rudyvdbrink/CitationDatabase huggingface dataset:
Nuclear Dishevelled targets gene regulatory regions and promotes tumor growth.
EMBO reports, 2021

Dishevelled (DVL) critically regulates Wnt signaling and contributes to a wide spectrum of diseases and is important in normal and pathophysiological settings. However, how it mediates diverse cellular functions remains poorly understood. Recent discoveries have revealed that constitutive Wnt pathway activation contributes to breast cancer malignancy, but the mechanisms by which this occurs are unknown and very few studies have examined the nuclear role of DVL. Here, we have performed DVL3 ChIP-seq analyses and identify novel target genes bound by DVL3. We show that DVL3 depletion alters KMT2D binding to novel targets and changes their epigenetic marks and mRNA levels. We further demonstrate that DVL3 inhibition leads to decreased tumor growth in two different breast cancer models in vivo. Our data uncover new DVL3 functions through its regulation of multiple genes involved in developmental biology, antigen presentation, metabolism, chromatin remodeling, and tumorigenesis. Overall, our study provides unique insight into the function of nuclear DVL, which helps to define its role in mediating aberrant Wnt signaling.
Dendritic spine morphology and memory formation depend on postsynaptic Caskin proteins.
Scientific reports, 2019

CASK-interactive proteins, Caskin1 and Caskin2, are multidomain neuronal scaffold proteins. Recent data from Caskin1 knockout animals indicated only a mild role of Caskin1 in anxiety and pain perception. In this work, we show that deletion of both Caskins leads to severe deficits in novelty recognition and spatial memory. Ultrastructural analyses revealed a reduction in synaptic profiles and dendritic spine areas of CA1 hippocampal pyramidal neurons of double knockout mice. Loss of Caskin proteins impaired LTP induction in hippocampal slices, while miniature EPSCs in dissociated hippocampal cultures appeared to be unaffected. In cultured Caskin knockout hippocampal neurons, overexpressed Caskin1 was enriched in dendritic spine heads and increased the amount of mushroom-shaped dendritic spines. Chemically induced LTP (cLTP) mediated enlargement of spine heads was augmented in the knockout mice and was not influenced by Caskin1. Immunocytochemistry and immunoprecipitation confirmed that Shank2, a master scaffold of the postsynaptic density, and Caskin1 co-localized within the same complex. Phosphorylation of AMPA receptors was specifically altered by Caskin deficiency and was not elevated by cLTP treatment further. Taken together, our results prove a previously unnoticed postsynaptic role of Caskin scaffold proteins and indicate that Caskins influence learning abilities via regulating spine morphology and AMPA receptor localisation.
Diagnosing autism spectrum disorder in community settings using the Development and Well-Being Assessment: validation in a UK population-based twin sample.
Journal of child psychology and psychiatry, and allied disciplines, 2016

Increasing numbers of people are being referred for the assessment of autism spectrum disorder (ASD). The NICE (UK) and the American Academy of Pediatrics recommend gathering a developmental history using a tool that operationalises ICD/DSM criteria. However, the best-established diagnostic interview instruments are time consuming, costly and rarely used outside national specialist centres. What is needed is a brief, cost-effective measure validated in community settings. We tested the Development and Well-Being Assessment (DAWBA) for diagnosing ASD in a sample of children/adolescents representative of those presenting in community mental health settings.
Exosomes secreted by cardiomyocytes subjected to ischaemia promote cardiac angiogenesis.
Cardiovascular research, 2017

Myocardial infarction (MI) is the leading cause of morbidity and mortality worldwide and results from an obstruction in the blood supply to a region of the heart. In an attempt to replenish oxygen and nutrients to the deprived area, affected cells release signals to promote the development of new vessels and confer protection against MI. However, the mechanisms underlying the growth of new vessels in an ischaemic scenario remain poorly understood. Here, we show that cardiomyocytes subjected to ischaemia release exosomes that elicit an angiogenic response of endothelial cells (ECs).
Setting the scene for the Second Stroke Recovery and Rehabilitation Roundtable.
International journal of stroke : official journal of the International Stroke Society, 2019

