rudyvdbrink/CitationDatabase huggingface dataset:
Efficient enzymatic cyclization of an inhibitory cystine knot-containing peptide.
Biotechnology and bioengineering, 2016

Disulfide-rich peptides isolated from cone snails are of great interest as drug leads due to their high specificity and potency toward therapeutically relevant ion channels and receptors. They commonly contain the inhibitor cystine knot (ICK) motif comprising three disulfide bonds forming a knotted core. Here we report the successful enzymatic backbone cyclization of an ICK-containing peptide κ-PVIIA, a 27-amino acid conopeptide from Conus purpurascens, using a mutated version of the bacterial transpeptidase, sortase A. Although a slight loss of activity was observed compared to native κ-PVIIA, cyclic κ-PVIIA is a functional peptide that inhibits the Shaker voltage-gated potassium (Kv) channel. Molecular modeling suggests that the decrease in potency may be related to the loss of crucial, but previously unidentified electrostatic interactions between the N-terminus of the peptide and the Shaker channel. This hypothesis was confirmed by testing an N-terminally acetylated κ-PVIIA, which shows a similar decrease in activity. We also investigated the conformational dynamics and hydrogen bond network of cyc-PVIIA, both of which are important factors to be considered for successful cyclization of peptides. We found that cyc-PVIIA has the same conformational dynamics, but different hydrogen bond network compared to those of κ-PVIIA. The ability to efficiently cyclize ICK peptides using sortase A will enable future protein engineering for this class of peptides and may help in the development of novel therapeutic molecules. Biotechnol. Bioeng. 2016;113: 2202-2212. © 2016 Wiley Periodicals, Inc.
Mid-Frontal Theta Modulates Response Inhibition and Decision Making Processes in Emotional Contexts.
Brain sciences, 2019

Inhibitory control is an integral part of executive functions. In this study, we report event-related spectral perturbation (ERSP) results from 15 healthy adults performing an emotional stop-signal task with the use of happy, disgusted, and neutral emotional faces. Our ERSP results at the group level suggest that changes in low frequency oscillatory power for emotional and neutral conditions start at as early as 200 ms after stimulus onset and 300 ms before button press for successful go trials. To quantify the dynamics of trial-by-trial theta power, we applied the hierarchical drift diffusion model to single-trial ERSP at the mid-frontal electrode site for the go condition. Hierarchical drift diffusion modeling (HDDM) assigned higher frontal low-frequency oscillatory power for evidence accumulation in emotional contexts as compared to a neutral setting. Our results provide new evidence for dynamic modulation of sensory processing of go stimuli in inhibition and extend our knowledge for processing of response inhibition in emotional contexts.
Distinct molecular programs regulate synapse specificity in cortical inhibitory circuits.
Science (New York, N.Y.), 2019

How neuronal connections are established and organized into functional networks determines brain function. In the mammalian cerebral cortex, different classes of GABAergic interneurons exhibit specific connectivity patterns that underlie their ability to shape temporal dynamics and information processing. Much progress has been made toward parsing interneuron diversity, yet the molecular mechanisms by which interneuron-specific connectivity motifs emerge remain unclear. In this study, we investigated transcriptional dynamics in different classes of interneurons during the formation of cortical inhibitory circuits in mouse. We found that whether interneurons form synapses on the dendrites, soma, or axon initial segment of pyramidal cells is determined by synaptic molecules that are expressed in a subtype-specific manner. Thus, cell-specific molecular programs that unfold during early postnatal development underlie the connectivity patterns of cortical interneurons.
Vision adds to haptics when dyads perform a whole-body joint balance task.
Experimental brain research, 2017

