rudyvdbrink/CitationDatabase huggingface dataset:
MACF1 regulates the migration of pyramidal neurons via microtubule dynamics and GSK-3 signaling.
Developmental biology, 2014

Neuronal migration and subsequent differentiation play critical roles for establishing functional neural circuitry in the developing brain. However, the molecular mechanisms that regulate these processes are poorly understood. Here, we show that microtubule actin crosslinking factor 1 (MACF1) determines neuronal positioning by regulating microtubule dynamics and mediating GSK-3 signaling during brain development. First, using MACF1 floxed allele mice and in utero gene manipulation, we find that MACF1 deletion suppresses migration of cortical pyramidal neurons and results in aberrant neuronal positioning in the developing brain. The cell autonomous deficit in migration is associated with abnormal dynamics of leading processes and centrosomes. Furthermore, microtubule stability is severely damaged in neurons lacking MACF1, resulting in abnormal microtubule dynamics. Finally, MACF1 interacts with and mediates GSK-3 signaling in developing neurons. Our findings establish a cellular mechanism underlying neuronal migration and provide insights into the regulation of cytoskeleton dynamics in developing neurons.
Illumination influences working memory: an EEG study.
Neuroscience, 2013

Illumination conditions appear to influence working efficacy in everyday life. In the present study, we obtained electroencephalogram (EEG) correlates of working-memory load, and investigated how these waveforms are modulated by illumination conditions. We hypothesized that illumination conditions may affect cognitive performance. We designed an EEG study to monitor and record participants' EEG during the Sternberg working memory task under four different illumination conditions. Illumination conditions were generated with a factorial design of two color-temperatures (3000 and 7100 K) by two illuminance levels (150 and 700 lx). During a working memory task, we observed that high illuminance led to significantly lower frontal EEG theta activity than did low illuminance. These differences persisted despite no significant difference in task performance between illumination conditions. We found that the latency of an early event-related potential component, such as N1, was significantly modulated by the illumination condition. The fact that the illumination condition affects brain activity but not behavioral performance suggests that the lighting conditions used in the present study did not influence the performance stage of behavioral processing. Nevertheless, our findings provide objective evidence that illumination conditions modulate brain activity. Further studies are necessary to refine the optimal lighting parameters for facilitating working memory.
Attenuated audiovisual integration in middle-aged adults in a discrimination task.
Cognitive processing, 2018

Numerous studies have focused on the diversity of audiovisual integration between younger and older adults. However, consecutive trends in audiovisual integration throughout life are still unclear. In the present study, to clarify audiovisual integration characteristics in middle-aged adults, we instructed younger and middle-aged adults to conduct an auditory/visual stimuli discrimination experiment. Randomized streams of unimodal auditory (A), unimodal visual (V) or audiovisual stimuli were presented on the left or right hemispace of the central fixation point, and subjects were instructed to respond to the target stimuli rapidly and accurately. Our results demonstrated that the responses of middle-aged adults to all unimodal and bimodal stimuli were significantly slower than those of younger adults (p < 0.05). Audiovisual integration was markedly delayed (onset time 360 ms) and weaker (peak 3.97%) in middle-aged adults than in younger adults (onset time 260 ms, peak 11.86%). The results suggested that audiovisual integration was attenuated in middle-aged adults and further confirmed age-related decline in information processing.
Relationship between the tautomeric structures of curcumin derivatives and their Abeta-binding activities in the context of therapies for Alzheimer's disease.
Biomaterials, 2010

