rudyvdbrink/CitationDatabase huggingface dataset:
Intracellular formation of α-synuclein oligomers and the effect of heat shock protein 70 characterized by confocal single particle spectroscopy.
Biochemical and biophysical research communications, 2016

Synucleinopathies such as dementia with Lewy bodies or Parkinson's disease are characterized by intracellular deposition of pathologically aggregated α-synuclein. The details of the molecular pathogenesis of PD and especially the conditions that lead to intracellular aggregation of α-synuclein and the role of these aggregates in cell death remain unknown. In cell free in vitro systems considerable knowledge about the aggregation processes has been gathered. In comparison, the knowledge about these aggregation processes in cells is far behind. In cells α-synuclein aggregates can be toxic. However, the crucial particle species responsible for decisive steps in pathogenesis such as seeding a continuing aggregation process and triggering cell death remain to be identified. In order to understand the complex nature of intracellular α-synuclein aggregate formation, we analyzed fluorescent particles formed by venus and α-synuclein-venus fusion proteins and α-synuclein-hemi-venus fusion proteins derived from gently lyzed cells. With these techniques we were able to identify and characterize α-synuclein oligomers formed in cells. Especially the use of α-synuclein-hemi-venus fusion proteins enabled us to identify very small α-synuclein oligomers with high sensitivity. Furthermore, we were able to study the molecular effect of heat shock protein 70, which is known to inhibit α-synuclein aggregation in cells. Heat shock protein 70 does not only influence the size of α-synuclein oligomers, but also their quantity. In summary, this approach based on fluorescence single particle spectroscopy, that is suited for high throughput measurements, can be used to detect and characterize intracellularly formed α-synuclein aggregates and characterize the effect of molecules that interfere with α-synuclein aggregate formation.
Astrogliosis: An integral player in the pathogenesis of Alzheimer's disease.
Progress in neurobiology, 2016

Alzheimer's disease is the main cause of dementia in the elderly and begins with a subtle decline in episodic memory followed by a more general decline in overall cognitive abilities. Though the exact trigger for this cascade of events remains unknown the presence of the misfolded amyloid-beta protein triggers reactive gliosis, a prominent neuropathological feature in the brains of Alzheimer's patients. The cytoskeletal and morphological changes of astrogliosis are its evident features, while changes in oxidative stress defense, cholesterol metabolism, and gene transcription programs are less manifest. However, these latter molecular changes may underlie a disruption in homeostatic regulation that keeps the brain environment balanced. Astrocytes in Alzheimer's disease show changes in glutamate and GABA signaling and recycling, potassium buffering, and in cholinergic, purinergic, and calcium signaling. Ultimately the dysregulation of homeostasis maintained by astrocytes can have grave consequences for the stability of microcircuits within key brain regions. Specifically, altered inhibition influenced by astrocytes can lead to local circuit imbalance with farther reaching consequences for the functioning of larger neuronal networks. Healthy astrocytes have a role in maintaining and modulating normal neuronal communication, synaptic physiology and energy metabolism, astrogliosis interferes with these functions. This review considers the molecular and functional changes occurring during astrogliosis in Alzheimer's disease, and proposes that astrocytes are key players in the development of dementia.
Minimal evidence of disease activity (MEDA) in relapsing-remitting multiple sclerosis.
Journal of neurology, neurosurgery, and psychiatry, 2020

This study aimed to define the minimal evidence of disease activity (MEDA) during treatment that can be tolerated without exposing patients with relapsing-remitting multiple sclerosis at risk of long-term disability.
Treatment gaps and challenges in epilepsy care in the Philippines.
Epilepsy & behavior : E&B, 2021

Epilepsy is a neurologic disease that carries a high disease burden and likely, a huge treatment gap especially in low-to-middle income countries (LMIC) such as the Philippines. This review aimed to examine the treatment gaps and challenges that burden Philippine epilepsy care.
Mechanisms of transthyretin inhibition of β-amyloid aggregation in vitro.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013