When two or more people aim to produce joint action outcomes they need to coordinate their individual actions in space and time. Successful joint action performance has been reported to depend, among others, on visual and somatosensory information provided to the joint actors. This study investigated whether and how the systematic manipulation of visual information modulates real-time joint action when dyads performed a whole-body joint balance task. To this end, we introduced the Joint Action Board (JAB) where partners guided a ball through a maze towards a virtual hole by jointly shifting their weight on the board under three visual conditions: (1) the Follower had neither visual access to the Leader nor to the maze; (2) the Follower had no visual access to the maze but to the Leader; (3) the Follower had full visual access to both the Leader and to the maze. Joint action performance was measured as completion time of the maze task; interpersonal coordination was examined by means of kinematic analyses of both partners' motor behaviour. We predicted that systematically adding visual to the available haptic information would result in a significant increase in joint performance and that Leaders would change their coordination behavior depending on these conditions. Results showed that adding visual information to haptics led to an increase in joint action performance in a Leader-Follower relationship in a joint balance task. In addition, interpersonal coordination behavior (i.e. sway range of motion, time-lag between partner's bodies etc.) changed dependent on the provided visual information between partners in the jointly executed task.
Atorvastatin and uptake of ultrasmall superparamagnetic iron oxide nanoparticles (Ferumoxtran-10) in human monocyte-macrophages: implications for magnetic resonance imaging.
Biomaterials, 2008

Ferumoxtran-10 is an ultrasmall superparamagnetic iron oxide nanoparticle potentially useful as a contrast material in magnetic resonance imaging for the diagnosis of inflammatory and degenerative disorders associated with high macrophage activity. In clinical trials, it is currently applied to monitor the effect of atorvastatin therapy on macrophage activity in human carotid plaques. A recent study reported the inhibition of iron oxide nanoparticle uptake in macrophages by lovastatin, an effect which could compromise the suitability of Ferumoxtran-10 as an MRI contrast material in patients on statin therapy. Therefore, we examined the effect of atorvastatin on human monocyte-macrophage uptake of Ferumoxtran-10 in vitro using biochemical assays, magnetic resonance imaging and transmission electron microscopy. Our study showed that non-toxic concentrations of atorvastatin did not affect the amount of Ferumoxtran-10 taken up by HMMs. Furthermore, the intracellular distribution of iron oxide nanoparticles and the resulting MRI signal intensities remained unchanged by statin treatment. These results were obtained using atorvastatin concentrations probably vastly exceeding those reached in patient plasma in vivo. Atorvastatin therapy itself is therefore unlikely to affect Ferumoxtran-10 based macrophage detection by MRI, a prerequisite for the use of this contrast material to monitor lesion macrophage burden during lipid-lowering therapy.
Human apolipoprotein E4 modulates the expression of Pin1, Sirtuin 1, and Presenilin 1 in brain regions of targeted replacement apoE mice.
Neuroscience, 2014

The apolipoprotein E4 (apoE4) allele is consistently associated with increased risk for Alzheimer's disease (AD). We investigated the molecular mechanism of this susceptibility by analyzing the levels of genes involved in AD pathogenesis in transgenic mice expressing human apoE3 or apoE4 isoforms. mRNA and protein levels of Pin1, Sirtuin 1 (Sirt1), Presenilin 1 (PS1), and pro-Brain-derived Neurotrophic Factor (BDNF) were analyzed in brain regions affected by neuropathological changes in AD. Pin1 mRNA was significantly higher in the hippocampus of apoE4 mice than in apoE3 controls, whereas lower expression was detected in the entorhinal and parietal cortices. Reduced Pin1 levels may increase neurofibrillary degeneration and amyloidogenic processes, while compensatory mechanisms may take place in the hippocampus to balance spatial memory deficits. Sirt1 levels were significantly reduced in the frontal cortex of apoE4 mice. Sirt1 reduction may hinder its protective role against the formation of plaques and tangles and diminish its anti-inflammatory actions. Sirt1 decrease may also play a role in apoE4-associated memory impairments. Moreover, in apoE4 mice PS1 mRNA levels were lower in the frontal cortex. Lower PS1 expression may hamper γ-secretase function, thus affecting amyloid precursor protein processing. Pro-BDNF mRNA levels did not differ between apoE3 and apoE4 mice in any region analyzed. This study showed dysregulated expression of Pin1, Sirt1, and PS1 genes in different cerebral areas of apoE4 mice, suggesting that these changes may play a role in the mechanism of AD vulnerability.
Memory and motor control in patients with psychogenic nonepileptic seizures.
Epilepsy & behavior : E&B, 2019

