78 results on '"Vukojevic, V."'
Search Results
2. Cannabis-based product use in a multiple sclerosis cohort
- Author
-
Schabas, AJ, primary, Vukojevic, V, additional, Taylor, C, additional, Thu, Z, additional, Badyal, A, additional, Chan, JK, additional, Devonshire, V, additional, Traboulsee, A, additional, Sayao, AL, additional, and Carruthers, R, additional
- Published
- 2019
- Full Text
- View/download PDF
3. Noradrenergic activation of the basolateral amygdala maintains hippocampus-dependent accuracy of remote memory
- Author
-
Atucha Trevino, E., Vukojevic, V., Fornari, R.V., Ronzoni, G., Demougin, P., Peter, F., Atsak, P., Coolen, M.W., Papassotiropoulos, A., McGaugh, J.L., Quervain, D.J. de, Roozendaal, B., Atucha Trevino, E., Vukojevic, V., Fornari, R.V., Ronzoni, G., Demougin, P., Peter, F., Atsak, P., Coolen, M.W., Papassotiropoulos, A., McGaugh, J.L., Quervain, D.J. de, and Roozendaal, B.
- Abstract
Item does not contain fulltext, Emotional enhancement of memory by noradrenergic mechanisms is well-described, but the long-term consequences of such enhancement are poorly understood. Over time, memory traces are thought to undergo a neural reorganization, that is, a systems consolidation, during which they are, at least partly, transferred from the hippocampus to neocortical networks. This transfer is accompanied by a decrease in episodic detailedness. Here we investigated whether norepinephrine (NE) administration into the basolateral amygdala after training on an inhibitory avoidance discrimination task, comprising two distinct training contexts, alters systems consolidation dynamics to maintain episodic-like accuracy and hippocampus dependency of remote memory. At a 2-d retention test, both saline- and NE-treated rats accurately discriminated the training context in which they had received footshock. Hippocampal inactivation with muscimol before retention testing disrupted discrimination of the shock context in both treatment groups. At 28 d, saline-treated rats showed hippocampus-independent retrieval and lack of discrimination. In contrast, NE-treated rats continued to display accurate memory of the shock-context association. Hippocampal inactivation at this remote retention test blocked episodic-like accuracy and induced a general memory impairment. These findings suggest that the NE treatment altered systems consolidation dynamics by maintaining hippocampal involvement in the memory. This shift in systems consolidation was paralleled by time-regulated DNA methylation and transcriptional changes of memory-related genes, namely Reln and Pkmzeta, in the hippocampus and neocortex. The findings provide evidence suggesting that consolidation of emotional memories by noradrenergic mechanisms alters systems consolidation dynamics and, as a consequence, influences the maintenance of long-term episodic-like accuracy of memory.
- Published
- 2017
4. Modelling of the Hypothalamic-Pituitary-Adrenal Axis Perturbations by Externally Induced Cholesterol Pulses of Finite Duration and with Asymmetrically Distributed Concentration Profile
- Author
-
Stanojevic, A., Markovic, V. M., Čupić, Željko, Vukojevic, V., Kolar-Anić, Ljiljana, Stanojevic, A., Markovic, V. M., Čupić, Željko, Vukojevic, V., and Kolar-Anić, Ljiljana
- Abstract
A model was developed that can be used to study the effect of gradual cholesterol intake by food on the HPA axis dynamics. Namely, well defined oscillatory dynamics of vital neuroendocrine hypothalamic-pituitary-adrenal (HPA) axis has proven to be necessary for maintaining regular basal physiology and formulating appropriate stress response to various types of perturbations. Cholesterol, as a precursor of all steroid HPA axis hormones, can alter the dynamics of HPA axis. To analyse its particular influence on the HPA axis dynamics we used stoichiometric model of HPA axis activity, and simulate cholesterol perturbations in the form of finite duration pulses, with asymmetrically distributed concentration profile. Our numerical simulations showed that there is a complex, nonlinear dependence between the HPA axis responsiveness and different forms of applied cholesterol concentration pulses, indicating the significance of kinetic modelling, and dynamical systems theory for the understanding of large-scale self-regulatory, and homeostatic processes within this neuroendocrine system.
- Published
- 2017
5. In vitro uptake of alpha-Gal containing protein by human monocyte derived dendritic cells
- Author
-
Tran, T. A. T., Grundstrom, J., Krstic, M., Vukojevic, V., Apostolovic, D., Hamsten, C., Gafvelin, G., and Marianne van Hage
- Published
- 2016
6. PKC?± is genetically linked to memory capacity in healthy subjects and to risk for posttraumatic stress disorder in genocide survivors
- Author
-
de Quervain, D. J.- F., Kolassa, I.-T., Ackermann, S., Aerni, A., Boesiger, P., Demougin, P., Elbert, T., Ertl, V., Gschwind, L., Hadziselimovic, N., Hanser, E., Heck, A., Hieber, P., Huynh, K.-D., Klarhofer, M., Luechinger, R., Rasch, B., Scheffler, K., Spalek, K., Stippich, C., Vogler, C., Vukojevic, V., Stetak, A., and Papassotiropoulos, A.
- Published
- 2012
- Full Text
- View/download PDF
7. Integrated transcriptomic and proteomic analyses uncover regulatory roles of Nrf2 in the kidney
- Author
-
Shelton, L.M., Lister, A., Walsh, J., Jenkins, R.E., Wong, M.H., Rowe, C., Ricci, E., Ressel, L., Fang, Y., Demougin, P., Vukojevic, V., O'Neill, P.M., Goldring, C.E., Kitteringham, N.R., Park, B.K., Odermatt, A., and Copple, I.M.
- Subjects
Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,respiratory system ,digestive system ,environment and public health - Abstract
Item does not contain fulltext The transcription factor Nrf2 exerts protective effects in numerous experimental models of acute kidney injury, and is a promising therapeutic target in chronic kidney disease. To provide a detailed insight into the regulatory roles of Nrf2 in the kidney, we performed integrated transcriptomic and proteomic analyses of kidney tissue from wild-type and Nrf2 knockout mice treated with the Nrf2 inducer methyl-2-cyano-3,12-dioxooleano-1,9-dien-28-oate (CDDO-Me, also known as bardoxolone methyl). After 24 h, analyses identified 2561 transcripts and 240 proteins that were differentially expressed in the kidneys of Nrf2 knockout mice, compared with those of wild-type counterparts, and 3122 transcripts and 68 proteins that were differentially expressed in wild-type mice treated with CDDO-Me, compared with those of vehicle control. In the light of their sensitivity to genetic and pharmacological modulation of renal Nrf2 activity, genes/proteins that regulate xenobiotic disposition, redox balance, the intra/extracellular transport of small molecules, and the supply of NADPH and other cellular fuels were found to be positively regulated by Nrf2 in the kidney. This was verified by qPCR, immunoblotting, pathway analysis, and immunohistochemistry. In addition, the levels of NADPH and glutathione were found to be significantly decreased in the kidneys of Nrf2 knockout mice. Thus, Nrf2 regulates genes that coordinate homeostatic processes in the kidney, highlighting its potential as a novel therapeutic target. 01 december 2015
- Published
- 2015
8. New strategies to study endogenous opioid system regulation in alcoholism: evaluation of ethanol mechanisms by molecular imaging, genetic and epigenetic analysis
- Author
-
D'Addario, C, Vukojevic, V, Tantimonaco, M, Gunnar, A, Maccarrone, M, and Terenius, L
- Published
- 2014
9. Plasma membrane poration by opioid neuropeptides : a possible mechanism of pathological signal transduction
- Author
-
Maximyuk, O., Khmyz, V., Lindskog, C-J, Vukojevic, V., Ivanova, T., Bazov, Igor, Hauser, K. F., Bakalkin, Georgy, Krishtal, O., Maximyuk, O., Khmyz, V., Lindskog, C-J, Vukojevic, V., Ivanova, T., Bazov, Igor, Hauser, K. F., Bakalkin, Georgy, and Krishtal, O.
- Abstract
Neuropeptides induce signal transduction across the plasma membrane by acting through cell-surface receptors. The dynorphins, endogenous ligands for opioid receptors, are an exception; they also produce non-receptor-mediated effects causing pain and neurodegeneration. To understand non-receptor mechanism(s), we examined interactions of dynorphins with plasma membrane. Using fluorescence correlation spectroscopy and patch-clamp electrophysiology, we demonstrate that dynorphins accumulate in the membrane and induce a continuum of transient increases in ionic conductance. This phenomenon is consistent with stochastic formation of giant (similar to 2.7 nm estimated diameter) unstructured non-ion-selective membrane pores. The potency of dynorphins to porate the plasma membrane correlates with their pathogenic effects in cellular and animal models. Membrane poration by dynorphins may represent a mechanism of pathological signal transduction. Persistent neuronal excitation by this mechanism may lead to profound neuropathological alterations, including neurodegeneration and cell death.
- Published
- 2015
- Full Text
- View/download PDF
10. Ethanol Alters Opioid Regulation of Ca2+ Influx through L-type Ca2+ Channels in PC12 Cells
- Author
-
Gruol, D.L., Nelson, T.E., Hao, C., Michael, S., Vukojevic, V., Ming, Y., and Terenius, L.
