rudyvdbrink/CitationDatabase huggingface dataset:
Proteolytic cleavage of Opa1 stimulates mitochondrial inner membrane fusion and couples fusion to oxidative phosphorylation.
Cell metabolism, 2014

Mitochondrial fusion is essential for maintenance of mitochondrial function. The mitofusin GTPases control mitochondrial outer membrane fusion, whereas the dynamin-related GTPase Opa1 mediates inner membrane fusion. We show that mitochondrial inner membrane fusion is tuned by the level of oxidative phosphorylation (OXPHOS), whereas outer membrane fusion is insensitive. Consequently, cells from patients with pathogenic mtDNA mutations show a selective defect in mitochondrial inner membrane fusion. In elucidating the molecular mechanism of OXPHOS-stimulated fusion, we uncover that real-time proteolytic processing of Opa1 stimulates mitochondrial inner membrane fusion. OXPHOS-stimulated mitochondrial fusion operates through Yme1L, which cleaves Opa1 more efficiently under high OXPHOS conditions. Engineered cleavage of Opa1 is sufficient to mediate inner membrane fusion, regardless of respiratory state. Proteolytic cleavage therefore stimulates the membrane fusion activity of Opa1, and this feature is exploited to dynamically couple mitochondrial fusion to cellular metabolism.
CaMKIIα knockdown decreases anxiety in the open field and low serotonin-induced upregulation of GluA1 in the basolateral amygdala.
Behavioural brain research, 2016

Hyperactivation of the amygdala is implicated in anxiety and mood disorders, but the precise underlying mechanisms are unclear. We previously reported that depletion of serotonin (5-hydroxytryptamine, 5-HT) in the basolateral nucleus of the amygdala (BLA) using the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) potentiated learned fear and increased glutamate receptor (Glu) expression in BLA. Here we investigated the hypothesis that CaMKII facilitates anxiety-like behavior and increased Glu/AMPA receptor subunit A1 (GluA1) expression following depletion of 5-HT in the BLA. Infusion of 5,7-DHT into the BLA resulted in anxiety-like behavior in the open field test (OFT) and increased the phosphorylation of CaMKIIα (Thr-286) in the BLA. Knockdown of the CaMKIIα subunit using adeno-associated virus (AAV)-delivered shRNAi concomitantly attenuated anxiety-like behavior in the OFT and decreased GluA1 expression in the BLA. Our results suggest that the CaMKII signaling plays a key role in low 5-HT-induced anxiety and mood disturbances, potentially through regulation of GluA1 expression in the BLA.
Immunohistochemical determination of the site of antidepressant-like effects of glucagon-like peptide-2 in ACTH-treated mice.
Neuroscience, 2015

The intracerebroventicular administration (i.c.v.) of glucagon-like peptide-2 (GLP-2) had antidepressant-like effects on saline-treated mice in the forced-swim test. The GLP-2 treatment (3 μg, i.c.v.) for 6 days, but not that of imipramine had antidepressant-like effects on adrenocorticotropic hormone (ACTH)-treated mice. The immunohistochemical detection of the c-fos protein (Fos) revealed that the administration of GLP-2 induced Fos-immunoreactivity (Fos-IR) in the dorsomedial hypothalamic nucleus in saline-treated and ACTH-treated mice, and also in the hippocampal dentate gyrus in ACTH-treated mice, but not in saline-treated mice. In contrast, Fos-IR in the paraventricular nucleus of the hypothalamus decreased after the administration of GLP-2 to ACTH-treated mice. In ACTH-treated mice, the chronic administration of GLP-2 affected hippocampal neurogenesis, in addition to Fos-IR in hypothalamic GABAergic neurons and corticotrophin-releasing factor-containing neurons. These results suggest that GLP-2 acts on specific brain regions to regulate stress conditions, and induces antidepressant-like effects under imipramine-resistant conditions, which may be associated with the modulation of the hypothalamic-pituitary-adrenal-axis.
Presynaptically expressed long-term potentiation increases multivesicular release at parallel fiber synapses.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2009

