rudyvdbrink/CitationDatabase huggingface dataset:
iPSC-derived myelinoids to study myelin biology of humans.
Developmental cell, 2021

Myelination is essential for central nervous system (CNS) formation, health, and function. Emerging evidence of oligodendrocyte heterogeneity in health and disease and divergent CNS gene expression profiles between mice and humans supports the development of experimentally tractable human myelination systems. Here, we developed human iPSC-derived myelinating organoids ("myelinoids") and quantitative tools to study myelination from oligodendrogenesis through to compact myelin formation and myelinated axon organization. Using patient-derived cells, we modeled a monogenetic disease of myelinated axons (Nfasc155 deficiency), recapitulating impaired paranodal axo-glial junction formation. We also validated the use of myelinoids for pharmacological assessment of myelination-both at the level of individual oligodendrocytes and globally across whole myelinoids-and demonstrated reduced myelination in response to suppressed synaptic vesicle release. Our study provides a platform to investigate human myelin development, disease, and adaptive myelination.
Protective effects of Nesfatin-1 peptide on cerebral ischemia reperfusion injury via inhibition of neuronal cell death and enhancement of antioxidant defenses.
Metabolic brain disease, 2019

Nesfatin-1 is a novel peptide with anorexigenic and anti-hyperglycemic properties. According to previous studies, this multi-functional peptide protects dopaminergic cells against neurotoxicity via anti-apoptotic effects. In addition, Nesfatin-1 protects myocardial tissue after myocardial infarction via anti-inflammatory and anti-apoptotic mechanisms. In this study, we investigated the neuroprotective effects of nesfatin-1 against cerebral ischemia reperfusion injury in the CA1 area of hippocampus in rats. 56 male Wistar rats (240-270 g) were randomly selected and allocated into four groups: (1) sham, (2) nesfatin-1, (3) ischemia/reperfusion, (4) ischemia/reperfusion+nesfatin-1. Cerebral ischemia induced by the occlusion of the common carotid arteries for 20 min was followed by reperfusion. Saline as a vehicle and nesfatin-1 (20 μg/kg) were injected intraperitoneally (IP) at the start of cerebral reperfusion. Apoptotic and necrotic cell death was detected by TUNEL and Nissl staining. Malondialdehyde (MDA) and antioxidant enzymes (GSH and SOD) levels were measured by the ELISA method. The results showed that cerebral ischemia increased the apoptotic and necrotic cell death in the CA1 area of hippocampus, while, treatment with nesfatin-1significantly reduced apoptotic and necrotic cell death. Moreover, the MDA levels of the hippocampus in ischemic rats were higher, whereas in nesfatin-1-treated rats the MDA levels were decreased. Furthermore, the SOD and GSH levels in the ischemic rats were decreased, whilst in ischemic rats treated with nesfatin-1, the SOD and GSH levels were increased. This study for the first time found that nesfatin-1 treatment improves CA1 hippocampus injuries after cerebral ischemia through preventing neuronal cell death and enhancement of antioxidant defenses.
A novel tool for monitoring endogenous alpha-synuclein transcription by NanoLuciferase tag insertion at the 3'end using CRISPR-Cas9 genome editing technique.
Scientific reports, 2017

α-synuclein (α-SYN) is a major pathologic contributor to Parkinson's disease (PD). Multiplication of α-SYN encoding gene (SNCA) is correlated with early onset of the disease underlining the significance of its transcriptional regulation. Thus, monitoring endogenous transcription of SNCA is of utmost importance to understand PD pathology. We developed a stable cell line expressing α-SYN endogenously tagged with NanoLuc luciferase reporter using CRISPR/Cas9-mediated genome editing. This allows efficient measurement of transcriptional activity of α-SYN in its native epigenetic landscape which is not achievable using exogenous transfection-based luciferase reporter assays. The NanoLuc activity faithfully monitored the transcriptional regulation of SNCA following treatment with different drugs known to regulate α-SYN expression; while exogenous promoter-reporter assays failed to reproduce the similar outcomes. To our knowledge, this is the first report showing endogenous monitoring of α-SYN transcription, thus making it an efficient drug screening tool that can be used for therapeutic intervention in PD.
An online adaptive screening procedure for selective neuronal responses.
Journal of neuroscience methods, 2017

