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1.	Abbas, Abdul-Karim, 1959, et al. (författare) Long-term potentiation and insult conditioning in hippocampal slices from young rats: a role for protein synthesis under chemical stress? 2010 Ingår i: The 10th Biennial Meeting of the Asia-Pacific Society for Neurochemistry (APSN), October 17-20, 2010, Phuket, Thailand. Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract We have previously demonstrated that in young rats (12-20-day-old) a sustained long-term potentiation (LTP) can still be induced under conditions of protein synthesis inhibition. It was therefore suggested that sufficient and necessary proteins were already available at the induction time to accomplish LTP maintenance for several hours. Against this background, we have questioned whether hippocampal slices subjected to certain insult conditions might be more sensitive to protein synthesis inhibitors. High K+ concentration has previously been reported to cause an amnesic effect in vivo as well as increasing protein turnover in vitro. We have here employed a K+ insult model under conditions when protein synthesis was inhibited. Recordings were obtained from hippocampal slices for up to 9 h, with or without a cocktail of protein synthesis inhibitors, containing cycloheximide (60 µM) and anisomycin (25 µM). High potassium (50 mM) was transiently applied (5-15 min) shortly after inducing LTP in one of two separate pathways stimulated alternatively. Additionally, an NMDA-receptor antagonist AP5 was supplied after LTP induction to minimize effects related to depolarization-induced glutamate release. Following elimination of all responses for about 30 min, both test and control responses partly recovered. The degree of remaining LTP, defined as test/control ratio, was reduced in both groups of slices (NMDA-independent depotentiation) but was significantly smaller in the drug-treated ones. We are also running an insult model based on oxidative stress, applying hydrogen peroxide (4-5 mM) before or after LTP induction; however, the results are still insufficient for a final conclusion. The potency of cycloheximide, anisomycin or cocktail of the drugs was verified by measurement of incorporation of [3H]-leucine into trichloracetic acid (TCA) precipitable macromolecules. Cycloheximide, anisomycin or cocktail, at concentrations used here caused 95%, 97% and 95% blocking effect, respectively. Our data confirm the idea that sufficient and necessary constitutive proteins are available in the young hippocampus to maintain LTP under conditions of protein synthesis inhibition. They also reveal that LTP in slices subjected to certain insult conditions early after the induction is sensitive to protein synthesis inhibition, probably due to increase in constitutive proteins turnover.
2.	Trägårdh, Karin, et al. (författare) Risk Profiles of Female Perpetrators of Severe Violence 2019 Ingår i: 13th Nordic Symposium on Forensic Psychiatry. August 20-22, Gothenburg, Sweden. Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract Female offenders without a severe mental disorder show more criminogenic factors than those with. Both groups are characterized by mental health problems. We need to further characterize female offenders. Background Offenders of lethal/severe violence are in a majority of cases male, about 90% (Falk et al., 2014), and research has to a considerable extent focused on male violent offenders. Although less is known about female violent offenders than male offenders, previous research has indicated significant differences between male and female offenders of lethal/severe violence (Trägårdh et al., 2016; Yourstone et al., 2008). Since a majority of female perpetrators of lethal violence undergo a forensic psychiatric investigation (RPU/FPI), these documents contains important information about this group. Purpose The aim of this ongoing study is to characterize female perpetrators of severe violent crimes, and to compare female perpetrators sentenced to forensic psychiatric compulsory care with those sentenced to correctional treatment. Method This is an exploratory and descriptive study with a cross-sectional design. All forensic evaluations (FPI) made in Sweden between 2000-2014 (from The National Board of Forensic Medicine/RMV), and the subsequent court verdicts, in cases where women had used lethal/severe violence (n≈180) where used as the basis for data collection in this study. The present preliminary analyses (2-tests and ANOVA) contains approx. 26% (n=47) of the total group. Group differences were investigated regarding: Mental health (FPI) Risk factors (HCR-20 and PCL-R) Victim relation (FPI) Criminal behavior (FPI) Results Female offenders with and without a Severe mental disorder (SMD) seems to differ in some respects. For female offenders with a SMD, the crime was more likely to have been conducted in a less criminal context (see Table). For female offenders without a SMD, the following characteristics were more frequently present: Victim gender – male Substance abuse + Under the influence of substance (offender and victim) Previous violence between victim and offender Previous registered criminality Also, several common features between the SMD and non-SMD group of female offenders were found. The majority of all female offenders had: Previous psychiatric contact and diagnoses Previously attempted suicide No previously registered criminality Conclusions Preliminary results of the female perpetrators who had underwent a FPI seems to identify both substantial differences and similarities between those with versus without a SMD, where those without show more criminogenic factors. Both groups were also characterized by a high amount of mental illness. Also, these results supports previous research that female and male offenders of severe violence differ in important ways. Since a majority of female perpetrators of lethal violence undergo a forensic psychiatric investigation, these results should be generalizable to this group as a whole in Sweden. Based on these results, a great need to further characterize female offenders of severe/lethal violence remain.
3.	Mondal, Tanmoy, 1981, et al. (författare) Sense-antisense lncRNA pair encoded by locus 6p22.3 determines neuroblastoma susceptibility via the USP36-CHD7-SOX9 regulatory axis 2018 Ingår i: Cancer Cell. - : Elsevier BV. - 1535-6108 .- 1878-3686. ; 33:3 Tidskriftsartikel (refereegranskat)abstract Trait-associated loci often map to genomic regions encoding long noncoding RNAs (lncRNAs), but the role of these lncRNAs in disease etiology is largely unexplored. We show that a pair of sense/antisense lncRNA (6p22lncRNAs) encoded by CASC15 and NBAT1 located at the neuroblastoma (NB) risk-associated 6p22.3 locus are tumor suppressors and show reduced expression in high-risk NBs. Loss of functional synergy between 6p22lncRNAs results in an undifferentiated state that is maintained by a gene-regulatory network, including SOX9 located on 17q, a region frequently gained in NB. 6p22lncRNAs regulate SOX9 expression by controlling CHD7 stability via modulating the cellular localization of USP36, encoded by another 17q gene. This regulatory nexus between 6p22.3 and 17q regions may lead to potential NB treatment strategies.
4.	Mottahedin, Amin (författare) Developing brain and systemic inflammation: a "Toll-like" link with consequences 2017 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract The developing brain is vulnerable to external insults, and perinatal brain injury (PBI) is a major cause of life-long neurological syndromes such as cerebral palsy. Currently, no pharmaceutical intervention is available. Hypoxia/ischemia (HI), infections and inflammation are implicated in the pathogenesis of PBI. However, the crosstalk between these etiologies is not fully understood. Toll-like receptors (TLR) 3 and TLR2 are responsible for sensing viral and bacterial infections and initiating the inflammatory response. The aim of this thesis was to investigate the effect of systemic inflammation induced by activation of these TLRs on neonatal HI brain injury. We demonstrate that intraperitoneal administration of TLR3 and TLR2 ligands (PolyI:C and P3C, respectively) prior to HI increases the brain injury in neonatal mice. PolyI:C and P3C induced neuroinflammation and altered microglial phenotype as assessed by RT-qPCR, multiplex cytokine assay or flow cytometry. PolyI:C also upregulated the pro-apoptotic gene, Fasl, expression and reduced activation of pro-survival signaling molecule Akt. On the other hand, P3C suppressed mitochondrial respiration, a major mechanism of cellular energy production. P3C, unlike other TLR agonists, induced marked infiltration of leukocytes to the cerebral spinal fluid and brain of neonatal mice and rats. Confocal microscopy, Cre recombinase-mediated gene targeting and in vitro cell transmigra-tion assay revealed the choroid plexus as a site of leukocyte entry. RNA sequencing of the choroid plexus followed by transcriptome cluster analysis and Ingenuity Pathway Analysis revealed potential mechanisms of leukocyte infiltration, including a specific chemotaxis signature and cytoskeleton-related pathways. Finally, we show that N-acetylcysteine treatment inhibits TLR2-mediated leukocyte trafficking in vivo and in vitro. To conclude, this thesis describe a TLR-mediated link between systemic inflammation and developing brain with detrimental consequences on HI brain injury, suggesting potential novel therapeutic strategies.
5.	Nilsson, Maria H., et al. (författare) Psychometric properties of the general self-efficacy scale in Parkinson's disease 2015 Ingår i: Acta Neurologica Scandinavica. - : Wiley-Blackwell. - 0001-6314 .- 1600-0404. ; 132:2, s. 89-96 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: This study aimed to investigate the psychometric properties of the General Self-Efficacy Scale (GSE) in people with Parkinson's disease (PD). More specifically, we investigated data completeness, scaling assumptions, targeting, reliability, and construct validity.MATERIALS AND METHODS: This study involves data available from two different projects that included people diagnosed with PD for at least 1 year, yielding two samples (1 and 2). The combined total sample (N = 346; 60% men) had a mean (SD) age and PD duration of 71 (8.9) and 9 years (6.3), respectively. Both samples received a self-administered survey by mail, which was administered twice in sample 2. Additional data (e.g., clinical assessments) were available for Sample 1.RESULTS: Total GSE scores were computable for 336 participants (97%). Corrected item-total correlations exceeded 0.4. Principal component analyses identified one component (the eigenvalue of the first component extracted was 6.9), explaining 69% of the total variance. Floor and ceiling effects were < 6%. Internal consistency (coefficient alpha) was 0.95. Analyses of test-retest reliability yielded (ICC) values from 0.69 to 0.80. The highest value refers to those (n = 47) with identical self-ratings of mobility (in the on condition) at both tests; the standard error of measurement was 3.1 points. Construct validity was further supported by correlations in accordance with a priori expectations.CONCLUSIONS: This study provides support for the validity and reliability of GSE scores in people with PD; the GSE can thus serve as a valuable outcome measurement in clinical practice and research.