- Subjects
Calcium Channels, L-Type ,Ethanol ,Receptors, Opioid, kappa ,Receptors, Opioid, mu ,Enkephalin, Ala(2)-MePhe(4)-Gly(5) ,Dynorphins ,PC12 Cells ,Article ,Membrane Potentials ,Molecular Imaging ,Rats ,Potassium ,Animals ,Calcium ,Drug Interactions ,Signal Transduction - Abstract
Studies at the behavioral and synaptic level show that effects of ethanol on the central nervous system can involve the opioid signaling system. These interactions may alter the function of a common downstream target. In this study, we examined Ca(2+) channel function as a potential downstream target of interactions between ethanol and μ or κ opioid receptor signaling.The studies were carried out in a model system, undifferentiated PC12 cells transfected with μ or κ opioid receptors. The PC12 cells express L-type Ca(2+) channels, which were activated by K(+) depolarization. Ca(2+) imaging was used to measure relative Ca(2+) flux during K(+) depolarization and the modulation of Ca(2+) flux by opioids and ethanol.Ethanol, μ receptor activation, and κ receptor activation all reduced the amplitude of the Ca(2+) signal produced by K(+) depolarization. Pretreatment with ethanol or combined treatment with ethanol and μ or κ receptor agonists caused a reduction in the amplitude of the Ca(2+) signal that was comparable to or smaller than that observed for the individual drugs alone, indicating an interaction by the drugs at a downstream target (or targets) that limited the modulation of Ca(2+) flux through L-type Ca(2+) channels.These studies provide evidence for a cellular mechanism that could play an important role in ethanol regulation of synaptic transmission and behavior through interactions with the opioid signaling.
- Published
- 2011
11. The CCDC55 couples cannabinoid receptor CNR1 to a putative DISC1 schizophrenia pathway
- Author
-
Xie, J., primary, Gizatullin, R., additional, Vukojevic, V., additional, and Leopardi, R., additional
- Published
- 2015
- Full Text
- View/download PDF
12. Opioid neuropeptides make pores in plasma membrane : possible mechanism of signal transduction
- Author
-
Krishtal, O., Maximyuk, O., Khmyz, V., Lindskog, C., Vukojevic, V., Ivanova, T., Rajnisz, A., Solecka, J., Lipkowski, A., Hauser, K., Bakalkin, Georgy, Krishtal, O., Maximyuk, O., Khmyz, V., Lindskog, C., Vukojevic, V., Ivanova, T., Rajnisz, A., Solecka, J., Lipkowski, A., Hauser, K., and Bakalkin, Georgy
- Published
- 2014
13. Epigenetic modification of the glucocorticoid receptor gene is linked to traumatic memory and post-traumatic stress disorder risk in genocide survivors
- Author
-
Vukojevic, V., Kolassa, I.T., Fastenrath, M., Gschwind, L., Spalek, K., Milnik, A., Heck, A., Vogler, C., Wilker, S., Demougin, P., Peter, F., Atucha Trevino, E., Stetak, A., Roozendaal, B., Elbert, T., Papassotiropoulos, A., Quervain, D.J. de, Vukojevic, V., Kolassa, I.T., Fastenrath, M., Gschwind, L., Spalek, K., Milnik, A., Heck, A., Vogler, C., Wilker, S., Demougin, P., Peter, F., Atucha Trevino, E., Stetak, A., Roozendaal, B., Elbert, T., Papassotiropoulos, A., and Quervain, D.J. de
- Abstract
Contains fulltext : 135874.pdf (publisher's version ) (Open Access), Recent evidence suggests that altered expression and epigenetic modification of the glucocorticoid receptor gene (NR3C1) are related to the risk of post-traumatic stress disorder (PTSD). The underlying mechanisms, however, remain unknown. Because glucocorticoid receptor signaling is known to regulate emotional memory processes, particularly in men, epigenetic modifications of NR3C1 might affect the strength of traumatic memories. Here, we found that increased DNA methylation at the NGFI-A (nerve growth factor-induced protein A) binding site of the NR3C1 promoter was associated with less intrusive memory of the traumatic event and reduced PTSD risk in male, but not female survivors of the Rwandan genocide. NR3C1 methylation was not significantly related to hyperarousal or avoidance symptoms. We further investigated the relationship between NR3C1 methylation and memory functions in a neuroimaging study in healthy subjects. Increased NR3C1 methylation-which was associated with lower NR3C1 expression-was related to reduced picture recognition in male, but not female subjects. Furthermore, we found methylation-dependent differences in recognition memory-related brain activity in men. Together, these findings indicate that an epigenetic modification of the glucocorticoid receptor gene promoter is linked to interindividual and gender-specific differences in memory functions and PTSD risk.
- Published
- 2014
14. Mu-opioid receptor activation in live cells
- Author
-
Vukojevic, V, Ming, Y, D'Addario, Claudio, Hansen, M, Langel, U, Schulz, R, Johansson, B, Rigler, R, and Terenius, L.
- Published
- 2008
15. Epigenetic Modification of the Glucocorticoid Receptor Gene Is Linked to Traumatic Memory and Post-Traumatic Stress Disorder Risk in Genocide Survivors
- Author
-
Vukojevic, V., primary, Kolassa, I.-T., additional, Fastenrath, M., additional, Gschwind, L., additional, Spalek, K., additional, Milnik, A., additional, Heck, A., additional, Vogler, C., additional, Wilker, S., additional, Demougin, P., additional, Peter, F., additional, Atucha, E., additional, Stetak, A., additional, Roozendaal, B., additional, Elbert, T., additional, Papassotiropoulos, A., additional, and de Quervain, D. J.- F., additional
- Published
- 2014
- Full Text
- View/download PDF
16. Protein oligomerization induced by oleic acid at the solidliquid interface : equine lysozyme cytotoxic complexes
- Author
-
Wilhelm, Kristina, Darinskas, A, Noppe, W, Duchardt, E, Mok, KH, Vukojevic, V, Schleucher, Jürgen, Morozova-Roche, Ludmilla, Wilhelm, Kristina, Darinskas, A, Noppe, W, Duchardt, E, Mok, KH, Vukojevic, V, Schleucher, Jürgen, and Morozova-Roche, Ludmilla
- Abstract
Protein oligomeric complexes have emerged as a major target of current research because of their key role in aggregation processes in living systems and in vitro. Hydrophobic and charged surfaces may favour the self-assembly process by recruiting proteins and modifying their interactions. We found that equine lysozyme assembles into multimeric complexes with oleic acid (ELOA) at the solid–liquid interface within an ion-exchange chromatography column preconditioned with oleic acid. The properties of ELOA were characterized using NMR, spectroscopic methods and atomic force microscopy, and showed similarity with both amyloid oligomers and the complexes with oleic acid and its structural homologous protein α-lactalbumin, known as humanα-lactalbumin made lethal for tumour cells (HAMLET). As determined by NMR diffusion measurements, ELOA may consist of 4–30 lysozyme molecules. Each lysozyme molecule is able to bind 11–48 oleic acids in various preparations. Equine lysozyme acquired a partially unfolded conformation in ELOA, as evident from its ability to bind hydrophobic dye 8-anilinonaphthalene-1-sulfonate. CD and NMR spectra. Similar to amyloid oligomers, ELOA also interacts with thioflavin-T dye, shows a spherical morphology, assembles into ring-shaped structures, as monitored by atomic force microscopy, and exerts a toxic effect in cells. Studies of well-populated ELOA shed light on the nature of the amyloid oligomers and HAMLET complexes, suggesting that they constitute one large family of cytotoxic proteinaceous species. The hydrophobic surfaces can be used profitably to produce complexes with very distinct properties compared to their precursor proteins.
