rudyvdbrink/CitationDatabase huggingface dataset:
Oxidative stress: a systemic factor implicated in the pathogenesis of hepatic encephalopathy.
Metabolic brain disease, 2013

Although ammonia is considered the main factor involved in the pathogenesis of hepatic encephalopathy (HE), it correlates well with the severity of HE in acute liver failure, but not in chronic liver disease. Oxidative stress is another factor believed to play a role in the pathogenesis of this syndrome; it represents an imbalance between the production and neutralization of reactive oxygen species, which leads to cellular dysfunction. In the setting of liver disease, oxidative stress represents a systemic phenomenon induced by several mechanisms: decreased antioxidant synthesis, increased systemic release of oxidant enzymes, generation of reactive oxygen species, and impaired neutrophil function. High ammonia concentrations induce cerebral oxidative stress, thus contributing to severe hepatic encephalopathy, as observed in acute liver failure. In chronic liver disease, significantly lower degrees of hyperammonemia (<500 μM) do not induce cerebral nor systemic oxidative stress. Data from both animal and human studies sustain that there is a synergistic effect between systemic oxidative stress, and ammonia that is implicated in the pathogenesis of hepatic encephalopathy.
Mathematical framework for large-scale brain network modeling in The Virtual Brain.
NeuroImage, 2015

In this article, we describe the mathematical framework of the computational model at the core of the tool The Virtual Brain (TVB), designed to simulate collective whole brain dynamics by virtualizing brain structure and function, allowing simultaneous outputs of a number of experimental modalities such as electro- and magnetoencephalography (EEG, MEG) and functional Magnetic Resonance Imaging (fMRI). The implementation allows for a systematic exploration and manipulation of every underlying component of a large-scale brain network model (BNM), such as the neural mass model governing the local dynamics or the structural connectivity constraining the space time structure of the network couplings. Here, a consistent notation for the generalized BNM is given, so that in this form the equations represent a direct link between the mathematical description of BNMs and the components of the numerical implementation in TVB. Finally, we made a summary of the forward models implemented for mapping simulated neural activity (EEG, MEG, sterotactic electroencephalogram (sEEG), fMRI), identifying their advantages and limitations.
Novel reproductive technologies to prevent mitochondrial disease.
Human reproduction update, 2017

The use of nuclear transfer (NT) has been proposed as a novel reproductive treatment to overcome the transmission of maternally-inherited mitochondrial DNA (mtDNA) mutations. Pathogenic mutations in mtDNA can cause a wide-spectrum of life-limiting disorders, collectively known as mtDNA disease, for which there are currently few effective treatments and no known cures. The many unique features of mtDNA make genetic counselling challenging for women harbouring pathogenic mtDNA mutations but reproductive options that involve medical intervention are available that will minimize the risk of mtDNA disease in their offspring. This includes PGD, which is currently offered as a clinical treatment but will not be suitable for all. The potential for NT to reduce transmission of mtDNA mutations has been demonstrated in both animal and human models, and has recently been clinically applied not only to prevent mtDNA disease but also for some infertility cases. In this review, we will interrogate the different NT techniques, including a discussion on the available safety and efficacy data of these technologies for mtDNA disease prevention. In addition, we appraise the evidence for the translational use of NT technologies in infertility.
The role of the mammalian DNA end-processing enzyme polynucleotide kinase 3'-phosphatase in spinocerebellar ataxia type 3 pathogenesis.
PLoS genetics, 2015