At a number of synapses, long-term potentiation (LTP) can be expressed by an increase in presynaptic strength, but it is unknown whether presynaptic LTP is expressed solely through an increase in the probability that a single vesicle is released or whether it can increase multivesicular release (MVR). Here, we show that presynaptic LTP decreases inhibition of AMPA receptor EPSCs by a low-affinity antagonist at parallel fiber-molecular layer interneuron (PF-MLI) synapses. This indicates that LTP induction results in larger glutamate concentration transients in the synaptic cleft, a result indicative of MVR, and suggests that MVR can be modified by long-term plasticity. A similar decrease in inhibition was observed when release probability (PR) was increased by forskolin, elevated extracellular Ca2+, and paired-pulse facilitation. Furthermore, we show that MVR may occur under baseline physiological conditions, as inhibition increased when P(R) was lowered by reducing extracellular Ca2+ or by activating presynaptic adenosine receptors. These results suggest that at PF-MLI synapses, MVR occurs under control conditions and is increased when PR is elevated by both short- and long-term plasticity mechanisms.
Functional connectivity and integrative properties of globus pallidus neurons.
Neuroscience, 2011

The globus pallidus consists of the external (GPe) and the internal (GPi) segments. The GPe and GPi have different functional roles. The GPe is located centrally within multiple basal ganglia feedforward and feedback connections. The GPi is an output nucleus of the basal ganglia. A complex interplay between intrinsic pacemaking conductances and the balance of glutamatergic and GABAergic input largely determines the rate and pattern of firing of pallidal neurons. The initial part of this article introduces recent findings made in vivo that are related to the roles of glutamatergic and GABAergic inputs in the control of pallidal activity. The latter part describes the roles of intrinsic mechanisms of GPe neurons in the integration of the synaptic inputs. The presence of dendritic voltage-gated sodium channels may allow the initiation of dendritic spikes, giving distal inputs on the long and thin GPe dendrites an opportunity to strongly shape spiking activity. Basal ganglia disorders including Parkinson's disease, hemiballismus, and dystonias are accompanied by increased irregularity and synchronized bursts of pallidal activity. These changes may be in part due to changes in the GABA release in the GPe and GPi, but also involve intrinsic cellular changes in pallidal neurons.
Neuroprotection and immunomodulation of progesterone in the gut of a mouse model of Parkinson's disease.
Journal of neuroendocrinology, 2020

Gastrointestinal symptoms appear in Parkinson's disease patients many years before motor symptoms, suggesting the implication of dopaminergic neurones of the gut myenteric plexus. Inflammation is also known to be increased in PD. We previously reported neuroprotection with progesterone in the brain of mice lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and hypothesised that it also has neuroprotective and immunomodulatory activities in the gut. To test this hypothesis, we investigated progesterone administered to adult male C57BL/6 mice for 10 days and treated with MPTP on day 5. In an additional experiment, progesterone was administered for 5 days following MPTP treatment. Ilea were collected on day 10 of treatment and microdissected to isolate the myenteric plexus. Dopaminergic neurones were reduced by approximately 60% and pro-inflammatory macrophages were increased by approximately 50% in MPTP mice compared to intact controls. These changes were completely prevented by progesterone administered before and after MPTP treatment and were normalised by 8 mg kg
Polyacrylate/polyacrylate-PEG biomaterials obtained by high internal phase emulsions (HIPEs) with tailorable drug release and effective mechanical and biological properties.
Materials science & engineering. C, Materials for biological applications, 2019

The paper focuses on the preparation of polyacrylate based biomaterials designed as patches for dermal/transdermal drug delivery using materials obtained by the high internal phase emulsion (HIPE) technique. In particular, butyl acrylate and glycidyl methacrylate were selected, respectively, as backbone and functional monomer while two different crosslinkers, bifunctional or trifunctional, were used to form the covalent network. The influence of PEG on the main properties of the materials was also investigated. The obtained materials show a characteristic and interconnected internal structure as confirmed by SEM studies. By an industrial point of view, an interesting feature of this system is that it can be shaped as needed, in any form and thickness. The physiochemically characterized materials showed a tailorable curcumin (model of hydrophobic drugs) drug release, effective mechanical properties and cell viability and resulted neither pro nor anti-angiogenic as demonstrated in vivo by the chick embryo choriallantoic membrane (CAM) assay. Based on these results, the obtained polyHIPEs could be proposed as devices for dermal/transdermal drug delivery and/or for the direct application on wounded skin.
How Informative Are Self-Reported Adult Attention-Deficit/Hyperactivity Disorder Symptoms? An Examination of the Agreement Between the Adult Attention-Deficit/Hyperactivity Disorder Self-Report Scale V1.1 and Adult Attention-Deficit/Hyperactivity Disorder Investigator Symptom Rating Scale.
Journal of child and adolescent psychopharmacology, 2018