6.	Rostami, Elham, 1979-, et al. (författare) β-adrenoreceptor activation in brain, lung and adipose tissue, measured by microdialysis in pig. 2012 Ingår i: Advances in Medical Sciences. - : Elsevier BV. - 1896-1126 .- 1898-4002. ; 57:1, s. 136-141 Tidskriftsartikel (refereegranskat)
7.	Winder, Michael, 1980 (författare) The ambiguous role of nitric oxide in the urinary bladder 2017 Ingår i: 7th National Symposium on Advances in Gastrointestinal & Urogenital Research, 2017, Gold Coast, Australia. Konferensbidrag (övrigt vetenskapligt/konstnärligt)
8.	Bhandage, Amol K., 1988- (författare) Glutamate and GABA signalling components in the human brain and in immune cells 2016 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Glutamate and γ-aminobutyric acid (GABA) are the principal excitatory and inhibitory neurotransmitters in the central nervous system (CNS). They both can activate their ionotropic and metabotropic receptors. Glutamate activates ionotropic glutamate receptors (iGlu - AMPA, kainate and NMDA receptors) and GABA activates GABA-A receptors which are modulated by many types of drugs and substances including alcohol. Using real time quantitative polymerase chain reaction, I have shown that iGlu and/or GABA-A receptor subunits were expressed in the hippocampus dentate gyrus (HDG), orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DL-PFC), central amygdala (CeA), caudate and putamen of the human brain and their expression was altered by chronic excessive alcohol consumption. It indicates that excitatory and inhibitory neurotransmission may have been altered in the brain of human alcoholics. It is possible that changes in one type of neurotransmitter system may drive changes in another. These brain regions also play a role in brain reward system. Any changes in them may lead to changes in the normal brain functions.Apart from the CNS, glutamate and GABA are also present in the blood and can be synthesised by pancreatic islet cells and immune cells. They may act as immunomodulators of circulating immune cells and can affect immune function through glutamate and GABA receptors. I found that T cells from human, rat and mouse lymph nodes expressed the mRNAs and proteins for specific GABA-A receptor subunits. GABA-evoked transient and tonic currents recorded using the patch clamp technique demonstrate the functional GABA-A channel in T cells. Furthermore, the mRNAs for specific iGlu, GABA-A and GABA-B receptor subunits and chloride cotransporters were detected in peripheral blood mononuclear cells (PBMCs) from men, non-pregnant women, healthy and depressed pregnant women. The results indicate that the expression of iGlu, GABA-A and GABA-B receptors is related to gender, pregnancy and mental health and support the notion that glutamate and GABA receptors may modulate immune function. Intra- and interspecies variability exists in the expression and it is further influenced by physiological conditions.
9.	Rostami, Elham, 1979- (författare) Traumatic brain injury in humans and animal models 2012 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)
10.	Sukhovey, Yurij G., et al. (författare) Functional Conjugation of the Different Regulatory Responses to the Stress Stimuli in Healthy Human Subjects 2016 Ingår i: Open Journal of Applied Sciences. - : Scientific Research Publishing, Inc.. - 2165-3917 .- 2165-3925. ; 6, s. 489-500 Tidskriftsartikel (refereegranskat)abstract Present article discusses the physiological mechanisms of the state employees adaptation duringactive training in temporary groups. It is suggested that adaptive mechanisms to adverse effectsmay be studied basing on the concept of functional isomorphism of the psychic and immune systems.Adaptive mechanisms were studied through the monitoring of the stress factors’ impact upon thelaw enforcement officers when training outside the places of permanent deployment. The specificpurpose of present study was to evaluate the physiological indicators of the psychic, immune andendocrine systems dynamics at different stages of adaptation of the live organism to a stressfulsituation, hoping to get better insight into possible relations between psychic and immune domains.Through monitoring of the dynamics of the endocrine and immune responses to the psychic stimuli,it was possible to correlate the stages of the stress onset to the phases of specific immune reactions.Strong correlations between the parameters characterizing activation of the psychic and immuneresponses support the hypothesis of the presence of “strong cooperation” between psychic andimmune domains. It supports earlier hypothesis that we are monitoring
11.	Fritz, Michael, 1981-, et al. (författare) Interferon-ɣ mediated signaling in the brain endothelium is critical for inflammation-induced aversion 2018 Ingår i: Brain, behavior, and immunity. - Maryland Heights : Academic Press. - 0889-1591 .- 1090-2139. ; 67, s. 54-58 Tidskriftsartikel (refereegranskat)abstract Systemic inflammation elicits malaise and a negative affective state. The mechanism underpinning the aversive component of inflammation include cerebral prostaglandin synthesis and modulation of dopaminergic reward circuits, but the messengers that mediate the signaling between the peripheral inflammation and the brain have not been sufficiently characterized. Here we investigated the role of interferon-ɣ (IFN-ɣ) in the aversive response to systemic inflammation induced by a low dose (10μg/kg) of lipopolysaccharide (LPS) in mice. LPS induced IFN-ɣ expression in the blood and deletion of IFN-ɣ or its receptor prevented the development of conditioned place aversion to LPS. LPS induced expression of the chemokine Cxcl10 in the striatum of normal mice, but this induction was absent in mice lacking IFN-ɣ receptors or Myd88 in blood brain barrier endothelial cells. Furthermore, inflammation-induced aversion was blocked in mice lacking Cxcl10 or its receptor Cxcr3. Finally, mice with a selective deletion of the IFN-ɣ receptor in brain endothelial cells did not develop inflammation-induced aversion, demonstrating that the brain endothelium is the critical site of IFN-ɣ action. Collectively, these findings show that circulating IFN-ɣ that binds to receptors on brain endothelial cells and induces Cxcl10, is a central link in the signaling chain eliciting inflammation-induced aversion.
12.	Klawonn, Anna, 1985- (författare) Molecular Mechanisms of Reward and Aversion 2017 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Various molecular pathways in the brain shape our understanding of good and bad, as well as our motivation to seek and avoid such stimuli. This work evolves around how systemic inflammation causes aversion; and why general unpleasant states such as sickness, stress, pain and nausea are encoded by our brain as undesirable; and contrary to these questions, how drugs of abuse can subjugate the motivational neurocircuitry of the brain. A common feature of these various disease states is involvement of the motivational neurocircuitry - from mesolimbic to striatonigral pathways. Having an intact motivational system is what helps us evade negative outcomes and approach natural positive reinforcers, which is essential for our survival. During disease-states the motivational neurocircuitry may be overthrown by the molecular mechanisms that originally were meant to aid us.In study I, to investigate how inflammation is perceived as aversive, we used a behavioral test based on Pavlovian place conditioning with the aversive inflammatory stimulus E. coli lipopolysaccharide (LPS). Using a combination of cell-type specific gene deletions, pharmacology, and chemogenetics, we uncovered that systemic inflammation triggered aversion by MyD88-dependent activation of the brain endothelium followed by COX1-mediated cerebral prostaglandin E2 (PGE2) synthesis. Moreover, we showed that inflammation-induced PGE2 targeted EP1 receptors on striatal dopamine D1 receptor–expressing neurons and that this signaling sequence induced aversion through GABA-mediated inhibition of dopaminergic cells. Finally, inflammation-induced aversion was not an indirect consequence of fever or anorexia but constituted an independent inflammatory symptom triggered by a unique molecular mechanism. Collectively, these findings demonstrate that PGE2-mediated modulation of the dopaminergic circuitry is a key mechanism underlying inflammation-induced aversion.In study II, we investigate the role of peripheral IFN-γ in LPS induced conditioned place aversion by employing a strategy based on global and cell-type specific gene deletions, combined with measures of gene-expression. LPS induced IFN-ɣ expression in the blood, and deletion of IFN-ɣ or its receptor prevented conditioned place aversion (CPA) to LPS. LPS increased the expression of chemokine Cxcl10 in the striatum of normal mice. This induction was absent in mice lacking IFN-ɣ receptors or Myd88 in blood brain barrier endothelial cells. Furthermore, inflammation-induced aversion was blocked in mice lacking Cxcl10 or its receptor Cxcr3. Finally, mice with a selective deletion of the IFN-ɣ receptor in brain endothelial cells did not develop inflammation-induced aversion. Collectively, these findings demonstrate that circulating IFN-ɣ binding to receptors on brain endothelial cells which induces Cxcl10, is a central link in the signaling chain eliciting inflammation-induced aversion.In study III, we explored the role of melanocortin 4 receptors (MC4Rs) in aversive processing using genetically modified mice in CPA to various stimuli. In normal mice, robust aversions were induced by systemic inflammation, nausea, pain and kappa opioid receptor-induced dysphoria. In sharp contrast, mice lacking MC4Rs displayed preference towards most of the aversive stimuli, but were indifferent to pain. The unusual flip from aversion to reward in mice lacking MC4Rs was dopamine-dependent and associated with a change from decreased to increased activity of the dopamine system. The responses to aversive stimuli were normalized when MC4Rs were re-expressed on dopamine D1 receptor-expressing cells or in the striatum of mice otherwise lacking MC4Rs. Furthermore, activation of arcuate nucleus proopiomelanocortin neurons projecting to the ventral striatum increased the activity of striatal neurons in a MC4R-dependent manner and elicited aversion. Our findings demonstrate that melanocortin signaling through striatal MC4Rs is critical for assigning negative motivational valence to harmful stimuli.The neurotransmitter acetylcholine has been implied in reward learning and drug addiction. However, the role of cholinergic receptor subtypes in such processes remains elusive. In study IV we investigated the function of muscarinic M4Rs on dopamine D1R expressing neurons and acetylcholinergic neurons, using transgenic mice in various reward-enforced behaviors and in a “waiting”-impulsivity test. Mice lacking M4-receptors from D1-receptor expressing neurons exhibited an escalated reward seeking phenotype towards cocaine and natural reward, in Pavlovian conditioning and an operant self-administration task, respectively. In addition, the M4-D1RCre mice showed impaired waiting impulsivity in the 5-choice-serial-reaction-time-task. On the contrary, mice without M4Rs in acetylcholinergic neurons were unable to learn positive reinforcement to natural reward and cocaine, in an operant runway paradigm and in Pavlovian conditioning. Immediate early gene expression mirrored the behavioral findings arising from M4R-D1R knockout, as cocaine induced cFos and FosB was significantly increased in the forebrain of M4-D1RCre mice, whereas it remained normal in the M4R-ChatCre mice. Our study illustrates that muscarinic M4Rs on specific neural populations, either cholinergic or D1R-expressing, are pivotal for learning processes related to both natural reward and drugs of abuse, with opposing functionality.