Curcumin, which can exist in an equilibrium between keto and enol tautomers, binds to beta-amyloid (Abeta) fibrils/aggregates. The aim of this study was to assess the relationship between the tautomeric structures of curcumin derivatives and their Abeta-binding activities. Curcumin derivatives with keto-enol tautomerism showed high levels of binding to Abeta aggregates but not to Abeta monomers. The binding activity of the keto form analogue of curcumin to Abeta aggregates was found to be much weaker than that of curcumin derivatives with keto-enol tautomerism. The color of a curcumin derivative with keto-enol tautomerism, which was substituted at the C-4 position, changed from yellow to orange within 30 min of being combined with Abeta aggregates in physiological buffer. This resulted from a remarkable increase in the enol form with extended conjugation of double bonds upon binding. These findings suggest that curcumin derivatives exist predominantly in the enol form during binding to Abeta aggregates, and that the enolization of curcumin derivatives is crucial for binding to Abeta aggregates. The keto-enol tautomerism of curcumin derivatives may be a novel target for the design of amyloid-binding agents that can be used both for therapy and for amyloid detection in Alzheimer's disease.
Late-onset Parkinsonism in NFκB/c-Rel-deficient mice.
Brain : a journal of neurology, 2012

Activation of the nuclear factor κB/c-Rel can increase neuronal resilience to pathological noxae by regulating the expression of pro-survival manganese superoxide dismutase (MnSOD, now known as SOD2) and Bcl-xL genes. We show here that c-Rel-deficient (c-rel(-/-)) mice developed a Parkinson's disease-like neuropathology with ageing. At 18 months of age, c-rel(-/-) mice exhibited a significant loss of dopaminergic neurons in the substantia nigra pars compacta, as assessed by tyrosine hydroxylase-immunoreactivity and Nissl staining. Nigral degeneration was accompanied by a significant loss of dopaminergic terminals and a significant reduction of dopamine and homovanillic acid levels in the striatum. Mice deficient of the c-Rel factor exhibited a marked immunoreactivity for fibrillary α-synuclein in the substantia nigra pars compacta as well as increased expression of divalent metal transporter 1 (DMT1) and iron staining in both the substantia nigra pars compacta and striatum. Aged c-rel(-/-) mouse brain were characterized by increased microglial reactivity in the basal ganglia, but no astrocytic reaction. In addition, c-rel(-/-) mice showed age-dependent deficits in locomotor and total activity and various gait-related deficits during a catwalk analysis that were reminiscent of bradykinesia and muscle rigidity. Both locomotor and gait-related deficits recovered in c-rel(-/-) mice treated with l-3,4-dihydroxyphenylalanine. These data suggest that c-Rel may act as a regulator of the substantia nigra pars compacta resilience to ageing and that aged c-rel(-/-) mice may be a suitable model of Parkinson's disease.
Six3 regulates optic nerve development via multiple mechanisms.
Scientific reports, 2016

Malformations of the optic nerve lead to reduced vision or even blindness. During optic nerve development, retinal ganglion cell (RGC) axons navigate across the retina, exit the eye to the optic stalk (OS), and cross the diencephalon midline at the optic chiasm en route to their brain targets. Many signalling molecules have been implicated in guiding various steps of optic nerve pathfinding, however much less is known about transcription factors regulating this process. Here we show that in zebrafish, reduced function of transcription factor Six3 results in optic nerve hypoplasia and a wide repertoire of RGC axon pathfinding errors. These abnormalities are caused by multiple mechanisms, including abnormal eye and OS patterning and morphogenesis, abnormal expression of signalling molecules both in RGCs and in their environment and anatomical deficiency in the diencephalic preoptic area, where the optic chiasm normally forms. Our findings reveal new roles for Six3 in eye development and are consistent with known phenotypes of reduced SIX3 function in humans. Hence, the new zebrafish model for Six3 loss of function furthers our understanding of the mechanisms governing optic nerve development and Six3-mediated eye and forebrain malformations.
Practical help for specifying the target difference in sample size calculations for RCTs: the DELTA
Health technology assessment (Winchester, England), 2019

The randomised controlled trial is widely considered to be the gold standard study for comparing the effectiveness of health interventions. Central to its design is a calculation of the number of participants needed (the sample size) for the trial. The sample size is typically calculated by specifying the magnitude of the difference in the primary outcome between the intervention effects for the population of interest. This difference is called the 'target difference' and should be appropriate for the principal estimand of interest and determined by the primary aim of the study. The target difference between treatments should be considered realistic and/or important by one or more key stakeholder groups.
In vitro-in vivo correlations of scalable PLGA-risperidone implants for the treatment of schizophrenia.
Pharmaceutical research, 2010