- Published
- 2009
- Full Text
- View/download PDF
17. Translocation of dynorphin neuropeptides across the plasma membrane : A putative mechanism of signal transmission.
- Author
-
Marinova, Z, Vukojevic, V, Surcheva, S, Yakovleva, T, Cebers, G, Pasikova, N, Usynin, I, Hugonin, L, Fang, W, Hallberg, M, Hirschberg, D, Bergman, T, Langel, U, Hauser, KF, Pramanik, A, Aldrich, JV, Graslund, A, Terenius, L, Bakalkin, G, Marinova, Z, Vukojevic, V, Surcheva, S, Yakovleva, T, Cebers, G, Pasikova, N, Usynin, I, Hugonin, L, Fang, W, Hallberg, M, Hirschberg, D, Bergman, T, Langel, U, Hauser, KF, Pramanik, A, Aldrich, JV, Graslund, A, Terenius, L, and Bakalkin, G
- Published
- 2005
18. Povrede jetre - nasa iskustva u tretmanu
- Author
-
Vukovic, G., primary, Stefanovic, B., additional, Kaljevic, G., additional, Vukojevic, V., additional, Resanovic, V., additional, and Lausevic, Z., additional
- Published
- 2010
- Full Text
- View/download PDF
19. Determination of heavy metal deposition in the county of Obrenovac (Serbia) using mosses as bioindicators, IV: Manganese (Mn), Molybdenum (Mo), and Nickel (Ni)
- Author
-
Vukojevic, V., primary, Sabovljevic, M., additional, Sabovljevic, Aneta, additional, Mihajlovic, Nevena, additional, Drazic, Gordana, additional, and Vucinic, Z., additional
- Published
- 2009
- Full Text
- View/download PDF
20. Determination of heavy metal deposition in the county of Obrenovac (Serbia) using mosses as bioindicators, III: Copper (Cu), Iron (Fe) and Mercury (Hg)
- Author
-
Sabovljevic, M., primary, Vukojevic, V., additional, Sabovljevic, Aneta, additional, Mihajlovic, Nevena, additional, Drazic, Gordana, additional, and Vucinic, Z., additional
- Published
- 2007
- Full Text
- View/download PDF
21. Determination of heavy metal deposition in the county of Obrenovac (Serbia) using mosses as bioindicators II: Cadmium (CD), cobalt (CO), and chromium (CR)
- Author
-
Vukojevic, V., primary, Sabovljevic, M., additional, Sabovljevic, Aneta, additional, Mihajlovic, Nevena, additional, Drazic, Gordana, additional, and Vucinic, Z., additional
- Published
- 2006
- Full Text
- View/download PDF
22. Determination of heavy metal deposition in the county of Obrenovac (Serbia) using mosses as bioindicators: I. Aluminum (Al), arsenic (As), and boron (B)
- Author
-
Sabovljevic, M., primary, Vukojevic, V., additional, Mihajlovic, Nevena, additional, Drazic, Gordana, additional, and Vucinic, Z., additional
- Published
- 2005
- Full Text
- View/download PDF
23. Quenching Analysis of the Briggs-Rauscher Reaction
- Author
-
Vukojevic, V., Sørensen, Palle Gravgaard, Hynne, F., Vukojevic, V., Sørensen, Palle Gravgaard, and Hynne, F.
- Published
- 1993
24. Quenching analysis of the Briggs-Rauscher reaction
- Author
-
Vukojevic, V., primary, Soerensen, P. Graae, additional, and Hynne, F., additional
- Published
- 1993
- Full Text
- View/download PDF
25. Investigation of the Influence of Heavy Water on Kinetic Pathways in the Bray−Liebhafsky Reaction
- Author
-
Stanisavljev, D. R. and Vukojevic, V. B.
- Abstract
A more detailed investigation of the influence of heavy water on the two main kinetic pathways underlying the mechanism of the Bray−Liebhafsky (BL) reaction is performed. The course of the BL reaction at four temperatures was monitored with an improved experimental setup, enabling simultaneous recordings of the potential of the platinum electrode, the concentration of I
2 , and the oxygen production rate. It is confirmed that by replacing ordinary water with heavy water, the oxidation pathway is more effectively accelerated than the reduction pathway. Influence of the isotopic substitution on the acidity of the BL system, VIS spectra of iodine in D2 O, and the reaction between iodine and deuterated peroxide are investigated in separate experiments. It is concluded that the observed enhancement of the oxidation pathway cannot be simply explained by the isotopic effect. Hence, the possible role of bulk water in the process of shifting the whole reaction mechanism toward the oxidation pathway is discussed.- Published
- 2002
- Full Text
- View/download PDF
26. Investigation of Dynamic Behavior of the Bray−Liebhafsky Reaction in the CSTR. Determination of Bifurcation Points
- Author
-
Vukojevic, V., Anic, S., and Kolar-Anic, Lj.
- Abstract
Experimental results obtained by operating the Bray−Liebhafsky (BL) reaction in the CSTR are presented. The dynamic behavior of the BL reaction is examined at several operation points in the concentration phase space, by varying different parameters, the specific flow rate, temperature, and mixed inflow concentrations of the feed species, one at a time. Different types of bifurcation leading to simple periodic orbits, supercritical and subcritical Hopf bifurcations, saddle node infinite period bifurcation (SNIPER), saddle loop infinite period bifurcation, and jug handle bifurcation, are observed. Moreover, complex dynamic behavior, including transition from simple periodic oscillations to complex mixed-mode oscillations and chaos, and bistability are also discovered.
- Published
- 2000
27. Influence of Heavy Water on the Bray−Liebhafsky Oscillating Reaction
- Author
-
Stanisavljev, D., Begovic, N., and Vukojevic, V.
- Abstract
The influence of heavy water on the Bray−Liebhafsky (BL) oscillating reaction was investigated for varying amounts of D
2 O, at three different temperatures. Evolution of the system was monitored potentiometrically. Simultaneous recordings of gaseous oxygen over the reaction solution were also performed. In separate experiments the iodine concentration was monitored spectrophotometrically. Replacement of H2 O by D2 O progressively intensifies the reactions of oxidation of the iodine species, compared to the reactions of their reduction. As a result there is a critical ratio of D2 O/H2 O, after which the dynamics of the system is considerably altered. The same effect is observed at all temperatures, but it is more pronounced at lower temperatures. Two possible explanations for the progressively intensified oxidation are discussed: the reverse isotope effect and the selective energy transfer. It is established that the oxidation and reduction of the iodine species in the BL reaction do not proceed through the same intermediates. The important role of bulk water in surmounting the high activation energy threshold of the oxidation branch is revealed in the experiments.- Published
- 1998
28. Differential methylation of linoleic acid pathway genes is associated with PTSD symptoms - a longitudinal study with Burundian soldiers returning from a war zone.
- Author
-
Crombach A, Rukundo-Zeller AC, Vukojevic V, Nandi C, Bambonye M, de Quervain DJ, Papassotiropoulos A, and Elbert T
- Subjects
- Humans, Linoleic Acid, Longitudinal Studies, DNA Methylation, Stress Disorders, Post-Traumatic genetics, Stress Disorders, Post-Traumatic diagnosis, Military Personnel
- Abstract
Soldiers may be exposed to traumatic stress during combat deployment and thus are at risk for developing posttraumatic stress disorder (PTSD). Genetic and epigenetic evidence suggests that PTSD is linked to forming stress-related memories. In the current study, we investigated post-deployment associations of PTSD symptoms with differential DNA methylation in a sample of Burundian soldiers returning from the African Union Mission in Somalia's war zone. We used a matched longitudinal study design to explore epigenetic changes associated with PTSD symptoms in N = 191 participants. PTSD symptoms and saliva samples were collected at 1-3 (t1) and 9-14 months (t2) after the return of the soldiers to their home base. Individuals with either worsening or improving PTSD symptoms were matched for age, stressful, traumatic and self-perpetrated events prior to the post-assessment, traumatic and violent experiences between the post- and the follow-up assessment, and violence experienced during childhood. A mixed model analysis was conducted to identify top nominally significantly differentially methylated genes, which were then used to perform a gene enrichment analysis. The linoleic acid metabolism pathway was significantly associated with post-deployment PTSD symptoms, after accounting for multiple comparisons. Linoleic acid has been linked to memory and immune related processes in previous research. Our findings suggest that differential methylation of linoleic acid pathway genes is associated with PTSD and thus may merit closer inspection as a possible mediator of resilience., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
29. Naltrexone blocks alcohol-induced effects on kappa-opioid receptors in the plasma membrane.
- Author
-
Terenius L, Oasa S, Sezgin E, Ma Y, Horne D, Radmiković M, Jovanović-Talisman T, Martin-Fardon R, and Vukojevic V
- Abstract
Naltrexone (NTX), a homologue of the opiate antidote naloxone, is an orally active long-acting mu-opioid receptor (MOP) antagonist used in the treatment of opiate dependence. NTX is also found to relieve craving for alcohol and is one of the few FDA-approved drugs for alcohol use disorder (AUD). Reports that NTX blocks the actions of endogenous opioids released by alcohol are not convincing, suggesting that NTX interferes with alcohol actions by affecting opioid receptors. MOP and kappa-opioid receptor (KOP) are structurally related but functionally different. MOP is mainly located in interneurons activated by enkephalins while KOP is located in longer projections activated by dynorphins. While the actions of NTX on MOP are well established, the interaction with KOP and addiction is not well understood. We used sensitive fluorescence-based methods to study the influence of alcohol on KOP and the interaction between KOP and NTX. Here we report that alcohol interacts with KOP and its environment in the plasma membrane. These interactions are affected by NTX and are exerted both on KOP directly and on the plasma membrane (lipid) structures ("off-target"). The actions of NTX are stereospecific. Selective KOP antagonists, recently in early clinical trials for major depressive disorder, block the receptor but do not show the full action profile of NTX. The therapeutic effect of NTX treatment in AUD may be due to direct actions on KOP and the receptor environment., Competing Interests: CONFLICT OF INTEREST The authors have no competing interests.
- Published
- 2023
- Full Text
- View/download PDF
30. Epigenetics of traumatic stress: The association of NR3C1 methylation and posttraumatic stress disorder symptom changes in response to narrative exposure therapy.