A common problem in neurophysiology is to identify stimuli that elicit neuronal responses in a given brain region. Particularly in situations where electrode positions are fixed, this can be a time-consuming task that requires presentation of a large number of stimuli. Such a screening for response-eliciting stimuli is employed, e.g., as a standard procedure to identify 'concept cells' in the human medial temporal lobe.
Neuronal Cell Death Mechanisms in Major Neurodegenerative Diseases.
International journal of molecular sciences, 2018

Neuronal cell death in the central nervous system has always been a challenging process to decipher. In normal physiological conditions, neuronal cell death is restricted in the adult brain, even in aged individuals. However, in the pathological conditions of various neurodegenerative diseases, cell death and shrinkage in a specific region of the brain represent a fundamental pathological feature across different neurodegenerative diseases. In this review, we will briefly go through the general pathways of cell death and describe evidence for cell death in the context of individual common neurodegenerative diseases, discussing our current understanding of cell death by connecting with renowned pathogenic proteins, including Tau, amyloid-beta, alpha-synuclein, huntingtin and TDP-43.
State dependence of network output: modeling and experiments.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2008

Emerging experimental evidence suggests that both networks and their component neurons respond to similar inputs differently, depending on the state of network activity. The network state is determined by the intrinsic dynamical structure of the network and may change as a function of neuromodulation, the balance or stochasticity of synaptic inputs to the network, and the history of network activity. Much of the knowledge on state-dependent effects comes from comparisons of awake and sleep states of the mammalian brain. Yet, the mechanisms underlying these states are difficult to unravel. Several vertebrate and invertebrate studies have elucidated cellular and synaptic mechanisms of state dependence resulting from neuromodulation, sensory input, and experience. Recent studies have combined modeling and experiments to examine the computational principles that emerge when network state is taken into account; these studies are highlighted in this article. We discuss these principles in a variety of systems (mammalian, crustacean, and mollusk) to demonstrate the unifying theme of state dependence of network output.
Proprioceptive signals contribute to the sense of body ownership.
The Journal of physiology, 2011

The sense of body ownership, knowledge that parts of our body ‘belong’ to us, is presumably developed using sensory information. Cutaneous signals seem ideal for this and can modify the sense of ownership. For example, an illusion of ownership over an artificial rubber hand can be induced by synchronously stroking both the subject’s hidden hand and a visible artificial hand. Like cutaneous signals, proprioceptive signals (e.g. frommuscle receptors) exclusively signal events occurring in the body, but the influence of proprioceptors on the sense of body ownership is not known. We developed a technique to generate an illusion of ownership over an artificial plastic finger, using movement at the proximal interphalangeal joint as the stimulus. We then examined this illusion in 20 subjects when their index finger was intact and when the cutaneous and joint afferents from the finger had been blocked by local anaesthesia of the digital nerves. Subjects still experienced an illusion of ownership, induced by movement, over the plastic finger when the digital nerves were blocked. This shows that local cutaneous signals are not essential for the illusion and that inputs arising proximally, presumably from receptors in muscles which move the finger, can influence the sense of body ownership. Contrary to other studies, we found no evidence that voluntary movements induce stronger illusions of body ownership than those induced by passive movement. It seems that the congruence of sensory stimuli ismore important to establish body ownership than the presence of multiple sensory signals.
CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral sclerosis.
Brain : a journal of neurology, 2020