Assess agreement between self-ratings via the adult attention-deficit/hyperactivity disorder (ADHD) Self-Report Scale (ASRS)-v1.1 Symptom Checklist and clinician ratings via the adult ADHD Investigator Symptom Rating Scale (AISRS) expanded version using DSM-5 adult ADHD patients (referred sample) and ADHD controls (recruited from a primary care physician practice).
IL-1 receptor-antagonist (IL-1Ra) knockout mice show anxiety-like behavior by aging.
Neuroscience letters, 2015

Interleukin 1 (IL-1) plays a critical role in stress responses, and its mRNA is induced in the brain by restraint stress. Previously, we reported that IL-1 receptor antagonist (IL-1Ra) knockout (KO) mice, which lacked IL-1Ra molecules that antagonize the IL-1 receptor, showed anti-depression-like behavior via adrenergic modulation at the age of 8 weeks. Here, we report that IL-1Ra KO mice display an anxiety-like phenotype that is induced spontaneously by aging in the elevated plus-maze (EPM) test. This anxiety-like phenotype was improved by the administration of diazepam. The expression of the anxiety-related molecule glucocorticoid receptor (GR) was significantly reduced in 20-week-old but not in 11-week-old IL-1Ra KO mice compared to wild-type (WT) littermates. The expression of the mineralocorticoid receptor (MR) was not altered between IL-1Ra KO mice and WT littermates at either 11 or 20 weeks old. Analysis of monoamine concentration in the hippocampus revealed that tryptophan, the serotonin metabolite 5-hydroxyindole acetic acid (5-HIAA), and the dopamine metabolite homovanillic acid (HVA) were significantly increased in 20-week-old IL-1Ra KO mice compared to littermate WT mice. These findings strongly suggest that the anxiety-like behavior observed in older mice was caused by the complicated alteration of monoamine metabolism and/or GR expression in the hippocampus.
Discrete modulation of anti-predatory and agonistic behaviors by sensory communication signals in juvenile crayfish.
The Journal of experimental biology, 2020

We investigated how the exchange of sensory signals modulates the individual behaviors of juvenile crayfish in an anti-predatory context as well as during intraspecific agonistic encounters. We first compared crayfish housed in total sensory isolation or in pairs with access to chemical and visual cues. After 1 week of housing, we analysed their individual responses to a visual danger signal while they were foraging. We found that crayfish previously housed in pairs with exchange of sensory signals responded to a simulated predator attack predominantly with freezing behavior, whereas animals deprived of all sensory communication mostly responded by performing escape tail-flips. Next, we used the same housing conditions in between repeated fights in pairs of crayfish. Aggressive and submissive behaviors increased in subsequent fights both after total isolation and after exchange of olfactory and visual signals. Thus, unlike responses to simulated predator attacks, intraspecific agonistic behavior was not modulated by exposure to the same sensory signals. However, when we tested the effects of olfactory or visual communication independently, aggression increased dramatically after the exchange of olfactory signals, which also led to a high number of rank reversals in second fights, suggesting a destabilization of the original dominance relationship. Exposure to visual cues during the 1-week separation, however, produced the opposite effect, reducing agonistic behaviors and rank reversals. These findings demonstrate that exchange of sensory signals modulates future anti-predatory decision-making and intraspecific agonistic behaviors discretely, suggesting that the effect of these signals on shared neural circuitry is context dependent.
Inhibition of BMP signaling suppresses metastasis in mammary cancer.
Oncogene, 2015

Bone morphogenetic proteins (BMPs) are secreted cytokines/growth factors that have differing roles in cancer. BMPs are overexpressed in human breast cancers, but loss of BMP signaling in mammary carcinomas can accelerate metastasis. We show that human breast cancers display active BMP signaling, which is rarely downregulated or homozygously deleted. We hypothesized that systemic inhibition of BMP signaling in both the tumor and the surrounding microenvironment could prevent tumor progression and metastasis. To test this hypothesis, we used DMH1, a BMP antagonist, in MMTV.PyVmT expressing mice. Treatment with DMH1 reduced lung metastasis and the tumors were less proliferative and more apoptotic. In the surrounding tumor microenvironment, treatment with DMH1 altered fibroblasts, lymphatic vessels and macrophages to be less tumor promoting. These results indicate that inhibition of BMP signaling may successfully target both the tumor and the surrounding microenvironment to reduce tumor burden and metastasis.
Joint modelling of confounding factors and prominent genetic regulators provides increased accuracy in genetical genomics studies.
PLoS computational biology, 2012

