Angiotensin IV (Ang IV), a metabolite of Angiotensin II, is a bioactive hexapeptide that inhibits the insulin-regulated aminopeptidase (IRAP). This transmembrane zinc metallopeptidase with many ...biological functions has in recent years emerged as a new pharmacological target. IRAP is expressed in a variety of tissues and can be found in high density in the hippocampus and neocortex, brain regions associated with cognition. Ang IV is known to improve memory tasks in experimental animals. One of the most potent IRAP inhibitors known today is the macrocyclic compound HA08 that is significantly more stable than the endogenous Ang IV. HA08 combines structural elements from Ang IV and the physiological substrates oxytocin and vasopressin, and binds to the catalytic site of IRAP. In the present study we evaluate whether HA08 can restore cell viability in rat primary cells submitted to hydrogen peroxide damage. After damaging the cells with hydrogen peroxide and subsequently treating them with HA08, the conceivable restoring effects of the IRAP inhibitor were assessed. The cellular viability was determined by measuring mitochondrial activity and lactate dehydrogenase (LDH) release. The mitochondrial activity was significantly higher in primary hippocampal cells, whereas the amount of LDH was unaffected. We conclude that the cell viability can be restored in this cell type by blocking IRAP with the potent macrocyclic inhibitor HA08, although the mechanism by which HA08 exerts its effects remains unclear.
Anxiety disorders affect up to one third of the population. Caffeine, an adenosine receptor antagonist, is thought to have a dose-dependent effect on anxiety. We recently showed that a high dose of ...caffeine (50 mg/kg) differentially affected anxiety-like behavior in rats with high or low baseline anxiety-like behavior, replicating findings using relatively high doses in human patient samples. It is not known if low doses of caffeine have similar effects. The elevated plus maze (EPM) was used to categorize male Wistar rats (13 weeks of age) into groups of high or low anxiety-like behavior. Behavior was evaluated using the multivariate concentric square field (MCSF) test and the EPM after a low 10 mg/kg dose of caffeine. Multivariate data analysis demonstrated that caffeine decreased the differences between the high and low anxiety group, whereas the separation remained for the high and low control groups. For the caffeine treated rats, univariate statistics showed an increase in parameters regarding activity in the EPM and duration in the slope of the MCSF. Regarding risk-taking, shelter-seeking, and exploratory behavior, caffeine did not affect the groups differently. In conclusion, these results demonstrate increased activity in the caffeine-treated rats, together with a potentially anxiolytic effect and increased impulsivity that did not differ between the baseline anxiety groups. In contrast to high caffeine doses, a low dose does not generally affect rats with high anxiety at baseline differently than rats with low anxiety-like behavior. Further studies are warranted to fully elucidate the effects of caffeine in anxiety.
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•Rats were categorized as having a high or low anxiety-like behavior using EPM.•Low dose of caffeine seems to diminish the difference in baseline anxiety.•Low dose caffeine increased open arm time in rats with low baseline anxiety.•Caffeine alters the behavioral profile in male rats.
Anxiety disorders are common psychiatric conditions with a partially elucidated neurobiology. Caffeine, an unspecific adenosine receptor antagonist, is a common psychostimulant with anxiogenic ...effects in sensitive individuals. High doses of caffeine produce anxiety-like behavior in rats but it is not known if this is specific for rats with high baseline anxiety-like behavior. Thus, the aim of this study was to investigate general behavior, risk-taking, and anxiety-like behavior, as well as mRNA expression (adenosine A2A and A1, dopamine D2, and, μ, κ, δ opioid, receptors, BDNF, c-fos, IGF-1) in amygdala, caudate putamen, frontal cortex, hippocampus, hypothalamus, after an acute dose of caffeine. Untreated rats were screened using the elevated plus maze (EPM), giving each rat a score on anxiety-like behavior based on their time spent in the open arms, and categorized into a high or low anxiety-like behavior group accordingly. Three weeks after categorization, the rats were treated with 50 mg/kg caffeine and their behavior profile was studied in the multivariate concentric square field (MCSF) test, and one week later in the EPM. qPCR was performed on selected genes and corticosterone plasma levels were measured using ELISA. The results demonstrated that the high anxiety-like behavior rats treated with caffeine spent less time in risk areas of the MCSF and resituated towards the sheltered areas, a behavior accompanied by lower mRNA expression of adenosine A2A receptors in caudate putamen and increased BDNF expression in hippocampus. These results support the hypothesis that caffeine affects individuals differently depending on their baseline anxiety-like behavior, possibly involving adenosine receptors. This highlights the importance of adenosine receptors as a possible drug target for anxiety disorders, although further research is needed to fully elucidate the neurobiological mechanisms of caffeine on anxiety disorders.