Frontotemporal dementia and amyotrophic lateral sclerosis are clinically and pathologically overlapping disorders with shared genetic causes. We previously identified a disease locus on chromosome 16p12.1-q12.2 with genome-wide significant linkage in a large European Australian family with autosomal dominant inheritance of frontotemporal dementia and amyotrophic lateral sclerosis and no mutation in known amyotrophic lateral sclerosis or dementia genes. Here we demonstrate the segregation of a novel missense variant in CYLD (c.2155A>G, p.M719V) within the linkage region as the genetic cause of disease in this family. Immunohistochemical analysis of brain tissue from two CYLD p.M719V mutation carriers showed widespread glial CYLD immunoreactivity. Primary mouse neurons transfected with CYLDM719V exhibited increased cytoplasmic localization of TDP-43 and shortened axons. CYLD encodes a lysine 63 deubiquitinase and CYLD cutaneous syndrome, a skin tumour disorder, is caused by mutations that lead to reduced deubiquitinase activity. In contrast with CYLD cutaneous syndrome-causative mutations, CYLDM719V exhibited significantly increased lysine 63 deubiquitinase activity relative to the wild-type enzyme (paired Wilcoxon signed-rank test P = 0.005). Overexpression of CYLDM719V in HEK293 cells led to more potent inhibition of the cell signalling molecule NF-κB and impairment of autophagosome fusion to lysosomes, a key process in autophagy. Although CYLD mutations appear to be rare, CYLD's interaction with at least three other proteins encoded by frontotemporal dementia and/or amyotrophic lateral sclerosis genes (TBK1, OPTN and SQSTM1) suggests that it may play a central role in the pathogenesis of these disorders. Mutations in several frontotemporal dementia and amyotrophic lateral sclerosis genes, including TBK1, OPTN and SQSTM1, result in a loss of autophagy function. We show here that increased CYLD activity also reduces autophagy function, highlighting the importance of autophagy regulation in the pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.
Association of rs1344706 in the ZNF804A gene with schizophrenia in a case/control sample from Indonesia.
Schizophrenia research, 2013

Association of rs1344706 in the ZNF804A gene (2q32.1) with schizophrenia was first reported in a genome wide scan conducted in a sample of 479 cases and replicated in 6666 cases. Subsequently, evidence by replication was obtained in several samples with European- and Asian ancestral background.
Third International Stroke Trial 3: an update.
Current opinion in neurology, 2014

The third International Stroke Trial (IST-3) was a randomized controlled trial of thrombolysis with intravenous recombinant tissue plasminogen activator in patients with acute ischemic stroke within 6 h of onset. It sought to determine whether a wider variety of patients might benefit from treatment than were eligible under the prevailing European Union approval for the drug, especially among those aged over 80 years.
Fibroblast growth factor rescues brain endothelial cells lacking presenilin 1 from apoptotic cell death following serum starvation.
Scientific reports, 2016

Presenilin 1 (Psen1) is important for vascular brain development and is known to influence cellular stress responses. To understand the role of Psen1 in endothelial stress responses, we investigated the effects of serum withdrawal on wild type (wt) and Psen1-/- embryonic brain endothelial cells. Serum starvation induced apoptosis in Psen1-/- cells but did not affect wt cells. PI3K/AKT signaling was reduced in serum-starved Psen1-/- cells, and this was associated with elevated levels of phospho-p38 consistent with decreased pro-survival AKT signaling in the absence of Psen1. Fibroblast growth factor (FGF1 and FGF2), but not vascular endothelial growth factor (VEGF) rescued Psen1-/- cells from serum starvation induced apoptosis. Inhibition of FGF signaling induced apoptosis in wt cells under serum withdrawal, while blocking γ-secretase activity had no effect. In the absence of serum, FGF2 immunoreactivity was distributed diffusely in cytoplasmic and nuclear vesicles of wt and Psen1-/- cells, as levels of FGF2 in nuclear and cytosolic fractions were not significantly different. Thus, sensitivity of Psen1-/- cells to serum starvation is not due to lack of FGF synthesis but likely to effects of Psen1 on FGF release onto the cell surface and impaired activation of the PI3K/AKT survival pathway.
Systemic administration of ghrelin induces conditioned place preference and stimulates accumbal dopamine.
Addiction biology, 2008