Nonadherence to antipsychotic medications is a major obstacle preventing optimal outcomes for patients with schizophrenia. Extended release systems exist in the form of depot injections, but these formulations exhibit several disadvantages. To address these concerns, we previously demonstrated proof of concept for an antipsychotic implant containing risperidone and the biodegradable polymer poly(lactic-co-glycolic) acid (PLGA).
DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis.
The Lancet. Oncology, 2017

The WHO classification of brain tumours describes 15 subtypes of meningioma. Nine of these subtypes are allotted to WHO grade I, and three each to grade II and grade III. Grading is based solely on histology, with an absence of molecular markers. Although the existing classification and grading approach is of prognostic value, it harbours shortcomings such as ill-defined parameters for subtypes and grading criteria prone to arbitrary judgment. In this study, we aimed for a comprehensive characterisation of the entire molecular genetic landscape of meningioma to identify biologically and clinically relevant subgroups.
Empathy networks in the parental brain and their long-term effects on children's stress reactivity and behavior adaptation.
Neuropsychologia, 2018

Parental empathy is a key component of sensitive parenting that supports children's social adaptation throughout life. Consistent with a two dissociable network perspective on empathy, we measured within- and between-network integrity of two empathy-related networks in the parental brain as predictors of children's social outcomes across the first six years of life. We focused on two empathy networks; embodied simulation, which supports parents' capacity to resonate with infant state and emotions and implicates cingulo-insulary structures, and mentalizing, which underpins parents' theory-of-mind and mental attributions via prefrontal-temporo-parietal circuit. We followed 87 first-time parents across the first six years of family formation, including heterosexual and homosexual parents. In infancy, parents' brain response to own versus unfamiliar infant stimuli was imaged; in preschool, children's cortisol production and emotion regulation were assessed; and at six years, children's behavior problems were reported. Parents' intra- and inter- network integrity increased when viewing their own infant compared to unfamiliar infant, suggesting that attachment stimuli increase network coherence in the parental brain. Functional connectivity within the parent's embodied simulation network in infancy predicted lower child cortisol production while inter-network connectivity among the embodied simulation and mentalizing networks was associated with more advanced child emotion regulation skills in preschool and lower internalizing problems at six years. Children's emotion regulation capacities mediated the link between inter-network integrity in the parental brain and internalizing symptoms. Our findings, the first to demonstrate that integrity of empathy-related networks in the parental brain shape children's long-term stress reactivity and emotional adaptation, highlight the brain component of the parental empathy attribute, suggest that increased coherence within the "parental caregiving network" marks a key feature of parent-infant attachment, and contribute to discussion on biobehavioral mechanisms underpinning the cross-generation transmission of human stress reactivity and sociality.
Diffusion dynamics of a conductance-based neuronal population.
Physical review. E, 2019

We study the spatiotemporal dynamics of a conductance-based neuronal cable. The processes of one-dimensional (1D) and 2D diffusion are considered for a single variable, which is the membrane voltage. A 2D Morris-Lecar (ML) model is introduced to investigate the nonlinear responses of an excitable conductance-based neuronal cable. We explore the parameter space of the uncoupled ML model and, based on the bifurcation diagram (as a function of stimulus current), we analyze the 1D diffusion dynamics in three regimes: phasic spiking, coexistence states (tonic spiking and phasic spiking exist together), and a quiescent state. We show (depending on parameters) that the diffusive system may generate regular and irregular bursting or spiking behavior. Further, we explore a 2D diffusion acting on the membrane voltage, where striped and hexagonlike patterns can be observed. To validate our numerical results and check the stability of the existing patterns generated by 2D diffusion, we use amplitude equations based on multiple-scale analysis. We incorporate 1D diffusion in an extended 3D version of the ML model, in which irregular bursting emerges for a certain diffusion strength. The generated patterns may have potential applications in nonlinear neuronal responses and signal transmission.
Dynamics of population response to changes of motion direction in primary visual cortex.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011

