rudyvdbrink/CitationDatabase huggingface dataset:
Capturing the Conformational Ensemble of the Mixed Folded Polyglutamine Protein Ataxin-3.
Structure (London, England : 1993), 2021

Ataxin-3 is a deubiquitinase involved in protein quality control and other essential cellular functions. It preferentially interacts with polyubiquitin chains of four or more units attached to proteins delivered to the ubiquitin-proteasome system. Ataxin-3 is composed of an N-terminal Josephin domain and a flexible C terminus that contains two or three ubiquitin-interacting motifs (UIMs) and a polyglutamine tract, which, when expanded beyond a threshold, leads to protein aggregation and misfolding and causes spinocerebellar ataxia type 3. The high-resolution structure of the Josephin domain is available, but the structural and dynamical heterogeneity of ataxin-3 has so far hindered the structural description of the full-length protein. Here, we characterize non-expanded and expanded variants of ataxin-3 in terms of conformational ensembles adopted by the proteins in solution by jointly using experimental data from nuclear magnetic resonance and small-angle X-ray scattering with coarse-grained simulations. Our results pave the way to a molecular understanding of polyubiquitin recognition.
Patient Safety Incidents Involving Sick Children in Primary Care in England and Wales: A Mixed Methods Analysis.
PLoS medicine, 2017

The UK performs poorly relative to other economically developed countries on numerous indicators of care quality for children. The contribution of iatrogenic harm to these outcomes is unclear. As primary care is the first point of healthcare contact for most children, we sought to investigate the safety of care provided to children in this setting.
Prognostic factors and outcome in anorexia nervosa: a follow-up study.
Eating and weight disorders : EWD, 2016

Anorexia nervosa is an eating disorder characterized by food restriction, irrational fear of gaining weight and consequent weight loss. High mortality rates have been reported, mostly due to suicide and malnutrition. Good outcomes largely vary between 18 and 42%. We aimed to assess outcome and prognostic factors of a large group of patients with anorexia nervosa. Moreover we aimed to identify clusters of prognostic factors related to specific outcomes.
Serotonin modulates striatal responses to fairness and retaliation in humans.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013

Humans are willing to incur personal costs to punish others who violate social norms. Such "costly punishment" is an important force for sustaining human cooperation, but the causal neurobiological determinants of punishment decisions remain unclear. Using a combination of behavioral, pharmacological, and neuroimaging techniques, we show that manipulating the serotonin system in humans alters costly punishment decisions by modulating responses to fairness and retaliation in the striatum. Following dietary depletion of the serotonin precursor tryptophan, participants were more likely to punish those who treated them unfairly, and were slower to accept fair exchanges. Neuroimaging data revealed activations in the ventral and dorsal striatum that were associated with fairness and punishment, respectively. Depletion simultaneously reduced ventral striatal responses to fairness and increased dorsal striatal responses during punishment, an effect that predicted its influence on punishment behavior. Finally, we provide behavioral evidence that serotonin modulates specific retaliation, rather than general norm enforcement: depleted participants were more likely to punish unfair behavior directed toward themselves, but not unfair behavior directed toward others. Our findings demonstrate that serotonin modulates social value processing in the striatum, producing context-dependent effects on social behavior.
Performance of a non-contact infrared thermometer in healthy newborns.
BMJ open, 2016

To evaluate the performance of a non-contact infrared thermometer (NCIT) in comparison with digital axillary thermometer (DAT) and infrared tympanic thermometers (ITT) in a population of healthy at term and preterm newborns nursed in incubators.
Rescue of prepulse inhibition deficit and brain mitochondrial dysfunction by pharmacological stimulation of the central serotonin receptor 7 in a mouse model of CDKL5 Deficiency Disorder.
Neuropharmacology, 2019

