rudyvdbrink/CitationDatabase huggingface dataset:
A biphasic effect of TNF-α in regulation of the Keap1/Nrf2 pathway in cardiomyocytes.
Redox biology, 2016

Antagonizing TNF-α signaling attenuates chronic inflammatory disease, but is associated with adverse effects on the cardiovascular system. Therefore the impact of TNF-α on basal control of redox signaling events needs to be understand in more depth. This is particularly important for the Keap1/Nrf2 pathway in the heart and in the present study we hypothesized that inhibition of a low level of TNF-α signaling attenuates the TNF-α dependent activation of this cytoprotective pathway. HL-1 cardiomyocytes and TNF receptor1/2 (TNFR1/2) double knockout mice (DKO) were used as experimental models. TNF-α (2-5ng/ml, for 2h) evoked significant nuclear translocation of Nrf2 with increased DNA/promoter binding and transactivation of Nrf2 targets. Additionally, this was associated with a 1.5 fold increase in intracellular glutathione (GSH). Higher concentrations of TNF-α (>10-50ng/ml) were markedly suppressive of the Keap1/Nrf2 response and associated with cardiomyocyte death marked by an increase in cleavage of caspase-3 and PARP. In vivo experiments with TNFR1/2-DKO demonstrates that the expression of Nrf2-regulated proteins (NQO1, HO-1, G6PD) were significantly downregulated in hearts of the DKO when compared to WT mice indicating a weakened antioxidant system under basal conditions. Overall, these results indicate that TNF-α exposure has a bimodal effect on the Keap1/Nrf2 system and while an intense inflammatory activation suppresses expression of antioxidant proteins a low level appears to be protective.
Connexin36 (Cx36) expression and protein detection in the mouse carotid body and myenteric plexus.
Acta histochemica, 2013

Although connexin36 (Cx36) has been studied in several tissues, it is notable that no data are available on Cx36 expression in the carotid body and the intestine. The present study was undertaken to evaluate using immunohistochemistry, PCR and Western blotting procedures, whether Cx36 was expressed in the mouse carotid body and in the intestine at ileum and colon level. In the carotid body, Cx36 was detected as diffuse punctate immunostaining and as protein by Western blotting and mRNA by RT-PCR. Cx36 punctate immunostaining was also evident in the intestine with localization restricted to the myenteric plexus of both the ileum and the colon, and this detection was also confirmed by Western blotting and RT-PCR. All the data obtained were validated using Cx36 knockout mice. Taken together the present data on localization of Cx36 gap-junctions in two tissues of neural crest-derived neuroendocrine organs may provide an anatomical basis for future functional investigations.
Zebrafish calls for reinterpretation for the roles of P/Q calcium channels in neuromuscular transmission.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013

A long-held tenet of neuromuscular transmission is that calcium-dependent neurotransmitter release is mediated by N-type calcium channels in frog but P/Q-type channels in mammals. The N-type assignment in frog is based principally on pharmacological sensitivity to ω-conotoxin GVIA. Our studies show that zebrafish neuromuscular transmission is also sensitive to ω-conotoxin GVIA. However, positional cloning of a mutant line with compromised neuromuscular function identified a mutation in a P/Q- rather than N-type channel. Cloning and heterologous expression of this P/Q-type channel confirmed a block by ω-conotoxin GVIA raising the likelihood that all vertebrates, including frog, use the P/Q-type calcium channel for neuromuscular transmission. In addition, our P/Q defective mutant line offered a means of testing the ability of roscovitine, known to potentiate frog neuromuscular transmission, to mediate behavioral and functional rescue. Acute treatment led to rapid improvement of both, pointing to potential therapeutic benefit for myasthenic disorders involving calcium channel dysfunction.
Gadolinium Retention in the Brain: An MRI Relaxometry Study of Linear and Macrocyclic Gadolinium-Based Contrast Agents in Multiple Sclerosis.
AJNR. American journal of neuroradiology, 2019

