rudyvdbrink/CitationDatabase huggingface dataset:
Inhibitory designer receptors aggravate memory loss in a mouse model of down syndrome.
Neurobiology of disease, 2020

The pontine nucleus locus coeruleus (LC) is the primary source of noradrenergic (NE) projections to the brain and is important for working memory, attention, and cognitive flexibility. Individuals with Down syndrome (DS) develop Alzheimer's disease (AD) with high penetrance and often exhibit working memory deficits coupled with degeneration of LC-NE neurons early in the progression of AD pathology. Designer receptors exclusively activated by designer drugs (DREADDs) are chemogenetic tools that allow targeted manipulation of discrete neuronal populations in the brain without the confounds of off-target effects. We utilized male Ts65Dn mice (a mouse model for DS), and male normosomic (NS) controls to examine the effects of inhibitory DREADDs delivered via an AAV vector under translational control of the synthetic PRSx8, dopamine β hydroxylase (DβH) promoter. This chemogenetic tool allowed LC inhibition upon administration of the inert DREADD ligand, clozapine-N-oxide (CNO). DREADD-mediated LC inhibition impaired performance in a novel object recognition task and reversal learning in a spatial task. DREADD-mediated LC inhibition gave rise to an elevation of α-adrenoreceptors both in NS and in Ts65Dn mice. Further, microglial markers showed that the inhibitory DREADD stimulation led to increased microglial activation in the hippocampus in Ts65Dn but not in NS mice. These findings strongly suggest that LC signaling is important for intact memory and learning in Ts65Dn mice and disruption of these neurons leads to increased inflammation and dysregulation of adrenergic receptors.
The impairment of MAGMAS function in human is responsible for a severe skeletal dysplasia.
PLoS genetics, 2014

Impairment of the tightly regulated ossification process leads to a wide range of skeletal dysplasias and deciphering their molecular bases has contributed to the understanding of this complex process. Here, we report a homozygous mutation in the mitochondria-associated granulocyte macrophage colony stimulating factor-signaling gene (MAGMAS) in a novel and severe spondylodysplastic dysplasia. MAGMAS, also referred to as PAM16 (presequence translocase-associated motor 16), is a mitochondria-associated protein involved in preprotein translocation into the matrix. We show that MAGMAS is specifically expressed in trabecular bone and cartilage at early developmental stages and that the mutation leads to an instability of the protein. We further demonstrate that the mutation described here confers to yeast strains a temperature-sensitive phenotype, impairs the import of mitochondrial matrix pre-proteins and induces cell death. The finding of deleterious MAGMAS mutations in an early lethal skeletal dysplasia supports a key role for this mitochondrial protein in the ossification process.
Hippocampal-dorsolateral prefrontal coupling as a species-conserved cognitive mechanism: a human translational imaging study.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2015

Hippocampal-prefrontal cortex (HC-PFC) interactions are implicated in working memory (WM) and altered in psychiatric conditions with cognitive impairment such as schizophrenia. While coupling between both structures is crucial for WM performance in rodents, evidence from human studies is conflicting and translation of findings is complicated by the use of differing paradigms across species. We therefore used functional magnetic resonance imaging together with a spatial WM paradigm adapted from rodent research to examine HC-PFC coupling in humans. A PFC-parietal network was functionally connected to hippocampus (HC) during task stages requiring high levels of executive control but not during a matched control condition. The magnitude of coupling in a network comprising HC, bilateral dorsolateral PFC (DLPFC), and right supramarginal gyrus explained one-fourth of the variability in an independent spatial WM task but was unrelated to visual WM performance. HC-DLPFC coupling may thus represent a systems-level mechanism specific to spatial WM that is conserved across species, suggesting its utility for modeling cognitive dysfunction in translational neuroscience.
Co-morbid personality disorder in early intervention psychosis clients is associated with greater key worker emotional involvement.
Early intervention in psychiatry, 2018