Tissue-specific overexpression of the human systemic amyloid precursor transthyretin (TTR) ameliorates Alzheimer's disease (AD) phenotypes in APP23 mice. TTR-β-amyloid (Aβ) complexes have been isolated from APP23 and some human AD brains. We now show that substoichiometric concentrations of TTR tetramers suppress Aβ aggregation in vitro via an interaction between the thyroxine binding pocket of the TTR tetramer and Aβ residues 18-21 (nuclear magnetic resonance and epitope mapping). The K(D) is micromolar, and the stoichiometry is <1 for the interaction (isothermal titration calorimetry). Similar experiments show that engineered monomeric TTR, the best inhibitor of Aβ fibril formation in vitro, did not bind Aβ monomers in liquid phase, suggesting that inhibition of fibrillogenesis is mediated by TTR tetramer binding to Aβ monomer and both tetramer and monomer binding of Aβ oligomers. The thousand-fold greater concentration of tetramer relative to monomer in vivo makes it the likely suppressor of Aβ aggregation and disease in the APP23 mice.
Intense pain soon after wrist fracture strongly predicts who will develop complex regional pain syndrome: prospective cohort study.
The journal of pain, 2014

Complex regional pain syndrome (CRPS) is a distressing and difficult-to-treat complication of wrist fracture. Estimates of the incidence of CRPS after wrist fracture vary greatly. It is not currently possible to identify who will go on to develop CRPS after wrist fracture. In this prospective cohort study, a nearly consecutive sample of 1,549 patients presenting with wrist fracture to 1 of 3 hospital-based fracture clinics and managed nonsurgically was assessed within 1 week of fracture and followed up 4 months later. Established criteria were used to diagnose CRPS. The incidence of CRPS in the 4 months after wrist fracture was 3.8% (95% confidence interval = 2.9-4.8%). A prediction model based on 4 clinical assessments (pain, reaction time, dysynchiria, and swelling) discriminated well between patients who would and would not subsequently develop CRPS (c index .99). A simple assessment of pain intensity (0-10 numerical rating scale) provided nearly the same level of discrimination (c index .98). One in 26 patients develops CRPS within 4 months of nonsurgically managed wrist fracture. A pain score of ≥5 in the first week after fracture should be considered a "red flag" for CRPS.
Automatic assessment of glioma burden: a deep learning algorithm for fully automated volumetric and bidimensional measurement.
Neuro-oncology, 2019

Longitudinal measurement of glioma burden with MRI is the basis for treatment response assessment. In this study, we developed a deep learning algorithm that automatically segments abnormal fluid attenuated inversion recovery (FLAIR) hyperintensity and contrast-enhancing tumor, quantitating tumor volumes as well as the product of maximum bidimensional diameters according to the Response Assessment in Neuro-Oncology (RANO) criteria (AutoRANO).
Interneuron dysfunction in psychiatric disorders.
Nature reviews. Neuroscience, 2012

Schizophrenia, autism and intellectual disabilities are best understood as spectrums of diseases that have broad sets of causes. However, it is becoming evident that these conditions also have overlapping phenotypes and genetics, which is suggestive of common deficits. In this context, the idea that the disruption of inhibitory circuits might be responsible for some of the clinical features of these disorders is gaining support. Recent studies in animal models demonstrate that the molecular basis of such disruption is linked to specific defects in the development and function of interneurons - the cells that are responsible for establishing inhibitory circuits in the brain. These insights are leading to a better understanding of the causes of schizophrenia, autism and intellectual disabilities, and may contribute to the development of more-effective therapeutic interventions.
Nanometric agents in the service of neuroscience: Manipulation of neuronal growth and activity using nanoparticles.
Nanomedicine : nanotechnology, biology, and medicine, 2015

Nerve regeneration and recovery could provide great therapeutic benefits for individuals suffering from nerve damage post trauma or degenerative diseases. However, manipulation of nerves presents a huge challenge for neuroscientists and is not yet clinically feasible. In recent years, nanoparticles have emerged as novel effective agents for control of neuronal growth and behavior. Nanoparticles may facilitate the needed nerve manipulation abilities for therapeutic and diagnostic purposes including within the brain. This review aims at presenting the currently available literature regarding the interactions between inorganic nanoparticles and neurons. A wide range of nanoparticles are presented, including gold, iron oxide, cerium oxide, nanotubes and quantum-dots. The nanoparticles enhance neuronal differentiation and survival, direct growth and regulate electrical activity. The studies are summarized in a concise table, arranged by the function and type of nanoparticle. The latest studies present a novel interdisciplinary approach, which could be harnessed for clinical applications in nanomedicine.
Training improves cochlear implant rate discrimination on a psychophysical task.
The Journal of the Acoustical Society of America, 2014