Ghrelin, preferably via hypothalamic circuits, is known to play a role in the control of energy balance, body weight homeostasis and appetite. In addition, it has recently been found that ghrelin injection into key structures of the mesolimbic dopamine (DA) system increases food intake in rodents and induces locomotor stimulation as well as accumbal DA overflow in mice. Thus, centrally administered ghrelin activates the mesolimbic DA system. However, ghrelin is mainly produced in and secreted from peripheral tissues. The present series of experiments were therefore undertaken to investigate the effects of peripherally injected ghrelin on mesolimbic DA system activity and, herewith, associated behaviours. It was found that intraperitoneal administration of ghrelin (0.33 mg/kg) induces locomotor stimulation, conditioned place preference and accumbal DA-overflow in mice. In conclusion, peripherally produced ghrelin, e.g. in the stomach, may activate the mesolimbic DA system. This suggests that the pre-prandial rise in plasma ghrelin may, via this system, increase the incentive value for motivated behaviours such as food seeking.
Self-Made, Cost-Reducing Hemostatic Agent for Use in Spine Surgery.
World neurosurgery, 2017

Operative bleeding complications can lead to patient morbidity and mortality as well as longer and increased hospitalization costs. Matrix hemostatic sealants are used commonly to shorten the time to hemostasis, operative times, and the need for blood transfusion. Commercially available hemostatic powders are used in spine surgery because of their ability to conform to wounds and decrease bleeding in difficult-to-access surgical sites. Hospital costs for these agents are variable and are dependent on negotiated institutional contracted prices. We present our technique for mixing and use of our own hemostatic agent that has been used by our senior spine surgeons for more than a decade. It uses supplies that are commonly found in the hospital for a fraction of the cost and at different concentrations of thrombin. We hope that this report serves to assist surgeons working in hospitals with limited resources and enriches their armamentarium of hemostatic agents.
Mutations in the BLOC-1 subunits dysbindin and muted generate divergent and dosage-dependent phenotypes.
The Journal of biological chemistry, 2014

Post-mortem analysis has revealed reduced levels of the protein dysbindin in the brains of those suffering from the neurodevelopmental disorder schizophrenia. Consequently, mechanisms controlling the cellular levels of dysbindin and its interacting partners may participate in neurodevelopmental processes impaired in that disorder. To address this question, we studied loss of function mutations in the genes encoding dysbindin and its interacting BLOC-1 subunits. We focused on BLOC-1 mutants affecting synapse composition and function in addition to their established systemic pigmentation, hematological, and lung phenotypes. We tested phenotypic homogeneity and gene dosage effects in the mouse null alleles muted (Bloc1s5(mu/mu)) and dysbindin (Bloc1s8(sdy/sdy)). Transcripts of NMDA receptor subunits and GABAergic interneuron markers, as well as expression of BLOC-1 subunit gene products, were affected differently in the brains of Bloc1s5(mu/mu) and Bloc1s8(sdy/sdy) mice. Unlike Bloc1s8(sdy/sdy), elimination of one or two copies of Bloc1s5 generated indistinguishable pallidin transcript phenotypes. We conclude that monogenic mutations abrogating the expression of a protein complex subunit differentially affect the expression of other complex transcripts and polypeptides as well as their downstream effectors. We propose that the genetic disruption of different subunits of protein complexes and combinations thereof diversifies phenotypic presentation of pathway deficiencies, contributing to the wide phenotypic spectrum and complexity of neurodevelopmental disorders.
Time and distance estimation in children using an egocentric navigation task.
Scientific reports, 2018