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•Rats with high or low anxiety-like behavior respond differently to caffeine.•Caffeine reduced risk-taking behavior in rats with a high anxiety-like behavior.•Striatal A2A expression differs in rats with high or low anxiety-like behavior.•Caffeine increased BDNF in hippocampus in rats with a high anxiety-like behavior.
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•Structurally different anabolic steroids exhibit diverse neurotoxic properties.•Trenbolone, testosterone, and nandrolone reduce neurite outgrowth.•Trenbolone downregulates the Tubb3 ...gene expression and decreases cell viability.•Altered neurons may contribute to the mental health problems seen in AAS users.
The illicit use of anabolic androgenic steroids (AAS) among adolescents and young adults is a major concern due to the unknown and unpredictable impact of AAS on the developing brain and the consequences of this on mental health, cognitive function and behaviour. The present study aimed to investigate the effects of supra-physiological doses of four structurally different AAS (testosterone, nandrolone, stanozolol and trenbolone) on neurite development and cell viability using an in vitro model of immature primary rat cortical cell cultures. A high-throughput screening image-based approach, measuring the neurite length and number of neurons, was used for the analysis of neurite outgrowth. In addition, cell viability and expression of the Tubb3 gene (encoding the protein beta-III tubulin) were investigated. Testosterone, nandrolone, and trenbolone elicited adverse effects on neurite outgrowth as deduced from an observed reduced neurite length per neuron. Trenbolone was the only AAS that reduced the cell viability as indicated by a decreased number of neurons and declined mitochondrial function. Moreover, trenbolone downregulated the Tubb3 mRNA expression. The adverse impact on neurite development was neither inhibited nor supressed by the selective androgen receptor (AR) antagonist, flutamide, suggesting that the observed effects result from another mechanism or mechanisms of action that are operating apart from AR activation. The results demonstrate a possible AAS-induced detrimental effect on neuronal development and regenerative functions. An impact on these events, that are essential mechanisms for maintaining normal brain function, could possibly contribute to behavioural alterations seen in AAS users.
Long-term use of anabolic androgenic steroids (AAS) in supratherapeutic doses is associated with severe adverse effects, including physical, mental, and behavioral alterations. When used for ...recreational purposes several AAS are often combined, and in scientific studies of the physiological impact of AAS either a single compound or a cocktail of several steroids is often used. Because of this, steroid-specific effects have been difficult to define and are not fully elucidated. The present study used male Wistar rats to evaluate potential somatic and behavioral effects of three different AAS; the decanoate esters of nandrolone, testosterone, and trenbolone. The rats were exposed to 15 mg/kg of nandrolone decanoate, testosterone decanoate, or trenbolone decanoate every third day for 24 days. Body weight gain and organ weights (thymus, liver, kidney, testis, and heart) were measured together with the corticosterone plasma levels. Behavioral effects were studied in the novel object recognition-test (NOR-test) and the multivariate concentric square field-test (MCSF-test). The results conclude that nandrolone decanoate, but neither testosterone decanoate nor trenbolone decanoate, caused impaired recognition memory in the NOR-test, indicating an altered cognitive function. The behavioral profile and stress hormone level of the rats were not affected by the AAS treatments. Furthermore, the study revealed diverse AAS-induced somatic effects i.e., reduced body weight development and changes in organ weights. Of the three AAS included in the study, nandrolone decanoate was identified to cause the most prominent impact on the male rat, as it affected body weight development, the weights of multiple organs, and caused an impaired memory function.