Brain gadolinium retention is consistently reported for linear gadolinium-based contrast agents, while the results for macrocyclics are contradictory and potential clinical manifestations remain controversial. Furthermore, most previous studies are based on conventional T1-weighted MR imaging. We therefore aimed to quantitatively investigate longitudinal and transversal relaxation in the brain in relation to previous gadolinium-based contrast agent administration and explore associations with disability in multiple sclerosis.
Examining the predictive association of irritability with borderline personality disorder in a clinical sample of female adolescents.
Personality and mental health, 2020

Borderline personality disorder (BPD) is a disorder associated with emotion dysregulation and is common in clinical samples of adolescents. The identification and delineation of BPD from other disorders is important, yet methods for effectively screening for BPD are lacking. Here, we examine whether irritability can be used as a screening item for BPD in adolescents at risk for the disorder.
Principles of tactile search over the body.
Journal of neurophysiology, 2020

Although we routinely experience complex tactile patterns over our entire body, how we selectively experience multisite touch over our bodies remains poorly understood. Here, we characterized tactile search behavior over the full body using a tactile analog of the classic visual search task. On each trial, participants judged whether a target stimulus (e.g., 10-Hz vibration) was present or absent anywhere on the body. When present, the target stimulus could occur alone or simultaneously with distractor stimuli (e.g., 30-Hz vibrations) on other body locations. We systematically varied the number and spatial configurations of the distractors as well as the target and distractor frequencies and measured the impact of these factors on tactile search response times. First, we found that response times were faster on target-present trials compared with target-absent trials. Second, response times increased with the number of stimulated sites, suggesting a serial search process. Third, search performance differed depending on stimulus frequencies. This frequency-dependent behavior may be related to perceptual grouping effects based on timing cues. We constructed linear models to explore how the locations of the target and distractor cues influenced tactile search behavior. Our modeling results reveal that, in isolation, cues on the index fingers make relatively greater contributions to search performance compared with stimulation experienced on other body sites. Additionally, costimulation of sites within the same limb or simply on the same body side preferentially influence search behavior. Our collective findings identify some principles of attentional search that are common to vision and touch, but others that highlight key differences that may be unique to body-based spatial perception.
A meta-analysis of diffusion tensor imaging studies of the corpus callosum in schizophrenia.
Schizophrenia research, 2011

The corpus callosum has been hypothesized to play an important role in neurobiological models of schizophrenia. Diffusion tensor imaging studies have provided evidence for a disruption in corpus callosum morphology in schizophrenia, but the regional distribution of abnormalities is not well known.
Proposal of an optimized strategy for intraoperative testing of speech and language during awake mapping.
Neurosurgical review, 2017

In this paper, we review the literature about the definitions of errors observed by direct electrical stimulation during language testing. As a practical application, we propose an optimized strategy for differentiating accurately motor arrest, speech arrest, and anomia in the context of intraoperative mapping. Finally, we also discuss the anatomical correlates of the networks sustaining these different errors, both cortically and axonally.
Immunomodulatory Effects of Hydroxychloroquine and Chloroquine in Viral Infections and Their Potential Application in Retinal Gene Therapy.
International journal of molecular sciences, 2020

Effective treatment of retinal diseases with adeno-associated virus (AAV)-mediated gene therapy is highly dependent on the proportion of successfully transduced cells. However, due to inflammatory reactions at high vector doses, adjunctive treatment may be necessary to enhance the therapeutic outcome. Hydroxychloroquine and chloroquine are anti-malarial drugs that have been successfully used in the treatment of autoimmune diseases. Evidence suggests that at high concentrations, hydroxychloroquine and chloroquine can impact viral infection and replication by increasing endosomal and lysosomal pH. This effect has led to investigations into the potential benefits of these drugs in the treatment of viral infections, including human immunodeficiency virus and severe acute respiratory syndrome coronavirus-2. However, at lower concentrations, hydroxychloroquine and chloroquine appear to exert immunomodulatory effects by inhibiting nucleic acid sensors, including toll-like receptor 9 and cyclic GMP-AMP synthase. This dose-dependent effect on their mechanism of action supports observations of increased viral infections associated with lower drug doses. In this review, we explore the immunomodulatory activity of hydroxychloroquine and chloroquine, their impact on viral infections, and their potential to improve the efficacy and safety of retinal gene therapy by reducing AAV-induced immune responses. The safety and practicalities of delivering hydroxychloroquine into the retina will also be discussed.
Long-lasting effect of obesity on skeletal muscle transcriptome.
BMC genomics, 2017