13.	Hogenkamp, Pleunie S, et al. (författare) Sweet taste perception not altered after acute sleep deprivation in healthy young men. 2013 Ingår i: Somnologie : Schlafforschung und Schlafmedizin = Somnology : sleep research and sleep medicine. - : Springer Science and Business Media LLC. - 1432-9123 .- 1439-054X. ; 17:2, s. 111-114 Tidskriftsartikel (refereegranskat)abstract We hypothesized that acutely sleep-deprived participants would rate ascending concentrations of sucrose as more intense and pleasant, than they would do after one night of normal sleep. Such a finding would offer a potential mechanism through which acute sleep loss could promote overeating in humans.
14.	Giddaluru, Sudheer, et al. (författare) Genetics of structural connectivity and information processing in the brain 2016 Ingår i: Brain Structure and Function. - : Springer Science and Business Media LLC. - 1863-2653 .- 1863-2661. ; 221:9, s. 4643-4661 Tidskriftsartikel (refereegranskat)abstract Understanding the genetic factors underlying brain structural connectivity is a major challenge in imaging genetics. Here, we present results from genome-wide association studies (GWASs) of whole-brain white matter (WM) fractional anisotropy (FA), an index of microstructural coherence measured using diffusion tensor imaging. Data from independent GWASs of 355 Swedish and 250 Norwegian healthy adults were integrated by meta-analysis to enhance power. Complementary GWASs on behavioral data reflecting processing speed, which is related to microstructural properties of WM pathways, were performed and integrated with WM FA results via multimodal analysis to identify shared genetic associations. One locus on chromosome 17 (rs145994492) showed genome-wide significant association with WM FA (meta P value = 1.87 × 10(-08)). Suggestive associations (Meta P value <1 × 10(-06)) were observed for 12 loci, including one containing ZFPM2 (lowest meta P value = 7.44 × 10(-08)). This locus was also implicated in multimodal analysis of WM FA and processing speed (lowest Fisher P value = 8.56 × 10(-07)). ZFPM2 is relevant in specification of corticothalamic neurons during brain development. Analysis of SNPs associated with processing speed revealed association with a locus that included SSPO (lowest meta P value = 4.37 × 10(-08)), which has been linked to commissural axon growth. An intergenic SNP (rs183854424) 14 kb downstream of CSMD1, which is implicated in schizophrenia, showed suggestive evidence of association in the WM FA meta-analysis (meta P value = 1.43 × 10(-07)) and the multimodal analysis (Fisher P value = 1 × 10(-07)). These findings provide novel data on the genetics of WM pathways and processing speed, and highlight a role of ZFPM2 and CSMD1 in information processing in the brain.
15.	Xin, D. L., et al. (författare) Effectiveness of conservative interventions for sickness and pain behaviors induced by a high repetition high force upper extremity task 2017 Ingår i: BMC Neuroscience. - : BioMed Central. - 1471-2202. ; 18 Tidskriftsartikel (refereegranskat)abstract Background: Systemic inflammation is known to induce sickness behaviors, including decreased social interaction and pain. We have reported increased serum inflammatory cytokines in a rat model of repetitive strain injury (rats perform an upper extremity reaching task for prolonged periods). Here, we sought to determine if sickness behaviors are induced in this model and the effectiveness of conservative treatments.Methods: Experimental rats underwent initial training to learn a high force reaching task (10 min/day, 5 days/week for 6 weeks), with or without ibuprofen treatment (TRHF vs. TRHF + IBU rats). Subsets of trained animals went on to perform a high repetition high force (HRHF) task for 6 or 12 weeks (2 h/day, 3 days/week) without treatment, or received two secondary interventions: ibuprofen (HRHF + IBU) or a move to a lower demand low repetition low force task (HRHF-to-LRLF), beginning in task week 5. Mixed-effects models with repeated measures assays were used to assay duration of social interaction, aggression, forepaw withdrawal thresholds and reach performance abilities. One-way and two-way ANOVAs were used to assay tissue responses. Corrections for multiple comparisons were made.Results: TRHF + IBU rats did not develop behavioral declines or systemic increases in IL-1beta and IL-6, observed in untreated TRHF rats. Untreated HRHF rats showed social interaction declines, difficulties performing the operant task and forepaw mechanical allodynia. Untreated HRHF rats also had increased serum levels of several inflammatory cytokines and chemokines, neuroinflammatory responses (e.g., increased TNFalpha) in the brain, median nerve and spinal cord, and Substance P and neurokinin 1 immunoexpression in the spinal cord. HRHF + IBU and HRHF-to-LRLF rats showed improved social interaction and reduced inflammatory serum, nerve and brain changes. However, neither secondary treatment rescued HRHF-task induced forepaw allodynia, or completely attenuated task performance declines or spinal cord responses.Conclusions: These results suggest that inflammatory mechanisms induced by prolonged performance of high physical demand tasks mediate the development of social interaction declines and aggression. However, persistent spinal cord sensitization was associated with persistent behavioral indices of discomfort, despite use of conservative secondary interventions indicating the need for prevention or more effective interventions.
16.	Adermark, Louise, 1974 (författare) Astrocyte Function in Alcohol Reward and Addiction 2015 Ingår i: Journal of Alcoholism & Drug Dependence. - : OMICS Publishing Group. - 2329-6488. ; 3 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract Glial cells, particularly astrocytes, play essential roles in the regulation of neurotransmission, metabolism, and supply of energy substrates for synaptic transmission. One astrocyte can receive inputs from several hundreds of synapses, and synchronized neuronal activity correlates with astrocyte calcium signaling. Astrocyte pathology is a common feature of ethanol exposure in both humans and animal models, and brief alcohol intake is sufficient to cause long-lasting changes in astrocyte gene expression, activity and proliferation. Recent research also suggests that astrocytes shape the rewarding sensation of ethanol, and might be involved in modulating alcohol consumption. Considering the role of astrocytes in regulating glutamate homeostasis, a crucial component of alcohol abuse disorders, the astrocyte might be an important target for the development of new pharmacological treatments of alcoholism.
17.	Karlsson, Oskar, et al. (författare) Neonatal exposure to the cyanobacterial toxin BMAA induces changes in protein expression and neurodegeneration in adult hippocampus. 2012 Ingår i: Toxicological Sciences. - : Oxford University Press (OUP). - 1096-0929 .- 1096-6080. ; 130:2, s. 391-404 Tidskriftsartikel (refereegranskat)abstract The cyanobacterial toxin β-N-methylamino-L-alanine (BMAA) has been proposed to contribute to neurodegenerative disease. We have previously reported a selective uptake of BMAA in the mouse neonatal hippocampus and that exposure during the neonatal period causes learning and memory impairments in adult rats. The aim of this study was to characterize effects in the brain of 6-month-old rats treated neonatally (postnatal days 9-10) with the glutamatergic BMAA. Protein changes were examined using the novel technique Matrix-Assisted Laser Desorption Ionization (MALDI) imaging mass spectrometry (IMS) for direct imaging of proteins in brain cryosections, and histological changes were examined using immunohistochemistry and histopathology. The results showed long-term changes including a decreased expression of proteins involved in energy metabolism and intracellular signaling in the adult hippocampus at a dose (150 mg/kg) that gave no histopathological lesions in this brain region. Developmental exposure to a higher dose (460 mg/kg) also induced changes in the expression of S100β, histones, calcium- and calmodulin-binding proteins, and guanine nucleotide-binding proteins. At this dose, severe lesions in the adult hippocampus including neuronal degeneration, cell loss, calcium deposits, and astrogliosis were evident. The data demonstrate subtle, sometimes dose-dependent, but permanent effects of a lower neonatal dose of BMAA in the adult hippocampus suggesting that BMAA could potentially disturb many processes during the development. The detection of BMAA in seafood stresses the importance of evaluating the magnitude of human exposure to this neurotoxin.
18.	Lindberg, Olle R, et al. (författare) Epidermal growth factor treatment of the adult brain subventricular zone leads to focal microglia/macrophage accumulation and angiogenesis. 2014 Ingår i: Stem cell reports. - : Elsevier BV. - 2213-6711. ; 2:4, s. 440-8 Tidskriftsartikel (refereegranskat)abstract One of the major components of the subventricular zone (SVZ) neurogenic niche is the specialized vasculature. The SVZ vasculature isthought to be important in regulating progenitor cell proliferation and migration. Epidermal growth factor (EGF) is a mitogen witha wide range of effects. When stem and progenitor cells in the rat SVZ are treated with EGF, using intracerebroventricular infusion,dysplastic polyps are formed. Upon extended infusion, blood vessels are recruited into the polyps. In the current study we demonstrate how polyps develop through distinct stages leading up to angiogenesis. As polyps progress, microglia/macrophages accumulate in the polyp core concurrent with increasing cell death. Both microglia/macrophage accumulation and cell death peak during angiogenesis and subsequently decline following polyp vascularization. This model of inducible angiogenesis in the SVZ neurogenic niche suggests involvement of microglia/macrophages in acquired angiogenesis and can be used in detail to study angiogenesis inthe adult brain.