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•Different types of anabolic steroids (AAS) induce AAS-specific effects in male rats.•The AAS alter body weight development and organ weights to different degree.•The AAS differently affect episodic-like memory.•The AAS do not affect the behavioral profile or stress levels.
Growth hormone (GH) is widely known for its peripheral effects during growth and development. However, numerous reports also suggest that GH exert pro-cognitive, restorative, and protective ...properties in the brain. In in vitro studies, the detection of dendritic spines, small protrusions extending from axons, can act as a marker for cognition-related function as spine formation is considered to be associated with learning and memory. Here we show that an acute 24-hour treatment of GH can increase dendritic spine density in primary hippocampal cell cultures.
Primary hippocampal cells were harvested from embryonic Wistar rats and cultured for 14 days. Cells were treated with supra-physiological doses of GH (10-1000 nM) and subjected to a high-throughput screening protocol. Images were acquired and analyzed using automated image analysis and the number of spines, spines per neurite length, neurite length, and mean area of spines, was reported.
GH treatment (1000 nM) increased the number of dendritic spines by 83% and spines per neurite length by 82% when compared to control. For comparison BDNF, a known inducer of spine densities, produced statistically non-significant increase in this setting.
The results was found significant using the highest supra-physiological dose of GH, and the present study further confirms a potential role of the hormone in the treatment of cognitive dysfunction.
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•This study was designed using a novel high-throughput screening technique.•GH increases dendritic spine density in primary hippocampal cell cultures.•The results further confirm the role of GH as a cognitive enhancer.
This report is a part of a diploma work, conducted as a part of a Master of Science degree. The diploma work consists of a preliminary study, two case studies, a user study, a paper and this report. ...It was created at the Linköping University for the department of Science and Technology, in cooperation with Unilever Research in the UK, and partly with the EC founded project, Smartdoc IST-2000-28137. Hand-held, mobile devices like Personal Digital Assistances (PDAs) are becoming increasingly popular in today’s wireless world. While trying to pack all the possible information into a small window, a nightmarish scenario is created for the interface designer to deal with. The goal for this project was to investigate different Visual User Interfaces (VUIs)on PDAs, and how to apply desktop interaction techniques to PDAs. A VUI model based on Zooming User Interface (ZUI) techniques, to adapt two complete different visualisation application areas; on-line brand-based shopping and flood warning system for PDAs, is presented. The on-line brand- based shopping was evaluated in a benchmark usability study comparing it to traditional PC based on-line shopping.
Visual User Interface for PDAs Ricknäs Daniel , Linköpings universitet, Institutionen för teknik och naturvetenskap; Stam Frida , Linköpings universitet, Institutionen för teknik och naturvetenskap; Ricknäs Daniel, Lköpping University, Department of Technology and Science ...
2003
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This report is a part of a diploma work, conducted as a part of a Master of Science degree. The diploma work consists of a preliminary study, two case studies, a user study, a paper and this report. ...It was created at the Linköping University for the department of Science and Technology, in cooperation with Unilever Research in the UK, and partly with the EC founded project, Smartdoc IST-2000-28137.
Hand-held, mobile devices like Personal Digital Assistances (PDAs) are becoming increasingly popular in today’s wireless world. While trying to pack all the possible information into a small window, a nightmarish scenario is created for the interface designer to deal with. The goal for this project was to investigate different Visual User Interfaces (VUIs)on PDAs, and how to apply desktop interaction techniques to PDAs.
A VUI model based on Zooming User Interface (ZUI) techniques, to adapt two complete different visualisation application areas; on-line brand-based shopping and flood warning system for PDAs, is presented. The on-line brand- based shopping was evaluated in a benchmark usability study comparing it to traditional PC based on-line shopping.
Självständigt arbete på grundnivå (yrkesexamen)
Självständigt arbete på grundnivå (yrkesexamen)
This report is a part of a diploma work, conducted as a part of a Master of Science degree. The diploma work consists of a preliminary study, two case studies, a user study, a paper and this report. It was created at the Linköping University for the department of Science and Technology, in cooperation with Unilever Research in the UK, and partly with the EC founded project, Smartdoc IST-2000-28137.