Expression quantitative trait loci (eQTL) studies are an integral tool to investigate the genetic component of gene expression variation. A major challenge in the analysis of such studies are hidden confounding factors, such as unobserved covariates or unknown subtle environmental perturbations. These factors can induce a pronounced artifactual correlation structure in the expression profiles, which may create spurious false associations or mask real genetic association signals. Here, we report PANAMA (Probabilistic ANAlysis of genoMic dAta), a novel probabilistic model to account for confounding factors within an eQTL analysis. In contrast to previous methods, PANAMA learns hidden factors jointly with the effect of prominent genetic regulators. As a result, this new model can more accurately distinguish true genetic association signals from confounding variation. We applied our model and compared it to existing methods on different datasets and biological systems. PANAMA consistently performs better than alternative methods, and finds in particular substantially more trans regulators. Importantly, our approach not only identifies a greater number of associations, but also yields hits that are biologically more plausible and can be better reproduced between independent studies. A software implementation of PANAMA is freely available online at http://ml.sheffield.ac.uk/qtl/.
A randomized, double-blind placebo-controlled trial of oral creatine monohydrate augmentation for enhanced response to a selective serotonin reuptake inhibitor in women with major depressive disorder.
The American journal of psychiatry, 2012

Antidepressants targeting monoaminergic neurotransmitter systems, despite their immediate effects at the synaptic level, usually require several weeks of administration to achieve clinical efficacy. The authors propose a strategy of adding creatine monohydrate (creatine) to a selective serotonin reuptake inhibitor (SSRI) in the treatment of patients with major depressive disorder. Such augmentation may lead to a more rapid onset of antidepressant effects and a greater treatment response, potentially by restoring brain bioenergetics at the cellular level.
Interaction between hippocampal serotonin and cannabinoid systems in reactivity to spatial and object novelty detection.
Behavioural brain research, 2017

Functional interaction between cannabinoid and serotonin neuronal systems have been reported in different tasks related to memory assessment. The present study investigated the effect of serotonin 5-HT4 agents into the dorsal hippocampus (the CA1 region) on spatial and object novelty detection deficits induced by activation of cannabinoid CB1 receptors (CB1Rs) using arachidonylcyclopropylamide (ACPA) in a non-associative behavioral task designed to forecast the ability of rodents to encode spatial and non-spatial relationships between distinct stimuli. Post-training, intra-CA1 microinjection of 5-HT4 receptor agonist RS67333 or 5-HT4 receptor antagonist RS23597 both at the dose of 0.016μg/mouse impaired spatial memory, while cannabinoid CB1R antagonist AM251 (0.1μg/mouse) facilitated object novelty memory. Also, post-training, intraperitoneal administration of CB1R agonist ACPA (0.005-0.05mg/kg) impaired both memories. However, a subthreshold dose of RS67333 restored ACPA response on both memories. Moreover, a subthreshold dose of RS23597 potentiated ACPA (0.01mg/kg) and reversed ACPA (0.05mg/kg) responses on spatial memory, while it potentiated ACPA response at the dose of 0.005 or 0.05mg/kg on object novelty memory. Furthermore, effective dose of AM251 restored ACPA response at the higher dose. AM251 blocked response induced by combination of RS67333 or RS23597 and the higher dose of ACPA on both memories. Our results highlight that hippocampal 5-HT4 receptors differently affect cannabinoid signaling in spatial and object novelty memories. The inactivation of CB1 receptors blocks the effect of 5-HT4 agents into the CA1 region on memory deficits induced by activation of CB1Rs via ACPA.
Immunohistochemical localization of exoribonucleases (DIS3L2 and XRN1) in intranuclear inclusion body disease.
Neuroscience letters, 2018