19.	Rask-Andersen, Mathias, et al. (författare) Advances in kinase targeting : current clinical use and clinical trials 2014 Ingår i: TIPS - Trends in Pharmacological Sciences. - : Elsevier BV. - 0165-6147 .- 1873-3735. ; 35:11, s. 60-76 Forskningsöversikt (refereegranskat)abstract Phosphotransferases, also known as kinases, are the most intensively studied protein drug target category in current pharmacological research, as evidenced by the vast number of kinase-targeting agents enrolled in active clinical trials. This development has emerged following the great success of small-molecule, orally available protein kinase inhibitors for the treatment of cancer, starting with the introduction of imatinib (Gleevec (R)) in 2003. The pharmacological utility of kinase-targeting has expanded to include treatment of inflammatory diseases, and rapid development is ongoing for kinase-targeted therapies in a broad array of indications in ophthalmology, analgesia, central nervous system (CNS) disorders, and the complications of diabetes, osteoporosis, and otology. In this review we highlight specifically the kinase drug targets and kinase-targeting agents being explored in current clinical trials. This analysis is based on a recent estimate of all established and clinical trial drug mechanisms of action, utilizing private and public databases to create an extensive dataset detailing aspects of more than 3000 approved and experimental drugs.
20.	Risling, M, et al. (författare) Mechanisms of blast induced brain injuries, experimental studies in rats 2011 Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 54:1, s. 89-97 Tidskriftsartikel (refereegranskat)
21.	Karlsson, Oskar, et al. (författare) Imaging mass spectrometry in drug development and toxicology 2017 Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 91:6, s. 2283-2294 Forskningsöversikt (refereegranskat)abstract During the last decades, imaging mass spectrometry has gained significant relevance in biomedical research. Recent advances in imaging mass spectrometry have paved the way for in situ studies on drug development, metabolism and toxicology. In contrast to whole-body autoradiography that images the localization of radiolabeled compounds, imaging mass spectrometry provides the possibility to simultaneously determine the discrete tissue distribution of the parent compound and its metabolites. In addition, imaging mass spectrometry features high molecular specificity and allows comprehensive, multiplexed detection and localization of hundreds of proteins, peptides and lipids directly in tissues. Toxicologists traditionally screen for adverse findings by histopathological examination. However, studies of the molecular and cellular processes underpinning toxicological and pathologic findings induced by candidate drugs or toxins are important to reach a mechanistic understanding and an effective risk assessment strategy. One of IMS strengths is the ability to directly overlay the molecular information from the mass spectrometric analysis with the tissue section and allow correlative comparisons of molecular and histologic information. Imaging mass spectrometry could therefore be a powerful tool for omics profiling of pharmacological/toxicological effects of drug candidates and toxicants in discrete tissue regions. The aim of the present review is to provide an overview of imaging mass spectrometry, with particular focus on MALDI imaging mass spectrometry, and its use in drug development and toxicology in general.
22.	Karlsson, Oskar, et al. (författare) MALDI imaging delineates hippocampal glycosphingolipid changes associated with neurotoxin induced proteopathy following neonatal BMAA exposure. 2017 Ingår i: Biochimica et Biophysica Acta. - : Elsevier BV. - 0006-3002 .- 1878-2434. ; 1865:7, s. 740-746 Tidskriftsartikel (refereegranskat)abstract The environmental toxin β-N-methylamino-L-alanine (BMAA) has been proposed to contribute to neurodegenerative diseases. We have previously shown that neonatal exposure to BMAA results in dose-dependent cognitive impairments, proteomic alterations and progressive neurodegeneration in the hippocampus of adult rats. A high BMAA dose (460mg/kg) also induced intracellular fibril formation, increased protein ubiquitination and enrichment of proteins important for lipid transport and metabolism. The aim of this study was therefore to elucidate the role of neuronal lipids in BMAA-induced neurodegeneration. By using matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS), we characterized the spatial lipid profile in the hippocampus of six month-old rats that were treated neonatally (postnatal days 9-10) with 460mg/kg BMAA. Multivariate statistical analysis revealed long-term changes in distinct ganglioside species (GM, GD, GT) in the dentate gyrus. These changes could be a consequence of direct effects on ganglioside biosynthesis through the b-series (GM3-GD3-GD2-GD1b-GT1b) and may be linked to astrogliosis. Complementary immunohistochemistry experiments towards GFAP and S100β further verified the role of increased astrocyte activity in BMAA-induced brain damage. This highlights the potential of imaging MS for probing chemical changes associated with neuropathological mechanisms in situ. This article is part of a Special Issue entitled: MALDI Imaging, edited by Dr. Corinna Henkel and Prof. Peter Hoffmann.
23.	Sundén, Henrik, 1978, et al. (författare) Chiral Dihydrobenzofuran Acids Show Potent Retinoid X Receptor-Nuclear Receptor Related 1 Protein Dimer Activation 2016 Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 59:3, s. 1232-1238 Tidskriftsartikel (refereegranskat)abstract The nuclear receptor Nurr1 can be activated by RXR via heterodimerization (RXR-Nurr1) and is a promising target for treating neurodegenerative diseases. We herein report the enantioselective synthesis and SAR of sterically constricted benzofurans at RXR. The established SAR, using whole cell functional assays, lead to the full agonist 9a at RXR (pEC50 of 8.2) and RXR-Nurr1. The X-ray structure shows enantiomeric discrimination where 9a optimally addresses the ligand binding pocket of RXR.
24.	Wolff, Anette, et al. (författare) In vitro blood-brain barrier models : An overview of established models and new microfluidic approaches 2015 Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 104:9, s. 2727-2746 Tidskriftsartikel (refereegranskat)abstract The societal need for new central nervous system (CNS) medicines is substantial, because of the global increase in life expectancy and the accompanying increase in age-related CNS diseases. Low blood-brain barrier (BBB) permeability has been one of the major causes of failure for new CNS drug candidates. There has therefore been a great interest in cell models, which mimic BBB permeation properties. In this review, we present an overview of the performance of monocultured, cocultured, and triple-cultured primary cells and immortalized cell lines, including key parameters such as transendothelial electrical resistance values, permeabilities of paracellular flux markers, and expression of BBB-specific marker proteins. Microfluidic systems are gaining ground as a new automated technical platform for cell culture and systematic analysis. The performance of these systems was compared with current state-of-the-art models and it was noted that, although they show great promise, these systems have not yet reached beyond the proof-of-concept stage. In general, it was found that there were large variations in experimental protocols, BBB phenotype markers, and paracellular flux markers used. It is the author's opinion that the field may benefit greatly from developing standardized methodologies and initiating collaborative efforts on optimizing culture protocols.
25.	Aziz, Abdul Maruf Asif (författare) Neuropeptide Receptors as Treatment Targets in Alcohol Use Disorders 2017 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Alcohol use disorder (AUD) is a complex disorder with multiple pathophysiological processes contributing to the initiation, progression and development of the disease state. AUD is a chronic relapsing disease with escalation of alcohol-intake over time in repeated cycles of tolerance, abstinence and relapse and hence, it is very difficult to treat. There are only a few currently available treatments with narrow efficacy and variable patient response. Thus it is important to find new, more effective medications to increase the number of patients who can benefit from pharmacological treatment of AUD.The research presented in this thesis work focuses on the critical involvement of central neuropeptides in alcohol-related behaviors. The overall aim was to evaluate the nociceptin/orphanin FQ (NOP) receptor, the neuropeptide Y (NPY) Y2 receptor and the melanin-concentrating hormone (MCH) receptor 1 as novel and potential pharmacological treatment targets for AUD by testing the NOP receptor agonist SR-8993, the NPY-Y2 receptor antagonist CYM-9840 and the MCH1 receptor antagonist GW803430 in established animal models.In the first study (Paper I), the novel and selective NOP agonist SR-8993 was assessed in rat models of motivation to obtain alcohol and relapse to alcohol seeking behavior using the operant self-administration (SA) paradigm. Firstly, treatment with SR-8993 (1 mg/kg) showed a mildly anxiolytic effect and reversed acute alcohol withdrawal-induced “hangover” anxiety in the elevated plus-maze (EPM). Next, it potently attenuated alcohol SA and motivation to obtain alcohol in the progressive ratio responding (PRR) and reduced both alcohol cue-induced and yohimbine stress-induced reinstatement of alcohol seeking, without affecting the pharmacology and metabolism of alcohol nor other control behaviors. To extend these findings, SR-8993 was evaluated in escalated alcohol-intake in rats. Treatment with SR-8993 significantly suppressed alcohol-intake and preference in rats that were trained to consume high amounts of alcohol in the two-bottle free choice intermittent access (IA) paradigm. SR-8993 also blocked operant SA of alcohol in rats that showed robust escalation in operant alcohol SA following chronic IA exposure to alcohol.In the second study (Paper II), SR-8993 was further evaluated in a model for escalated alcohol-intake induced by long-term IA exposure to alcohol. The effect of previous experience on operant alcohol SA on two-bottle free choice preference drinking was evaluated and sensitivity to treatment with SR-8993 was tested in rats selected for escalated and non-escalated alcohol seeking behavior. We found that rats exposed to the combined SA-IA paradigm showed greater sensitivity to SR-8993 treatment. In addition, acute escalation of alcohol SA after a three-week period of abstinence was completely abolished by pretreatment with SR-8993.In the third study (Paper III), the effects of the novel, small molecule NPY-Y2 antagonist CYM-9840 were tested in operant alcohol SA, PRR which is a model for motivation to work for alcohol and reinstatement of alcohol-seeking behavior. Treatment with CYM-9840 (10 mg/kg) potently attenuated alcohol SA, progressive ratio responding and stress-induced reinstatement using yohimbine as the stressor, while alcohol cue-induced reinstatement was unaffected. Moreover, a range of control behaviors including taste sensitivity, locomotor and pharmacological sensitivity to the sedative effects of alcohol remained unaffected by CYM-9840 pretreatment, indicating that its effects are specific to the rewarding and motivational aspects of alcohol-intake and related behaviors. CYM-9840 also reversed acute alcohol withdrawal-induced “hangover” anxiety measured in the EPM and reduced alcohol-intake in the 4 hour limited access two-bottle free choice preference drinking model.Finally, in the fourth study (Paper IV), the selective MCH1-R antagonist GW803430 was tested in rat models of escalated alcohol-intake. Pretreatment with GW803430 (effective at 10 & 30 mg/kg) dose-dependently reduced alcohol and food-intake in rats that consumed high amounts of alcohol during IA, while it only decreased food-intake in rats that consumed low amounts of alcohol during IA, likely due to a floor effect. Upon protracted abstinence following IA, GW803430 significantly reduced operant alcohol SA and this was associated with adaptations in MCH and MCH1-R gene-expression. In contrast, GW803430 did not affect escalated alcohol SA induced by chronic alcohol vapor exposure and this was accompanied by no change in MCH or MCH1-R gene expression. Overall, these results suggest that the MCH1-R antagonist affects alcohol-intake through regulation of both motivation for caloric-intake and the rewarding properties of alcohol.In conclusion, our results suggest critical roles for these central neuropeptides in the regulation of anxiety and of alcohol reward, making them potential pharmacological targets in the treatment of AUD.
