivery of liposomal methylprednisolone improved therapeutic efficacy in a model of neuroinflammation.

Neuroinflammation contributes to a wide range of disorders of the central nervous system (CNS). Of the available anti-inflammatory drugs, only glucocorticoids have shown central efficacy in CNS-related disorders, such as multiple sclerosis (MS). However, their side effects are dose limiting.

Two-fold emission from the S-shell of PbSe/CdSe core/shell quantum dots.

The optical properties of PbSe/CdSe core/shell quantum dots with core sizes smaller than 4 nm in the 5-300 K range are reported. The photoluminescence spectra show two peaks, which become increasingly separated in energy as the core diameter is reduced below 4 nm. It is shown that these peaks are due to intrinsic exciton transitions in each quantum dot, rather than emission from different quantum dot sub-ensembles.

Leukocyte cathepsin S is a potent regulator of both cell and matrix turnover in advanced atherosclerosis.

Objective: A dysbalance of proteases and their inhibitors is instrumental in remodeling of atherosclerotic plaques. One of the proteases implicated in matrix degradation is cathepsin-S (CatS). To address its role in advanced lesion composition, we generated chimeric LDLr(-/-) mice deficient in leukocyte CatS by transplantation with CatS(-/-)xLDLr(-/-) or with LDLr(-/-) bone marrow and administered a high-fat diet.

bis-Cholesteryl-conjugated phosphorothioate oligodeoxynucleotides are highly selectively taken up by the liver.

We previously modulated, by conjugating a single cholesterol, plasma protein binding and liver cell uptake of a phosphorothioate oligodeoxynucleotide (PS-ODN). In this study, we investigated the biological fate of a PS-ODN, denoted ISIS-9389 (3',5'-bis-cholesteryl-conjugated ISIS 3082), provided with two cholesteryl moieties. After intravenous injection of into rats, [(3)H]ISIS-9389 was cleared from plasma with a half-life of 23.

Delivery of cholesteryl-conjugated phosphorothioate oligodeoxynucleotides to Kupffer cells by lactosylated low-density lipoprotein.

The efficacy of antisense oligonucleotides depends on the ability to reach in vivo their target cells. We aim to develop strategies to enhance uptake of phosphorothioate oligodeoxynucleotides by Kupffer cells. To this end, we conjugated cholesterol to ISIS-3082, a phosphorothioate oligodeoxynucleotide specific for intercellular adhesion molecule-1.

A Rett syndrome patient with a ring X chromosome: further evidence for skewing of X inactivation and heterogeneity in the aetiology of the disease.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder, characterised by regression of development in young females. Recently, mutations in the MECP2 gene were found to be present in 80% of sporadic cases, but in much lower frequency (< 30%) among familial cases. Several reports claim that the pattern of X chromosome inactivation (XCI) relates to the penetrance of RTT; in some cases skewed XCI is seen in Rett patients, and in others it is observed among normal carriers.

Atrial fibrillation in the goat induces changes in monophasic action potential and mRNA expression of ion channels involved in repolarization.

Introduction: Sustained atrial fibrillation (AF) is characterized by a marked shortening of the atrial effective refractory period (AERP) and a decrease or reversal of its physiologic adaptation to heart rate. The aim of the present study was to investigate whether the AF-induced changes in AERP in the goat are associated with changes in the atrial monophasic action potential (MAP) and whether an abnormal expression of specific ion channels underlies such changes.

Methods And Results: Following thoracotomy, MAPs were recorded from the free wall of the right atrium both before induction of AF (control) and after cardioversion of sustained AF (>2 months) in chronically instrumented goats.

Modulation of plasma protein binding and in vivo liver cell uptake of phosphorothioate oligodeoxynucleotides by cholesterol conjugation.

Several studies have shown improved efficacy of cholesteryl-conjugated phosphorothioate antisense oligodeoxynucleotides. To gain insight into the mechanisms of the improved efficacy in vivo, we investigated the disposition of ISIS-9388, the 3'-cholesterol analog of the ICAM-1-specific phosphorothioate oligodeoxynucleotide ISIS-3082, in rats. Intravenously injected [(3)H]ISIS-9388 was cleared from the circulation with a half-life of 49.