The Stroke Recovery and Rehabilitation Roundtable (SRRR) meetings bring together an international group of preclinical and clinical researchers along with statisticians, methodologists, funders and consumers, working to accelerate the development of effective treatments for stroke recovery and to support best-evidence uptake in rehabilitation practice. The first meeting (2016) focused on four recommendation areas: translation of preclinical evidence into human discovery trials; recovery biomarkers to provide knowledge of therapeutic targets and prognosis in human stroke; intervention development, monitoring, and reporting standards; and standardized measurement in motor recovery trials. The impact of SRRR is growing, with uptake of recommendations emerging, and funders exploring ways to incorporate research targets and recommendations. At our second meeting (SRRR2, 2018), we worked on new priority areas: (1) cognitive impairment, (2) standardizing metrics for measuring quality of movement, (3) improving development of recovery trials, and (4) moving evidence-based treatments into practice. To accelerate progress towards breakthrough treatments, formation of an International Stroke Recovery and Rehabilitation Alliance is our next step, where working groups will take recommendations and build partnerships needed to achieve our goals.
The late phase of post-stroke neurorepair in aged rats is reflected by MRI-based measures.
Neuroscience, 2014

Non-invasive criteria determining the progress of brain healing are especially important in aging, providing a case-specific therapeutic strategy in populations with dysregulated neurorepair mechanisms. We hypothesized that temporal evolution of magnetic resonance imaging (MRI) of T2 tissue relaxation values correlate with neurological severity scores (NS), and provide a robust indicator of healing in the aging brain after stroke. Pre-treatment of aged rats with brain-only proton irradiation was undertaken to pre-condition the inflammatory system. Irradiation was performed 10days prior to right middle cerebral artery occlusion (MCAO) for 50min (MCAO+Rad). Control rats included naïve (no ischemia, no radiation), irradiated-only (Rad), irradiated ischemic, or ischemic-only (MCAO). MRI and NS were obtained at 3, 14 and 28days post-stroke. At 28days post-stroke, immunofluorescence for visualizing blood vessels (Von Willebrand factor; vWF), neurons (neuronal nuclear antigen; NeuN), astrocytes (glial fibrillary acidic protein; GFAP), activated microglia/macrophages (ionized calcium-binding adapter molecule 1, Iba1), T-lymphocytes (CD3), phagocytes (ED1) and apoptotic cells (caspase-3) was assessed. We found a positive T2-NS correlation in irradiated, ischemic rats that corresponded to late-stage brain recovery. Late-stage brain recovery was characterized by improved neovascularization, formation of glio-vascular complexes (visualized by GFAP/vWF) and enhanced neuronal viability (by NeuN/caspase-3) in the peri-lesional zone. The immune response plateaued at the late stage of repair as evidenced by significantly decreased expression (41.7%) and distribution of phagocytes (phagocytic rim decreased 44.6%). We also found reduced infiltration of T-lymphocytes (CD3) in the brain and normalization of blood lymphocytes. The observed T2-NS correlations may provide a simple MRI-based criterion for recognition of regenerative brain transformation in aged patients following stroke. Selective activation of innate immunity and accelerated transition from pro-inflammatory to pro-healing macrophage phenotypes induced by localized brain irradiation is a potential mechanism for enhancing repair ability in the elderly.
Systematic Review of Auditory Training in Pediatric Cochlear Implant Recipients.
Journal of speech, language, and hearing research : JSLHR, 2019

Objective The purpose of this systematic review is to evaluate the published research in auditory training (AT) for pediatric cochlear implant (CI) recipients. This review investigates whether AT in children with CIs leads to improvements in speech and language development, cognition, and/or quality of life and whether improvements, if any, remain over time post AT intervention. Method A systematic search of 7 databases identified 96 review articles published up until January 2017, 9 of which met the inclusion criteria. Data were extracted and independently assessed for risk of bias and quality of study against a PICOS (participants, intervention, control, outcomes, and study) framework. Results All studies reported improvements in trained AT tasks, including speech discrimination/identification and working memory. Retention of improvements over time was found whenever it was assessed. Transfer of learning was measured in 4 of 6 studies, which assessed generalization. Quality of life was not assessed. Overall, evidence for the included studies was deemed to be of low quality. Conclusion Benefits of AT were illustrated through the improvement in trained tasks, and this was observed in all reviewed studies. Transfer of improvement to other domains and also retention of benefits post AT were evident when assessed, although rarely done. However, higher quality evidence to further examine outcomes of AT in pediatric CI recipients is needed.
Juvenile/Adolescent Idiopatic Scoliosis and Rapid Palatal Expansion. A Pilot Study.
Children (Basel, Switzerland), 2021