26.	Deming, Y., et al. (författare) The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk 2019 Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 11:505 Tidskriftsartikel (refereegranskat)abstract Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer's disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 obtained from the Alzheimer's Disease Neuroimaging Initiative. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with CSF sTREM2 concentrations (rs1582763; P = 1.15 x 10(-15)); this was replicated in independent datasets. The variants associated with increased CSF sTREM2 concentrations were associated with reduced AD risk and delayed age at onset of disease. The single-nucleotide polymorphism rs1582763 modified expression of the MS4A4A and MS4A6A genes in multiple tissues, suggesting that one or both of these genes are important for modulating sTREM2 production. Using human macrophages as a proxy for microglia, we found that MS4A4A and TREM2 colocalized on lipid rafts at the plasma membrane, that sTREM2 increased with MS4A4A overexpression, and that silencing of MS4A4A reduced sTREM2 production. These genetic, molecular, and cellular findings suggest that MS4A4A modulates sTREM2. These findings also provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk-variant carriers but also in those with sporadic disease.
27.	Guerreiro, R., et al. (författare) Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study 2018 Ingår i: Lancet Neurology. - 1474-4422. ; 17:1, s. 64-74 Tidskriftsartikel (refereegranskat)abstract Background Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson's disease, and Alzheimer's disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder. Methods In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected after participant examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also only in participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage. Findings This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2.40, 95% CI 2.14-2.70; p=1.05 x 10-48), SNCA (rs7681440; OR 0.73, 0.66-0.81; p=6.39 x 10(-10)), and GBA (rs35749011; OR 2.55, 1.88-3.46; p=1.78 x 10(-9)). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1.51, 1.27-1.79; p=2.32 x 10(-6)); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%. Interpretation Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease.
28.	Gustafsson, Gabriel, et al. (författare) Secretion and uptake of α-synuclein via extracellular vesicles in cultured cells 2018 Ingår i: Cellular and molecular neurobiology. - : Springer Science and Business Media LLC. - 0272-4340 .- 1573-6830. ; 38:8, s. 1539-1550 Tidskriftsartikel (refereegranskat)abstract In Parkinson’s disease and other Lewy body disorders, the propagation of pathology has been accredited to the spreading of extracellular α-synuclein (α-syn). Although the pathogenic mechanisms are not fully understood, cell-to-cell transfer of α-syn via exosomes and other extracellular vesicles (EVs) has been reported. Here, we investigated whether altered molecular properties of α-syn can influence the distribution and secretion of α-syn in human neuroblastoma cells. Different α-syn variants, including α-syn:hemi-Venus and disease-causing mutants, were overexpressed and EVs were isolated from the conditioned medium. Of the secreted α-syn, 0.1–2% was associated with vesicles. The major part of EV α-syn was attached to the outer membrane of vesicles, whereas a smaller fraction was found in their lumen. For α-syn expressed with N-terminal hemi-Venus, the relative levels associated with EVs were higher than for WT α-syn. Moreover, such EV-associated α-syn:hemi-Venus species were internalized in recipient cells to a higher degree than the corresponding free-floating forms. Among the disease-causing mutants, A53T α-syn displayed an increased association with EVs. Taken together, our data suggest that α-syn species with presumably lost physiological functions or altered aggregation properties may shift the cellular processing towards vesicular secretion. Our findings thus lend further support to the tenet that EVs can mediate spreading of harmful α-syn species and thereby contribute to the pathology in α-synucleinopathies.
29.	Hansson, Elisabeth, 1955, et al. (författare) Therapeutic innovation: Inflammatory-reactive astrocytes as targets of inflammation 2016 Ingår i: IBRO Reports. - : Elsevier BV. - 2451-8301. ; 1, s. 1-9 Tidskriftsartikel (refereegranskat)abstract This study aimed to test pharmaceutical compounds targeting astrocytes showing inflammatory dysregulation. The primary rat brain cultures were treated with different batches of serum with or without microglia added to make the cells inflammatory-reactive. Lipopolysaccharide (LPS) and tryptase were used as inflammatory inducers. Expression levels of Toll-like receptor 4 (TLR4), Na+/K+-ATPase, and matrix metalloprotease-13 (MMP-13), as well as actin filament organization, pro-inflammatory cytokines, and intracellular Ca2+ release, were evaluated. LPS combined with tryptase upregulated TLR4 expression, whereas Na+/K+-ATPase expression was downregulated, ATP-evoked Ca2+ transients were increased, actin filaments were reorganized and ring structures instead of stress fibers were observed. Other aims of the study were to prevent astrocytes from becoming inflammatory-reactive and to restore inflammatory dysregulated cellular changes. A combination of the μ-opioid antagonist (−)-naloxone in ultra-low concentrations, the non-addictive μ-opioid agonist (−)-linalool, and the anti-epileptic agent levetiracetam was examined. The results indicated that this drug cocktail prevented the LPS- and tryptase-induced inflammatory dysregulation. The drug cocktail could also restore the LPS- and tryptase-treated cells back to a normal physiological level in terms of the analyzed parameters. © 2016 The Author(s)
30.	Lilja, T, et al. (författare) Like a rolling histone: epigenetic regulation of neural stem cells and brain development by factors controlling histone acetylation and methylation 2013 Ingår i: Biochimica et biophysica acta. - : Elsevier BV. - 0006-3002 .- 0304-4165. ; 1830:2, s. 2354-2360 Tidskriftsartikel (refereegranskat)
31.	LoParo, D., et al. (författare) Rigorous Tests of Gene-Environment Interactions in a Lab Study of the Oxytocin Receptor Gene (OXTR), Alcohol Exposure, and Aggression 2016 Ingår i: American Journal of Medical Genetics Part B-Neuropsychiatric Genetics. - : Wiley. - 1552-4841. ; 171:5, s. 589-602 Tidskriftsartikel (refereegranskat)abstract Naturalistic studies of gene-environment interactions (G X E) have been plagued by several limitations, including difficulty isolating specific environmental risk factors from other correlated aspects of the environment, gene-environment correlation (r(GE)), and the use of a single genetic variant to represent the influence of a gene. We present results from 235 Finnish young men in two lab studies of aggression and alcohol challenge that attempt to redress these limitations of the extant G X E literature. Specifically, we use a latent variable modeling approach in an attempt to more fully account for genetic variation across the oxytocin receptor gene (OXTR) and to robustly test its main effects on aggression and its interaction with alcohol exposure. We also modeled aggression as a latent variable comprising various indices, including the average and maximum levels of aggression, the earliest trial on which aggression was expressed, and the proportion of trials on which the minimum and maximum levels of aggression were expressed. The best fitting model for the genetic variation across OXTR included six factors derived from an exploratory factor analysis, roughly corresponding to six haplotype blocks. Aggression levels were higher on trials in which participants were administered alcohol, won, or were provoked. There was a significant main effect of OXTR on aggression across studies after controlling for covariates. The interaction of OXTR and alcohol was also significant across studies, such that OXTR had stronger effects on aggression in the alcohol administration condition. (C) 2015 Wiley Periodicals, Inc.
32.	Merwood, Andrew, et al. (författare) Genetic associations between the ADHD symptom dimensions and Cloninger's temperament dimensions in adult twins 2013 Ingår i: European Neuropsychopharmacology. - Amsterdam, Netherlands : Elsevier. - 0924-977X .- 1873-7862. ; 23:6, s. 416-425 Tidskriftsartikel (refereegranskat)abstract Previous studies have identified phenotypic associations between Cloninger's temperament dimensions and the symptoms of attention deficit hyperactivity disorder (ADHD) in adults. However the underlying aetiology of these associations remains unclear. We investigate the extent to which genetic and environmental influences contribute to the relationship between temperament and ADHD, examining the ADHD symptoms of inattention (IA) and hyperactivity/impulsivity (HI) separately. Participants were 886 adult twin pairs aged 19-20 years. ADHD symptoms of IA and HI were measured using a DSM-IV based rating scale. Temperament was measured using Cloninger's Temperament and Character Inventory (TCI), across four dimensions: novelty seeking (NS), harm avoidance (HA), reward dependence (RD) and persistence (PS). The twin method was used to decompose phenotypic variance/covariance among these variables into genetic and environmental components. We found that NS was genetically associated with both ADHD symptom dimensions (IA and HI), but that HA was genetically associated with IA only. There was also some evidence of genetic association between PS, IA and HI. These findings suggest that unique profiles of temperament are genetically related to the two ADHD symptom dimensions in adults. Further work is now needed to elucidate the mechanisms that underlie both the combined and separate symptom factor domains of ADHD.
