rudyvdbrink/CitationDatabase huggingface dataset:
Agrin and LRP4 antibodies as new biomarkers of myasthenia gravis.
Annals of the New York Academy of Sciences, 2018

Myasthenia gravis (MG) is a common disorder that affects the neuromuscular junction. It is caused by antibodies against acetylcholine receptor and muscle-specific tyrosine kinase; however, some MG patients do not have antibodies against either of the proteins. Recent studies have revealed antibodies against agrin and its receptor LRP4-both critical for neuromuscular junction formation and maintenance-in MG patients from various populations. Results from experimental autoimmune MG animal models indicate that anti-LRP4 antibodies are causal to MG. Clinical studies have begun to reveal the significance of the new biomarkers. With their identification, MG appears to be a complex disease entity that can be classified into different subtypes with different etiology, each with unique symptoms. Future systematic studies of large cohorts of well-diagnosed MG patients are needed to determine whether each subtype of patients would respond to different therapeutic strategies. Results should contribute to the goal of precision medicine for MG patients. Anti-agrin and anti-LRP4 antibodies are also detectable in some patients with amyotrophic lateral sclerosis or Lou Gehrig's disease; however, whether they are a cause or response to the disorder remains unclear.
Longitudinal changes in cerebral blood flow velocities in different clinical courses of migraine.
Cephalalgia : an international journal of headache, 2017

Objective To assess longitudinal changes in cerebral blood flow velocities (ΔCBFVs) according to the clinical course of migraine. Methods We retrospectively included migraine patients with two or more attacks per month at baseline who were followed up within 2 years with transcranial Doppler in a tertiary headache clinic. ΔCBFVs were analyzed in relation to clinical courses, defined as remission (0-1 headache days/month), persistence (2-14/month), or progression (≥15/month) in episodic migraine (EM), and conversion to EM (<15/month) and persistence (≥15/month) in chronic migraine (CM). Results A total of 166 patients (90 EM and 76 CM) were included. In EM, the remission group ( n = 30) showed a decrease in CBFV in the middle cerebral artery (MCA) and the basilar artery (BA). The progression group ( n = 10) showed increasing CBFVs in the bilateral MCAs. Patients with the persistence course ( n = 50) showed generally unchanged CBFVs. In CM, ΔCBFVs decreased in the BA and increased in the posterior cerebral artery (PCA) after conversion to EM ( n = 61), whereas they remained unchanged in the persistence group ( n = 15). In all patients, % change in headache days was positively correlated with the %ΔCBFVs of the bilateral MCAs and the BA. Conclusions CBFV changes are associated with the different clinical courses of migraine. The association is more prominent in EM than CM.
Fragile X mental retardation protein regulates synaptic and behavioral plasticity to repeated cocaine administration.
Neuron, 2014

Repeated cocaine exposure causes persistent, maladaptive alterations in brain and behavior, and hope for effective therapeutics lies in understanding these processes. We describe here an essential role for fragile X mental retardation protein (FMRP), an RNA-binding protein and regulator of dendritic protein synthesis, in cocaine conditioned place preference, behavioral sensitization, and motor stereotypy. Cocaine reward deficits in FMRP-deficient mice stem from elevated mGluR5 (or GRM5) function, similar to a subset of fragile X symptoms, and do not extend to natural reward. We find that FMRP functions in the adult nucleus accumbens (NAc), a critical addiction-related brain region, to mediate behavioral sensitization but not cocaine reward. FMRP-deficient mice also exhibit several abnormalities in NAc medium spiny neurons, including reduced presynaptic function and premature changes in dendritic morphology and glutamatergic neurotransmission following repeated cocaine treatment. Together, our findings reveal FMRP as a critical mediator of cocaine-induced behavioral and synaptic plasticity.
Developmental deprivation-induced perceptual and cortical processing deficits in awake-behaving animals.
eLife, 2018