Reduced physical activity and increased intake of calorically-dense diets are the main risk factors for obesity, glucose intolerance, and type 2 diabetes. Chronic overnutrition and hyperglycemia can alter gene expression, contributing to long-term obesity complications. While caloric restriction can reduce obesity and glucose intolerance, it is currently unknown whether it can effectively reprogram transcriptome to a pre-obesity level. The present study addressed this question by the preliminary examination of the transcriptional dynamics in skeletal muscle after exposure to overnutrition and following caloric restriction.
Neural Substrates of Depression and Resilience.
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2017

There is an urgent need for more effective medications to treat major depressive disorder, as fewer than half of depressed patients achieve full remission and many are not responsive with currently available antidepressant medications or psychotherapy. It is known that prolonged stressful events are an important risk factor for major depressive disorder. However, there are prominent individual variations in response to stress: a relatively small proportion of people (10-20%) experiencing prolonged stress develop stress-related psychiatric disorders, including depression (susceptibility to stress), whereas most stress-exposed individuals maintain normal psychological functioning (resilience to stress). There have been growing efforts to investigate the neural basis of susceptibility versus resilience to depression. An accumulating body of evidence is revealing the genetic, epigenetic, and neurophysiological mechanisms that underlie stress susceptibility, as well as the active mechanisms that underlie the resilience phenotype. In this review, we discuss, mainly based on our own work, key pathological mechanisms of susceptibility that are identified as potential therapeutic targets for depression treatment. We also review novel mechanisms that promote natural resilience as an alternative strategy to achieve treatment efficacy. These studies are opening new avenues to develop conceptually novel therapeutic strategies for depression treatment.
Serum and cerebrospinal neurofilament light chain levels in patients with acquired peripheral neuropathies.
Journal of the peripheral nervous system : JPNS, 2018

Neurofilament light chain (NFL) levels reflect axonal damage in different inflammatory and neurodegenerative central nervous system conditions, in correlation with disease severity. Our aim was to determine the possible diagnostic and prognostic value of serum and cerebrospinal fluid (CSF) NFL levels in subjects with different forms of acquired peripheral neuropathies (PN). Paired serum and CSF samples of 25 patients with acquired PN were analysed for NFL using an ultrasensitive technique (Quanterix, Simoa, Lexington, MA, USA) and compared with a group of 25 age-matched healthy subjects. Demographic, clinical, CSF and neurophysiological data were reviewed. Cases with Guillain-Barré syndrome (N = 5), multifocal motor neuropathy (N = 3), chronic inflammatory demyelinating polyneuropathy (CIDP) and variants (N = 12), anti-myelin-associated glycoprotein (MAG) neuropathy (N = 3), both CIDP and anti-MAG neuropathy (N = 1), and non-systemic vasculitic neuropathy (N = 1) were studied. NFL levels were significantly (P < 0.001) increased in patients with PN and were higher in the CSF (median: 1407 pg/mL, range: 140.2-12 661) than in serum (median: 31.52 pg/mL, range: 4.33-1178). A statistically significant correlation was observed between serum and CSF levels in cases with blood-nerve-barrier damage (r = 0.71, P < 0.01), and between serum NFL levels and disease activity at sampling (r = 0.52, P < 0.01) and at last follow-up (r = 0.53, P < 0.01) in all subjects. The increase of NFL values in both serum and CSF of patients with acquired PN and the significant correlation between serum NFL levels, disease severity and final outcome support the possible role of NFL as disease activity and prognostic biomarker also in peripheral nervous system disorders.
Caenorhabditis elegans Rab escort protein (REP-1) differently regulates each Rab protein function and localization in a tissue-dependent manner.
Genes to cells : devoted to molecular & cellular mechanisms, 2008