Psychogenic nonepileptic seizures (PNES) are of the most elusive phenomena in epileptology. Patients with PNES present episodes resembling epileptic seizures in their semiology yet lacking the underlying epileptic brain activity. These episodes are assumed to be related to psychological distress from past trauma, yet the underlying mechanism of this manifestation is still unknown. Using resting-state functional magnetic resonance imaging (fMRI), we investigated functional connectivity changes within and between large-scale brain networks in 9 patients with PNES, compared with a group of 13 age- and gender-matched healthy controls. Functional magnetic resonance imaging analyses identified functional connectivity disturbances between the medial temporal lobe (MTL) and the sensorimotor cortex and between the MTL and ventral attention networks in patients with PNES. Within network connectivity reduction was found within the visual network. Our findings suggest that PNES relate to changes in connectivity in between areas that are involved in memory processing and motor activity and attention control. These results may shed new light on the way by which traumatic memories may relate to PNES.
Protease-Mediated Suppression of DRG Neuron Excitability by Commensal Bacteria.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2017

Peripheral pain signaling reflects a balance of pronociceptive and antinociceptive influences; the contribution by the gastrointestinal microbiota to this balance has received little attention. Disorders, such as inflammatory bowel disease and irritable bowel syndrome, are associated with exaggerated visceral nociceptive actions that may involve altered microbial signaling, particularly given the evidence for bacterial dysbiosis. Thus, we tested whether a community of commensal gastrointestinal bacteria derived from a healthy human donor (microbial ecosystem therapeutics; MET-1) can affect the excitability of male mouse DRG neurons. MET-1 reduced the excitability of DRG neurons by significantly increasing rheobase, decreasing responses to capsaicin (2 μm) and reducing action potential discharge from colonic afferent nerves. The increase in rheobase was accompanied by an increase in the amplitude of voltage-gated K
Xenopus SOX5 enhances myogenic transcription indirectly through transrepression.
Developmental biology, 2018

In anamniotes, somite compartimentalization in the lateral somitic domain leads simultaneously to myotome and dermomyotome formation. In the myotome, Xenopus Sox5 is co-expressed with Myod1 in the course of myogenic differentiation. Here, we studied the function of Sox5 using a Myod1-induced myogenic transcription assay in pluripotent cells of animal caps. We found that Sox5 enhances myogenic transcription of muscle markers Des, Actc1, Ckm and MyhE3. The use of chimeric transactivating or transrepressive Sox5 proteins indicates that Sox5 acts as a transrepressor and indirectly stimulates myogenic transcription except for the slow muscle-specific genes Myh7L, Myh7S, Myl2 and Tnnc1. We showed that this role is shared by Sox6, which is structurally similar to Sox5, both belonging to the SoxD subfamily of transcription factors. Moreover, Sox5 can antagonize the inhibitory function of Meox2 on myogenic differentiation. Meox2 which is a dermomyotome marker, represses myogenic transcription in Myod-induced myogenic transcription assay and in Nodal5-induced mesoderm from animal cap assay. The inhibitory function of Meox2 and the pro-myogenic function of Sox5 were confirmed during Xenopus normal development by the use of translation-blocking oligomorpholinos and dexamethasone inducible chimeric Sox5 and Meox2 proteins. We have therefore identified a new function for SoxD proteins in muscle cells, which can indirectly enhance myogenic transcription through transrepression, in addition to the previously identified function as a direct repressor of slow muscle-specific genes.
Event Boundaries Trigger Rapid Memory Reinstatement of the Prior Events to Promote Their Representation in Long-Term Memory.
Current biology : CB, 2017