33.	Rostami, Elham, 1979-, et al. (författare) On acute gene expression changes after ventral root replantation. 2011 Ingår i: Frontiers in Neurology. - : Frontiers Media SA. - 1664-2295. ; 4:1, s. 159- Tidskriftsartikel (refereegranskat)
34.	Tour, Jeanette, et al. (författare) Gene-to-gene interactions regulate endogenous pain modulation in fibromyalgia patients and healthy controls-antagonistic effects between opioid and serotonin-related genes. 2017 Ingår i: Pain. - : Ovid Technologies (Wolters Kluwer Health). - 0304-3959 .- 1872-6623. ; 158:7, s. 1194-1203 Tidskriftsartikel (refereegranskat)abstract Chronic pain is associated with dysfunctional endogenous pain modulation, involving both central opioid and serotonergic (5-HT) signaling. Fibromyalgia (FM) is a chronic pain syndrome, characterized by widespread musculoskeletal pain and reduced exercise-induced hypoalgesia (EIH). In this study, we assessed the effects of 3 functional genetic polymorphisms on EIH in 130 patients with FM and 132 healthy controls. Subjects were genotyped regarding the mu-opioid receptor (OPRM1) gene (rs1799971), the serotonin transporter (5-HTT) gene (5-HTTLPR/rs25531), and the serotonin-1a receptor (5-HT1a) gene (rs6296). The patients with FM had increased pain sensitivity and reduced EIH compared with healthy controls. None of the polymorphisms had an effect on EIH on their own. We found significant gene-to-gene interactions between OPRM1 x 5-HTT and OPRM1 x 5-HT1a regarding activation of EIH, with no statistically significant difference between groups. Better EIH was found in individuals with genetically inferred strong endogenous opioid signaling (OPRM1 G) in combination with weak 5-HT tone (5-HTT low/5-HT1a G), compared with strong 5-HT tone (5-HTT high/5-HT1a CC). Based on the proposed mechanisms of these genetic variants, the findings indicate antagonistic interactions between opioid and serotonergic mechanisms during EIH. Moreover, despite different baseline pain level, similar results were detected in FM and controls, not supporting an altered interaction between opioid and 5-HT mechanisms as the basis for dysfunction of EIH in patients with FM. In summary, our results suggest that, by genetic association, the mu-opioid receptor interacts with 2 major serotonergic structures involved in 5-HT reuptake and release, to modulate EIH.
35.	Vizlin-Hodzic, Dzeneta, et al. (författare) Early onset of inflammation during ontogeny of bipolar disorder: the NLRP2 inflammasome gene distinctly differentiates between patients and healthy controls in the transition between iPS cell and neural stem cell stages 2017 Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 7:1 Tidskriftsartikel (refereegranskat)abstract Neuro-inflammation and neuronal communication are considered as mis-regulated processes in the aetiology and pathology of bipolar disorder (BD). Which and when specific signal pathways become abnormal during the ontogeny of bipolar disorder patients is unknown. To address this question, we applied induced pluripotent stem cell (iPSC) technology followed by cortical neural differentiation on adipocyte-derived cells from BD type I patients (with psychotic episodes in psychiatric history) and healthy volunteers (controls). RNA sequencing in iPSC and cortical neural stem cell (NSC) lines were used to examine alterations between the transcriptomes from BD I and control samples during transition from the pluripotent stage towards the neural developmental stage. At the iPSC stage, the most highly significant differentially expressed gene (DEG) was the NLRP2 inflammasome (P = 2.66 × 10-10). Also among 42 DEGs at the NSC stage, NLRP2 showed the strongest statistical significance (P = 3.07 × 10-19). In addition, we have also identified several cytoskeleton-associated genes as DEGs from the NSC stage, such as TMP2, TAGLN, and ACTA2; the former two genes are recognised for the first time to be associated with BD. Our results also suggest that iPSC-derived BD-cortical NSCs carry several abnormalities in dopamine and GABA receptor canonical pathways, underlining that our in vitro BD model reflects pathology in the CNS. This would indicate that mis-regulated gene expression of inflammatory, neurotransmitter, and cytoskeletal signalling occurs during early foetal brain development of BD I patients.
36.	Yusof, Siti R, et al. (författare) Rate and extent of mitragynine and 7-hydroxymitragynine blood-brain barrier transport and their intra-brain distribution : the missing link in pharmacodynamic studies 2019 Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 24:5, s. 935-945 Tidskriftsartikel (refereegranskat)abstract Mitragyna speciosa is reported to be beneficial for the management of chronic pain and opioid withdrawal in the evolving opioid epidemic. Data on the blood-brain barrier (BBB) transport of mitragynine and 7-hydroxymitragynine, the active compounds of the plant, are still lacking and inconclusive. Here, we present for the first time the rate and the extent of mitragynine and 7-hydroxymitragynine transport across the BBB, with an investigation of their post-BBB intra-brain distribution. We utilized an in vitro BBB model to study the rate of BBB permeation of the compounds and their interaction with efflux transporter P-glycoprotein (P-gp). Mitragynine showed higher apical-to-basolateral (A-B, i.e. blood-to-brain side) permeability than 7-hydroxymitragynine. 7-Hydroxymitragynine showed a tendency to efflux, with efflux ratio (B-A/A-B) of 1.39. Both were found to inhibit the P-gp and are also subject to efflux by the P-gp. Assessment of the extent of BBB transport in vivo in rats from unbound brain to plasma concentration ratios (Kp,uu,brain ) revealed extensive efflux of both compounds, with less than 10 percent of unbound mitragynine and 7-hydroxymitragynine in plasma crossing the BBB. By contrast, the extent of intra-brain distribution was significantly different, with mitragynine having 18-fold higher brain tissue uptake in brain slice assay compared with 7-hydroxymitragynine. Mitragynine showed a moderate capacity to accumulate inside brain parenchymal cells, while 7-hydroxymitragynine showed restricted cellular barrier transport. The presented findings from this systematic investigation of brain pharmacokinetics of mitragynine and 7-hydroxymitragynine are essential for design and interpretation of in vivo experiments aiming to establish exposure-response relationship.
37.	Zetterberg, Madeleine, 1969, et al. (författare) Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) S18Y polymorphism in Alzheimer's disease. 2010 Ingår i: Molecular neurodegeneration. - : Springer Science and Business Media LLC. - 1750-1326. ; 5 Tidskriftsartikel (refereegranskat)abstract ABSTRACT: Alzheimer's disease (AD) is characterized by protein aggregates, i.e. senile plaques and neurofibrillary tangles. The ubiquitin-proteasome system has been proposed a role in proteolytic removal of these protein aggregates. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a de-ubiquitinating enzyme with important functions in recycling of ubiquitin. The S18Y polymorphism of the UCHL1 gene confers protection against Parkinson's disease. In this study, the genotype and allele frequencies of the UCHL1 S18Y polymorphism were investigated in 452 AD patients and 234 control subjects, recruited from four memory clinics in Sweden. Using a binary logistic regression model including UCHL1 allele A and APOE epsilon4 allele positivity, age and sex as covariates with AD diagnosis as dependent variable, an adjusted OR of 0.82 ([95% CI 0.55-1.24], P = 0.35) was obtained for a positive UCHL1 allele A carrier status. The present study thus do not support a protective effect of the UCHL1 S18Y polymorphism against AD.
38.	Munthe, Christian, 1962, et al. (författare) The Return of Lombroso? Ethical Aspects of (Visions of) Preventive Forensic Screening 2015 Ingår i: Public Health Ethics. - : Oxford University Press (OUP). - 1754-9973 .- 1754-9981. ; 8:3, s. 270-283 Tidskriftsartikel (refereegranskat)abstract The vision of legendary criminologist Cesare Lombroso to use scientific theories of individual causes of crime as a basis for screening and prevention programmes targeting individuals at risk for future criminal behaviour has resurfaced, following advances in genetics, neuroscience and psychiatric epidemiology. This article analyses this idea and maps its ethical implications from a public health ethical standpoint. Twenty-seven variants of the new Lombrosian vision of forensic screening and prevention are distinguished, and some scientific and technical limitations are noted. Some lures, biases and structural factors, making the application of the Lombrosian idea likely in spite of weak evidence are pointed out and noted as a specific type of ethical aspect. Many classic and complex ethical challenges for health screening programmes are shown to apply to the identified variants and the choice between them, albeit with peculiar and often provoking variations. These variations are shown to actualize an underlying theoretical conundrum in need of further study, pertaining to the relationship between public health ethics and the ethics and values of criminal law policy.
39.	Abbas, Abdul-Karim, 1959, et al. (författare) Pharmacological characteristics of protein synthesis inhibitors by radioactive leucine incorporation in rat hippocampal slices: experimental evidence and pre-clinical implications 2011 Ingår i: The 23rd Biennial Meeting of the International Society for Neurochemistry (ISN), August 28-September 1 2011, Athens, Greece. Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract Protein synthesis inhibitors (PSIs) constitute a major tool to validate the hypothesis of protein synthesis-dependent phase of synaptic plasticity and memory consolidation. However, several reports have showed inconsistent findings about the effect of these drugs on behavioral learning and synaptic plasticity. Testing the potencies of these drugs is hence crucial for validating such negative findings and in planning future studies. It is also necessary to examine the dose dependence, onset dynamics and reversibility, and possible effects on basal proteins. Here we used the labeled leucine as marker for the newly synthesized proteins. The fraction of leucine incorporation, following 50 min of pre-incubation, was compared between two groups of slices: a PSI-treated and a control group. Both anisomycin and cycloheximide revealed a dose-dependent but time-independent manner of inhibition reaching over 92% at concentrations well below those used in previous experiments which revealed effects on synaptic plasticity and learning. Surprisingly, washout of a “reversible” inhibitor, anisomycin was not followed by rapid reversibility of the action of the drug, the case that differs with cycloheximide. Interestingly, emetine revealed a time-dependent inhibition of protein synthesis, where levels above 80% needed drug pre-incubation for as long as 90 min. Since the duration of labeling relates to the half-life of the proteins, short-time labeling as used in this study will result in radioactivity incorporation into short-lived proteins and proteins that are synthesized in large quantities. We therefore studied the availability of newly synthesized proteins at 8-10 h following leucine incorporation. The results revealed virtually the same protein content as in slices retrieved for analysis immediately following the labeling period, indicating that the main pool of the newly synthesized proteins is of intracellular long-lived pool. This likely reflects a stable metabolic state of our prepared slices. These findings challenge current idea on the role of de novo protein synthesis in synaptic plasticity as well as brain changes underlying several neurological and psychiatric disorders.