Co-morbid personality disorder (PD) is associated with poorer outcomes in psychosis patients, but it is not known whether these patterns are present at illness onset. This study investigated the prevalence of co-morbid PD in clients of an Early Intervention in Psychosis Service (EIPS) and compared key worker engagement and service use between patients with and without co-morbid PD.
Renal functional reserve: from physiological phenomenon to clinical biomarker and beyond.
American journal of physiology. Regulatory, integrative and comparative physiology, 2020

Glomerular filtration rate (GFR) is acutely increased following a high-protein meal or systemic infusion of amino acids. The mechanisms underlying this renal functional response remain to be fully elucidated. Nevertheless, they appear to culminate in preglomerular vasodilation. Inhibition of the tubuloglomerular feedback signal appears critical. However, nitric oxide, vasodilator prostaglandins, and glucagon also appear important. The increase in GFR during amino acid infusion reveals a "renal reserve," which can be utilized when the physiological demand for single nephron GFR increases. This has led to the concept that in subclinical renal disease, before basal GFR begins to reduce, renal functional reserve can be recruited in a manner that preserves renal function. The extension of this concept is that once a decline in basal GFR can be detected, renal disease is already well progressed. This concept likely applies both in the contexts of chronic kidney disease and acute kidney injury. Critically, its corollary is that deficits in renal functional reserve have the potential to provide early detection of renal dysfunction before basal GFR is reduced. There is growing evidence that the renal response to infusion of amino acids can be used to identify patients at risk of developing either chronic kidney disease or acute kidney injury and as a treatment target for acute kidney injury. However, large multicenter clinical trials are required to test these propositions. A renewed effort to understand the renal physiology underlying the response to amino acid infusion is also warranted.
MRI scanner environment increases pain perception in a standardized nociceptive paradigm.
Brain imaging and behavior, 2015

Functional magnetic resonance imaging (MRI) has been widely used in neuroscientific studies to investigate neural correlates of perception and higher cognitive functions. Early on, the MR-scanning procedure itself has been identified to create discomfort and anxiety in some individuals, which may influence task performance and perception. The present study analyzed behavioral differences in pain intensity ratings obtained in two distinct situations: MR environment and laboratory setting. Within our longitudinal study design twenty healthy volunteers were exposed daily to an identical paradigm consisting of 60 repeated noxious heat stimuli (46 °C) on 21 consecutive days. After each block of ten stimuli, participants were prompted to rate pain intensity on a visual analog scale (VAS). On days 1, 8, 14, and 21 ratings scores were obtained during a functional imaging scan, whereas on the remaining days the sessions were conducted in a laboratory. It has come to our attention that pain intensity ratings acquired in MR environment were significantly higher than behavioral data collected in the lab setting. Given that the stimuli were standardized and no task or distraction confounded the ratings, it is likely that the attentional focus on noxious stimulation was identical in both conditions. It seems that the highly artificial scanner environment as such is sufficient to increase awareness/alertness. Given that salience rather than pure nociceptive input has been suggested to explain functional imaging results in painful conditions, these findings highlight concerns regarding the comparability of behavioral data assembled across inconsistent settings.
The positive allosteric modulator morantel binds at noncanonical subunit interfaces of neuronal nicotinic acetylcholine receptors.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2009

We are interested in the positive allosteric modulation of neuronal nicotinic acetylcholine (ACh) receptors and have recently shown that the anthelmintic compound morantel potentiates by enhancing channel gating of the alpha3beta2 subtype. Based on the demonstration that morantel-elicited currents were inhibited by the classic ACh competitor dihydro-beta-erythroidine in a noncompetitive manner and that morantel still potentiates at saturating concentrations of agonist (Wu et al., 2008), we hypothesized that morantel binds at the noncanonical beta2(+)/alpha3(-) subunit interface. In the present study, we created seven cysteine-substituted subunits by site-directed mutagenesis, choosing residues in the putative morantel binding site with the aid of structural homology models. We coexpressed the mutant subunits and their respective wild-type partners in Xenopus oocytes and characterized the morantel potentiation of ACh-evoked currents, as well as morantel-evoked currents, before and after treatment with a variety of methanethiosulfonate (MTS)-based compounds, using voltage-clamp recordings. The properties of four of the seven mutants, two residues on each side of the interface, were changed by MTS treatments. Coapplication with ACh enhanced the extent of MTS modification for alpha3A106Cbeta2 and alpha3beta2S192C receptors. The activities of two mutants, alpha3T115Cbeta2 and alpha3beta2T150C, were dramatically altered by MTS modification. For alpha3beta2T150C, while peak current amplitudes were reduced, potentiation was enhanced. For alpha3T115Cbeta2, both current amplitudes and potentiation were reduced. MTS modification and morantel were mutually inhibitory: MTS treatment decreased morantel-evoked currents and morantel decreased the rate of MTS modification. We conclude that the four residues showing MTS effects contribute to the morantel binding site.
Metabolic alterations induced by sucrose intake and Alzheimer's disease promote similar brain mitochondrial abnormalities.
Diabetes, 2012