- Author
-
Wilker S, Vukojevic V, Schneider A, Pfeiffer A, Inerle S, Pauly M, Elbert T, Papassotiropoulos A, de Quervain D, and Kolassa IT
- Subjects
- Male, Female, Humans, Glucocorticoids therapeutic use, Epigenesis, Genetic, DNA Methylation, Receptors, Glucocorticoid genetics, Receptors, Glucocorticoid metabolism, Stress Disorders, Post-Traumatic genetics, Stress Disorders, Post-Traumatic therapy, Implosive Therapy
- Abstract
Epigenetic processes allow plasticity in gene regulation in response to significant environmental events. Accumulating evidence suggests that effective psychotherapy is accompanied by epigenetic changes, rendering DNA methylation a potential biomarker of therapy success. Due to the central role of glucocorticoid dynamics in stress regulation and the alteration of aversive memories, glucocorticoid receptors are likely involved in the molecular processes that are required to successfully treat Posttraumatic Stress Disorder (PTSD). This study aimed to investigate the relationship between methylation at the glucocorticoid receptor gene (NR3C1) and PTSD treatment success of evidence-based psychotherapy. A sample of N = 153 conflict survivors from Northern Uganda (98 females and 55 males) with PTSD were treated with Narrative Exposure Therapy (NET). Diagnostic interviews and saliva sampling took place at pretreatment and 4 and 10 months after treatment completion. We investigated potential associations between PTSD symptom development and methylation changes at 38 CpG sites spanning NR3C1 over the three times of measurement using the repeated measures correlation. After accounting for multiple comparisons, DNA methylation at CpG site cg25535999 remained negatively associated with PTSD symptoms. These results were followed up by mixed models as well as structural equation modelling. These analyses revealed that treatment responders had a significant cg25535999 methylation increase after treatment with NET. Furthermore, lower methylation at cg25535999 pretreatment predicted a higher symptom improvement. Our results suggest different epigenetic profile dynamics at NR3C1 cg25535999 in therapy responders compared to non-responders and underscore the central role of glucocorticoid signaling in trauma-focused therapy., (© 2023. The Author(s).)
- Published
- 2023
- Full Text
- View/download PDF
31. Plaque Evaluation by Ultrasound and Transcriptomics Reveals BCLAF1 as a Regulator of Smooth Muscle Cell Lipid Transdifferentiation in Atherosclerosis.
- Author
-
Rykaczewska U, Zhao Q, Saliba-Gustafsson P, Lengquist M, Kronqvist M, Bergman O, Huang Z, Lund K, Waden K, Pons Vila Z, Caidahl K, Skogsberg J, Vukojevic V, Lindeman JHN, Roy J, Hansson GK, Treuter E, Leeper NJ, Eriksson P, Ehrenborg E, Razuvaev A, Hedin U, and Matic L
- Subjects
- Animals, Cell Transdifferentiation, Humans, Lipids, Mice, Myocytes, Smooth Muscle metabolism, Proto-Oncogene Proteins c-bcl-2 metabolism, Repressor Proteins genetics, Transcriptome, Tumor Suppressor Proteins genetics, Ultrasonography, Atherosclerosis diagnostic imaging, Atherosclerosis genetics, Atherosclerosis metabolism, Plaque, Atherosclerotic pathology, Repressor Proteins metabolism
- Abstract
Background: Understanding the processes behind carotid plaque instability is necessary to develop methods for identification of patients and lesions with stroke risk. Here, we investigated molecular signatures in human plaques stratified by echogenicity as assessed by duplex ultrasound., Methods: Lesion echogenicity was correlated to microarray gene expression profiles from carotid endarterectomies (n=96). The findings were extended into studies of human and mouse atherosclerotic lesions in situ, followed by functional investigations in vitro in human carotid smooth muscle cells (SMCs)., Results: Pathway analyses highlighted muscle differentiation, iron homeostasis, calcification, matrix organization, cell survival balance, and BCLAF1 (BCL2 [B-cell lymphoma 2]-associated transcription factor 1) as the most significant signatures. BCLAF1 was downregulated in echolucent plaques, positively correlated to proliferation and negatively to apoptosis. By immunohistochemistry, BCLAF1 was found in normal medial SMCs. It was repressed early during atherogenesis but reappeared in CD68+ cells in advanced plaques and interacted with BCL2 by proximity ligation assay. In cultured SMCs, BCLAF1 was induced by differentiation factors and mitogens and suppressed by macrophage-conditioned medium. BCLAF1 silencing led to downregulation of BCL2 and SMC markers, reduced proliferation, and increased apoptosis. Transdifferentiation of SMCs by oxLDL (oxidized low-denisty lipoprotein) was accompanied by upregulation of BCLAF1, CD36, and CD68, while oxLDL exposure with BCLAF1 silencing preserved MYH (myosin heavy chain) 11 expression and prevented transdifferentiation. BCLAF1 was associated with expression of cell differentiation, contractility, viability, and inflammatory genes, as well as the scavenger receptors CD36 and CD68 . BCLAF1 expression in CD68+/BCL2+ cells of SMC origin was verified in plaques from MYH11 lineage-tracing atherosclerotic mice. Moreover, BCLAF1 downregulation associated with vulnerability parameters and cardiovascular risk in patients with carotid atherosclerosis., Conclusions: Plaque echogenicity correlated with enrichment of distinct molecular pathways and identified BCLAF1 , previously not described in atherosclerosis, as the most significant gene. Functionally, BCLAF1 seems necessary for survival and transdifferentiation of SMCs into a macrophage-like phenotype. The role of BCLAF1 in plaque vulnerability should be further evaluated.
- Published
- 2022
- Full Text
- View/download PDF
32. DNA methylation changes following narrative exposure therapy in a randomized controlled trial with female former child soldiers.
- Author
-
Carleial S, Nätt D, Unternährer E, Elbert T, Robjant K, Wilker S, Vukojevic V, Kolassa IT, Zeller AC, and Koebach A
- Subjects
- Adolescent, Adult, Aggression, Antigens, CD genetics, Armed Conflicts, Cell Adhesion Molecules genetics, Cell Adhesion Molecules, Neuronal genetics, Child, Democratic Republic of the Congo, Female, Fetal Proteins genetics, Humans, Microfilament Proteins genetics, Stress Disorders, Post-Traumatic therapy, Sulfurtransferases genetics, Adverse Childhood Experiences, DNA Methylation, Implosive Therapy, Stress Disorders, Post-Traumatic genetics
- Abstract
The aftermath of traumatization lives on in the neural and epigenetic traces creating a momentum of affliction in the psychological and social realm. Can psychotherapy reorganise these memories through changes in DNA methylation signatures? Using a randomised controlled parallel group design, we examined methylome-wide changes in saliva samples of 84 female former child soldiers from Eastern DR Congo before and six months after Narrative Exposure Therapy. Treatment predicted differentially methylated positions (DMPs) related to ALCAM, RIPOR2, AFAP1 and MOCOS. In addition, treatment associations overlapped at gene level with baseline clinical and social outcomes. Treatment related DMPs are involved in memory formation-the key agent in trauma focused treatments-and enriched for molecular pathways commonly affected by trauma related disorders. Results were partially replicated in an independent sample of 53 female former child soldiers from Northern Uganda. Our results suggest a molecular impact of psychological treatment in women with war-related childhood trauma.Trial registration: Addressing Heightened Levels of Aggression in Traumatized Offenders With Psychotherapeutic Means (ClinicalTrials.gov Identifier: NCT02992561, 14/12/2016)., (© 2021. The Author(s).)
- Published
- 2021
- Full Text
- View/download PDF
33. NTRK2 methylation is related to reduced PTSD risk in two African cohorts of trauma survivors.
- Author
-
Vukojevic V, Coynel D, Ghaffari NR, Freytag V, Elbert T, Kolassa IT, Wilker S, McGaugh JL, Papassotiropoulos A, and de Quervain DJ
- Subjects
- Adult, Aged, Brain metabolism, DNA Methylation genetics, Epigenesis, Genetic genetics, Female, Glucocorticoids metabolism, Humans, Male, Membrane Glycoproteins metabolism, Memory physiology, Middle Aged, Polymorphism, Single Nucleotide genetics, Receptor, trkB metabolism, Receptors, Glucocorticoid metabolism, Risk Factors, Rwanda epidemiology, Stress Disorders, Post-Traumatic metabolism, Survivors, Uganda epidemiology, Membrane Glycoproteins genetics, Receptor, trkB genetics, Stress Disorders, Post-Traumatic genetics
- Abstract
Extensive pharmacologic, genetic, and epigenetic research has linked the glucocorticoid receptor (GR) to memory processes, and to risk and symptoms of posttraumatic stress disorder (PTSD). In the present study we investigated the epigenetic pattern of 12 genes involved in the regulation of GR signaling in two African populations of heavily traumatized individuals: Survivors of the rebel war in northern Uganda ( n = 463) and survivors of the Rwandan genocide ( n = 350). The strongest link between regional methylation and PTSD risk and symptoms was observed for NTRK2 , which encodes the transmembrane receptor tropomyosin-related kinase B, binds the brain-derived neurotrophic factor, and has been shown to play an important role in memory formation. NTRK2 methylation was not related to trauma load, suggesting that methylation differences preexisted the trauma. Because NTRK2 methylation differences were predominantly associated with memory-related PTSD symptoms, and because they seem to precede traumatic events, we next investigated the relationship between NTRK2 methylation and memory in a sample of nontraumatized individuals ( n = 568). We found that NTRK2 methylation was negatively associated with recognition memory performance. Furthermore, fMRI analyses revealed NTRK2 methylation-dependent differences in brain network activity related to recognition memory. The present study demonstrates that NTRK2 is epigenetically linked to memory functions in nontraumatized subjects and to PTSD risk and symptoms in traumatized populations., Competing Interests: The authors declare no competing interest.