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause CDKL5 Deficiency Disorder (CDD), a rare neurodevelopmental syndrome characterized by severe behavioural and physiological symptoms. No cure is available for CDD. CDKL5 is a kinase that is abundantly expressed in the brain and plays a critical role in neurodevelopmental processes, such as neuronal morphogenesis and plasticity. This study provides the first characterization of the neurobehavioural phenotype of 1 year old Cdkl5-null mice and demonstrates that stimulation of the serotonin receptor 7 (5-HT
The Errors of Our Ways: Understanding Error Representations in Cerebellar-Dependent Motor Learning.
Cerebellum (London, England), 2016

The cerebellum is essential for error-driven motor learning and is strongly implicated in detecting and correcting for motor errors. Therefore, elucidating how motor errors are represented in the cerebellum is essential in understanding cerebellar function, in general, and its role in motor learning, in particular. This review examines how motor errors are encoded in the cerebellar cortex in the context of a forward internal model that generates predictions about the upcoming movement and drives learning and adaptation. In this framework, sensory prediction errors, defined as the discrepancy between the predicted consequences of motor commands and the sensory feedback, are crucial for both on-line movement control and motor learning. While many studies support the dominant view that motor errors are encoded in the complex spike discharge of Purkinje cells, others have failed to relate complex spike activity with errors. Given these limitations, we review recent findings in the monkey showing that complex spike modulation is not necessarily required for motor learning or for simple spike adaptation. Also, new results demonstrate that the simple spike discharge provides continuous error signals that both lead and lag the actual movements in time, suggesting errors are encoded as both an internal prediction of motor commands and the actual sensory feedback. These dual error representations have opposing effects on simple spike discharge, consistent with the signals needed to generate sensory prediction errors used to update a forward internal model.
Enriched environment effects on remote object recognition memory.
Neuroscience, 2017

Since Ebbinghaus' classical work on oblivion and saving effects, we know that declarative memories may become at first spontaneously irretrievable and only subsequently completely extinguished. Recently, this time-dependent path toward memory-trace loss has been shown to correlate with different patterns of brain activation. Environmental enrichment (EE) enhances learning and memory and affects system memory consolidation. However, there is no evidence on whether and how EE could affect the time-dependent path toward oblivion. We used Object Recognition Test (ORT) to assess in adult mice put in EE for 40days (EE mice) or left in standard condition (SC mice) memory retrieval of the familiar objects 9 and 21days after learning with or without a brief retraining performed the day before. We found that SC mice show preferential exploration of new object at day 9 only with retraining, while EE mice do it even without. At day 21 SC mice do not show preferential exploration of novel object, irrespective of the retraining, while EE mice are still capable to benefit from retraining, even if they were not able to spontaneously recover the trace. Analysis of c-fos expression 20days after learning shows a different pattern of active brain areas in response to the retraining session in EE and SC mice, with SC mice recruiting the same brain network as naïve SC or EE mice following de novo learning. This suggests that EE promotes formation of longer lasting object recognition memory, allowing a longer time window during which saving is present.
Animal models of neurodegenerative diseases.
Nature neuroscience, 2018

Animal models of adult-onset neurodegenerative diseases have enhanced the understanding of the molecular pathogenesis of Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Nevertheless, our understanding of these disorders and the development of mechanistically designed therapeutics can still benefit from more rigorous use of the models and from generation of animals that more faithfully recapitulate human disease. Here we review the current state of rodent models for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and amyotrophic lateral sclerosis. We discuss the limitations and utility of current models, issues regarding translatability, and future directions for developing animal models of these human disorders.
The hypothalamic-pituitary-adrenal axis as a substrate for stress resilience: Interactions with the circadian clock.
Frontiers in neuroendocrinology, 2020