Navigation crucially depends on the capability to estimate time elapsed and distance covered during movement. From adults it is known that magnitude estimation is subject to characteristic biases. Most intriguing is the regression effect (central tendency), whose strength depends on the stimulus distribution (i.e. stimulus range), a second characteristic of magnitude estimation known as range effect. We examined regression and range effects for time and distance estimation in eleven-year-olds and young adults, using an egocentric virtual navigation task. Regression effects were stronger for distance compared to time and depended on stimulus range. These effects were more pronounced in children compared to adults due to a more heterogeneous performance among the children. Few children showed veridical estimations similar to adults; most children, however, performed less accurate displaying stronger regression effects. Our findings suggest that children use magnitude processing strategies similar to adults, but it seems that these are not yet fully developed in all eleven-year-olds and are further refined throughout adolescence.
Cognitive resources related to speech recognition with a competing talker in young and older listeners.
Neuroscience, 2013

Speech recognition in a multi-talker situation poses high demands on attentional and other central resources. This study examines the relationship between age, cognition and speech recognition in tasks that require selective or divided attention in a multi-talker setting. Two groups of normal-hearing adults (one younger and one older group) were asked to repeat utterances from either one or two concurrent speakers. Cognitive abilities were then inspected by neuropsychological tests. Speech recognition scores approached its ceiling and did not significantly differ between age groups for tasks that demanded selective attention. However, when divided attention was required, performance in older listeners was reduced as compared to the younger group. When selective attention was required, speech recognition was strongly related to working memory skills, as determined by a regression model. In comparison, speech recognition for tests requiring divided attention could be more strongly determined by neuropsychological probes of fluid intelligence. The findings of this study indicate that - apart from hearing impairment - cognitive aspects account for the typical difficulties of older listeners in a multi-speaker setting. Our results are discussed in the context of evidence showing that frontal lobe functions in terms of working memory and fluid intelligence generally decline with age.
The effects of vasopressin deficiency on aggression and impulsiveness in male and female rats.
Psychoneuroendocrinology, 2014

The role of vasopressin in aggression received much attention in recent years. However, vasopressin has complex roles on social behavior, which are affected by social experience, motivation and hormonal background, suggesting that its effects depend on the condition of subjects. This hypothesis was tested here by studying the impact of vasopressin deficiency on aggressiveness in reproductively naive and reproductively experienced males, as well as in lactating females, with special reference to the patterns and contexts of attack behavior. We also studied effects on impulsiveness, a behavioral feature strongly related to aggression. Vasopressin deficiency did not affect aggressiveness in reproductively experienced males, decreased the share of violent attacks in reproductively inexperienced males without affecting total attack counts, and suppressed maternal aggression in both early and late phases of lactation; violent forms of attack were decreased in the latter but not the former phase. Changes in aggression appeared unrelated to general changes in maternal behaviors. Impulsivity in the delay discounting task was markedly decreased by vasopressin deficiency in lactating females but not males. Taken together, our findings confirm that vasopressin has an impact on aggressiveness, but show that this impact depends on the condition of subjects, and suggest that the effects of vasopressin on maternal aggression develop in conjunction with impulsivity. Interestingly, overall effects on aggression and specific effects on violent attacks dissociated in both males and females, which hints to the possibility that vasopressin has distinct roles in the development of escalated forms of aggression.
The c-Abl inhibitor, nilotinib, as a potential therapeutic agent for chronic cerebellar ataxia.
Journal of neuroimmunology, 2017

Nilotinib is a potent inhibitor of tyrosine kinase BCR-ABL that penetrates the blood-brain barrier. To evaluate the effect of nilotinib in chronic cerebellar ataxia, twelve patients with chronic cerebellar ataxia nonresponsive to other treatment options (modified Rankin scale [mRS] scores: >2) and received nilotinib therapy (daily doses: 150-300mg) for >4 (range 5-16) weeks were reviewed. At follow-up, improved mRS scores were found in 7/12 (58.3%) patients and favorable mRS scores (≤2) were found in 6/12 (50.0%) patients. No severe adverse event was observed. Atrophy in the cerebellar vermis appeared to be negatively associated with favorable outcomes.