Rab proteins play a critical role in intracellular vesicle trafficking and require post-translational modification by adding lipids at the C-terminus for proper functions. This modification is preceded by the formation of a trimeric protein complex with the Rab escort protein (REP) and the Rab geranylgeranyltransferase (RabGGTase). However, the genetic hierarchy among these proteins and the tissue-specificity of each protein function are not yet clearly understood. Here we identified the Caenorhabditis elegans rep-1 gene and found that a rep-1 mutant showed a mild defect in synaptic transmission and defecation behaviors. Genetic analyses using the exocytic Rab mutants rab-3 or rab-27 suggested that rep-1 functions only in the RAB-27 pathway, and not in the RAB-3 pathway, for synaptic transmission at neuromuscular junctions. However, the disruption of REP-1 did not cause defecation defects compared to severe defects in either RAB-27 or RabGGTase disruption, suggesting that REP-1 is not essential for RAB-27 signaling in defection. Some Rab proteins did not physically interact with REP-1, and localization of these Rab proteins was not severely affected by REP-1 disruption. These findings suggest that REP-1 functions are required in specific Rab pathways and in specific tissues, and that some Rab proteins are functionally prenylated without REP-1.
The Role of Cholinergic Midbrain Neurons in Startle and Prepulse Inhibition.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2018

One of the two major cholinergic centers of the mammalian brain is located in the midbrain, i.e., the pedunculopontine tegmentum (PPTg) and the adjacent laterodorsal tegmentum. These cholinergic neurons have been shown to be important for e.g., arousal, reward associations, and sleep. They also have been suggested to mediate sensorimotor gating, measured as prepulse inhibition of startle (PPI). PPI disruptions are a hallmark of schizophrenia and are observed in various other psychiatric disorders, where they are associated with, and often predictive of, other cognitive symptoms. PPI has been proposed to be mediated by a short midbrain circuitry including inhibitory cholinergic projections from PPTg to the startle pathway. Although the data indicating the involvement of the PPTg is very robust, some more recent evidence challenges that there is a cholinergic contribution to PPI. We here use transient optogenetic activation of specifically the cholinergic PPTg neurons in male and female rats to address their role in startle modulation in general, and in PPI specifically. Although we could confirm the crucial role of PPTg cholinergic neurons in associative reward learning, validating our experimental approach, we found that activation of cholinergic PPTg neurons did not inhibit startle responses. In contrast, activation of cholinergic PPTg neurons enhanced startle, which is in accordance with their general role in arousal and indicate a potential involvement in sensitization of startle. We conclude that noncholinergic PPTg neurons mediate PPI in contrast to the longstanding hypothetical view that PPI is mediated by cholinergic PPTg neurons.
Spirituality and the health professional.
Substance use & misuse, 2013

The inclusion of spirituality in addictions recovery began with the 12-steps program of Alcoholics Anonymous. Cofounded by Bill Wilson, the 12-steps' spiritual orientation is based on Wilson's own recovery from alcoholism that was associated with a spiritual experience. His correspondence with Carl Jung, who verified the importance of Wilson's experience, empowered Wilson to make spirituality central to the 12 steps. Spirituality remains a source of misunderstanding between the scientific, empirically informed mental health community, and the 12-step recovery movement. This article offers an outline of spiritual development, based on neuroscience, which the professional can utilize in the spiritual aspect of a patient's recovery.
FK506-protective effects against trimethyltin neurotoxicity in rats: hippocampal expression analyses reveal the involvement of periarterial osteopontin.
Neuroscience, 2008