- Published
- 2020
- Full Text
- View/download PDF
34. Evolutionary conserved role of neural cell adhesion molecule-1 in memory.
- Author
-
Vukojevic V, Mastrandreas P, Arnold A, Peter F, Kolassa IT, Wilker S, Elbert T, de Quervain DJ, Papassotiropoulos A, and Stetak A
- Subjects
- Animals, CD56 Antigen, Conditioning, Psychological, Humans, Learning, Neural Cell Adhesion Molecules genetics, Neuronal Plasticity, Sialic Acids, Caenorhabditis elegans, Neural Cell Adhesion Molecule L1
- Abstract
The neural cell adhesion molecule 1 (NCAM-1) has been implicated in several brain-related biological processes, including neuronal migration, axonal branching, fasciculation, and synaptogenesis, with a pivotal role in synaptic plasticity. Here, we investigated the evolutionary conserved role of NCAM-1 in learning and memory. First, we investigated sustained changes in ncam-1 expression following aversive olfactory conditioning in C. elegans using molecular genetic methods. Furthermore, we examined the link between epigenetic signatures of the NCAM1 gene and memory in two human samples of healthy individuals (N = 568 and N = 319) and in two samples of traumatized individuals (N = 350 and N = 463). We found that olfactory conditioning in C. elegans induced ncam-1 expression and that loss of ncam-1 function selectively impaired associative long-term memory, without causing acquisition, sensory, or short-term memory deficits. Reintroduction of the C. elegans or human NCAM1 fully rescued memory impairment, suggesting a conserved role of NCAM1 for memory. In parallel, DNA methylation of the NCAM1 promoter in two independent healthy Swiss cohorts was associated with memory performance. In two independent Sub-Saharan populations of conflict zone survivors who had faced severe trauma, DNA methylation at an alternative promoter of the NCAM1 gene was associated with traumatic memories. Our results support a role of NCAM1 in associative memory in nematodes and humans, and might, ultimately, be helpful in elucidating diagnostic markers or suggest novel therapy targets for memory-related disorders, like PTSD.
- Published
- 2020
- Full Text
- View/download PDF
35. Methylation of Brain Derived Neurotrophic Factor (BDNF) Val66Met CpG site is associated with early onset bipolar disorder.
- Author
-
Nassan M, Veldic M, Winham S, Frye MA, Larrabee B, Colby C, Biernacka J, Bellia F, Pucci M, Terenius L, Vukojevic V, and D'Addario C
- Subjects
- Adult, Alleles, Genotype, Humans, Infant, Methylation, Polymorphism, Single Nucleotide, Young Adult, Bipolar Disorder genetics, Brain-Derived Neurotrophic Factor genetics
- Abstract
Background: The brain-derived neurotrophic factor (BDNF) rs6265 (Val66Met) Met allele is associated with early onset (≤ 19 years old) bipolar disorder (BD). Val66Met (G196A) creates a CpG site when the Val/G allele is present. We sought to study the methylation of the BDNF promoter and its interaction with Val66Met genotype in BD., Methods: Sex/age-matched previously genotyped DNA samples from BD-Type 1 cases [N = 166: early onset (≤ 19 years old) n = 79, late onset (> 20 years old) n = 87] and controls (N = 162) were studied. Pyrosequencing of four CpGs in Promoter-I, four CpGs in promoter-IV, and two CpGs in Promoter-IX (CpG2 includes G= Val allele) was performed. Logistic regression adjusting for batch effect was used to compare cases vs. controls. Analyses also included stratification by disease onset and adjustment for Val66Met genotype. Secondary exploratory analyses for the association of life stressors, comorbid substance abuse, and psychotropic use with methylation patterns were performed., Results: Comparing all BD cases vs. controls and adjusting for Val66Met genotype, BD cases had significantly higher methylation in promoter -IX/CPG-2 (p = 0.0074). This was driven by early onset cases vs. controls (p = 0.00039) and not late onset cases vs. controls (p = 0.2)., Limitation: Relatively small sample size., Conclusion: Early onset BD is associated with increased methylation of CpG site created by Val=G allele of the Val66Met variance. Further studies could include larger sample size and postmortem brain samples in an attempt to replicate these findings., Competing Interests: Declaration of Competing Interest Mark A. Frye: Previous Grant Support: Assurex Health, Mayo Foundation, Medibio. Consultancies: Actify Neurotherapies, Allergan, Intra-Cellular Therapies, Inc., Janssen, Myriad, Neuralstem Inc.,Takeda, Teva Pharmaceuticals. CME/Travel/Honoraria: American Physician Institute, CME Outfitters, Global Academy for Medical Education. None of the other authors have any reportable potential conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)
- Published
- 2020
- Full Text
- View/download PDF
36. Loss of TSC complex enhances gluconeogenesis via upregulation of Dlk1-Dio3 locus miRNAs.
- Author
-
Liko D, Rzepiela A, Vukojevic V, Zavolan M, and Hall MN
- Subjects
- Animals, Calcium-Binding Proteins genetics, Genetic Loci, Genomic Imprinting, Gluconeogenesis genetics, Iodide Peroxidase genetics, Liver metabolism, Male, Mechanistic Target of Rapamycin Complex 1 metabolism, Mice, Mice, Knockout, MicroRNAs genetics, Sequence Analysis, Signal Transduction, Transcriptome, Tuberous Sclerosis Complex 1 Protein genetics, Calcium-Binding Proteins metabolism, Gluconeogenesis physiology, Iodide Peroxidase metabolism, MicroRNAs metabolism, Tuberous Sclerosis Complex 1 Protein metabolism, Up-Regulation
- Abstract
Loss of the tumor suppressor tuberous sclerosis complex 1 ( Tsc1 ) in the liver promotes gluconeogenesis and glucose intolerance. We asked whether this could be attributed to aberrant expression of small RNAs. We performed small-RNA sequencing on liver of Tsc1 -knockout mice, and found that miRNAs of the delta-like homolog 1 ( Dlk1 )-deiodinase iodothyronine type III ( Dio3 ) locus are up-regulated in an mTORC1-dependent manner. Sustained mTORC1 signaling during development prevented CpG methylation and silencing of the Dlk1-Dio3 locus, thereby increasing miRNA transcription. Deletion of miRNAs encoded by the Dlk1-Dio3 locus reduced gluconeogenesis, glucose intolerance, and fasting blood glucose levels. Thus, miRNAs contribute to the metabolic effects observed upon loss of TSC1 and hyperactivation of mTORC1 in the liver. Furthermore, we show that miRNA is a downstream effector of hyperactive mTORC1 signaling., Competing Interests: The authors declare no competing interest.
- Published
- 2020
- Full Text
- View/download PDF
37. Integrated genetic, epigenetic, and gene set enrichment analyses identify NOTCH as a potential mediator for PTSD risk after trauma: Results from two independent African cohorts.
- Author
-
Conrad D, Wilker S, Schneider A, Karabatsiakis A, Pfeiffer A, Kolassa S, Freytag V, Vukojevic V, Vogler C, Milnik A, Papassotiropoulos A, J-F de Quervain D, Elbert T, and Kolassa IT
- Subjects
- Adult, Cohort Studies, CpG Islands, Humans, Polymorphism, Single Nucleotide, Receptor, Notch3 genetics, Risk, Rwanda, Uganda, DNA Methylation genetics, Epigenesis, Genetic genetics, Nerve Tissue Proteins genetics, Psychological Trauma complications, Signal Transduction genetics, Stress Disorders, Post-Traumatic etiology, Stress Disorders, Post-Traumatic genetics
- Abstract
The risk of developing posttraumatic stress disorder (PTSD) increases with the number of traumatic event types experienced (trauma load) in interaction with other psychobiological risk factors. The NOTCH (neurogenic locus notch homolog proteins) signaling pathway, consisting of four different trans-membrane receptor proteins (NOTCH1-4), constitutes an evolutionarily well-conserved intercellular communication pathway (involved, e.g., in cell-cell interaction, inflammatory signaling, and learning processes). Its association with fear memory consolidation makes it an interesting candidate for PTSD research. We tested for significant associations of common genetic variants of NOTCH1-4 (investigated by microarray) and genomic methylation of saliva-derived DNA with lifetime PTSD risk in independent cohorts from Northern Uganda (N
1 = 924) and Rwanda (N2 = 371), and investigated whether NOTCH-related gene sets were enriched for associations with lifetime PTSD risk. We found associations of lifetime PTSD risk with single nucleotide polymorphism (SNP) rs2074621 (NOTCH3) (puncorrected = 0.04) in both cohorts, and with methylation of CpG site cg17519949 (NOTCH3) (puncorrected = 0.05) in Rwandans. Yet, none of the (epi-)genetic associations survived multiple testing correction. Gene set enrichment analyses revealed enrichment for associations of two NOTCH pathways with lifetime PTSD risk in Ugandans: NOTCH binding (pcorrected = 0.003) and NOTCH receptor processing (pcorrected = 0.01). The environmental factor trauma load was significant in all analyses (all p < 0.001). Our integrated methodological approach suggests NOTCH as a possible mediator of PTSD risk after trauma. The results require replication, and the precise underlying pathophysiological mechanisms should be illuminated in future studies., (© 2018 The Authors. Psychophysiology published by Wiley Periodicals, Inc. on behalf of Society for Psychophysiological Research.)- Published