Hand-held, mobile devices like Personal Digital Assistances (PDAs) are becoming increasingly popular in today’s wireless world. While trying to pack all the possible information into a small window, a nightmarish scenario is created for the interface designer to deal with. The goal for this project was to investigate different Visual User Interfaces (VUIs)on PDAs, and how to apply desktop interaction techniques to PDAs.
A VUI model based on Zooming User Interface (ZUI) techniques, to adapt two complete different visualisation application areas; on-line brand-based shopping and flood warning system for PDAs, is presented. The on-line brand- based shopping was evaluated in a benchmark usability study comparing it to traditional PC based on-line shopping.
To identify potential regulators of propagation and self-renewal of Acute Lymphoblastic Leukaemia (ALL), we performed an explorative genome-wide RNAi screen followed by CRISPR ex vivo and in vivo ...validation screens in the t(4;11)-positive ALL cell line SEM. These screens identified the splicing factor PHF5A as a crucial component of the leukemic program. PHF5A is a subunit of the SF3b protein complex, which directs alternative splicing by binding to the branchpoint of pre-mRNA. Mutations in members of this complex including SF3B1 have been implicated in several haematological malignancies.
Functional perturbation experiments demonstrated that PHF5A depletion impairs proliferation, viability and clonogenicity in a range of ALL and AML cell lines strongly suggesting that PHF5A is required for leukemic propagation and self-renewal. To identify genetic programs affected by PHF5A inhibition, we performed RNA-seq followed by analysis of differential gene expression and splicing events. We identified 473 genes with differential expression upon PHF5A knockdown. In addition, we performed in-depth analysis of splicing patterns by examining both differential exon/intron usage and exon junction formation. These analyses demonstrated that loss of PHF5A affects splicing of more than 2500 genes with exon skipping and intron retention being the most frequent splicing events.
In order to identify processes and pathways affected by PHF5A, we performed gene set enrichment analysis (GSEA) on both differential expression and splicing. While gene sets associated with RNA processing including splicing, turnover and translation were enriched in both data sets, the differential gene expression signature was also linked to DNA repair processes including base excision, mismatch and homologous recombination repair.
In line with these findings, knockdown of either PHF5A or its partner protein SF3B1 induced DNA strand breaks as indicated by comet assay and increased y-H2AX levels. Furthermore, both PHF5A and SF3B1 depletion sensitized ALL cells towards the DNA crosslinking agent mitomycin C. Closer inspection of RNA-seq datasets revealed reduced FANCD2 expression and skipping of exon 22 associated with impaired mono-ubiquitination of the FANCD2 protein as a consequence of PHF5A and SF3B1 knockdown. Furthermore, expression of RAD51, a key component of double strand break repair, also decreased upon PHF5A and SF3B1 knockdown. Notably, in vitro pharmacological inhibition of SF3b complex activity using H3B-8800 (or Pladienolide B) showed a very similar effect on FANCD2 expression, and ubiquitination as well as decrease of RAD51 and an increase in y-H2AX levels on a dose and time-dependent manner. This strongly suggests a mechanistic link between impaired RNA splicing and the repair of DNA double-strand breaks.
These combined data show that leukemic cells are highly dependent on a functional SF3b splicing complex. Interference with its function results in DNA damage and also sensitizes towards DNA damaging agents pointing towards a possible benefit of the combined application of inhibitors targeting the SF3b complex with more conventional chemotherapy.
Ponthan:Epistem Ltd: Employment. Zwaan:Sanofi: Consultancy; Incyte: Consultancy; BMS: Research Funding; Roche: Consultancy; Janssen: Consultancy; Daiichi Sankyo: Consultancy; Servier: Consultancy; Jazz Pharmaceuticals: Other: Travel support; Pfizer: Research Funding; Celgene: Consultancy, Research Funding. Vormoor:Abbvie (uncompensated): Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding; AstraZeneca: Research Funding.