Sensory deprivation during development induces lifelong changes to central nervous system function that are associated with perceptual impairments. However, the relationship between neural and behavioral deficits is uncertain due to a lack of simultaneous measurements during task performance. Therefore, we telemetrically recorded from auditory cortex neurons in gerbils reared with developmental conductive hearing loss as they performed an auditory task in which rapid fluctuations in amplitude are detected. These data were compared to a measure of auditory brainstem temporal processing from each animal. We found that developmental HL diminished behavioral performance, but did not alter brainstem temporal processing. However, the simultaneous assessment of neural and behavioral processing revealed that perceptual deficits were associated with a degraded cortical population code that could be explained by greater trial-to-trial response variability. Our findings suggest that the perceptual limitations that attend early hearing loss are best explained by an encoding deficit in auditory cortex.
Structure and Mechanism of DHHC Protein Acyltransferases.
Journal of molecular biology, 2020

S-acylation, whereby a fatty acid chain is covalently linked to a cysteine residue by a thioester linkage, is the most prevalent kind of lipid modification of proteins. Thousands of proteins are targets of this post-translational modification, which is catalyzed by a family of eukaryotic integral membrane enzymes known as DHHC protein acyltransferases (DHHC-PATs). Our knowledge of the repertoire of S-acylated proteins has been rapidly expanding owing to development of the chemoproteomic techniques. There has also been an increasing number of reports in the literature documenting the importance of S-acylation in human physiology and disease. Recently, the first atomic structures of two different DHHC-PATs were determined using X-ray crystallography. This review will focus on the insights gained into the molecular mechanism of DHHC-PATs from these structures and highlight representative data from the biochemical literature that they help explain.
The neurobiology of psychopathy.
The Psychiatric clinics of North America, 2008

Numerous studies have tackled the complex challenge of understanding the neural substrates of psychopathy, revealing that brain abnormalities exist on several levels and in several structures. As we discover more about complex neural networks, it becomes increasingly difficult to clarify how these systems interact with each other to produce the distinct pattern of behavioral and personality characteristics observed in psychopathy. The authors review the recent research on the neurobiology of psychopathy, beginning with molecular neuroscience work and progressing to the level of brain structures and their connectivity. Potential factors that may affect the development of brain impairments, as well as how some systems may be targeted for potential treatment, are discussed.
Dynamics of sensory integration of olfactory and mechanical stimuli within the response patterns of moth antennal lobe neurons.
Journal of theoretical biology, 2021

Odors emanating from a biologically relevant source are rapidly embedded within a windy, turbuluent medium that folds and spins filaments into fragmented strands of varying sizes. Environmental odor plumes therefore exhibit complex spatiotemporal dynamics, and rarely yield an easily discernible concentration gradient marking an unambiguous trail to an odor source. Thus, sensory integration of chemical input, encoding odor identity or concentration, and mechanosensory input, encoding wind speed, is a critical task that animals face in resolving the complex dynamics of odor plumes and tracking an odor source. In insects, who employ olfactory navigation as their primary means of foraging for food and finding mates, the antennal lobe (AL) is the first brain structure that processes sensory odor information. Although the importance of chemosensory and mechanosensory integration is widely recognized, the AL itself has traditionally been viewed purely from the perspective of odor encoding, with little attention given to its role as a bimodal integrator. In this work, we seek to explore the AL as a model for studying sensory integration - it boasts well-understood architecture, well-studied olfactory responses, and easily measurable cells. Using a moth model, we present experimental data that clearly demonstrates that AL neurons respond, in dynamically distinct ways, to both chemosensory and mechanosensory input; mechanosensory responses are transient and temporally precise, while olfactory responses are long-lasting but lack temporal precision. We further develop a computational model of the AL, show that our model captures odor response dynamics reported in the literature, and examine the dynamics of our model with the inclusion of mechanosensory input; we then use our model to pinpoint dynamical mechanisms underlying the bimodal AL responses revealed in our experimental work. Finally, we propose a novel hypothesis about the role of mechanosensory input in sculpting AL dynamics and the implications for biological odor tracking.
Functional characterisation of human synaptic genes expressed in the Drosophila brain.
Biology open, 2016