The question of whether orthodontic therapy by means of rapid palatal expansion (RPE) affects the spine during development is important in clinical practice. RPE is an expansive, fixed therapy conducted with heavy forces to separate the midpalatal suture at a rate of 0.2-0.5 mm/day. The aim of the study was to evaluate the influence of RPE on the curves of the spine of juvenile/adolescent idiopathic scoliosis patients. Eighteen patients under orthopedic supervision for juvenile/adolescent idiopathic scoliosis and independently treated with RPE for orthodontic reasons were included in the study: Group A, 10 subjects (10.4 ± 1.3 years), first spinal radiograph before the application of the RPE, second one during the orthodontic therapy with RPE; Group B, 8 patients (11.3 ± 1.6 years), first radiograph during the use of RPE second one after the removal. Group A showed a significant worsening of the Cobb angle (
NMDA receptor antagonists ketamine and Ro25-6981 inhibit evoked release of glutamate in vivo in the subiculum.
Translational psychiatry, 2014

Preclinical and clinical data have identified ketamine, a non-selective NMDAR (N-methyl-D-aspartate receptor) antagonist, as a promising medication for patients who do not respond to treatment with monoamine-based antidepressants. Moreover, unlike the current monoamine-based antidepressants, ketamine has a long-lasting effect already after a single dose. The mechanisms of ketamine action remain to be fully understood. Using a recently developed microelectrode array (MEA), which allows sub-second measurements of fluctuating glutamate concentrations, we studied here the effects of in vivo local application of the ketamine and of the N2B subunit-specific antagonist Ro25-6981 upon evoked glutamate release. Both ligands inhibit glutamate release in subregions of the hippocampus and prefrontal cortex. Likewise, acute systemic ketamine treatment, at an antidepressant dose, caused a reduction in evoked glutamate release in the subiculum. We suggest that the effects of ketamine and Ro25-6981 in the subiculum could involve blockade of presynaptic NMDA receptors containing N2B subunits.
GFR-α1 Expression in Substantia Nigra Increases Bilaterally Following Unilateral Striatal GDNF in Aged Rats and Attenuates Nigral Tyrosine Hydroxylase Loss Following 6-OHDA Nigrostriatal Lesion.
ACS chemical neuroscience, 2019

Glial cell line-derived neurotrophic factor (GDNF) improved motor function in Parkinson's disease (PD) patients in Phase I clinical trials, and these effects persisted months after GDNF discontinuation. Conversely, phase II clinical trials reported no significant effects on motor improvement vs placebo. The disease duration and the quantity, infusion approach, and duration of GDNF delivery may affect GDNF efficacy in PD treatment. However, identifying mechanisms activated by GDNF that affect nigrostriatal function may reveal additional avenues to partially restore nigrostriatal function. In PD and aging models, GDNF affects tyrosine hydroxylase (TH) expression or phosphorylation in substantia nigra (SN), long after a single GDNF injection in striatum. In aged rats, the GDNF family receptor, GFR-α1, increases TH expression and phosphorylation in SN. To determine if GFR-α1 could be a mechanistic link in long-term GDNF impact, we conducted two studies; first to determine if a single unilateral striatal delivery of GDNF affected GFR-α1 and TH over time (1 day, 1 week, and 4 weeks) in the striatum or SN in aged rats, and second, to determine if soluble GFR-α1 could mitigate TH loss following 6-hydroxydopamine (6-OHDA) lesion. In aged rats, GDNF bilaterally increased ser31 TH phosphorylation and GFR-α1 expression in SN at 1 day and 4 weeks after GDNF, respectively. In striatum, GFR-α1 expression decreased 1 week after GDNF, only on the GDNF-injected side. In 6-OHDA-lesioned rats, recombinant soluble GFR-α1 mitigated nigral, but not striatal, TH protein loss following 6-OHDA. Together, these results show GDNF has immediate and long-term impact on dopamine regulation in the SN, which includes a gradual increase in GFR-α1 expression that may sustain TH expression and dopamine function therein.
Similarities and Differences in Extracellular Vesicle Profiles between Ischaemic Stroke and Myocardial Infarction.
Biomedicines, 2020