Widening of the excitable gap during pharmacological cardioversion of atrial fibrillation in the goat: effects of cibenzoline, hydroquinidine, flecainide, and d-sotalol.

Background: Previous studies suggest that the antifibrillatory action of class I and III drugs is due to prolongation of the atrial wavelength. The aim of the present study was to directly evaluate the electrophysiological action of antifibrillatory drugs in a goat model of chronic atrial fibrillation (AF).

Methods And Results: Six goats were instrumented with multiple atrial electrodes, and sustained AF was induced by electrical remodeling.

Repetitive electrical remodeling by paroxysms of atrial fibrillation in the goat: no cumulative effect on inducibility or stability of atrial fibrillation.

Introduction: Episodes of atrial fibrillation (AF) are known to cause both a rapid reduction in atrial refractoriness (atrial electrical remodeling) and a more delayed increase in AF stability in the chronic goat model. The aims of this study were to examine (1) the hypothesis that an AF-induced increase in AF stability might be due to a mechanism with a longer onset and offset than that of changes in refractoriness and (2) the possibility that repeated paroxysms of maintained AF might cause a cumulative increase in AF stability independent of changes in atrial refractoriness.

Methods And Results: AF was maintained by rapid atrial pacing in seven goats for three consecutive 5-day periods, each separated from each other by 48 hours of sinus rhythm.

Pharmacologic cardioversion of chronic atrial fibrillation in the goat by class IA, IC, and III drugs: a comparison between hydroquinidine, cibenzoline, flecainide, and d-sotalol.

Introduction: Recently, we reported that repetitive induction of atrial fibrillation (AF) in the goat causes electrical remodeling of the atria leading to the development of sustained AF. The aim of the present study was to compare Class IA, IC, and III drugs in their ability to cardiovert chronic AF in remodeled atria.

Methods And Results: In 16 goats with sustained AF, hydroquinidine (HQ), cibenzoline (Ci), flecainide (FI), and d-sotalol (dS) were infused.

Mechanisms of pharmacologic cardioversion of atrial fibrillation by Class I drugs.

Introduction: We recently developed a goat model of sustained atrial fibrillation (AF) in which repetitive induction of AF by burst pacing shortened the atrial effective refractory period (AERP) (electrophysiologic remodeling) and progressively prolonged the paroxysms of AF to become sustained (24 hours) within 1 to 3 weeks (atrial fibrillation begets atrial fibrillation). The aim of the present study was to study the effect of Class I drugs in this animal model of chronic AF.

Methods And Results: The effects of hydroquinidine (HQ) on seven chronically fibrillating goats and of flecainide (Fl) on nine goats were studied.

Electrical remodeling due to atrial fibrillation in chronically instrumented conscious goats: roles of neurohumoral changes, ischemia, atrial stretch, and high rate of electrical activation.

Background: Recently, we developed a goat model of chronic atrial fibrillation (AF). Due to AF, the atrial effective refractory period (AERP) shortened and its physiological rate adaptation inversed, whereas the rate and stability of AF increased. The goal of the present study was to evaluate the role of (1) the autonomic nervous system, (2) ischemia, (3) stretch, (4) atrial natriuretic factor (ANF), and (5) rapid atrial pacing in this process of electrical remodeling.

Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats.

Background: In this study we tested the hypothesis that atrial fibrillation (AF) causes electrophysiological changes of the atrial myocardium which might explain the progressive nature of the arrhythmia.

Methods And Results: Twelve goats were chronically instrumented with multiple electrodes sutured to the epicardium of both atria. Two to 3 Weeks after implantation, the animals were connected to a fibrillation pacemaker which artificially maintained AF.

The protective mechanism of action of amines in diphtheria toxin treated Vero cells.

The mechanisms by which a number of alkylamines and ethylenediamine derivatives protect Vero cells from diphtheria toxin were studied. The protective alkylamines and ethylenediamine compounds blocked the cellular degradation of diphtheria toxin, but did not prevent bulk toxin uptake. Specific antibody neutralized the inhibitory effects of toxin on protein synthesis in amine-treated cells when added at 37 degrees C, but was ineffective when added at 4 degrees C.