The purpose of this study was to determine the extent to which cochlear implant (CI) rate discrimination can be improved through training. Six adult CI users took part in a study that included 32 h of training and assessment on rate discrimination measures. Rate difference limens (DLs) were measured from 110 to 3520 Hz in octave steps using 500 ms biphasic pulse trains; the target and standard stimuli were loudness-balanced with the target always at an adaptively lower rate. DLs were measured at four electrode positions corresponding to basal, mid-basal, mid-apical, and apical locations. Procedural variations were implemented to determine if rate discrimination was impacted by random variations in stimulus amplitude or by amplitude modulation. DLs improved by more than a factor of 2 across subjects, electrodes, and standard rates. Factor analysis indicated that the effect of training was comparable for all electrodes and standard rates tested. Neither level roving nor amplitude modulation had a significant effect on rate DLs. In conclusion, the results demonstrate that training can significantly improve CI rate discrimination on a psychophysical task.
Botulinum Toxin Type A Injection After Failure of Augmentation Enterocystoplasty Performed for Neurogenic Detrusor Overactivity: Preliminary Results of a Salvage Strategy. The ENTEROTOX Study.
Urology, 2019

To evaluate the clinical efficacy, urodynamic effect and safety of Botulinum Toxin A (BTXA) injections after failure of augmentation enterocystoplasty (AE) performed for neurogenic detrusor overactivity.
HIV gp120 Protein Increases the Function of Connexin 43 Hemichannels and Pannexin-1 Channels in Astrocytes: Repercussions on Astroglial Function.
International journal of molecular sciences, 2020

At least half of human immunodeficiency virus (HIV)-infected individuals suffer from a wide range of cognitive, behavioral and motor deficits, collectively known as HIV-associated neurocognitive disorders (HAND). The molecular mechanisms that amplify damage within the brain of HIV-infected individuals are unknown. Recently, we described that HIV augments the opening of connexin-43 (Cx43) hemichannels in cultured human astrocytes, which result in the collapse of neuronal processes. Whether HIV soluble viral proteins such as gp120, can regulate hemichannel opening in astrocytes is still ignored. These channels communicate the cytosol with the extracellular space during pathological conditions. We found that gp120 enhances the function of both Cx43 hemichannels and pannexin-1 channels in mouse cortical astrocytes. These effects depended on the activation of IL-1β/TNF-α, p38 MAP kinase, iNOS, cytoplasmic Ca
Role of the NMDA receptor in cognitive deficits, anxiety and depressive-like behavior in juvenile and adult mice after neonatal dexamethasone exposure.
Neurobiology of disease, 2014

Postnatal dexamethasone (DEX) therapy has been used to treat or prevent chronic lung disease after premature births. However, there are many reports of long-term negative neurodevelopmental sequelae following this treatment. In contrast, hydrocortisone (HYD), which has fewer neurodevelopment adverse effects, is used as an alternative for DEX. In this study, we report that neonatal DEX exposure (days 1-3) caused alterations of amino acids affecting N-methyl-d-aspartate (NMDA) receptor neurotransmission in mouse brains. Neonatal DEX, but not HYD, exposure (days 1-3) significantly decreased the GluN2B subunit of NMDA receptor in the hippocampus at juvenile and adult stages. Mice treated with DEX showed cognitive deficits, as well as anxiety and depressive-like behavior at juvenile and adult stages. In contrast, mice treated with HYD (days 1-3) showed no behavioral abnormalities at these stages. In the DEX suppression test, plasma levels of corticosterone in mice exposed neonatally to DEX and HYD were significantly higher at juvenile, but not adult stages. Pretreatment with Ro 63-1908, an antagonist at GluN2B subunit, 30min before each injection of DEX, prevented cognitive deficits, as well as anxiety and depressive-like behavior in juvenile and adult mice. Interestingly, subsequent repeated (days 29-33) administration of Ro 63-1908 or L701324, an antagonist of the glycine modulatory site on the NMDA receptor, significantly suppressed behavioral abnormalities in juvenile and adult mice after neonatal DEX exposure. These results indicate that neonatal DEX, but not HYD, exposure produced behavioral abnormalities in juvenile and adult mice by altering glutamatergic neurotransmission via the NMDA receptor. The NMDA receptor antagonists may prevent or treat these DEX-induced neonatal behavioral abnormalities in later life.
Amyloid precursor protein and amyloid precursor-like protein 2 have distinct roles in modulating myelination, demyelination, and remyelination of axons.
Glia, 2019