mRNA turnover controls gene expression under various conditions in aging and neurodegenerative diseases. Polyglutamine (polyQ) diseases and intranuclear inclusion body disease (INIBD) are neurodegenerative diseases characterized by the formation of nuclear inclusions. These inclusions are immunopositive for several proteins associated with amyotrophic lateral sclerosis. In amyotrophic lateral sclerosis, the processing of RNA from gene transcription through degradation (RNA metabolism) has been reported to be altered. We hypothesized that the proteins associated with RNA metabolism are also involved in the formation of nuclear inclusions in polyQ diseases and INIBD. 3'-5' exoribonuclease DIS3L2 and 5'-3' exoribonuclease XRN1 play critical roles in mRNA decay. Using immunohistochemistry with antibodies against DIS3L2 and XRN1, we examined the brains of patients with polyQ diseases and INIBD and normal control subjects. In controls, immunoreactivity for DIS3L2 and XRN1 was found in the neuronal cytoplasm and neuropil, respectively. In INIBD, immunoreactivity for DIS3L2 and XRN1 was present in neuronal and glial nuclear inclusions. Co-localization of ubiquitin and DIS3L2 or XRN1 was demonstrated in these inclusions. In polyQ diseases, however, nuclear inclusions were immunonegative for DIS3L2 and XRN1. These findings suggest that sequestration of exoribonucleases to nuclear inclusions may be related to the pathogenesis of INIBD.
Predicting the clinical efficacy and potential adverse effects of a humanized anticocaine monoclonal antibody.
Immunotherapy, 2012

The effects of a humanized monoclonal antibody (mAb) having high affinity and specificity for cocaine in animal models are reviewed. The mAb reduced the concentration of cocaine in the brain of mice after intravenous injection of cocaine. In addition, the mAb increased the concentration of cocaine required to reinstate cocaine self-administration. These effects may predict clinical efficacy of a passive immunotherapy for reducing the probability of cocaine-induced relapse. However, in the presence of the mAb, once cocaine self-administration was reinstated, the consumption rate of cocaine was increased. This effect is hypothesized to result from a pharmacokinetic/pharmacodynamic interaction. A humanized mAb should minimize adverse events related to the immunogenicity of the mAb protein, and the specificity for cocaine should avoid adverse events related to interactions with physiologically relevant endogenous proteins.
Perioperative pain management in cardiac surgery: a systematic review.
Minerva anestesiologica, 2018

Every year, more than 1.5 million patients, who undergo cardiac surgery worldwide, are exposed to a series of factors that can trigger acute postoperative pain associated with hemodynamic instability, respiratory complications, and psychological disorders. Through an evaluation of literature data about postoperative pain in cardiac surgery we define unmet needs and potential objectives for future research on this often-underestimated problem.
Transgenic mice lacking serotonin neurons have severe apnea and high mortality during development.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2009

Central serotonin (5-HT) neurons modulate many vital brain functions, including respiratory control. Whether breathing depends critically on 5-HT neurons, or whether their influence is excitatory or inhibitory, remains controversial. Here we show that neonatal Lmx1b(flox/flox;ePet-Cre/+) mice (also called Lmx1b(f/f/p) mice), which selectively lack serotonin neurons, display frequent and severe apnea lasting as long as 55 s. This was associated with a marked decrease in ventilation to less than one-half of normal. These respiratory abnormalities were most severe during the postnatal period, markedly improving by the time the pups were 2-4 weeks old. Despite the severe breathing dysfunction, many of these mice survived, but there was a high perinatal mortality, and those that survived had a decrease in growth rate until the age at which the respiratory defects resolved. Consistent with these in vivo observations, respiratory output was markedly reduced in isolated brainstem-spinal cord preparations from neonatal Lmx1b(f/f/p) mice and completely blocked in perfused brain preparations from neonatal rats treated with selective antagonists of 5-HT(2A) and neurokinin 1 (NK-1) receptors. The ventilatory deficits in neonatal Lmx1b(f/f/p) mice were reversed in vitro and in vivo with agonists of 5-HT(2A) and/or NK-1 receptors. These results demonstrate that ventilatory output in the neonatal period is critically dependent on serotonin neurons, which provide excitatory drive to the respiratory network via 5-HT(2A) and NK-1 receptor activation. These findings provide insight into the mechanisms of sudden infant death syndrome, which has been associated with abnormalities of 5-HT neurons and of cardiorespiratory control.