Extracellular vesicles (EVs) are involved in intercellular signalling through the transfer of molecules during physiological and pathological conditions, such as ischaemic disease. EVs might therefore play a role in ischaemic stroke (IS) and myocardial infarction (MI). In the present study, we analysed the similarities and differences in the content of circulating EVs in patients with IS and MI. This prospective observational study enrolled 140 participants (81 patients with IS, 37 with MI and 22 healthy controls [HCs]). We analysed the protein and microRNA content from EVs using proteomics and reverse transcription quantitative real-time polymerase chain reaction and compared it between the groups. In the patients with IS and MI, we identified 14 common proteins. When comparing IS and MI, we found differences in the protein profiles (apolipoprotein B, alpha-2-macroglobulin, fibronectin). We also found lower levels of miR-340 and miR-424 and higher levels of miR-29b in the patients with IS and MI compared with the HCs. Lastly, we found higher miR-340 levels in IS than in MI. In conclusion, proteomic and miRNA analyses suggest a relationship between circulating EV content and the patient's disease state. Although IS and MI affect different organs (brain and heart) with distinct histological characteristics, certain EV proteins and miRNAs appear to participate in both diseases, while others are present only in patients with IS.
Excision of pediatric craniopharyngioma: pattern of recurrence in 35 patients at a tertiary care hospital in Saudi Arabia.
Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery, 2020

Craniopharyngiomas are benign tumors of central nervous system which are known to affect both adults and children. Despite their benign origin, the recurrence is still one of the main postoperative challenges. The aim of this study was to investigate in retrospect factors related to recurrence of craniopharyngioma in a tertiary center in Riyadh, Saudi Arabia.
Biopsychosocial model of resilience in young adults with multiple sclerosis (BPS-ARMS): an observational study protocol exploring psychological reactions early after diagnosis.
BMJ open, 2019

Multiple sclerosis (MS), the most common neurological disease causing disability in young adults, is widely recognised as a major stress factor. Studies have shown that the first years after the diagnosis are distressing in terms of adjustment to the disease and that MS negatively affects patients' psychological well-being, quality of life (QoL) and social functioning. However, the links between disease-specific variables at diagnosis, resilience and psychological adjustment of patients with MS remain largely unexplored, especially in adolescents and young adults. This observational study aims to fill the gap of knowledge on
The Mixed Sellar Barrier: A New Subtype of this Novel Concept.
World neurosurgery, 2019

The use of the recent concept of sellar barrier revealed that a specific group of patients were difficult to categorize. For this reason, we propose to add a new subtype: the mixed sellar barrier. The aim of this work was to define the new mixed barrier subtype and analyze this in a series of operated patients.
Homeobox genes in melatonin-producing pinealocytes: Otx2 and Crx act to promote hormone synthesis in the mature rat pineal gland.
Journal of pineal research, 2019

Homeobox genes encode transcription factors that regulate developmental processes; however, in the pineal gland, a neuroendocrine organ responsible for nocturnal melatonin synthesis, expression of the homeobox genes Otx2 (orthodenticle homeobox 2) and Crx (cone-rod homeobox) persists postnatally. We here show that OTX2 and CRX are exclusively present in melatonin-producing pinealocytes of the rat pineal gland. To understand the roles of Otx2 and Crx in the mature pineal gland, we used siRNA technology in cultured rat pinealocytes with the nocturnal situation mimicked by adding norepinephrine to the culture media. siRNA-induced knockdown of Otx2 was found to reduce expression levels of the enzymes involved in melatonin synthesis at both transcript and protein levels. Similar results were obtained when knocking down Crx. Knocking down Otx2 and Crx simultaneously produced an even larger reduction in both transcript and protein levels of the melatonin-producing enzymes and also reduced the levels of melatonin released to the culture media. These results suggest that Otx2 and Crx, both alone and in combination, act to control pineal melatonin synthesis.
Ionotropic Receptor-dependent cool cells control the transition of temperature preference in Drosophila larvae.
PLoS genetics, 2021