40.	Jiao, K, et al. (författare) Efficacy of PARP inhibition in Pde6a mutant mouse models for retinitis pigmentosa depends on the quality and composition of individual human mutations 2016 Ingår i: Cell death discovery. - : Springer Science and Business Media LLC. - 2058-7716. ; 2 Tidskriftsartikel (refereegranskat)abstract Retinitis pigmentosa (RP), an inherited blinding disease, is caused by a variety of different mutations that affect retinal photoreceptor function and survival. So far there is neither effective treatment nor cure. We have previously shown that poly(ADP-ribose)polymerase (PARP) acts as a common and critical denominator of cell death in photoreceptors, qualifying it as a potential target for future therapeutic intervention. A significant fraction of RP-causing mutations affect the genes for the rod photoreceptor phosphodiesterase 6A (PDE6A) subunit, but it is not known whether they all engage the same death pathway. Analysing three homozygous point mutations (Pde6a R562W, D670G, and V685M) and one compound heterozygous Pde6a (V685M/R562W) mutation in mouse models that match human RP patients, we demonstrate excessive activation of PARP, which correlated in time with the progression of photoreceptor degeneration. The causal involvement of PARP activity in the neurodegenerative process was confirmed in organotypic retinal explant cultures treated with the PARP-selective inhibitor PJ34, using different treatment time-points and durations. Remarkably, the neuroprotective efficacy of PARP inhibition correlated inversely with the strength of the genetically induced insult, with the D670G mutant showing the best treatment effects. Our results highlight PARP as a target for neuroprotective interventions in RP caused by PDE6A mutations and are a first attempt towards personalized, genotype-matched therapy development for RP. In addition, for each of the different mutant situations, our work identifies windows of opportunity for an optimal treatment regimen for further in vivo experimentation and possibly clinical studies.
41.	Osman, Ayman (författare) Autophagy in Peripheral Neuropathy 2017 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Peripheral neuropathy includes a wide range of diseases affecting millions around the world, and many of these diseases have unknown etiology. Peripheral neuropathy in diabetes represents a large proportion of peripheral neuropathies. Nerve damage can also be caused by trauma. Peripheral neuropathies are a significant clinical problem and efficient treatments are largely lacking. In the case of a transected nerve, different methods have been used to repair or reconstruct the nerve, including the use of nerve conduits, but functional recovery is usually poor.Autophagy, a cellular mechanism that recycles damaged proteins, is impaired in the brain in many neurodegenerative diseases affecting animals and humans. No research, however, has investigated the presence of autophagy in the human peripheral nervous system. In this study, I present the first structural evidence of autophagy in human peripheral nerves. I also show that the density of autophagy structures is higher in peripheral nerves of patients with chronic idiopathic axonal polyneuropathy (CIAP) and inflammatory neuropathy than in controls. The density of these structures increases with the severity of the neuropathy.In animal model, using Goto-Kakizaki (GK) rats with diabetes resembling human type 2 diabetes, activation of autophagy by local administration of rapamycin incorporated in collagen conduits that were used for reconnection of the transected sciatic nerve led to an increase in autophagy proteins LC3 and a decrease in p62 suggesting that the autophagic flux was activated. In addition, immunoreactivity of neurofilaments, which are parts of the cytoskeleton of axons, was increased indicating increased axonal regeneration. I also show that many proteins involved in axonal regeneration and cell survival were up-regulated by rapamycin in the injured sciatic nerve of GK rats four weeks after injury.Taken together, these findings provide new knowledge about the involvement of autophagy in neuropathy and after peripheral nerve injury and reconstruction using collagen conduits.
42.	Xu, Bo, 1980- (författare) Evolutionary and Pharmacological Studies of NPY and QRFP Receptors 2014 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract The neuropeptide Y (NPY) system consists of 3-4 peptides and 4-7 receptors in vertebrates. It has powerful effects on appetite regulation and is involved in many other biological processes including blood pressure regulation, bone formation and anxiety. This thesis describes studies of the evolution of the NPY system by comparison of several vertebrate species and structural studies of the human Y2 receptor, which reduces appetite, to identify amino acid residues involved in peptide-receptor interactions.The NPY system was studied in zebrafish (Danio rerio), western clawed frog (Xenopus tropicalis), and sea lamprey (Petromyzon marinus). The receptors were cloned and functionally expressed and their pharmacological profiles were determined using the native peptides in either binding studies or a signal transduction assay. Some peptide-receptor preferences were observed, indicating functional specialization.A receptor family closely related to the NPY receptors, called the QRFP receptors, was investigated. A QRFP receptor was cloned from amphioxus, Branchistoma floridae, showing that the receptor arose before the origin of the vertebrates. Evolutionary studies demonstrated that the ancestral vertebrate had as many as four QRFP receptors, only one of which remains in mammals today. This correlates with the NPY receptor family, located in the same chromosomal regions, which had seven members in the ancestral vertebrate but only 4-5 in living mammals. Some vertebrates have considerably more complex NPY and QRFP receptor systems than humans and other mammals.Two studies investigated interactions of NPY-family peptides with the human Y2 receptor. Candidate residues, selected based on structural modeling and docking, were mutated to disrupt possible interactions with peptide ligands. The modified receptors were expressed in cultured cells and investigated by measuring binding and functional responses. Several receptor residues were found to influence peptide-receptor interactions, some of which are involved in maintaining receptor structure. In a pilot study, the kinetics of peptide-receptor interaction were found to be very slow, of the order several hours.In conclusion, this thesis clarifies evolutionary relationships for the complex NPY and QRFP peptide-receptor systems and improves the structural models of the human NPY-family receptors, especially Y2. These results will hopefully facilitate drug design for targeting of NPY-family receptors.
43.	Nyberg, Lars, et al. (författare) Longitudinal evidence for diminished frontal-cortex function in aging 2010 Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 107:52, s. 22682-22686 Tidskriftsartikel (refereegranskat)abstract Cross-sectional estimates of age-related changes in brain structure and function were compared with 6-y longitudinal estimates. The results indicated increased sensitivity of the longitudinal approach as well as qualitative differences. Critically, the cross-sectional analyses were suggestive of age-related frontal overrecruitment, whereas the longitudinal analyses revealed frontal underrecruitment with advancing age. The cross-sectional observation of overrecruitment reflected a select elderly sample. However, when followed over time, this sample showed reduced frontal recruitment. These findings dispute inferences of true age changes on the basis of age differences, hence challenging some contemporary models of neurocognitive aging, and demonstrate age-related decline in frontal brain volume as well as functional response.
44.	Salami, Alireza, et al. (författare) Age-related white matter microstructural differences partly mediate age-related decline in processing speed but not cognition 2012 Ingår i: Biochimica et Biophysica Acta - Molecular Basis of Disease. - : Elsevier. - 0925-4439 .- 1879-260X. ; 1822:3, s. 408-415 Tidskriftsartikel (refereegranskat)abstract Aging is associated with declining cognitive performance as well as structural changes in brain gray and white matter (WM). The WM deterioration contributes to a disconnection among distributed brain networks and may thus mediate age-related cognitive decline. The present diffusion tensor imaging (DTI) study investigated age-related differences in WM microstructure and their relation to cognition (episodic memory, visuospatial processing, fluency, and speed) in a large group of healthy subjects (n = 287) covering 6 decades of the human life span. Age related decreases in fractional anisotropy (FA) and increases in mean diffusivity (MD) were observed across the entire WM skeleton as well as in specific WM tracts, supporting the WM degeneration hypothesis. The anterior section of the corpus callosum was more susceptible to aging compared to the posterior section, lending support to the anterior-posterior gradient of WM integrity in the corpus callosum. Finally, and of critical interest. WM integrity differences were found to mediate age-related reductions in processing speed but no significant mediation was found for episodic memory, visuospatial ability, or fluency. These findings suggest that compromised WM integrity is not a major contributing factor to declining cognitive performance in normal aging. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.
45.	Andreasson, K. I., et al. (författare) Targeting innate immunity for neurodegenerative disorders of the central nervous system 2016 Ingår i: Journal of Neurochemistry. - : Wiley. - 0022-3042. ; , s. 653-693 Tidskriftsartikel (refereegranskat)abstract Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7–9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview of physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, and concluded by a presentation of technical challenges and solutions when working with microglia and astrocyte cultures. Microglial ontogeny and induced pluripotent stem cell-derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimer's disease are further contributions to this article. (Figure presented.) Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7–9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer's disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview on physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, and concluded by a presentation of technical challenges and solutions when working with microglia cultures. Microglial ontogeny and induced pluripotent stem cell-derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimer's disease are further contributions to this article. © 2016 International Society for Neurochemistry
46.	Bergman, Petra, et al. (författare) Next-generation sequencing identifies microRNAs that associate with pathogenic autoimmune neuroinflammation in rats. 2013 Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 190:8, s. 4066-75 Tidskriftsartikel (refereegranskat)abstract MicroRNAs (miRNAs) are known to regulate most biological processes and have been found dysregulated in a variety of diseases, including multiple sclerosis (MS). In this study, we characterized miRNAs that associate with susceptibility to develop experimental autoimmune encephalomyelitis (EAE) in rats, a well-established animal model of MS. Using Illumina next-generation sequencing, we detected 544 miRNAs in the lymph nodes of EAE-susceptible Dark Agouti and EAE-resistant Piebald Virol Glaxo rats during immune activation. Forty-three miRNAs were found differentially expressed between the two strains, with 81% (35 out of 43) showing higher expression in the susceptible strain. Only 33% of tested miRNAs displayed differential expression in naive lymph nodes, suggesting that a majority of regulated miRNAs are EAE dependent. Further investigation of a selected six miRNAs indicates differences in cellular source and kinetics of expression. Several of the miRNAs, including miR-146a, miR-21, miR-181a, miR-223, and let-7, have previously been implicated in immune system regulation. Moreover, 77% (33 out of 43) of the miRNAs were associated with MS and other autoimmune diseases. Target genes likely regulated by the miRNAs were identified using computational predictions combined with whole-genome expression data. Differentially expressed miRNAs and their targets involve functions important for MS and EAE, such as immune cell migration through targeting genes like Cxcr3 and cellular maintenance and signaling by regulation of Prkcd and Stat1. In addition, we demonstrated that these three genes are direct targets of miR-181a. Our study highlights the impact of multiple miRNAs, displaying diverse kinetics and cellular sources, on development of pathogenic autoimmune inflammation.