There is little information on the molecular mechanisms in FK506-mediated neuroprotection. In the present study, we investigated the protective effect of FK506, an immunosuppressant and neuroprotectant, on trimethyltin (TMT)-induced neurotoxicity in the rat hippocampus. Histologically, TMT-induced neuronal damage was partially prevented by FK506 in the hippocampal CA1 region, but not in CA3. FK506 treatment significantly reduced the number of apoptotic cells in CA1, but not in CA3, and also prevented induction of cognitive deficits by TMT. Microarray analysis of the rat hippocampus detected 14 genes with TMT-induced alteration of mRNA expression that was rescued by FK506 treatment. Subsequent quantitative RT-PCR analysis confirmed elevated mRNA levels for four inflammatory genes, glutathione S-transferase, lysozyme, matrix Gla protein, and osteopontin after TMT treatment. Upregulation of these genes was reversed by FK506 treatment at 5 days postgavage. Immunohistochemistry revealed that FK506 reduced osteopontin (OPN) induction by TMT in the periarterial area at 5 days postgavage. Our data suggest that inflammatory gene expression is involved in TMT-induced damage to the hippocampal CA1 region, resulting in apoptosis, and that this process is initiated by periarterial OPN activation, and can be alleviated by FK506.
Can neuroimaging studies identify pain endophenotypes in humans?
Nature reviews. Neurology, 2011

Pain is a complex, multidimensional experience that has defied our understanding for centuries. Through the advent of noninvasive neuroimaging techniques, we have been able to examine the human brain and its response to nociceptive inputs. As a result, our knowledge of which brain regions are critical for generating an acute pain experience has grown, as has our understanding of how cognitive, emotional, contextual and various physiological factors influence the pain experience. Furthermore, we have been able to identify key processes within the brain that underpin the transition to and maintenance of chronic pain states, as well as highlight the dramatic consequences of chronic pain on the brain's structure and neurochemistry. Building upon this knowledge, we are now in a position to consider whether any of these brain imaging 'phenotypes' of acute or chronic pain should be considered as useful endophenotypes; thereby enabling us to relate the complex genetics that underpin everyday pain sensitivity or chronic pain states to intermediate biomarkers. This endophenotypic approach-the focus of this Review-simplifies the connection between genes and behavior and is needed for complex disorders like chronic pain.
Behavior in the open field predicts the number of KCl-induced cortical spreading depressions in rats.
Behavioural brain research, 2013

Anxiety disorders are known to be comorbid with migraine, and cortical spreading depression (CSD) is the most likely cause of the migraine aura. To search for possible correlations between susceptibility to CSD and anxiety we used the open field test in male Sprague-Dawley rats chronically treated with the preventive anti-migraine drugs valproate or riboflavin. Animals avoiding the central area of the open field chamber and those with less exploratory activity (i.e. rearing) were considered more anxious. After 4 weeks of treatment CSDs were elicited by application of 1M KCl over the occipital cortex and the number of CSDs occurring over a 2h period was compared to the previously assessed open field behavior. Higher anxiety-like behavior was significantly correlated with a higher frequency of KCl-induced CSDs. In saline-treated animals, fewer rearings were found in animals with more frequent CSDs (R=-1.00). The duration of ambulatory episodes in the open field center correlated negatively with number of CSDs in the valproate group (R=-0.83; p<0.005) and in riboflavin treated group (R=-0.69; p<0.05) as well as total time spent in the open field center in both groups (R=-0.75; p<0.05 and R=-0.58; p<0.1 respectively). These results suggest that anxiety symptoms are associated with susceptibility to CSD and might explain why it can be an aggravating factor in migraine with aura.
Reduction in IL-10 producing B cells (Breg) in multiple sclerosis is accompanied by a reduced naïve/memory Breg ratio during a relapse but not in remission.
Journal of neuroimmunology, 2011

In this study, we assessed B cell subsets, including Bregs, during stable and active disease in relapsing remitting multiple sclerosis (RRMS) patients and related B cell subsets to vitamin D status. We report that RRMS patients have a decreased percentage of both memory B cells and Bregs compared to healthy controls. During a relapse, the reduction in Bregs involved in particular naïve Bregs. We found no correlation between vitamin D status and B cell subsets. An effect of vitamin D on Bregs cannot be ruled out, since it might be the function that is interfered with instead of relative numbers.