Drosophila melanogaster is an established and versatile model organism. Here we describe and make available a collection of transgenic Drosophila strains expressing human synaptic genes. The collection can be used to study and characterise human synaptic genes and their interactions and as controls for mutant studies. It was generated in a way that allows the easy addition of new strains, as well as their combination. In order to highlight the potential value of the collection for the characterisation of human synaptic genes we also use two assays, investigating any gain-of-function motor and/or cognitive phenotypes in the strains in this collection. Using these assays we show that among the strains made there are both types of gain-of-function phenotypes investigated. As an example, we focus on the three strains expressing human tyrosine protein kinase Fyn, the small GTPase Rap1a and human Arc, respectively. Of the three, the first shows a cognitive gain-of-function phenotype while the second a motor gain-of-function phenotype. By contrast, Arc, which has no Drosophila ortholog, shows no gain-of-function phenotype.
Neuroimaging for Lewy body disease: is the in vivo molecular imaging of α-synuclein neuropathology required and feasible?
Brain research reviews, 2010

Alpha-synuclein aggregation is a neuropathological hallmark of many neurodegenerative diseases including Parkinson's disease (PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB), collectively termed the α-synucleinopathies. Substantial advances in clinical criteria and neuroimaging technology over the last 20 years have allowed great strides in the detection and differential diagnosis of these disorders. Nevertheless, it is clear that whilst the array of different imaging modalities in clinical use allow for a robust diagnosis of α-synucleinopathy in comparison to healthy subjects, there is no clear diagnostic imaging marker that affords a reliable differential diagnosis between the different forms of Lewy body disease (LBD) or that could facilitate tracking of disease progression. This has led to a call for a biomarker based on the pathological hallmarks of these diseases, namely α-synuclein-positive Lewy bodies (LBs). This potentially may be advantageous in terms of early disease detection, but may also be leveraged into a potential marker of disease progression. We here aim to firstly review the current status of neuroimaging biomarkers in PD and related synucleinopathies. Secondly, we outline the rationale behind α-synuclein imaging as a potential novel biomarker as well as the potential benefits and limitations of this approach. Thirdly, we attempt to illustrate the likely technical hurdles to be overcome to permit successful in vivo imaging of α-synuclein pathology in the diseased brain. Our overriding aim is to provide a framework for discussion of how to address this major unmet clinical need.
External trial deep brain stimulation device for the application of desynchronizing stimulation techniques.
Journal of neural engineering, 2009

In the past decade deep brain stimulation (DBS)-the application of electrical stimulation to specific target structures via implanted depth electrodes-has become the standard treatment for medically refractory Parkinson's disease and essential tremor. These diseases are characterized by pathological synchronized neuronal activity in particular brain areas. We present an external trial DBS device capable of administering effectively desynchronizing stimulation techniques developed with methods from nonlinear dynamics and statistical physics according to a model-based approach. These techniques exploit either stochastic phase resetting principles or complex delayed-feedback mechanisms. We explain how these methods are implemented into a safe and user-friendly device.
Iron, copper, and zinc distribution of the cerebellum.
Cerebellum (London, England), 2009

Synchrotron rapid-scanning X-ray fluorescence (RS-XRF) is employed for the first time to simultaneously map iron, copper, and zinc in the normal cerebellum. The cerebellum is a major repository of metals that are essential to normal function. Therefore, mapping the normal metal distribution is an important first step towards understanding how multiple metals may induce oxidative damage, protein aggregation, and neurotoxicity leading to cerebellar degeneration in a wide range of diseases. We found that cerebellar white and grey matter could be sharply defined based upon the unique metal content of each region. The dentate nucleus was particularly metal-rich with copper localized to the periphery and iron and zinc abundant centrally. We discuss how RS-XRF metal mapping in the normal brain may yield important clues to the mechanisms of degeneration in the dentate nucleus.
Unraveling the Molecular Players at the Cholinergic Efferent Synapse of the Zebrafish Lateral Line.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2021