Stress, primarily processed via the hypothalamic-pituitary-adrenal (HPA) axis, engages biological pathways throughout the brain and body which promote adaptation and survival to changing environmental demands. Adaptation to environmental challenges is compromised when these pathways are no longer functioning optimally. The physiological and behavioral mechanisms through which HPA axis function influences stress adaptation and resilience are not fully elucidated. Our understanding of stress biology and disease must take into account the complex interactions between the endocrine system, neural circuits, and behavioral coping strategies. In addition, further consideration must be taken concerning influences of other aspects of physiology, including the circadian clock which is critical for regulation of daily changes in HPA activity. While adding a layer of complexity, it also offers targets for intervention. Understanding the role of HPA function in mediating these diverse biological responses will lead to important insights about how to bolster successful stress adaptation and promote stress resilience.
The GBA p.Trp378Gly mutation is a probable French-Canadian founder mutation causing Gaucher disease and synucleinopathies.
Clinical genetics, 2018

Biallelic GBA mutations cause Gaucher disease (GD), and heterozygous carriers are at risk for synucleinopathies. No founder GBA mutations in French-Canadians are known. GBA was fully sequenced using targeted next generation and Sanger sequencing in French-Canadian Parkinson disease (PD) patients (n = 436), rapid eye movement (REM)-sleep behavior disorder (RBD) patients (n = 189) and controls (n = 891). Haplotype, identity-by-descent (IBD) and principal component analyses (PCA) were performed using single nucleotide polymorphism-chip data. Data on GD patients from Toronto and Montreal were collected from patients' files. A GBA p.Trp378Gly mutation was identified in two RBD and four PD patients (1% of all patients combined), and not in controls. The two RBD patients had converted to DLB within 3 years of their diagnosis. Haplotype, IBD and PCA analysis demonstrated that this mutation is from a single founder. Out of 167 GD patients screened, 15 (9.0%) carried the p.Trp378Gly mutation, all in trans with p.Asn370Ser. Three (20%) of the GD patients with the p.Trp378Gly mutation had developed Parkinsonism, and 11 patients had family history of PD. The p.Trp378Gly mutation is the first French-Canadian founder GBA mutation to be described, which leads to synucleinopathies and to GD type 1 when in compound heterozygosity with p.Asn370Ser.
When and where is binocular rivalry resolved in the visual cortex?
Journal of vision, 2010

Anatomically "early" visual areas including striate cortex (V1) are known to play a role in the resolution of binocular rivalry. However, the time course of such activity and its relationship with subjective perception are unclear. The present study used an intermittent stimulation design to measure event-related potentials (ERPs) associated with perception during binocular rivalry and during physical alternations of the same stimuli. When gratings of high or low spatial frequencies were presented in physical alternation, the amplitude of the earliest cortical ERP component (the C1, at 60-100 ms) was larger for high spatial frequencies. When the same two stimuli competed during rivalry, however, C1 amplitudes were equivalent for perceptions of high versus low spatial frequency. These findings suggest that rivalry is not resolved before or during the initial cortical response at 60-100 ms. At longer latencies (approximately 130-160 ms), however, occipital ERPs with similar topographies and estimated sources as the C1 differed according to perception in both the rivalry and physical alternation conditions. These results suggest that during rivalry, neural activity coupled with the dominant percept first emerges in anatomically early visual cortex, but at delayed latencies.
Nav1.1-Overexpressing Interneuron Transplants Restore Brain Rhythms and Cognition in a Mouse Model of Alzheimer's Disease.
Neuron, 2018

Inhibitory interneurons regulate the oscillatory rhythms and network synchrony that are required for cognitive functions and disrupted in Alzheimer's disease (AD). Network dysrhythmias in AD and multiple neuropsychiatric disorders are associated with hypofunction of Nav1.1, a voltage-gated sodium channel subunit predominantly expressed in interneurons. We show that Nav1.1-overexpressing, but not wild-type, interneuron transplants derived from the embryonic medial ganglionic eminence (MGE) enhance behavior-dependent gamma oscillatory activity, reduce network hypersynchrony, and improve cognitive functions in human amyloid precursor protein (hAPP)-transgenic mice, which simulate key aspects of AD. Increased Nav1.1 levels accelerated action potential kinetics of transplanted fast-spiking and non-fast-spiking interneurons. Nav1.1-deficient interneuron transplants were sufficient to cause behavioral abnormalities in wild-type mice. We conclude that the efficacy of interneuron transplantation and the function of transplanted cells in an AD-relevant context depend on their Nav1.1 levels. Disease-specific molecular optimization of cell transplants may be required to ensure therapeutic benefits in different conditions.
Prion protein-specific antibodies-development, modes of action and therapeutics application.
Viruses, 2014