The visual system is thought to represent the direction of moving objects in the relative activity of large populations of cortical neurons that are broadly tuned to the direction of stimulus motion, but how changes in the direction of a moving stimulus are represented in the population response remains poorly understood. Here we take advantage of the orderly mapping of direction selectivity in ferret primary visual cortex (V1) to explore how abrupt changes in the direction of a moving stimulus are encoded in population activity using voltage-sensitive dye imaging. For stimuli moving in a constant direction, the peak of the V1 population response accurately represented the direction of stimulus motion, but following abrupt changes in motion direction, the peak transiently departed from the direction of stimulus motion in a fashion that varied with the direction offset angle and was well predicted from the response to the component directions. We conclude that cortical dynamics and population coding mechanisms combine to place constraints on the accuracy with which abrupt changes in direction of motion can be represented by cortical circuits.
Pharmacological induction of the heat shock response improves myelination in a neuropathic model.
Neurobiology of disease, 2008

Misexpression and intracellular retention of peripheral myelin protein 22 (PMP22) is associated with hereditary neuropathies in humans, including Charcot-Marie-Tooth disease type 1A (CMT1A). Mice expressing extra copies of the human PMP22, termed C22, display morphologic and behavioral characteristics of CMT1A. In neuropathic Schwann cells, the turnover of the newly-synthesized PMP22 is decreased, leading to the formation of cytosolic protein aggregates. To aid the processing of PMP22 and alleviate the associated myelin defects, we pharmacologically stimulated the expression of protein chaperones by synthetic small-molecule inhibitors of heat shock protein 90 (HSP90). The exposure of Schwann cells to these compounds enhanced the levels of cytosolic chaperones in a time- and dose-dependent manner, with minimal cytotoxicity. Treatment of dorsal root ganglion (DRG) explants from neuropathic mice improved myelin formation and the processing of PMP22. These results warrant further studies with HSP90 inhibitors as potential therapeutic candidates for hereditary demyelinating neuropathies.
Localization of endogenous morphine-like compounds in the mouse spinal cord.
The Journal of comparative neurology, 2012

Morphine, codeine, morphine-6-glucuronide, and morphine-3-glucuronide are synthesized de novo in mammalian cells and in the central nervous system. Knowledge on endogenous morphine-like compound distribution in the adult mouse brain has been recently improved, and new hypotheses have been suggested about the potential implications in brain physiology. Endogenous morphine-like compounds have been shown to be synthesized in the spinal cord, but their localization is unknown. Here we describe the distribution of endogenous morphine-like compounds (morphine and/or its glucuronides and/or codeine) in the adult mouse spinal cord using a well-validated antibody. By using different microscopy approaches, we found the presence of morphine, codeine, or morphine glucuronides in γ-aminobutyric acid (GABA)-ergic neurons and astrocytes of the spinal cord. Whereas GABAergic neurons containing endogenous morphine-like compounds were located primarily in the ventral horn, astrocytes that were labeled for morphine-like compounds were found throughout the gray matter and the white matter. Our study demonstrates the possibility that endogenous morphine-like compounds in the central nervous system have other functions beyond their analgesic functions.
Late- but not early-onset blindness impairs the development of audio-haptic multisensory integration.
Developmental science, 2021

Integrating different senses to reduce sensory uncertainty and increase perceptual precision can have an important compensatory function for individuals with visual impairment and blindness. However, how visual impairment and blindness impact the development of optimal multisensory integration in the remaining senses is currently unknown. Here we first examined how audio-haptic integration develops and changes across the life span in 92 sighted (blindfolded) individuals between 7 and 70 years of age. We used a child-friendly task in which participants had to discriminate different object sizes by touching them and/or listening to them. We assessed whether audio-haptic performance resulted in a reduction of perceptual uncertainty compared to auditory-only and haptic-only performance as predicted by maximum-likelihood estimation model. We then compared how this ability develops in 28 children and adults with different levels of visual experience, focussing on low-vision individuals and blind individuals that lost their sight at different ages during development. Our results show that in sighted individuals, adult-like audio-haptic integration develops around 13-15 years of age, and remains stable until late adulthood. While early-blind individuals, even at the youngest ages, integrate audio-haptic information in an optimal fashion, late-blind individuals do not. Optimal integration in low-vision individuals follows a similar developmental trajectory as that of sighted individuals. These findings demonstrate that visual experience is not necessary for optimal audio-haptic integration to emerge, but that consistency of sensory information across development is key for the functional outcome of optimal multisensory integration.
Fetal extracellular matrix nerve wraps locally improve peripheral nerve remodeling after complete transection and direct repair in rat.
Scientific reports, 2018