- 2020
- Full Text
- View/download PDF
38. Does Prenatal Stress Shape Postnatal Resilience? - An Epigenome-Wide Study on Violence and Mental Health in Humans.
- Author
-
Serpeloni F, Radtke KM, Hecker T, Sill J, Vukojevic V, de Assis SG, Schauer M, Elbert T, and Nätt D
- Abstract
Stress during pregnancy widely associates with epigenetic changes and psychiatric problems during childhood. Animal studies, however, show that under specific postnatal conditions prenatal stress may have other, less detrimental consequences for the offspring. Here, we studied mental health and epigenome-wide DNA methylation in saliva following intimate partner violence (IPV) during pregnancy in São Gonçalo, a Brazilian city with high levels of violence. Not surprisingly, mothers exposed to pregnancy IPV expressed elevated depression, PTSD and anxiety symptoms. Children had similar psychiatric problems when they experienced maternal IPV after being born. More surprisingly, when maternal IPV occurred both during (prenatal) and after pregnancy these problems were absent. Following prenatal IPV, genomic sites in genes encoding the glucocorticoid receptor ( NR3C1 ) and its repressor FKBP51 ( FKBP5 ) were among the most differentially methylated and indicated an enhanced ability to terminate hormonal stress responses in prenatally stressed children. These children also showed more DNA methylation in heterochromatin-like regions, which previously has been associated with stress/disease resilience. A similar relationship was seen in prenatally stressed middle-eastern refugees of the same age as the São Gonçalo children but exposed to postnatal war-related violence. While our study is limited in location and sample size, it provides novel insights on how prenatal stress may epigenetically shape resilience in humans, possibly through interactions with the postnatal environment. This translates animal findings and emphasizes the importance to account for population differences when studying how early life gene-environment interactions affects mental health.
- Published
- 2019
- Full Text
- View/download PDF
39. Oral cadmium exposure affects skin immune reactivity in rats.
- Author
-
Tucovic D, Popov Aleksandrov A, Mirkov I, Ninkov M, Kulas J, Zolotarevski L, Vukojevic V, Mutic J, Tatalovic N, and Kataranovski M
- Subjects
- Administration, Oral, Animals, Cytokines immunology, Immunity, Innate drug effects, Male, Nitric Oxide immunology, Oxidative Stress drug effects, Rats, Skin immunology, Cadmium administration & dosage, Skin drug effects
- Abstract
Skin can acquire cadmium (Cd) by oral route, but there is paucity of data concerning cutaneous effects of this metal. Cd acquired by oral route can affect skin wound healing, but the effect of Cd on other activities involved in skin homeostasis, including skin immunity, are not explored. Using the rat model of 30-day oral administration of Cd (5 ppm and 50 ppm) in drinking water, basic aspects of immune-relevant activity of epidermal cells were examined. Dose-dependent Cd deposition in the the skin was observed (0.035 ± 0.02 µg/g and 0.127 ± 0.04 µg/g at 5 ppm and 50 ppm, respectively, compared to 0.012 ± 0.009 µg/g at 0 ppm of Cd). This resulted in skin inflammation (oxidative stress at both Cd doses and dose-dependent structural changes in the skin and the presence/activation of innate immunity cells). At low Cd dose inflammatory response (nitric oxide and IL-1β) was observed. Other inflammatory cytokines (IL-6 and TNF) response occurred at 50 ppm, which was increased further following skin sensitization with contact allergen dinitro-chlorobenzene (DNCB). Epidermal cells exposed to both Cd doses enhanced concanavalin A (ConA)-stimulated lymphocyte production of IL-17. This study showed for the first time the effect of the metal which gained access to the skin via gut on immune reactivity of epidermal cells. Presented data might be relevant for the link between dietary Cd and the risk of skin pathologies., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
40. Genetic variation is associated with PTSD risk and aversive memory: Evidence from two trauma-Exposed African samples and one healthy European sample.
- Author
-
Wilker S, Schneider A, Conrad D, Pfeiffer A, Boeck C, Lingenfelder B, Freytag V, Vukojevic V, Vogler C, Milnik A, Papassotiropoulos A, J-F de Quervain D, Elbert T, Kolassa S, and Kolassa IT
- Subjects
- Adult, Female, Follow-Up Studies, Humans, Male, Narrative Therapy methods, Polymorphism, Single Nucleotide, Resilience, Psychological, Risk, Rwanda, Switzerland, Uganda, Young Adult, Emotions physiology, Genocide, Genome-Wide Association Study, Implosive Therapy methods, Memory physiology, Outcome Assessment, Health Care, Stress Disorders, Post-Traumatic genetics, Stress Disorders, Post-Traumatic physiopathology, Stress Disorders, Post-Traumatic therapy, Survivors, War Exposure
- Abstract
The probability to develop posttraumatic stress disorder (PTSD), characterized by vivid, intrusive emotional memories of the encountered traumatic events, depends - among other factors - on the number of previous traumatic experiences (traumatic load) and individual genetic vulnerability. So far, our knowledge regarding the biological underpinnings of PTSD is relatively sparse. Genome-wide association studies (GWAS) followed by independent replication might help to discover novel, so far unknown biological mechanisms associated with the development of traumatic memories. Here, a GWAS was conducted in N = 924 Northern Ugandan rebel war survivors and identified seven suggestively significant single nucleotide polymorphisms (SNPs; p ≤ 1 × 10
-5 ) for lifetime PTSD risk. Of these seven SNPs, the association of rs3852144 on chromosome 5 was replicated in an independent sample of Rwandan genocide survivors (N = 370, p < .01). While PTSD risk increased with accumulating traumatic experiences, the vulnerability was reduced in carriers of the minor G-allele in an additive manner. Correspondingly, memory for aversive pictures decreased with higher number of the minor G-allele in a sample of N = 2698 healthy Swiss individuals. Finally, investigations on N = 90 PTSD patients treated with Narrative Exposure Therapy indicated an additive effect of genotype on PTSD symptom change from pre-treatment to four months after treatment, but not between pre-treatment and the 10-months follow-up. In conclusion, emotional memory formation seems to decline with increasing number of rs3852144 G-alleles, rendering individuals more resilient to PTSD development. However, the impact on therapy outcome remains preliminary and further research is needed to determine how this intronic marker may affect memory processes in detail.- Published
- 2018
- Full Text
- View/download PDF
41. Genetic estimators of DNA methylation provide insights into the molecular basis of polygenic traits.
- Author
-
Freytag V, Vukojevic V, Wagner-Thelen H, Milnik A, Vogler C, Leber M, Weinhold L, Böhmer AC, Riedel-Heller S, Maier W, de Quervain DJ, Ramirez A, and Papassotiropoulos A
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Female, Genotype, Humans, Male, Schizophrenia genetics, Young Adult, CpG Islands genetics, DNA Methylation genetics, Gene Expression genetics, Genetic Loci genetics, Genome-Wide Association Study methods, Multifactorial Inheritance genetics
- Abstract
The large biological distance between genetic risk loci and their mechanistic consequences in the tissue of interest limits the ability to establish functionality of susceptibility variants for genetically complex traits. Such a biological gap may be reduced through the systematic study of molecular mediators of genomic action, such as epigenetic modification. Here, we report the identification of robust genetic estimators of whole-blood CpG methylation, which can serve as intermediate molecular traits amenable to association testing with other genetically complex traits. We describe the relationship between these estimators and gene expression, demonstrate their genome-wide applicability to association testing even in the absence of individual genotypic data, and show that these estimators powerfully identify methylation-related genomic loci associated with polygenic traits and common diseases, such as schizophrenia. The use of genetic estimators for blood DNA methylation, which are made publically available, can serve as a valuable tool for the identification of epigenetic underpinnings of complex traits.
- Published
- 2018
- Full Text
- View/download PDF
42. Exhaustive search for epistatic effects on the human methylome.
- Author
-
Egli T, Vukojevic V, Sengstag T, Jacquot M, Cabezón R, Coynel D, Freytag V, Heck A, Vogler C, de Quervain DJ, Papassotiropoulos A, and Milnik A
- Subjects
- Adolescent, Adult, Cohort Studies, CpG Islands, Female, Genetic Association Studies, Humans, Male, Polymorphism, Single Nucleotide, Young Adult, DNA Methylation, Epigenesis, Genetic
- Abstract
Studies assessing the existence and magnitude of epistatic effects on complex human traits provide inconclusive results. The study of such effects is complicated by considerable increase in computational burden, model complexity, and model uncertainty, which in concert decrease model stability. An additional source introducing significant uncertainty with regard to the detection of robust epistasis is the biological distance between the genetic variation and the trait under study. Here we studied CpG methylation, a genetically complex molecular trait that is particularly close to genomic variation, and performed an exhaustive search for two-locus epistatic effects on the CpG-methylation signal in two cohorts of healthy young subjects. We detected robust epistatic effects for a small number of CpGs (N = 404). Our results indicate that epistatic effects explain only a minor part of variation in DNA-CpG methylation. Interestingly, these CpGs were more likely to be associated with gene-expression of nearby genes, as also shown by their overrepresentation in DNase I hypersensitivity sites and underrepresentation in CpG islands. Finally, gene ontology analysis showed a significant enrichment of these CpGs in pathways related to HPV-infection and cancer.