Prion diseases or Transmissible Spongiform Encephalopathies (TSEs) are lethal neurodegenerative disorders involving the misfolding of the host encoded cellular prion protein, PrPC. This physiological form of the protein is expressed throughout the body, and it reaches the highest levels in the central nervous system where the pathology occurs. The conversion into the pathogenic isoform denoted as prion or PrPSc is the key event in prion disorders. Prominent candidates for the treatment of prion diseases are antibodies and their derivatives. Anti-PrPC antibodies are able to clear PrPSc from cell culture of infected cells. Furthermore, application of anti-PrPC antibodies suppresses prion replication in experimental animal models. Major drawbacks of immunotherapy are immune tolerance, the risks of neurotoxic side effects, limited ability of compounds to cross the blood-brain barrier and their unfavorable pharmacokinetic. The focus of this review is to recapitulate the current understanding of the molecular mechanisms for antibody mediated anti-prion activity. Although relevant for designing immunotherapeutic tools, the characterization of key antibody parameters shaping the molecular mechanism of the PrPC to PrPSc conversion remains elusive. Moreover, this review illustrates the various attempts towards the development of anti-PrP antibody compounds and discusses therapeutic candidates that modulate PrP expression.
Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2008

To investigate the role of Dicer and microRNAs in the mammalian CNS, we used mice in which the second RNase III domain of Dicer was conditionally floxed. Conditional Dicer mice were bred with mice expressing an alpha-calmodulin kinase II Cre to selectively inactivate Dicer in excitatory forebrain neurons in vivo. Inactivation of Dicer results in an array of phenotypes including microcephaly, reduced dendritic branch elaboration, and large increases in dendritic spine length with no concomitant change in spine density. Microcephaly is likely caused by a 5.5-fold increase in early postnatal apoptosis in these animals as determined by active caspase-3 and TUNEL (terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling) staining in the cortex. Loss of Dicer function had no measurable effect on cortical lamination as determined by in situ hybridization, suggesting that microcephaly is not caused by defects in neuronal migration. Together, these results illustrate the in vivo significance of Dicer and miRNAs in the mammalian CNS and provide additional support for previous in vitro studies indicating that misregulation of this pathway may result in gross abnormalities in cell number and function that may contribute to a variety of neurological disorders.
Dopamine D3 receptor blockade rescues hyper-dopamine activity-induced deficit in novel object recognition memory.
Neuropharmacology, 2018

Patients afflicted with bipolar disorder demonstrate significant impairments in recognition and episodic memory during acute depressive and manic episodes. These impairments and the related pathophysiology may result from over-activation of the brain dopamine (DA) system. In order to model overactive DA transmission in a well-established novel object recognition (NOR) memory test, we used DA transporter knockdown (DAT-KD) mice, which exhibit reduced DAT expression and display hyper-dopaminergic phenotypes. DAT-KD mice exhibited impaired NOR memory compared to wild-type (WT) mice. This impairment was prevented by administration of FAUC365, a DA D
Cerebral white matter lesions and post-thrombolytic remote parenchymal hemorrhage.
Annals of neurology, 2016

Parenchymal hematoma (PH) following intravenous thrombolysis (IVT) in ischemic stroke can occur either within the ischemic area (iPH) or as a remote PH (rPH). The latter could be, at least partly, related to cerebral amyloid angiopathy, which belongs to the continuum of cerebral small vessel disease. We hypothesized that cerebral white matter lesions (WMLs)-an imaging surrogate of small vessel disease-are associated with a higher rate of rPH.
Xuefu Zhuyu decoction ameliorates obesity, hepatic steatosis, neuroinflammation, amyloid deposition and cognition impairment in metabolically stressed APPswe/PS1dE9 mice.
Journal of ethnopharmacology, 2017