Temperature sensation guides animals to avoid temperature extremes and to seek their optimal temperatures. The larval stage of Drosophila development has a dramatic effect on temperature preference. While early-stage Drosophila larvae pursue a warm temperature, late-stage larvae seek a significantly lower temperature. Previous studies suggest that this transition depends on multiple rhodopsins at the late larval stage. Here, we show that early-stage larvae, in which dorsal organ cool cells (DOCCs) are functionally blocked, exhibit similar cool preference to that of wild type late-stage larvae. The molecular thermoreceptors in DOCCs are formed by three members of the Ionotropic Receptor (IR) family, IR21a, IR93a, and IR25a. Early-stage larvae of each Ir mutant pursue a cool temperature, similar to that of wild type late-stage larvae. At the late larval stage, DOCCs express decreased IR proteins and exhibit reduced cool responses. Importantly, late-stage larvae that overexpress IR21a, IR93a, and IR25a in DOCCs exhibit similar warm preference to that of wild type early-stage larvae. These data suggest that IR21a, IR93a, and IR25a in DOCCs navigate early-stage larvae to avoid cool temperatures and the reduction of these IR proteins in DOCCs results in animals remaining in cool regions during the late larval stage. Together with previous studies, we conclude that multiple temperature-sensing systems are regulated for the transition of temperature preference in fruit fly larvae.
Pentoxifylline attenuates iminodipropionitrile-induced behavioral abnormalities in rats.
Behavioural pharmacology, 2009

This investigation was undertaken to study the effect of pentoxifylline (PTX) on iminodipropionitrile (IDPN)-induced behavioral abnormalities [excitation with choreiform and circling movements (ECC) syndrome] in rats. The animals were intraperitoneally injected with IDPN (100 mg/kg) daily for 7 days. PTX was administered daily 30 min before IDPN in the doses of 25, 50, and 100 mg/kg for 9 days. The animals were observed for neurobehavioral abnormalities including dyskinetic head movements, circling, tail hanging, air righting reflex, and contact inhibition of the righting reflex. The onset of ECC syndrome was observed on day 8 in the group treated with IDPN alone; all animals in this group became dyskinetic on day 10. Co-treatment with PTX dose dependently delayed the onset time and significantly reduced the incidence and severity of IDPN-induced ECC syndrome; high dose of PTX completely inhibited the abnormal behavioral signs in IDPN-treated rats. Administration of IDPN caused significant depletions in cerebral glutathione and vitamin E levels. Treatment with PTX dose dependently attenuated IDPN-induced oxidative stress in rats. The beneficial effects of PTX against IDPN toxicity may be attributed to its antioxidant and anti-inflammatory properties.
Intranasal insulin treatment of an experimental model of moderate traumatic brain injury.
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2017

Traumatic brain injury (TBI) results in learning and memory dysfunction. Cognitive deficits result from cellular and metabolic dysfunction after injury, including decreased cerebral glucose uptake and inflammation. This study assessed the ability of intranasal insulin to increase cerebral glucose uptake after injury, reduce lesion volume, improve memory and learning function and reduce inflammation. Adult male rats received a controlled cortical impact (CCI) injury followed by intranasal insulin or saline treatment daily for 14 days. PET imaging of [18F]-FDG uptake was performed at baseline and at 48 h and 10 days post-injury and MRI on days three and nine post injury. Motor function was tested with the beam walking test. Memory function was assessed with Morris water maze. Intranasal insulin after CCI significantly improved several outcomes compared to saline. Insulin-treated animals performed better on beam walk and demonstrated significantly improved memory. A significant increase in [18F]-FDG uptake was observed in the hippocampus. Intranasal insulin also resulted in a significant decrease in hippocampus lesion volume and significantly less microglial immunolabeling in the hippocampus. These data show that intranasal insulin improves memory, increases cerebral glucose uptake and decreases neuroinflammation and hippocampal lesion volume, and may therefore be a viable therapy for TBI.
Hypersensitivity to sertraline in the absence of hippocampal 5-HT
Environmental epigenetics, 2018

The male germ line is capable of transmitting a legacy of stress exposure to the next generation of offspring. This transgenerational process manifests by altering offspring affective behaviours, cognition and metabolism. Paternal early life trauma causes hippocampal serotonergic dysregulation in male offspring. We previously showed a transgenerational modification to male offspring anxiety-like behaviours by treatment of adult male breeders with corticosterone (CORT) prior to mating. In the present study, we used offspring from our paternal CORT model and characterised offspring serotonergic function by examining their responses to the 5HT