- Published
- 2017
- Full Text
- View/download PDF
43. Role of microglial amylin receptors in mediating beta amyloid (Aβ)-induced inflammation.
- Author
-
Fu W, Vukojevic V, Patel A, Soudy R, MacTavish D, Westaway D, Kaur K, Goncharuk V, and Jhamandas J
- Subjects
- Alzheimer Disease genetics, Alzheimer Disease pathology, Alzheimer Disease therapy, Animals, Caspase 1 metabolism, Cell Line, Transformed, Cells, Cultured, Cyclic AMP metabolism, Cytokines genetics, Cytokines metabolism, Female, Fetus cytology, Gene Expression Regulation drug effects, Gene Expression Regulation genetics, Humans, Lipopolysaccharides toxicity, Male, Mice, Mice, Transgenic, NLR Family, Pyrin Domain-Containing 3 Protein metabolism, Peptides, Cyclic pharmacology, Peptides, Cyclic therapeutic use, Amyloid beta-Peptides toxicity, Inflammation chemically induced, Microglia drug effects, Microglia metabolism, Peptide Fragments toxicity, Receptors, Islet Amyloid Polypeptide metabolism
- Abstract
Background: Neuroinflammation in the brain consequent to activation of microglia is viewed as an important component of Alzheimer's disease (AD) pathology. Amyloid beta (Aβ) protein is known to activate microglia and unleash an inflammatory cascade that eventually results in neuronal dysfunction and death. In this study, we sought to identify the presence of amylin receptors on human fetal and murine microglia and determine whether Aβ activation of the inflammasome complex and subsequent release of cytokines is mediated through these receptors., Methods: The presence of dimeric components of the amylin receptor (calcitonin receptor and receptor activity modifying protein 3) were first immunohistochemically identified on microglia. Purified human fetal microglial (HFM) cultures were incubated with an in vivo microglial marker, DyLight 594-conjugated tomato lectin, and loaded with the membrane-permeant green fluorescent dye, Fluo-8L-AM for measurements of intracellular calcium [Ca
2+ ]i. HFM and BV-2 cells were primed with lipopolysaccharide and then exposed to either human amylin or soluble oligomeric Aβ1-42 prior to treatment with and without the amylin receptor antagonist, AC253. Changes in the inflammasome complex, NLRP3 and caspase-1, were examined in treated cell cultures with Western blot and fluorometric assays. RT-PCR measurements were performed to assess cytokine release. Finally, in vivo studies were performed in transgenic mouse model of AD (5xFAD) to examine the effects of systemic administration of AC253 on markers of neuroinflammation in the brain., Results: Acute applications of human amylin or Aβ1-42 resulted in an increase in [Ca2+ ]i that could be blocked by the amylin receptor antagonist, AC253. Activation of the NLRP3 and caspase-1 and subsequent release of cytokines, TNFα and IL-1β, was diminished by AC253 pretreatment of HFMs and BV2 cells. In vivo, intraperitoneal administration of AC253 resulted in a reduction in microglial markers (Iba-1 and CD68), caspase-1, TNFα, and IL-1β. These reductions in inflammatory markers were accompanied by reduction in amyloid plaque and size in the brains of 5xFAD mice compared to controls., Conclusion: Microglial amylin receptors mediate Aβ-evoked inflammation, and amylin receptor antagonists therefore offer an attractive therapeutic target for intervention in AD.- Published
- 2017
- Full Text
- View/download PDF
44. Noradrenergic activation of the basolateral amygdala maintains hippocampus-dependent accuracy of remote memory.
- Author
-
Atucha E, Vukojevic V, Fornari RV, Ronzoni G, Demougin P, Peter F, Atsak P, Coolen MW, Papassotiropoulos A, McGaugh JL, de Quervain DJ, and Roozendaal B
- Subjects
- Adrenergic alpha-Agonists pharmacology, Animals, Avoidance Learning drug effects, Avoidance Learning physiology, Cell Adhesion Molecules, Neuronal genetics, DNA Methylation drug effects, Discrimination, Psychological drug effects, Discrimination, Psychological physiology, Extracellular Matrix Proteins genetics, GABA-A Receptor Agonists pharmacology, Hippocampus metabolism, Hippocampus physiology, Male, Memory, Long-Term physiology, Muscimol pharmacology, Nerve Tissue Proteins genetics, Norepinephrine administration & dosage, Rats, Sprague-Dawley, Reelin Protein, Serine Endopeptidases genetics, Transcriptome drug effects, Basolateral Nuclear Complex drug effects, Hippocampus drug effects, Memory, Long-Term drug effects, Norepinephrine pharmacology
- Abstract
Emotional enhancement of memory by noradrenergic mechanisms is well-described, but the long-term consequences of such enhancement are poorly understood. Over time, memory traces are thought to undergo a neural reorganization, that is, a systems consolidation, during which they are, at least partly, transferred from the hippocampus to neocortical networks. This transfer is accompanied by a decrease in episodic detailedness. Here we investigated whether norepinephrine (NE) administration into the basolateral amygdala after training on an inhibitory avoidance discrimination task, comprising two distinct training contexts, alters systems consolidation dynamics to maintain episodic-like accuracy and hippocampus dependency of remote memory. At a 2-d retention test, both saline- and NE-treated rats accurately discriminated the training context in which they had received footshock. Hippocampal inactivation with muscimol before retention testing disrupted discrimination of the shock context in both treatment groups. At 28 d, saline-treated rats showed hippocampus-independent retrieval and lack of discrimination. In contrast, NE-treated rats continued to display accurate memory of the shock-context association. Hippocampal inactivation at this remote retention test blocked episodic-like accuracy and induced a general memory impairment. These findings suggest that the NE treatment altered systems consolidation dynamics by maintaining hippocampal involvement in the memory. This shift in systems consolidation was paralleled by time-regulated DNA methylation and transcriptional changes of memory-related genes, namely Reln and Pkm ζ, in the hippocampus and neocortex. The findings provide evidence suggesting that consolidation of emotional memories by noradrenergic mechanisms alters systems consolidation dynamics and, as a consequence, influences the maintenance of long-term episodic-like accuracy of memory., Competing Interests: The authors declare no conflict of interest.
- Published
- 2017
- Full Text
- View/download PDF
45. Genome-Wide Temporal Expression Profiling in Caenorhabditis elegans Identifies a Core Gene Set Related to Long-Term Memory.
- Author
-
Freytag V, Probst S, Hadziselimovic N, Boglari C, Hauser Y, Peter F, Gabor Fenyves B, Milnik A, Demougin P, Vukojevic V, de Quervain DJ, Papassotiropoulos A, and Stetak A
- Subjects
- Animals, Association Learning physiology, Caenorhabditis elegans Proteins genetics, Chromosome Mapping, Gene Expression Profiling, Genome genetics, Proteome genetics, Caenorhabditis elegans physiology, Caenorhabditis elegans Proteins metabolism, Gene Expression Regulation physiology, Memory, Long-Term physiology, Nerve Tissue Proteins genetics, Proteome metabolism
- Abstract
The identification of genes related to encoding, storage, and retrieval of memories is a major interest in neuroscience. In the current study, we analyzed the temporal gene expression changes in a neuronal mRNA pool during an olfactory long-term associative memory (LTAM) in Caenorhabditis elegans hermaphrodites. Here, we identified a core set of 712 (538 upregulated and 174 downregulated) genes that follows three distinct temporal peaks demonstrating multiple gene regulation waves in LTAM. Compared with the previously published positive LTAM gene set (Lakhina et al., 2015), 50% of the identified upregulated genes here overlap with the previous dataset, possibly representing stimulus-independent memory-related genes. On the other hand, the remaining genes were not previously identified in positive associative memory and may specifically regulate aversive LTAM. Our results suggest a multistep gene activation process during the formation and retrieval of long-term memory and define general memory-implicated genes as well as conditioning-type-dependent gene sets. SIGNIFICANCE STATEMENT The identification of genes regulating different steps of memory is of major interest in neuroscience. Identification of common memory genes across different learning paradigms and the temporal activation of the genes are poorly studied. Here, we investigated the temporal aspects of Caenorhabditis elegans gene expression changes using aversive olfactory associative long-term memory (LTAM) and identified three major gene activation waves. Like in previous studies, aversive LTAM is also CREB dependent, and CREB activity is necessary immediately after training. Finally, we define a list of memory paradigm-independent core gene sets as well as conditioning-dependent genes., (Copyright © 2017 the authors 0270-6474/17/376661-12$15.00/0.)