Evidence shows that diabetes increases the risk of developing Alzheimer's disease (AD). Many efforts have been done to elucidate the mechanisms linking diabetes and AD. To demonstrate that mitochondria may represent a functional link between both pathologies, we compared the effects of AD and sucrose-induced metabolic alterations on mouse brain mitochondrial bioenergetics and oxidative status. For this purpose, brain mitochondria were isolated from wild-type (WT), triple transgenic AD (3xTg-AD), and WT mice fed 20% sucrose-sweetened water for 7 months. Polarography, spectrophotometry, fluorimetry, high-performance liquid chromatography, and electron microscopy were used to evaluate mitochondrial function, oxidative status, and ultrastructure. Western blotting was performed to determine the AD pathogenic protein levels. Sucrose intake caused metabolic alterations like those found in type 2 diabetes. Mitochondria from 3xTg-AD and sucrose-treated WT mice presented a similar impairment of the respiratory chain and phosphorylation system, decreased capacity to accumulate calcium, ultrastructural abnormalities, and oxidative imbalance. Interestingly, sucrose-treated WT mice presented a significant increase in amyloid β protein levels, a hallmark of AD. These results show that in mice, the metabolic alterations associated to diabetes contribute to the development of AD-like pathologic features.
Anaplastic Lymphoma Kinase Acts in the Drosophila Mushroom Body to Negatively Regulate Sleep.
PLoS genetics, 2015

Though evidence is mounting that a major function of sleep is to maintain brain plasticity and consolidate memory, little is known about the molecular pathways by which learning and sleep processes intercept. Anaplastic lymphoma kinase (Alk), the gene encoding a tyrosine receptor kinase whose inadvertent activation is the cause of many cancers, is implicated in synapse formation and cognitive functions. In particular, Alk genetically interacts with Neurofibromatosis 1 (Nf1) to regulate growth and associative learning in flies. We show that Alk mutants have increased sleep. Using a targeted RNAi screen we localized the negative effects of Alk on sleep to the mushroom body, a structure important for both sleep and memory. We also report that mutations in Nf1 produce a sexually dimorphic short sleep phenotype, and suppress the long sleep phenotype of Alk. Thus Alk and Nf1 interact in both learning and sleep regulation, highlighting a common pathway in these two processes.
Induced mood change and dysfunctional attitudes in remitted bipolar I affective disorder.
Journal of abnormal psychology, 2005

This study investigated the possibility that, in remitted bipolar I affective disorder, dysfunctional attitudes are mood-state dependent. Participants were 120 individuals with remitted bipolar I disorder, remitted unipolar depression, or no history of affective disorder. The Dysfunctional Attitudes Scale (DAS; Weissman, 1979) was completed before and after positive or negative mood challenge. Following mood increase, the bipolar group changed significantly less in DAS total score than did the other 2 groups, and in goal-striving and achievement attitudes relative to the unipolar group. These findings did not provide clear support for the mood-state dependency theory in bipolar disorder, arguing instead for the presence in bipolar I disorder of dysfunctional cognitions that show characteristic resilience in the face of minor positive mood increase.
Cerebellar brain inhibition is decreased in active and surround muscles at the onset of voluntary movement.
Experimental brain research, 2011