In peripheral nerve (PN) injuries requiring surgical repair, as in PN transection, cellular and ECM remodeling at PN epineurial repair sites is hypothesized to reduce PN functional outcomes by slowing, misdirecting, or preventing axons from regrowing appropriately across the repair site. Herein this study reports on deriving and analyzing fetal porcine urinary bladder extracellular matrix (fUB-ECM) by vacuum assisted decellularization, fabricating fUBM-ECM nerve wraps, and testing fUB-ECM nerve wrap biocompatibility and bioactivity in a trigeminal, infraorbital nerve (ION) branch transection and direct end-to-end repair model in rat. FUB-ECM nerve wraps significantly improved epi- and endoneurial organization and increased both neovascularization and growth associated protein-43 (GAP-43) expression at PN repair sites, 28-days post surgery. However, the number of neurofilament positive axons, remyelination, and whisker-evoked response properties of ION axons were unaltered, indicating improved tissue remodeling per se does not predict axon regrowth, remyelination, and the return of mechanoreceptor cortical signaling. This study shows fUB-ECM nerve wraps are biocompatible, bioactive, and good experimental and potentially clinical devices for treating epineurial repairs. Moreover, this study highlights the value provided by precise, analytic models, like the ION repair model, in understanding how PN tissue remodeling relates to axonal regrowth, remyelination, and axonal response properties.
Brain mediators of systemic oxidative stress on perceptual impairments in Parkinson's disease.
Journal of translational medicine, 2015

Parkinson's disease (PD) is well documented to be associated with elevated systemic oxidative stress and perceptual impairments. Furthermore, the striatum and extrastriatal cortical areas, which are involved in the coordination of perceptual functions, are impaired at an early stage of the disease. However, the possible pathophysiology involved in perceptual impairments remains unclear. This raises the possibility that structural abnormalities might mediate the relationship between oxidative stress and perceptual impairments.
Initiating Differentiation in Immortalized Multipotent Otic Progenitor Cells.
Journal of visualized experiments : JoVE, 2016

Use of human induced pluripotent stem cells (iPSC) or embryonic stem cells (ESC) for cell replacement therapies holds great promise. Several limitations including low yields and heterogeneous populations of differentiated cells hinder the progress of stem cell therapies. A fate restricted immortalized multipotent otic progenitor (iMOP) cell line was generated to facilitate efficient differentiation of large numbers of functional hair cells and spiral ganglion neurons (SGN) for inner ear cell replacement therapies. Starting from dissociated cultures of single iMOP cells, protocols that promote cell cycle exit and differentiation by basic fibroblast growth factor (bFGF) withdrawal were described. A significant decrease in proliferating cells after bFGF withdrawal was confirmed using an EdU cell proliferation assay. Concomitant with a decrease in proliferation, successful differentiation resulted in expression of molecular markers and morphological changes. Immunostaining of Cdkn1b (p27(KIP)) and Cdh1 (E-cadherin) in iMOP-derived otospheres was used as an indicator for differentiation into inner ear sensory epithelia while immunostaining of Cdkn1b and Tubb3 (neuronal β-tubulin) was used to identify iMOP-derived neurons. Use of iMOP cells provides an important tool for understanding cell fate decisions made by inner ear neurosensory progenitors and will help develop protocols for generating large numbers of iPSC or ESC-derived hair cells and SGNs. These methods will accelerate efforts for generating otic cells for replacement therapies.