DNA strand-breaks (SBs) with non-ligatable ends are generated by ionizing radiation, oxidative stress, various chemotherapeutic agents, and also as base excision repair (BER) intermediates. Several neurological diseases have already been identified as being due to a deficiency in DNA end-processing activities. Two common dirty ends, 3'-P and 5'-OH, are processed by mammalian polynucleotide kinase 3'-phosphatase (PNKP), a bifunctional enzyme with 3'-phosphatase and 5'-kinase activities. We have made the unexpected observation that PNKP stably associates with Ataxin-3 (ATXN3), a polyglutamine repeat-containing protein mutated in spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD). This disease is one of the most common dominantly inherited ataxias worldwide; the defect in SCA3 is due to CAG repeat expansion (from the normal 14-41 to 55-82 repeats) in the ATXN3 coding region. However, how the expanded form gains its toxic function is still not clearly understood. Here we report that purified wild-type (WT) ATXN3 stimulates, and by contrast the mutant form specifically inhibits, PNKP's 3' phosphatase activity in vitro. ATXN3-deficient cells also show decreased PNKP activity. Furthermore, transgenic mice conditionally expressing the pathological form of human ATXN3 also showed decreased 3'-phosphatase activity of PNKP, mostly in the deep cerebellar nuclei, one of the most affected regions in MJD patients' brain. Finally, long amplicon quantitative PCR analysis of human MJD patients' brain samples showed a significant accumulation of DNA strand breaks. Our results thus indicate that the accumulation of DNA strand breaks due to functional deficiency of PNKP is etiologically linked to the pathogenesis of SCA3/MJD.
Cortisol Awakening Response and Acute Stress Reactivity in First Nations People.
Scientific reports, 2017

First Nations people globally have a higher incidence of mental disorders and non-communicable diseases. These health inequalities are partially attributed to a complex network of social and environmental factors which likely converge on chronic psychosocial stress. We hypothesized that alterations in stress processing and the regulation of the hypothalamic-pituitary-adrenal axis might underlie health disparities in First Nations people. We assessed the cortisol awakening response and the dynamic response to a laboratory induced psychosocial stress of young Indigenous tertiary students (n = 11, mean age 23.82 years) and non-Indigenous students (n = 11) matched for age and gender. Indigenous participants had a blunted cortisol awakening response (27.40 (SD 35.00) vs. 95.24 (SD 55.23), p = 0.002), which was differentially associated with chronic experience of stress in Indigenous (r = -0.641, p = 0.046) and non-Indigenous (r = 0.652, p = 0.03) participants. The cortisol response to the laboratory induced psychosocial stress did not differ between groups. Self-reported racial discrimination was strongly associated with flattened cortisol response to stress (r = -0676, p = 0.022) and with heart rate variability (r = 0.654, p = 0.040). Our findings provide insight into potential biological factors underlying health discrepancies in ethnic minority groups.
Noncoding RNAs: new players in chronic pain.
Anesthesiology, 2014

Chronic pain, a common clinical symptom, is often treated inadequately or ineffectively in part due to the incomplete understanding of molecular mechanisms that initiate and maintain this disorder. Newly identified noncoding RNAs govern gene expression. Recent studies have shown that peripheral noxious stimuli drive expressional changes in noncoding RNAs and that these changes are associated with pain hypersensitivity under chronic pain conditions. This review first presents current evidence for the peripheral inflammation/nerve injury-induced change in the expression of two types of noncoding RNAs, microRNAs, and Kcna2 antisense RNA, in pain-related regions, particularly in the dorsal root ganglion. The authors then discuss how peripheral noxious stimuli induce such changes. The authors finally explore potential mechanisms of how expressional changes in dorsal root ganglion microRNAs and Kcna2 antisense RNA contribute to the development and maintenance of chronic pain. An understanding of these mechanisms may propose novel therapeutic strategies for preventing and/or treating chronic pain.
PPARγ agonists: Potential treatments for exudative age-related macular degeneration.
Life sciences, 2017

Choroidal neovascularization (CNV) characterizes the progression of exudative age-related macular degeneration (AMD) with the deterioration in the central vision. Vascular inflammation, and overproduction of inflammatory cytokines, growth factors and aberrant endothelial cell migration, initiate defective blood vessel proliferation in exudative AMD. CNV formation is initiated by the interplay between inflammation, the hallmark of exudative AMD, and the activation of WNT/β-catenin pathway. Upregulation of WNT/β-catenin pathway involves activation of PI3K/Akt pathway and then the Warburg effect to produce lactate. Lactate production generates VEGF expression and then participates to the initiation of CNV in exudative AMD. WNT/β-catenin pathway and PPARγ act in an opposite manner in several diseases. We focus this review on the interplay between PPARγ and canonical WNT/β-catenin pathway and the anti-inflammatory role of PPARγ in exudative AMD. In exudative AMD, PPARγ agonists downregulate inflammation and the WNT/β-catenin pathway. PPARγ agonists can appear as promising treatment against the initiation and the progression of CNV in exudative AMD.
Altered microRNAs related to synaptic function as potential plasma biomarkers for Alzheimer's disease.
Alzheimer's research & therapy, 2019