Highly selective activation of the desired muscles for each movement and inhibition of adjacent muscles is attributed to surround inhibition (SI) which differentially modulates corticospinal excitability in active and surrounding muscles. Cerebellar brain inhibition (CBI) is another inhibitory neuronal network which is known to be active at rest and during tonic muscle contraction. The way in which CBI may be modulated at movement onset and its relationship with SI has not previously been investigated. We assessed motor evoked potential (MEP) size and CBI in first dorsal interosseus (FDI) and abductor digiti minimi (ADM) muscles at rest and during a simple motor task where FDI was an active muscle and ADM was not involved in the movement (surround muscle). At onset of movement, MEP size in ADM was significantly suppressed, confirming the existence of SI. In contrast, CBI in both muscles was found to be significantly decreased at the onset of the movement. This was confirmed even after adjustments for changes in MEP size occurring due to onset of muscle activity in FDI and the effects of SI in ADM. Our findings fail to functionally link SI with CBI, but they do indicate a non-topographically specific modulation of CBI in association with initiation of voluntary movement.
Childhood emotional abuse and neglect in obese patients with and without binge eating disorder: Personality and psychopathology correlates in adulthood.
Psychiatry research, 2018

The link between childhood traumatic experiences such as sexual and physical abuse and EDs in adulthood has been widely demonstrated. To date, however, little research focused on the association between emotional abuse and neglect in childhood and Binge Eating Disorder (BED) and obesity in adulthood. We enrolled 127 patients [84 with BED and 43 obese] and 45 healthy controls (HCs). All participants were administered the same battery of psychometric tests. Between-group differences were explored and the relationship between emotional abuse and neglect in childhood and personality and psychopathology in adulthood was tested. Obese patients showed higher scores in emotional abuse and neglect and sexual abuse when compared to HCs. Within obese participants, those with BED reported higher emotional abuse and emotional neglect than obese without BED and HCs; the BED group differed in physical and sexual abuse from obese participants. The association between traumatic experiences in childhood and obesity in adulthood has been confirmed independently of the type of trauma. Therapists should take into account the traumatic etiology of BED, in particular psychological abuse, even in those patients who do not recall physical or sexual abuses. Specific techniques to approach traumatic experiences could be applied to BED or non-BED patients.
The swimming plus-maze test: a novel high-throughput model for assessment of anxiety-related behaviour in larval and juvenile zebrafish (Danio rerio).
Scientific reports, 2018

Larval zebrafish (Danio rerio) has the potential to supplement rodent models due to the availability of resource-efficient, high-throughput screening and high-resolution imaging techniques. Although behavioural models are available in larvae, only a few can be employed to assess anxiety. Here we present the swimming plus-maze (SPM) test paradigm, a tool to assess anxiety-related avoidance of shallow water bodies in early developmental stages. The "+" shaped apparatus consists of arms of different depth, representing different levels of aversiveness similarly to the rodent elevated plus-maze. The paradigm was validated (i) in larval and juvenile zebrafish, (ii) after administration of compounds affecting anxiety and (iii) in differentially aversive experimental conditions. Furthermore, we compared the SPM with conventional "anxiety tests" of zebrafish to identify their shared characteristics. We have clarified that the preference of deeper arms is ontogenetically conserved and can be abolished by anxiolytic or enhanced by anxiogenic agents, respectively. The behavioural readout is insensitive to environmental aversiveness and is unrelated to behaviours assessed by conventional tests involving young zebrafish. Taken together, we have developed a sensitive high-throughput test allowing the assessment of anxiety-related responses of zebrafish regardless of developmental stage, granting the opportunity to combine larva-based state-of-the-art methods with detailed behavioral analysis.
Chemokine CCL2 modulation of neuronal excitability and synaptic transmission in rat hippocampal slices.
Journal of neurochemistry, 2011