The identification of factors that regulate myelination provides important insight into the molecular mechanisms that coordinate nervous system development and myelin regeneration after injury. In this study, we investigated the role of amyloid precursor protein (APP) and its paralogue amyloid precursor-like protein 2 (APLP2) in myelination using APP and APLP2 knockout (KO) mice. Given that BACE1 regulates myelination and myelin sheath thickness in both the peripheral and central nervous systems, we sought to determine if APP and APLP2, as alternate BACE1 substrates, also modulate myelination, and therefore provide a better understanding of the events regulating axonal myelination. In the peripheral nervous system, we identified that adult, but not juvenile KO mice, have lower densities of myelinated axons in their sciatic nerves while in the central nervous system, axons within both the optic nerves and corpus callosum of both KO mice were significantly hypomyelinated compared to wild-type (WT) controls. Biochemical analysis demonstrated significant increases in BACE1 and myelin oligodendrocyte glycoprotein and decreased NRG1 and proteolipid protein levels in both KO brain tissue. The acute cuprizone model of demyelination/remyelination revealed that whereas axons in the corpus callosum of WT and APLP2-KO mice underwent similar degrees of demyelination and subsequent remyelination, the myelinated callosal axons in APP-KO mice were less susceptible to cuprizone-induced demyelination and showed a failure in remyelination after cuprizone withdrawal. These data identified APP and APLP2 as modulators of normal myelination and demyelination/remyelination conditions. Deletion of APP and APLP2 identifies novel interplays between the BACE1 substrates in the regulation of myelination.
Glycine receptor expression in the forebrain of male AA/ANA rats.
Brain research, 2009

Ethanol is known to directly interact with the glycine receptor (GlyR). GlyRs are membrane proteins and are constituted as either alpha-homomers or alpha-beta heteromers with a subunit stoichiometry of 2 alpha 3 beta. Previous studies by our group have suggested a role for GlyRs and its endogenous ligands glycine and taurine in the mesolimbic dopamine activating and reinforcing effects of ethanol. Here we use quantitative PCR (qPCR) to compare the relative GlyR expression in Alko Alcohol/Non-Alcohol (AA/ANA) rats. These animals have been selectively bred to create distinct populations regarding alcohol consumption and preference, presumably mainly due to genetic differences. The aim of this study was to examine the relative gene expression of GlyR subunits (alpha1-3 and beta) in different brain areas and relate it to alcohol consumption. The hypothesis was that AA/ANA rats are differently disposed to ethanol consumption due to their GlyR set-ups and/or compositions. Results from the present study indicate that alpha2 is the most widely expressed alpha-subunit in the forebrain regions and that the alpha 2 beta-heteromer seems to be the most common subunit composition in this part of the CNS. Despite displaying different drinking behaviours the anticipated differences in mRNA expression were few. However, correlations found between alcohol consumption and/or preference and GlyR expression support a role for GlyRs in alcohol consumption. Tentative differences between AA and ANA animals related to GlyR transmission could therefore lie in, for example, the regulation of the levels of the endogenous ligand(s) for the receptor or in mechanisms downstream to GlyR activation.
Response inhibition and ADHD traits: correlates and heritability in a community sample.
Journal of abnormal child psychology, 2013