Several evidences suggest that failure of synaptic function occurs at preclinical stages of Alzheimer's disease (AD) preceding neuronal loss and the classical AD pathological hallmarks. Nowadays, there is an urgent need to identify reliable biomarkers that could be obtained with non-invasive methods to improve AD diagnosis at early stages. Here, we have examined plasma levels of a group of miRNAs related to synaptic proteins in a cohort composed of cognitive healthy controls (HC), mild cognitive impairment (MCI) and AD subjects.
Effects of Fampridine in People with Multiple Sclerosis: A Systematic Review and Meta-analysis.
CNS drugs, 2019

Prolonged-release (PR) fampridine is a potassium channel blocker used as a symptomatic treatment for walking disability in patients with multiple sclerosis (MS). Its clinical effects in such patients have not been systematically reviewed, and may be more wide-ranging than expected.
Modest proteasomal inhibition by aberrant ubiquitin exacerbates aggregate formation in a Huntington disease mouse model.
Molecular and cellular neurosciences, 2010

UBB(+1), a mutant form of ubiquitin, is both a substrate and an inhibitor of the proteasome which accumulates in the neuropathological hallmarks of Huntington disease (HD). In vitro, expression of UBB(+1) and mutant huntingtin synergistically increase aggregate formation and polyglutamine induced cell death. We generated a UBB(+1) transgenic mouse line expressing UBB(+1) within the neurons of the striatum. In these mice lentiviral driven expression of expanded huntingtin constructs in the striatum results in a significant increase in neuronal inclusion formation. Although UBB(+1) transgenic mice show neither a decreased lifespan nor apparent neuronal loss, they appear to be more vulnerable to toxic insults like expanded polyglutamine proteins due to a modest proteasome inhibition. These findings underscore the relevance of an efficient ubiquitin-proteasome system in HD.
Associations between narcissism and emotion regulation difficulties: Respiratory sinus arrhythmia reactivity as a moderator.
Biological psychology, 2015

The aim of the current study was to examine the direct and interactive effects of two types of narcissism (overt and covert) and respiratory sinus arrhythmia (RSA) reactivity on emotion regulation difficulties in 227 undergraduate students. Overt and covert narcissism and emotion regulation difficulties were assessed with self-report measures (narcissistic personality inventory (NPI)-16, hypersensitive narcissism scale (HSNS), and difficulties in emotion regulation scale (DERS)), and physiological data were measured during the baseline, stress (a public-speaking task), and recovery periods in the laboratory. Results indicated that overt narcissism was negatively related to a lack of emotional awareness and emotional clarity, whereas covert narcissism was positively related to overall emotion regulation difficulties, nonacceptance of emotional responses, impulse control difficulties, limited access to emotion regulation strategies, and a lack of emotional clarity. RSA reactivity in response to a mock job interview moderated the associations between covert narcissism (as a predictor) and overall emotion regulation difficulties and impulse control difficulties (as outcomes). This finding showed that a greater stress-induced RSA decrease may serve as a protective factor and ameliorate the effect of covert narcissism on individuals' emotion regulation difficulties.
Developmental Disruption of Recurrent Inhibitory Feedback Results in Compensatory Adaptation in the Renshaw Cell-Motor Neuron Circuit.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2017

When activating muscles, motor neurons in the spinal cord also activate Renshaw cells, which provide recurrent inhibitory feedback to the motor neurons. The tight coupling with motor neurons suggests that Renshaw cells have an integral role in movement, a role that is yet to be elucidated. Here we used the selective expression of the nicotinic cholinergic receptor α2 (
Primary somatosensory cortex necessary for the perception of weight from other people's action: A continuous theta-burst TMS experiment.
NeuroImage, 2017