47.	Boij, Roland, 1952- (författare) Aspects of inflammation, angiogenesis and coagulation in preeclampsia 2016 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Preeclampsia is a major challenge to obstetricians, due to its impact on maternal and fetal morbidity and mortality and the lack of preventive and treatment strategies. The overall aim of this thesis is to increase the knowledge of the pathogenesis of preeclampsia including the role of inflammation, angiogenesis and coagulation, both locally at the fetomaternal interface and in the maternal circulation. Uncompensated maternal endothelial inflammatory responses to factors from stressed trophoblasts seem to be a major contributor to the syndrome, together with an imbalance in angiogenesis and an activated coagulation system. An increasing amount of data indicates an involvement of the immune system with defect tolerance to the conceptus as an integral part of the pathogenesis, at least in early-onset preeclampsia (EOP).We showed that a single administration of human preeclampsia serum in pregnant IL-10−/− mice induced the full spectrum of preeclampsia-like symptoms including hypoxic injury in uteroplacental tissues and endotheliosis in maternal kidneys. Importantly, preeclampsia serum, as early as 12 to 14 weeks of gestation, disrupted cross talk between trophoblasts and endothelial cells in an in vitro model of endovascular activity (Tube formation test). These results indicate that preeclamptic sera can be used to better understand the pathophysiology and to predict the disorder. Preeclampsia has been associated with increased inflammation, aberrant angiogenesis and activated coagulation, but their correlation and relative contribution are unknown. We found that markers for all these mechanisms were independently associated with preeclampsia. Cytokines, chemokines, and complement factors seem all to be part of a Th1-associated inflammatory reaction in preeclampsia, more pronounced in EOP than in late-onset preeclampsia (LOP), in line with a more homogeneous pathogenesis in EOP as based on placental pathology. In women with intrauterine growth restriction (IUGR), with an anticipated pathologic placentation, only differences in levels for sFlt-1 and PlGF were found in comparison with mothers without IUGR. Thus, sFlt-1 and PlGF seem to be indicators of placental pathology, while other biomarkers might also reflect maternal endothelial pathology. Chemokines, in contrast to cytokines, may prove to be useful markers in preeclampsia.A deficiency in regulatory T (Treg) cells causing reduced immune regulatory capacity has been proposed in preeclampsia. Utilizing recent advances in flow cytometry phenotyping, we found no major alterations in circulating Treg numbers in preeclamptic women compared with normal pregnant and non-pregnant women. However, preeclampsia was associated with increased fractions of CTLA-4+ and CCR4+ cells within Treg subpopulations, which is in line with a migratory defect of Treg cells, and potentially associated with a reduced number of suppressive Treg cells at the fetomaternal interface. As we found that corticosteroid treatment affected the results, it should be accounted for in studies of EOP. Chemokines are supposed to be part of the immune adaptation in pregnancy. We found a decreased expression of CCL18 (Th2/Tregassociated), in trophoblasts from preeclamptic compared to normal pregnant women, indicating a local regulatory defect in preeclampsia, in line with our finding of a possible migratory defect of circulating Treg cells. Due to increased expression of CCL20 (Th17) and CCL22 (Th2) in first trimester placenta and increased circulating levels of CXCL10 (Th1) and CCL20 (Th17) in third trimester preeclamptic women, we suggest that CCL20 and CCL22 may be important for implantation and early placentation while in third trimester of a preeclamptic pregnancy CXCL10 and CCL20 mainly mirror maternal increased endothelial inflammation and aberrant angiogenesis. In summary, we found that preeclampsia is associated with increased inflammation, aberrant angiogenesis and activated coagulation, caused by placental factors in maternal peripheral circulation, more pronounced in the early-onset form of preeclampsia. It also appears that there is a defective modulation of the immune system in preeclamptic pregnancies. The results provide a better understanding of the pathogenesis of preeclampsia and have given suggestions to predictive markers for preeclampsia in the future.
48.	Fuks, Jonas M, et al. (författare) GABAergic Signaling Is Linked to a Hypermigratory Phenotype in Dendritic Cells Infected by Toxoplasma gondii 2012 Ingår i: PLoS pathogens. - : Public Library of Science (PLoS). - 1553-7374. ; 8:12, s. e1003051- Tidskriftsartikel (refereegranskat)abstract During acute infection in human and animal hosts, the obligate intracellular protozoan Toxoplasma gondii infects a variety of cell types, including leukocytes. Poised to respond to invading pathogens, dendritic cells (DC) may also be exploited by T. gondii for spread in the infected host. Here, we report that human and mouse myeloid DC possess functional γ-aminobutyric acid (GABA) receptors and the machinery for GABA biosynthesis and secretion. Shortly after T. gondii infection (genotypes I, II and III), DC responded with enhanced GABA secretion in vitro. We demonstrate that GABA activates GABA(A) receptor-mediated currents in T. gondii-infected DC, which exhibit a hypermigratory phenotype. Inhibition of GABA synthesis, transportation or GABA(A) receptor blockade in T. gondii-infected DC resulted in impaired transmigration capacity, motility and chemotactic response to CCL19 in vitro. Moreover, exogenous GABA or supernatant from infected DC restored the migration of infected DC in vitro. In a mouse model of toxoplasmosis, adoptive transfer of infected DC pre-treated with GABAergic inhibitors reduced parasite dissemination and parasite loads in target organs, e.g. the central nervous system. Altogether, we provide evidence that GABAergic signaling modulates the migratory properties of DC and that T. gondii likely makes use of this pathway for dissemination. The findings unveil that GABA, the principal inhibitory neurotransmitter in the brain, has activation functions in the immune system that may be hijacked by intracellular pathogens.
49.	Gallini, Radiosa, et al. (författare) Isoform-Specific Modulation of Inflammation Induced by Adenoviral Mediated Delivery of Platelet-Derived Growth Factors in the Adult Mouse Heart 2016 Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:8 Tidskriftsartikel (refereegranskat)abstract Platelet-derived growth factors (PDGFs) are key regulators of mesenchymal cells in vertebrate development. To what extent PDGFs also exert beneficial homeostatic or reparative roles in adult organs, as opposed to adverse fibrogenic responses in pathology, are unclear. PDGF signaling plays critical roles during heart development, during which forced overexpression of PDGFs induces detrimental cardiac fibrosis; other studies have implicated PDGF signaling in post-infarct myocardial repair. Different PDGFs may exert different effects mediated through the two PDGF receptors (PDGFR alpha and PDGFR beta) in different cell types. Here, we assessed responses induced by five known PDGF isoforms in the adult mouse heart in the context of adenovirus vector-mediated inflammation. Our results show that different PDGFs have different, in some cases even opposing, effects. Strikingly, whereas the major PDGFRa agonists (PDGF-A and -C) decreased the amount of scar tissue and increased the numbers of PDGFR alpha-positive fibroblasts, PDGFR beta agonists either induced large scars with extensive inflammation (PDGF-B) or dampened the adenovirusinduced inflammation and produced a small and dense scar (PDGF-D). These results provide evidence for PDGF isoform-specific inflammation-modulating functions that may have therapeutic implications. They also illustrate a surprising complexity in the PDGF-mediated pathophysiological responses.
50.	Lundberg, Marcus (författare) Characterization of the Pancreas in Type 1 and Type 2 Diabetes 2018 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Diabetes is recognized by hyperglycaemia and polyuria. Complications, reduced quality of life and staggering health-care costs are all derived from the disease. Two subclasses of diabetes are Type 1 diabetes (T1D) and Type 2 diabetes (T2D). The beta cell mass is reduced in T1D, which is generally considered to be caused by an immune-mediated beta-cell destruction, but definitive evidence for this hypothesis remains absent. Development of insulin resistance and dysfunctional beta cells are commonly recognized as important factors that contribute to fulminant T2D. The literature that describes human T1D and T2D pancreata is sparse due to the limited number of specimens available for study. If more features of the respective pancreata are described, we might be able to elucidate the mechanisms involved in the pathoaetiology of the diseases.Accordingly, in this thesis pancreatic biopsies obtained from subjects with T1D or T2D have been examined with the aim to provide a more comprehensive picture of the respective pancreata. Paper I reports that aggregates of leucocytes substantiated mostly by macrophages are present in several T2D pancreata. Furthermore, as 28% of the T2D pancreata met the consensus definition of insulitis developed for T1D, a redefinition of insulitis is proposed. In Paper II, the density of parasympathetic axons was found to be reduced in the exocrine compartment in recent-onset T1D subjects compared to non-diabetic and long-standing T1D subjects. However, no alteration was discovered in islet-associated parasympathetic axons. In Paper III, interferon-stimulated genes were found to be over-expressed in recent-onset T1D islets, but no inducer explaining this expression has been discovered. Paper IV shows that T2D islets exhibit a stress response on a transcriptional level, and expression of these genes were investigated in islets from subjects with elevated HbA1c levels but without a clinical T2D diagnosis.In conclusion, this thesis explores several new areas of the pancreas in both T1D and T2D, and demonstrate several important findings that increase our knowledge on how diabetes develops.

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