The lateral line (LL) is a sensory system that allows fish and amphibians to detect water currents. LL responsiveness is modulated by efferent neurons that aid in distinguishing between external and self-generated stimuli, maintaining sensitivity to relevant cues. One component of the efferent system is cholinergic, the activation of which inhibits afferent activity. LL hair cells (HCs) share structural, functional, and molecular similarities with those of the cochlea, making them a popular model for studying human hearing and balance disorders. Because of these commonalities, one could propose that the receptor at the LL efferent synapse is a α9α10 nicotinic acetylcholine receptor (nAChR). However, the identities of the molecular players underlying ACh-mediated inhibition in the LL remain unknown. Surprisingly, through the analysis of single-cell expression studies and
Low dose tPA plus annexin A2 combination attenuates tPA delayed treatment-associated hemorrhage and improves recovery in rat embolic focal stroke.
Neuroscience letters, 2015

We previously have shown that tissue type plasminogen activator (tPA) in combination with its receptor annexin A2 (rA2) protein significantly improved tPA thrombolytic efficacy. In this study we aimed to examine the therapeutic effects of the combination when treated at delayed 4-hour window after stroke compared to standard conventional tPA alone in an embolic focal stroke rat model. We compared effects of intravenous tPA alone (10 mg/kg) versus a combination of low-dose tPA (5 mg/kg) plus 10 mg/kg rA2. Totally 152 rats were used. Our results showed that: (1) at 24 h after stroke, the combination slightly reduced brain infarction compared to saline (9.2% reduction), and tPA (7.4% reduction), although the reductions did not reach statistical significance; while the combination significantly reduced (22.2% reduction) the conventional tPA-elevated intracerebral hemorrhagic (ICH) transformation; (2) at 7 days after stroke, the combination significantly attenuated conventional tPA alone-elevated iron deposition at peri-lesion area (68.2% reduction); (3) at 28 days after stroke, the combination significantly improved performance of adhesive tape-removal test, which was accompanied by a significantly higher micro vessel density at peri- infarct areas compared to conventional tPA alone group.In conclusion, compared to conventional tPA alone, when treated at delayed 4-hour after stroke, the combination of low-dose tPA plus rA2 therapy provides a safer profile by lowering risk of ICH transformation and improves neurological function recovery after stroke.
Biological overlap of attention-deficit/hyperactivity disorder and autism spectrum disorder: evidence from copy number variants.
Journal of the American Academy of Child and Adolescent Psychiatry, 2014

Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) often co-occur and share genetic risks. The aim of this analysis was to determine more broadly whether ADHD and ASD share biological underpinnings.
Bex3 Dimerization Regulates NGF-Dependent Neuronal Survival and Differentiation by Enhancing trkA Gene Transcription.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015

The development of the nervous system is a temporally and spatially coordinated process that relies on the proper regulation of the genes involved. Neurotrophins and their receptors are directly responsible for the survival and differentiation of sensory and sympathetic neurons; however, it is not fully understood how genes encoding Trk neurotrophin receptors are regulated. Here, we show that rat Bex3 protein specifically regulates TrkA expression by acting at the trkA gene promoter level. Bex3 dimerization and shuttling to the nucleus regulate the transcription of the trkA promoter under basal conditions and also enhance nerve growth factor (NGF)-mediated trkA promoter activation. Moreover, qChIP assays indicate that Bex3 associates with the trkA promoter within a 150 bp sequence, immediately upstream from the transcription start site, which is sufficient to mediate the effects of Bex3. Consequently, the downregulation of Bex3 using shRNA increases neuronal apoptosis in NGF-dependent sensory neurons deprived of NGF and compromises PC12 cell differentiation in response to NGF. Our results support an important role for Bex3 in the regulation of TrkA expression and in NGF-mediated functions through modulation of the trkA promoter.
Maturation of social attribution skills in typically developing children: an investigation using the social attribution task.
Behavioral and brain functions : BBF, 2010

The assessment of social attribution skills in children can potentially identify and quantify developmental difficulties related to autism spectrum disorders and related conditions. However, relatively little is known about how these skills develop in typically developing children. Therefore the present study aimed to map the trajectory of social attribution skill acquisition in typically developing children from a young age.
Effect of an Intracerebroventricular Injection of Aggregated Beta-amyloid (1-42) on Daily Rhythms of Oxidative Stress Parameters in the Prefrontal Cortex.
Neuroscience, 2021