In addition to its well-characterized effects in immune system, chemokine CC motif ligand 2 (CCL2, formerly known as monocyte chemoattractant protein-1) is believed to play an important role in brain physiological and pathological processes. It has been shown that CCL2 and its cognate receptor chemokine CC motif receptor 2 are constitutively expressed in several brain regions including the hippocampus, and the expression is up-regulated under pathological conditions. Whereas most investigations have so far focused on its involvement in CNS pathology, few studies have examined the effects of CCL2 on neuronal and synaptic physiology. In this study, we tested the effects of CCL2 on neuronal excitability and excitatory synaptic transmission in the CA1 region of rat hippocampal slices using whole-cell patch clamp techniques. Bath application of CCL2 depolarized membrane potential and increased spike firing in CA1 neuronal cells. Bath application of CCL2 also produced an increase of excitatory post-synaptic currents recorded in Schaffer-collateral fibers to CA1 synapses. Quantal analysis revealed that CCL2 increased the frequency of spontaneous excitatory post-synaptic current occurrence and mean quantal content. Taken together, our data indicate that CCL2 enhances neuronal excitability and synaptic transmission via pre-synaptic mechanisms. These results support the emerging concept that chemokines function as neuromodulators in the CNS.
Minimally Invasive Surgical Techniques for Management of Painful Metastatic and Primary Spinal Tumors.
Cureus, 2017

Patients with metastatic spinal disease are affected by disabling pain. The treatment of spinal metastases is focused on pain reduction and improvement in quality of life. Until recently, many patients with metastatic spinal disease did not qualify as surgical candidates due to the risks of surgery and length of recovery period. However, recent advances in minimally invasive surgery such as kyphoplasty and vertebroplasty allow patients to safely undergo surgery for pain relief with a short recovery period. The studies reviewed here suggest that vertebral augmentation is successful in reducing pain and disability scores in patients with painful metastases and multiple myeloma and are a safe modality to provide lasting pain relief. As the use of kyphoplasty and vertebroplasty for treatment of vertebral metastases is becoming more common, new combinations of cement augmentation with other techniques such as percutaneous pedicle screws and radiofrequency ablation are being explored. The implementation of kyphoplasty and vertebroplasty, in conjunction with other minimally invasive surgical techniques as well as nonsurgical modalities, may lead to the best palliative management of cancer patients with spinal metastases and help them ultimately achieve a better quality of life.
Evaluation of [Ln(H2cmp)(H2O)] metal organic framework materials for potential application as magnetic resonance imaging contrast agents.
Inorganic chemistry, 2010

Aqueous suspensions of metal organic frameworks (MOF) containing different Ln(3+) ions, consisting of a series of layered Ln(3+) networks formulated as [Ln(H(2)cmp)(H(2)O)] (where H(5)cmp is (carboxymethyl)iminodi(methylphosphonic acid), with a relatively wide size distribution (400 nm to 1 microm) were studied by relaxometry. The water (1)H longitudinal (r(1)) and transverse (r(2)) relaxivities were obtained for aqueous suspensions of these materials with different lanthanide ions. The values of r(1) are very small and varied only slightly with the effective magnetic moment (mu(eff)) of the lanthanide ions, while r(2) values are larger and proportional to the value of mu(eff)(2). The dependence of R(2) on tau(CP) (the time interval between two consecutive refocusing pulses in the train of 180 degrees pulses applied in a CPMG pulse sequence) was evaluated. The value of R(2) initially increases with tau(CP) and then saturates at higher tau(CP) at a value that is about 3 to 5 times lower than R(2p)*. This can be explained by the static dephasing regime (SDR) theory, in which the diffusion effect is taken into account and where the condition tau(D) > Delta omega(r(p))(-1) holds (tau(D) = r(p)(2)/D, where D is the diffusion coefficient, r(p) is the radius of the particle, and Delta omega(r(p)) is the Larmor frequency shift at the particle's surface). Separation of the particles into two fractions with different particle sizes led to a significant enhancement of the r(2) relaxivity of the smaller particles with a narrow size distribution. Magnetometric measurements performed with the particles containing Dy(III), Ho(III), and Gd(III) showed a typical paramagnetic behavior from 4 to 100 K, used to determine the Curie constants.