Although everyday experiences unfold continuously over time, shifts in context, or event boundaries, can influence how those events come to be represented in memory [1-4]. Specifically, mnemonic binding across sequential representations is more challenging at context shifts, such that successful temporal associations are more likely to be formed within than across contexts [1, 2, 5-9]. However, in order to preserve a subjective sense of continuity, it is important that the memory system bridge temporally adjacent events, even if they occur in seemingly distinct contexts. Here, we used pattern similarity analysis to scalp electroencephalographic (EEG) recordings during a sequential learning task [2, 3] in humans and showed that the detection of event boundaries triggered a rapid memory reinstatement of the just-encoded sequence episode. Memory reactivation was detected rapidly (∼200-800 ms from the onset of the event boundary) and was specific to context shifts that were preceded by an event sequence with episodic content. Memory reinstatement was not observed during the sequential encoding of events within an episode, indicating that memory reactivation was induced specifically upon context shifts. Finally, the degree of neural similarity between neural responses elicited during sequence encoding and at event boundaries correlated positively with participants' ability to later link across sequences of events, suggesting a critical role in binding temporally adjacent events in long-term memory. Current results shed light onto the neural mechanisms that promote episodic encoding not only for information within the event, but also, importantly, in the ability to link across events to create a memory representation of continuous experience.
The role of EEG in the diagnosis and classification of the epilepsy syndromes: a tool for clinical practice by the ILAE Neurophysiology Task Force (Part 1).
Epileptic disorders : international epilepsy journal with videotape, 2017

The concept of epilepsy syndromes, introduced in 1989, was defined as "clusters of signs and symptoms customarily occurring together". Definition of epilepsy syndromes based on electro-clinical features facilitated clinical practice and, whenever possible, clinical research in homogeneous groups of patients with epilepsies. Progress in the fields of neuroimaging and genetics made it rapidly clear that, although crucial, the electro-clinical description of epilepsy syndromes was not sufficient to allow much needed development of targeted therapies and a better understanding of the underlying pathophysiological mechanisms of seizures. The 2017 ILAE position paper on Classification of the Epilepsies recognized that "as a critical tool for the practicing clinician, epilepsy classification must be relevant and dynamic to changes in thinking". The concept of "epilepsy syndromes" evolved, incorporating issues related to aetiologies and comorbidities. A comprehensive update (and revision where necessary) of the EEG diagnostic criteria in the light of the 2017 revised terminology and concepts was deemed necessary. The work was commissioned by the Neurophysiology Task Force of the ILAE Committee on the Diagnostic Methods. Diagnostic criteria and recording procedures were developed by group consensus, reached through an "informal", internal decision-making process. Each working group member was allocated a number of syndromes, and a standard structured template was used. International literature was extensively reviewed. We developed a simple diagnostic system that is applicable to all epilepsy syndromes which allows the physician (i) to rate the strength of EEG diagnosis (degree of diagnostic certainty) by weighting EEG findings in relation to the available clinical information or the specific clinical question, and ii) to suggest further EEG diagnostics where conclusive diagnostic evidence is lacking. We also propose a system of syndrome-specific recording protocols that, used with the relevant clinical presentation or specific clinical question, may maximize activation of epileptic discharges and ultimately help with standardization of EEG recording across departments, worldwide. Because recording methodology also depends on available resources, a two-tier system was developed to embrace clinical EEG services in resource-limited and industrialized countries. A clinical practice statement for each of the epilepsy syndromes discussed underscores the crucial role of the clinical information with regards to both the optimization of the EEG recording and mainly its meaningful interpretation. Part I covers Genetic (Idiopathic) generalized epilepsies and syndromes, Reflex epilepsies, structural and genetic focal (lobar) syndromes and Progressive Myoclonus Epilepsies [Published with educational EEG plates on www.epilepticdisorders.com].
Protection of primary neurons and mouse brain from Alzheimer's pathology by molecular tweezers.
Brain : a journal of neurology, 2012