Metabolic syndrome and vascular dysfunction was suggested to be the risk factors for Alzheimer's disease (AD). Xuefu Zhuyu decoction (XZD) is a traditional Chinese medicine used to treat metabolic syndrome and cardiac-cerebral vascular disease. The effects of XZD on ameliorating metabolic syndrome, amyloid-related pathologies and cognitive impairment in an animal model of AD with metabolic stress was investigated.
Cortical surface anatomy in pediatric patients with generalized anxiety disorder.
Journal of anxiety disorders, 2014

It is established that pediatric patients with generalized anxiety disorder (GAD) exhibit functional abnormalities and altered gray matter volumes in neural structures that subserve emotional processing, yet there are no data regarding the surface anatomy of the cerebral cortex in youth with GAD.
Design, synthesis, docking study and cytotoxic activity evaluation of some novel letrozole analogs.
Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences, 2014

Breast cancer is the most common type of female cancer. One class of hormonal therapy for breast cancer drugs -non steroidal aromatase inhibitors- are triazole analogues. In this work, some derivatives of these drugs was designed and synthesized. All synthesized compounds were evaluated for their cytotoxic activities on breast cancer cell lines (MDA-MB-231, T47D and MCF-7).
Limiting glutamate transmission in a Vglut2-expressing subpopulation of the subthalamic nucleus is sufficient to cause hyperlocomotion.
Proceedings of the National Academy of Sciences of the United States of America, 2014

The subthalamic nucleus (STN) is a key area of the basal ganglia circuitry regulating movement. We identified a subpopulation of neurons within this structure that coexpresses Vglut2 and Pitx2, and by conditional targeting of this subpopulation we reduced Vglut2 expression levels in the STN by 40%, leaving Pitx2 expression intact. This reduction diminished, yet did not eliminate, glutamatergic transmission in the substantia nigra pars reticulata and entopeduncular nucleus, two major targets of the STN. The knockout mice displayed hyperlocomotion and decreased latency in the initiation of movement while preserving normal gait and balance. Spatial cognition, social function, and level of impulsive choice also remained undisturbed. Furthermore, these mice showed reduced dopamine transporter binding and slower dopamine clearance in vivo, suggesting that Vglut2-expressing cells in the STN regulate dopaminergic transmission. Our results demonstrate that altering the contribution of a limited population within the STN is sufficient to achieve results similar to STN lesions and high-frequency stimulation, but with fewer side effects.
Ketamine as anaesthesia for ECT: is there room to improve a gold standard treatment?
The British journal of psychiatry : the journal of mental science, 2018

One meta-analysis of ketamine anaesthesia for electroconvulsive therapy found no improvement of end-point antidepressant outcomes; another meta-analysis with a broader range of included trials found that ketamine improved both early and late outcomes. If ketamine anaesthesia is useful, researchers may need to look for benefits earlier during the treatment course. Declaration of interest None.
Retinal stem cell transplantation: Balancing safety and potential.
Progress in retinal and eye research, 2020

Stem cell transplantation holds great promise as a potential treatment for currently incurable retinal degenerative diseases that cause poor vision and blindness. Recently, safety data have emerged from several Phase I/II clinical trials of retinal stem cell transplantation. These clinical trials, usually run in partnership with academic institutions, are based on sound preclinical studies and are focused on patient safety. However, reports of serious adverse events arising from cell therapy in other poorly regulated centers have now emerged in the lay and scientific press. While progress in stem cell research for blindness has been greeted with great enthusiasm by patients, scientists, doctors and industry alike, these adverse events have raised concerns about the safety of retinal stem cell transplantation and whether patients are truly protected from undue harm. The aim of this review is to summarize and appraise the safety of human retinal stem cell transplantation in the context of its potential to be developed into an effective treatment for retinal degenerative diseases.