The presence of a network of areas in the parietal and premotor cortices, which are active both during action execution and observation, suggests that we might understand the actions of other people by activating those motor programs for making similar actions. Although neurophysiological and imaging studies show an involvement of the somatosensory cortex (SI) during action observation and execution, it is unclear whether SI is essential for understanding the somatosensory aspects of observed actions. To address this issue, we used off-line transcranial magnetic continuous theta-burst stimulation (cTBS) just before a weight judgment task. Participants observed the right hand of an actor lifting a box and estimated its relative weight. In counterbalanced sessions, we delivered sham and active cTBS over the hand region of the left SI and, to test anatomical specificity, over the left motor cortex (M1) and the left superior parietal lobule (SPL). Active cTBS over SI, but not over M1 or SPL, impaired task performance relative to sham cTBS. Moreover, active cTBS delivered over SI just before participants were asked to evaluate the weight of a bouncing ball did not alter performance compared to sham cTBS. These findings indicate that SI is critical for extracting somatosensory features (heavy/light) from observed action kinematics and suggest a prominent role of SI in action understanding.
Social seeking declines in young adolescents.
Royal Society open science, 2017

The desire to engage with others is an important motivational force throughout our lifespan. It is known that social behaviour and preferences change from childhood to adulthood, but whether this change is linked with any changes in social motivation is not known. We evaluated 255 typically developing participants from ages 4-20 years on a behavioural paradigm 'Choose a Movie' (CAM). On every trial, participants had a choice between viewing social or non-social movies presented with different levels of effort (key presses/screen touch required). Hence, participants chose not only the movie they would watch but also how much effort they would make. The difference between the effort levels of the chosen and not chosen stimuli helps in quantifying the motivation to seek it. This task could be used with all the age groups with minimal adaptations, allowing comparison between the groups. Results showed that children (4-8 years), older adolescents (12-16 years) and young adults (17-20 years) made more effort to look at social movies. Counterintuitively, this preference was not seen in young adolescents (around 9-12 years), giving a U-shaped developmental trajectory over the population. We present the first evidence for non-monotonic developmental change in social motivation in typical participants.
The long-lasting impact of unemployment on life satisfaction: results of a longitudinal study over 20 years in East Germany.
Health and quality of life outcomes, 2020

Economic disruption in East Germany at the time of reunification (1990) resulted in a noticeable increase in unemployment. The present study provides data from a German cohort for over 20 years. The aim was to examine how the frequency of experiencing unemployment affects life satisfaction and whether their relationship changes over time.
5'-AMP-activated protein kinase activity is elevated early during primary brain tumor development in the rat.
International journal of cancer, 2011

We found that adenosine 5'-monophosphate-activated protein kinase (AMPK), which is considered the "fuel sensor" of mammalian cells because it directly responds to the depletion of the fuel molecule ATP, is strongly activated by tumor-like hypoxia and glucose deprivation. We also observed abundant AMPK activity in tumor cells in vivo, using subcutaneous tumor xenografts prepared from cells transformed with oncogenic H-Ras. Such rapidly growing transplants of tumor cells, however, represent fully developed tumors that naturally contain energetically stressed microenvironments that can activate AMPK. Therefore, to investigate the induction of AMPK activity during experimental tumorigenesis, we used an established model of brain tumor (glioma) development in the offspring of rats exposed prenatally to the mutagen N-ethyl-N-nitrosourea. We observed that immunostaining for a specific readout of AMPK activity (AMPK-dependent phosphorylation of acetyl-CoA carboxylase) was prominent during N-ethyl-N-nitrosourea-initiated neurocarcinogenesis, from the occurrence of early hyperplasia (microtumors) to the emergence of large gliomas. Moreover, we observed that immunostaining for activating phosphorylation of AMPK correlated with the same stages of glioma development, notably in mitotic tumor cells in which the signal showed punctate as well as cytoplasmic patterns associated with spindle formation. Based on these observations, we propose that neurocarcinogenesis requires AMPK-dependent regulation of cellular energy metabolism.
Effectiveness and cost-effectiveness of interferon beta and glatiramer acetate in the UK Multiple Sclerosis Risk Sharing Scheme at 6 years: a clinical cohort study with natural history comparator.
The Lancet. Neurology, 2015