Accumulation of amyloid peptides in the brain plays a key role in the pathogenesis of Alzheimer's disease (AD). Aggregated beta-amyloid (Aβ) peptide increases intracellular reactive oxygen species associated to a deficient antioxidant defense system. Prefrontal cortex plays a key role in memory and learning and is especially susceptible to oxidative stress. The objective of this work was to investigate the effects of an intracerebroventricular (i.c.v.) injection of Aβ (1-42) on 24 h patterns of oxidative stress parameters and antioxidant defenses in the rat prefrontal cortex. Four-month-old male Holtzman rats were divided into two groups defined as: control (CO) and Aβ-injected (Aβ). Rats were maintained under12 h-light:12 h-dark conditions and received water and food ad libitum. Tissues samples were isolated every 6 h during a 24 h period. Interestingly, we found that an i.c.v. injection of Aβ(1-42) increased lipid peroxidation, reduced total antioxidant capacity level, phase-shifted the daily peak of reduced glutathione, and had a differential effect on the oscillating catalase and glutathione peroxidase specific activity. Thus, elevated levels of Aβ aggregates-a pathogenic hallmark of AD, caused altered temporal patterns of the cellular redox state in prefrontal cortex rat. These findings might contribute, at least in part, to the understanding of the molecular and biochemical basis of redox changes caused by circadian rhythms alterations observed in AD patients.
Spontaneous Activity of Cochlear Hair Cells Triggered by Fluid Secretion Mechanism in Adjacent Support Cells.
Cell, 2015

Spontaneous electrical activity of neurons in developing sensory systems promotes their maturation and proper connectivity. In the auditory system, spontaneous activity of cochlear inner hair cells (IHCs) is initiated by the release of ATP from glia-like inner supporting cells (ISCs), facilitating maturation of central pathways before hearing onset. Here, we find that ATP stimulates purinergic autoreceptors in ISCs, triggering Cl(-) efflux and osmotic cell shrinkage by opening TMEM16A Ca(2+)-activated Cl(-) channels. Release of Cl(-) from ISCs also forces K(+) efflux, causing transient depolarization of IHCs near ATP release sites. Genetic deletion of TMEM16A markedly reduces the spontaneous activity of IHCs and spiral ganglion neurons in the developing cochlea and prevents ATP-dependent shrinkage of supporting cells. These results indicate that supporting cells in the developing cochlea have adapted a pathway used for fluid secretion in other organs to induce periodic excitation of hair cells.
Regulation of synaptic Pumilio function by an aggregation-prone domain.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2010

We identified Pumilio (Pum), a Drosophila translational repressor, in a computational search for metazoan proteins whose activities might be regulated by assembly into ordered aggregates. The search algorithm was based on evolutionary sequence conservation patterns observed for yeast prion proteins, which contain aggregation-prone glutamine/asparagine (Q/N)-rich domains attached to functional domains of normal amino acid composition. We examined aggregation of Pum and its nematode ortholog PUF-9 by expression in yeast. A domain of Pum containing the Q/N-rich sequence, denoted as NQ1, the entire Pum N terminus, and the complete PUF-9 protein localize to macroscopic aggregates (foci) in yeast. NQ1 and PUF-9 can generate the yeast Pin+ trait, which is transmitted by a heritable aggregate. NQ1 also assembles into amyloid fibrils in vitro. In Drosophila, Pum regulates postsynaptic translation at neuromuscular junctions (NMJs). To assess whether NQ1 affects synaptic Pum activity in vivo, we expressed it in muscles. We found that it negatively regulates endogenous Pum, producing gene dosage-dependent pum loss-of-function NMJ phenotypes. NQ1 coexpression also suppresses lethality and NMJ phenotypes caused by overexpression of Pum in muscles. The Q/N block of NQ1 is required for these phenotypic effects. Negative regulation of Pum by NQ1 might be explained by formation of inactive aggregates, but we have been unable to demonstrate that NQ1 aggregates in Drosophila. NQ1 could also regulate Pum by a "dominant-negative" effect, in which it would block Q/N-mediated interactions of Pum with itself or with cofactors required for translational repression.