Endophenotypes or intermediate phenotypes are of great interest in neuropsychiatric genetics because of their potential for facilitating gene discovery. We evaluated response inhibition, latency and variability measures derived from the stop task as endophenotypes of ADHD by testing whether they were related to ADHD traits in the general population, heritable and shared genetic risk with ADHD traits. Participants were 16,099 children and adolescents, ages 6 to 18 years who visited a local science center. We measured ADHD traits using the Strengths and Weaknesses of ADHD-symptoms and Normal-Behavior (SWAN) rating scale and performance on the stop signal task (SST)-response inhibition (SSRT), response latency (GoRT), and response variability (GoRTSD). Regression analysis was used to assess the relationship of cognitive measures and ADHD traits while controlling for family, age, sex, ethnicity, socioeconomic status and treatment status. Heritability of ADHD and cognitive traits was estimated using SOLAR in 7,483 siblings from 3,507 families that included multiple siblings. Bivariate relationships between pairs of variables were examined. Individuals with greater ADHD trait scores had worse response inhibition, slower response latency, and greater variability. Younger participants and girls had inferior performance although the gender effects were minimal and evident in youngest participants. Inhibition, latency, variability, total ADHD traits, inattention and hyperactivity-impulsivity scores were significantly heritable. ADHD traits and inhibition, but not latency or variability were coheritable. In the largest study in the general population, we found support for the validity of response inhibition as an endophenotype of ADHD.
Metabolomic profiling of blood plasma in patients with primary brain tumours: Basal plasma metabolites correlated with tumour grade and plasma biomarker analysis predicts feasibility of the successful statistical discrimination from healthy subjects - a preliminary study.
IUBMB life, 2019

The brain tumours represent a complex tissue that has its own characteristic metabolic features and is interfaced with the whole organism. We investigated changes in basal blood plasma metabolites in the presence of primary brain tumour, their correlation with tumour grade, as well as the feasibility of statistical discrimination based on plasma metabolites. Together 60 plasma samples from patients with clinically defined glioblastoma, meningioma, oligodendrioglioma, astrocytoma, and non-specific glial tumour and plasma samples from 28 healthy volunteers without any cancer history were measured by NMR spectroscopy. In blood plasma of primary brain tumour patients, we found significantly increased levels of glycolytic metabolites glucose and pyruvate, and significantly decreased level of glutamine and also metabolites participating in tricarboxylic acid (TCA) cycle, citrate and succinate, when compared with controls. Further, plasma metabolites levels: tyrosine, phenylalanine, glucose, creatine and creatinine correlated significantly with tumour grade. In general, observed changes are parallel to the biochemistry expected for tumourous tissue and metabolic changes in plasma seem to follow the similar rules in all primary brain tumours, with very subtle variations among tumour types. Only two plasma metabolites tyrosine and phenylalanine were increased exclusively in blood plasma of patients with glioblastoma. Based on metabolite levels, an excellent discrimination between plasma from patient's tumours and controls was attainable. The metabolites creatine, pyruvate, glucose, formate, creatinine and citrate were of the highest discriminatory power.
Using endogenous saccades to characterize fatigue in multiple sclerosis.
Multiple sclerosis and related disorders, 2017

Multiple Sclerosis (MS) is likely to cause dysfunction of neural circuits between brain regions increasing brain working load or a subjective overestimation of such working load leading to fatigue symptoms. The aim of this study was to investigate if saccades can reveal the effect of fatigue in patients with MS.
Adaptation disrupts motion integration in the primate dorsal stream.
Neuron, 2014

Sensory systems adjust continuously to the environment. The effects of recent sensory experience-or adaptation-are typically assayed by recording in a relevant subcortical or cortical network. However, adaptation effects cannot be localized to a single, local network. Adjustments in one circuit or area will alter the input provided to others, with unclear consequences for computations implemented in downstream circuits. Here, we show that prolonged adaptation with drifting gratings, which alters responses in the early visual system, impedes the ability of area MT neurons to integrate motion signals in plaid stimuli. Perceptual experiments reveal a corresponding loss of plaid coherence. A simple computational model shows how the altered representation of motion signals in early cortex can derail integration in MT. Our results suggest that the effects of adaptation cascade through the visual system, derailing the downstream representation of distinct stimulus attributes.