- Published
- 2017
- Full Text
- View/download PDF
46. A peripheral epigenetic signature of immune system genes is linked to neocortical thickness and memory.
- Author
-
Freytag V, Carrillo-Roa T, Milnik A, Sämann PG, Vukojevic V, Coynel D, Demougin P, Egli T, Gschwind L, Jessen F, Loos E, Maier W, Riedel-Heller SG, Scherer M, Vogler C, Wagner M, Binder EB, de Quervain DJ, and Papassotiropoulos A
- Subjects
- Adult, Aged, Aged, 80 and over, CpG Islands genetics, Depressive Disorder, Major genetics, Female, Genetic Variation genetics, Humans, Immune System cytology, Male, Middle Aged, Switzerland, Young Adult, Aging genetics, DNA Methylation genetics, Epigenesis, Genetic genetics, Immune System immunology, Memory physiology, Neocortex physiology
- Abstract
Increasing age is tightly linked to decreased thickness of the human neocortex. The biological mechanisms that mediate this effect are hitherto unknown. The DNA methylome, as part of the epigenome, contributes significantly to age-related phenotypic changes. Here, we identify an epigenetic signature that is associated with cortical thickness (P=3.86 × 10
-8 ) and memory performance in 533 healthy young adults. The epigenetic effect on cortical thickness was replicated in a sample comprising 596 participants with major depressive disorder and healthy controls. The epigenetic signature mediates partially the effect of age on cortical thickness (P<0.001). A multilocus genetic score reflecting genetic variability of this signature is associated with memory performance (P=0.0003) in 3,346 young and elderly healthy adults. The genomic location of the contributing methylation sites points to the involvement of specific immune system genes. The decomposition of blood methylome-wide patterns bears considerable potential for the study of brain-related traits.- Published
- 2017
- Full Text
- View/download PDF
47. Functional Analyses of the Crohn's Disease Risk Gene LACC1.
- Author
-
Assadi G, Vesterlund L, Bonfiglio F, Mazzurana L, Cordeddu L, Schepis D, Mjösberg J, Ruhrmann S, Fabbri A, Vukojevic V, Percipalle P, Salomons FA, Laurencikiene J, Törkvist L, Halfvarson J, and D'Amato M
- Subjects
- Cell Differentiation, Cell Line, Tumor, Fatty Acids metabolism, Gene Expression Profiling, HeLa Cells, Humans, Inflammasomes metabolism, Intracellular Signaling Peptides and Proteins, Leukocytes, Mononuclear cytology, Ligands, Macrophages cytology, Macrophages metabolism, Oxygen chemistry, RNA, Small Interfering metabolism, Reactive Oxygen Species metabolism, Signal Transduction, Crohn Disease genetics, Genetic Predisposition to Disease, Proteins genetics
- Abstract
Background: Genetic variation in the Laccase (multicopper oxidoreductase) domain-containing 1 (LACC1) gene has been shown to affect the risk of Crohn's disease, leprosy and, more recently, ulcerative colitis and juvenile idiopathic arthritis. LACC1 function appears to promote fatty-acid oxidation, with concomitant inflammasome activation, reactive oxygen species production, and anti-bacterial responses in macrophages. We sought to contribute to elucidating LACC1 biological function by extensive characterization of its expression in human tissues and cells, and through preliminary analyses of the regulatory mechanisms driving such expression., Methods: We implemented Western blot, quantitative real-time PCR, immunofluorescence microscopy, and flow cytometry analyses to investigate fatty acid metabolism-immune nexus (FAMIN; the LACC1 encoded protein) expression in subcellular compartments, cell lines and relevant human tissues. Gene-set enrichment analyses were performed to initially investigate modulatory mechanisms of LACC1 expression. A small-interference RNA knockdown in vitro model system was used to study the effect of FAMIN depletion on peroxisome function., Results: FAMIN expression was detected in macrophage-differentiated THP-1 cells and several human tissues, being highest in neutrophils, monocytes/macrophages, myeloid and plasmacytoid dendritic cells among peripheral blood cells. Subcellular co-localization was exclusively confined to peroxisomes, with some additional positivity for organelle endomembrane structures. LACC1 co-expression signatures were enriched for genes involved in peroxisome proliferator-activated receptors (PPAR) signaling pathways, and PPAR ligands downregulated FAMIN expression in in vitro model systems., Conclusion: FAMIN is a peroxisome-associated protein with primary role(s) in macrophages and other immune cells, where its metabolic functions may be modulated by PPAR signaling events. However, the precise molecular mechanisms through which FAMIN exerts its biological effects in immune cells remain to be elucidated., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2016
- Full Text
- View/download PDF
48. Common epigenetic variation in a European population of mentally healthy young adults.
- Author
-
Milnik A, Vogler C, Demougin P, Egli T, Freytag V, Hartmann F, Heck A, Peter F, Spalek K, Stetak A, de Quervain DJ, Papassotiropoulos A, and Vukojevic V
- Subjects
- Adult, DNA Methylation genetics, Epigenomics methods, Female, Gene Expression Profiling, Gene Expression Regulation, Genome-Wide Association Study, Healthy Volunteers, Humans, Male, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide genetics, Young Adult, CpG Islands genetics, Epigenesis, Genetic genetics, Mental Health
- Abstract
DNA methylation represents an important link between structural genetic variation and complex phenotypes. The study of genome-wide CpG methylation and its relation to traits relevant to psychiatry has become increasingly important. Here, we analyzed quality metrics of 394,043 CpG sites in two samples of 568 and 319 mentally healthy young adults. For 25% of all CpGs we observed medium to large common epigenetic variation. These CpGs were overrepresented in open sea and shore regions, as well as in intergenic regions. They also showed a strong enrichment of significant hits in association analyses. Furthermore, a significant proportion of common DNA methylation is at least partially genetically driven and thus may be observed similarly across tissues. These findings could be of particular relevance for studies of complex neuropsychiatric traits, which often rely on proxy tissues., (Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
49. Integrated transcriptomic and proteomic analyses uncover regulatory roles of Nrf2 in the kidney.
- Author
-
Shelton LM, Lister A, Walsh J, Jenkins RE, Wong MH, Rowe C, Ricci E, Ressel L, Fang Y, Demougin P, Vukojevic V, O'Neill PM, Goldring CE, Kitteringham NR, Park BK, Odermatt A, and Copple IM
- Abstract
The transcription factor Nrf2 exerts protective effects in numerous experimental models of acute kidney injury, and is a promising therapeutic target in chronic kidney disease. To provide a detailed insight into the regulatory roles of Nrf2 in the kidney, we performed integrated transcriptomic and proteomic analyses of kidney tissue from wild-type and Nrf2 knockout mice treated with the Nrf2 inducer methyl-2-cyano-3,12-dioxooleano-1,9-dien-28-oate (CDDO-Me, also known as bardoxolone methyl). After 24 h, analyses identified 2561 transcripts and 240 proteins that were differentially expressed in the kidneys of Nrf2 knockout mice, compared with those of wild-type counterparts, and 3122 transcripts and 68 proteins that were differentially expressed in wild-type mice treated with CDDO-Me, compared with those of vehicle control. In the light of their sensitivity to genetic and pharmacological modulation of renal Nrf2 activity, genes/proteins that regulate xenobiotic disposition, redox balance, the intra/extracellular transport of small molecules, and the supply of NADPH and other cellular fuels were found to be positively regulated by Nrf2 in the kidney. This was verified by qPCR, immunoblotting, pathway analysis, and immunohistochemistry. In addition, the levels of NADPH and glutathione were found to be significantly decreased in the kidneys of Nrf2 knockout mice. Thus, Nrf2 regulates genes that coordinate homeostatic processes in the kidney, highlighting its potential as a novel therapeutic target.
- Published
- 2015
- Full Text
- View/download PDF
50. Forgetting is regulated via Musashi-mediated translational control of the Arp2/3 complex.
- Author
-
Hadziselimovic N, Vukojevic V, Peter F, Milnik A, Fastenrath M, Fenyves BG, Hieber P, Demougin P, Vogler C, de Quervain DJ, Papassotiropoulos A, and Stetak A
- Subjects
- Actin-Related Protein 2-3 Complex metabolism, Actins metabolism, Amino Acid Sequence, Animals, Caenorhabditis elegans metabolism, Caenorhabditis elegans Proteins genetics, Molecular Sequence Data, Mutation, Nerve Tissue Proteins genetics, Protein Biosynthesis, RNA, Messenger metabolism, RNA-Binding Proteins genetics, Sequence Alignment, Synapses, Actin-Related Protein 2-3 Complex genetics, Caenorhabditis elegans Proteins metabolism, Interneurons metabolism, Memory, Nerve Tissue Proteins metabolism, RNA, Helminth metabolism, RNA-Binding Proteins metabolism
- Abstract
A plastic nervous system requires the ability not only to acquire and store but also to forget. Here, we report that musashi (msi-1) is necessary for time-dependent memory loss in C. elegans. Tissue-specific rescue demonstrates that MSI-1 function is necessary in the AVA interneuron. Using RNA-binding protein immunoprecipitation (IP), we found that MSI-1 binds to mRNAs of three subunits of the Arp2/3 actin branching regulator complex in vivo and downregulates ARX-1, ARX-2, and ARX-3 translation upon associative learning. The role of msi-1 in forgetting is also reflected by the persistence of learning-induced GLR-1 synaptic size increase in msi-1 mutants. We demonstrate that memory length is regulated cooperatively through the activation of adducin (add-1) and by the inhibitory effect of msi-1. Thus, a GLR-1/MSI-1/Arp2/3 pathway induces forgetting and represents a novel mechanism of memory decay by linking translational control to the structure of the actin cytoskeleton in neurons., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.