In 2002, the UK's National Institute for Clinical Excellence (NICE) concluded that interferon beta and glatiramer acetate would be cost effective as disease-modifying therapies (DMTs) for multiple sclerosis only if the short-term disability benefits reported in clinical trials were maintained. The UK Multiple Sclerosis Risk Sharing Scheme (RSS) was established to assess whether disability progression was consistent with a cost-effectiveness target of £36 000 per quality-adjusted life-year projected over 20 years. We aimed to evaluate the long-term effectiveness and cost-effectiveness of these DMTs by comparing a cohort of patients with relapsing-remitting multiple sclerosis enrolled in the UK RSS with a natural history cohort from British Columbia, Canada.
Local versus Global Dendritic Integration.
Neuron, 2019

While many studies indicate that dendrites can perform a range of local computations on their inputs, work from the Harnett lab in this issue of Neuron suggests that the vast majority of active dendritic events are synchronized across the somato-dendritic axis of cortical pyramidal neurons.
Improved correspondence of resting-state networks after macroanatomical alignment.
Human brain mapping, 2014

Resting state brain activity, as measured with functional magnetic resonance imaging (fMRI) in the absence of stimulation, is widely investigated in clinical, pharmacological, developmental and cross-species neuroscience research. However, despite the general and broad interest in understating the nature of resting state networks (RSNs), there has not been a thorough investigation into the relationship between these functional networks and their adherence to underling brain anatomy. We acquired resting state fMRI data from 10 subjects and extracted individual and group RSN maps respectively using independent component analysis (ICA) and self organising group-level ICA (sogICA). Cortex based alignment (CBA), an advanced surface based alignment technique which uses individual curvature information to align individual subjects' brains to a dynamic group average, was used to maximise anatomical correspondence across subjects. Cross subject spatial correlations of the RSN maps (independent components) were carried out with and without CBA. Seven RSNs, which are amongst the most reported and studied networks, were identified. We observed a systematic gain in the spatial correlation in all of them following CBA, although this gain was not uniform across RSNs. The observed increase in similarity of the functional RSNs after anatomical alignment illustrates that these functional networks are indeed related to underlying macroanatomical features. Moreover, our results demonstrate that by correcting for individual anatomical differences, advanced surface based alignment techniques increase the overlap of corresponding resting state networks across subjects, thereby providing a useful means to improve resting state group statistics with no need for substantial smoothing.
Phosphodiesterase-4D Knock-down in the Prefrontal Cortex Alleviates Chronic Unpredictable Stress-Induced Depressive-Like Behaviors and Memory Deficits in Mice.
Scientific reports, 2015

Phosphodiesterase 4 (PDE4) has four isoforms (PDE4A-D) with at least 25 splice variants. PDE4 subtype nonselective inhibitors produce potent antidepressant-like and cognition-enhancing effects via increased intracellular cyclic AMP (cAMP) signaling in the brain. Our previous data have demonstrated that long-form PDE4Ds appear to be involved in these pharmacological properties of PDE4 inhibitors in the normal animals. However, it is not clear whether long-form PDE4Ds are critical for the behaviors and related cellular signaling/neuronal plasticity/neuroendocrine alterations in the depressed animals. In the present study, animals exposed to the chronic unpredictable stress (CUS), a rodent model of depression, exhibited elevated corticosterone, depressive-like behavior, memory deficits, accompanied with decreased cAMP-PKA-CREB and cAMP-ERK1/2-CREB signaling and neuroplasticity. These alterations induced by CUS were reversed by RNA interference (RNAi)-mediated prefrontal cortex long-form PDE4Ds (especially PDE4D4 and PDE4D5) knock-down, similar to the effects of the PDE4 subtype nonselective inhibitor rolipram. Furthermore, these effects of RNAi were not enhanced by rolipram. These data indicate a predominant role of long-form PDE4Ds in the pharmacotherapies of PDE4 inhibitors for depression and concomitant memory deficits. Long-form PDE4Ds, especially PDE4D4 and PDE4D5, appear to be the promising targets for the development of antidepressants with high therapeutic indices.