Per Stam om CAROLINE HAUX FRAMKALLNING. SKRIFT, KONSUMTION OCH SEXUALITET I KARIN BOYES ASTARTE OCH HENRY PARLANDS SÖNDER Göteborg/Stockholm: Makadam, 2013, 359 s. (diss. Stockholm) Sofia Pulls om ...EVA SÖDERBERG, MIA ÖSTERLUND & BODIL FORMARK (RED.) FLICKTION. PERSPEKTIV PÅ FLICKAN I FIKTIONEN Malmö: Universus Academic Press, 2013, 328 s. Johan Alfredsson om MARTIN GLAZ SERUP RELATIONEL POESI Odense: Syddansk Universitetsforlag, 2013, 115 s. Lisbeth Stenberg om MARIA M. BERGLUND VÄRV OCH VERK. FÖRNYELSE OCH TRADITION I NORDISK KVINNOLITTERATURHISTORIA FRÅN TILLKOMST TILL TRYCKT BOK Karlstad University Studies, 2013:21. Karlstad: Institutionen för språk, litteratur och interkultur, Karlstads universitet, 320 s. (diss. Karlstad) Åsa Arping om EIVIND TJØNNELAND (RED.) KRITIKK FØR 1814. 1700-TALLETS POLITISKE OG LITTERÆRE OFFENTLIGHET Oslo: Dreyers forlag, 2014, 639 s. Jesper Olsson om MARKUS HUSS MOTSTÅNDETS AKUSTIK. SPRÅK OCH (O)LJUD HOS PETER WEISS 1946–1960 Lund: ellerströms, 2014, 297 s. (diss. Södertörn/Stockholm) Frida Beckman om MAGNUS ULLÉN (RED.) VÅLDSAMMA FANTASIER. STUDIER I FIKTIONSVÅLDETS FUNKTION OCH ATTRAKTION Kulturvetenskapliga skriftserien, 2:2014 Karlstad: Karlstads universitet, 2014, 230 s. Per-Olof Mattsson om CHRISTIAN BERRENBERG ”ES IST DEINE PFLICHT ZU BENUTZEN, WAS DU WEIßT!” LITERATUR UND LITERARISCHE PRAKTIKEN IN DER NORWEGISCHEN ARBEITERBEWEGUNG 1900–1931 Literarische Praktiken in Skandinavien; 3. Würzburg: Ergon, 2014, 476 s. (diss. Köln) Tilda Maria Forselius om EVA HÆTTNER AURELIUS, HEDDA GUNNENG & JON HELGASON (RED.) WOMEN’S LANGUAGE. AN ANALYSIS OF STYLE AND EXPRESSION IN LETTERS BEFORE 1800 Lund: Nordic Academic Press, 2012, 260 s. Jennie Nell om PETER LIND ”STRUNT ALT HVAD DU ORERAR”. CARL MICHAEL BELLMAN, ORDENSRETORIKEN OCH BACCHI ORDEN Studia Rhetorica Upsaliensa 4, red. Otto Fischer, Uppsala: Uppsala universitet, 2014, 322 s. (diss. Uppsala) Marianne Sandels om CARIN FRANZÉN JAG GAV HONOM INTE MIN KÄRLEK. OM HÖVISK KÄRLEK SOM KVINNLIG STRATEGI Stockholm: Ersatz, 2012, 174 s. Johannes Björk om MAGNUS NILSSON LITERATURE AND CLASS. AESTHETICAL-POLITICAL STRATEGIES IN MODERN SWEDISH WORKING-CLASS LITERATURE Berlin: Berliner Beiträge zur Skandinavistik Band 21, 2014, 172 s. Hilda Jakobsson om KRISTINA FJELKESTAM, HELENA HILL & DAVID TJEDER (RED.) KVINNORNA GÖR MANNEN. MASKULINITETSKONSTRUKTIONER I KVINNORS TEXT OCH BILD 1500–2000, Göteborg/Stockholm: Makadam, 2013, 351 s. Thomas Götselius om KNUT OVE ELIASSEN, ANNE FASTRUP & TUE ANDERSEN NEXØ (RED.) EUROPEISK LITTERATUR 1500–1800. BIND 1. VERDEN: FRA COLUMBUS TILL NAPOLEON Aarhus: Aarhus universitetsforlag, 2013, 260 s.
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