Alzheimer's disease is a devastating cureless neurodegenerative disorder affecting >35 million people worldwide. The disease is caused by toxic oligomers and aggregates of amyloid β protein and the microtubule-associated protein tau. Recently, the Lys-specific molecular tweezer CLR01 has been shown to inhibit aggregation and toxicity of multiple amyloidogenic proteins, including amyloid β protein and tau, by disrupting key interactions involved in the assembly process. Following up on these encouraging findings, here, we asked whether CLR01 could protect primary neurons from Alzheimer's disease-associated synaptotoxicity and reduce Alzheimer's disease-like pathology in vivo. Using cell culture and brain slices, we found that CLR01 effectively inhibited synaptotoxicity induced by the 42-residue isoform of amyloid β protein, including ∼80% inhibition of changes in dendritic spines density and long-term potentiation and complete inhibition of changes in basal synaptic activity. Using a radiolabelled version of the compound, we found that CLR01 crossed the mouse blood-brain barrier at ∼2% of blood levels. Treatment of 15-month-old triple-transgenic mice for 1 month with CLR01 resulted in a decrease in brain amyloid β protein aggregates, hyperphosphorylated tau and microglia load as observed by immunohistochemistry. Importantly, no signs of toxicity were observed in the treated mice, and CLR01 treatment did not affect the amyloidogenic processing of amyloid β protein precursor. Examining induction or inhibition of the cytochrome P450 metabolism system by CLR01 revealed minimal interaction. Together, these data suggest that CLR01 is safe for use at concentrations well above those showing efficacy in mice. The efficacy and toxicity results support a process-specific mechanism of action of molecular tweezers and suggest that these are promising compounds for developing disease-modifying therapy for Alzheimer's disease and related disorders.
Alterations in hippocampal excitability, synaptic transmission and synaptic plasticity in a neurodevelopmental model of schizophrenia.
Neuropharmacology, 2012

The risk of developing schizophrenia has been linked to perturbations in embryonic development, but the physiological alterations that result from such insults are incompletely understood. Here, we have investigated aspects of hippocampal physiology in a proposed neurodevelopmental model of schizophrenia, induced during gestation in rats by injection of the antimitotic agent methylazoxymethanol acetate (MAM) at embryonic day 17 (MAM(E17)). We observed a reduction in synaptic innervation and synaptic transmission in the dorsal hippocampus of MAM(E17) treated rats, accompanied by a pronounced increase in CA1 pyramidal neuron excitability. Pharmacological investigations suggested that a deficit in GABAergic inhibition could account for the increase in excitability; furthermore, some aspects of the hyper-excitability could be normalised by the GABA(A) receptor (GABA(A)R) potentiator diazepam. Despite these alterations, two major forms of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD) could be readily induced. In contrast, there was a substantial deficit in the reversal of LTP, depotentiation. These findings suggest that delivering neurodevelopmental insults at E17 may offer insights into some of the physiological alterations that underlie behavioural and cognitive symptoms observed in schizophrenia.
The neural circuit mechanisms underlying the retinal response to motion reversal.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014

To make up for delays in visual processing, retinal circuitry effectively predicts that a moving object will continue moving in a straight line, allowing retinal ganglion cells to anticipate the object's position. However, a sudden reversal of motion triggers a synchronous burst of firing from a large group of ganglion cells, possibly signaling a violation of the retina's motion prediction. To investigate the neural circuitry underlying this response, we used a combination of multielectrode array and whole-cell patch recordings to measure the responses of individual retinal ganglion cells in the tiger salamander to reversing stimuli. We found that different populations of ganglion cells were responsible for responding to the reversal of different kinds of objects, such as bright versus dark objects. Using pharmacology and designed stimuli, we concluded that ON and OFF bipolar cells both contributed to the reversal response, but that amacrine cells had, at best, a minor role. This allowed us to formulate an adaptive cascade model (ACM), similar to the one previously used to describe ganglion cell responses to motion onset. By incorporating the ON pathway into the ACM, we were able to reproduce the time-varying firing rate of fast OFF ganglion cells for all experimentally tested stimuli. Analysis of the ACM demonstrates that bipolar cell gain control is primarily responsible for generating the synchronized retinal response, as individual bipolar cells require a constant time delay before recovering from gain control.