| 1. |
- Fahrer, Jörg, et al.
(författare)
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Cytolethal distending toxin (CDT) is a radiomimetic agent and induces persistent levels of DNA double-strand breaks in human fibroblasts
- 2014
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Ingår i: DNA Repair. - : Elsevier. - 1568-7864 .- 1568-7856. ; 18, s. 31-43
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Tidskriftsartikel (refereegranskat)abstract
- Cytolethal distending toxin (CDT) is a unique genotoxin produced by several pathogenic bacteria. The tripartite protein toxin is internalized into mammalian cells via endocytosis followed by retrograde transport to the ER. Upon translocation into the nucleus, CDT catalyzes the formation of DNA double-strand breaks (DSBs) due to its intrinsic endonuclease activity. In the present study, we compared the DNA damage response (DDR) in human fibroblasts triggered by recombinant CDT to that of ionizing radiation (IR), a well-known DSB inducer. Furthermore, we dissected the pathways involved in the detection and repair of CDT-induced DNA lesions. qRT-PCR array-based mRNA and western blot analyses showed a partial overlap in the DDR pattern elicited by CDT and IR, with strong activation of both the ATM-Chk2 and the ATR-Chk1 axis. In line with its in vitro DNase I-like activity on plasmid DNA, neutral and alkaline Comet assay revealed predominant induction of DSBs in CDT-treated fibroblasts, whereas irradiation of cells generated higher amounts of SSBs and alkali-labile sites. Using confocal microscopy, the dynamics of the DSB surrogate marker γ-H2AX was monitored after pulse treatment with CDT or IR. In contrast to the fast induction and disappearance of γ-H2AX-foci observed in irradiated cells, the number of γ-H2AX-foci induced by CDT were formed with a delay and persisted. 53BP1 foci were also generated following CDT treatment and co-localized with γ-H2AX foci. We further demonstrated that ATM-deficient cells are very sensitive to CDT-induced DNA damage as reflected by increased cell death rates with concomitant cleavage of caspase-3 and PARP-1. Finally, we provided novel evidence that both homologous recombination (HR) and non-homologous end joining (NHEJ) protect against CDT-elicited DSBs. In conclusion, the findings suggest that CDT functions as a radiomimetic agent and, therefore, is an attractive tool for selectively inducing persistent levels of DSBs and unveiling the associated cellular responses.
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| 2. |
- Klein, Jan Philipp, et al.
(författare)
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The EVIDENT-trial: protocol and rationale of a multicenter randomized controlled trial testing the effectiveness of an online-based psychological intervention
- 2013
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Ingår i: BMC Psychiatry. - : BioMed Central. - 1471-244X. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundDepressive disorders are among the leading causes of worldwide disability with mild to moderate forms of depression being particularly common. Low-intensity treatments such as online psychological treatments may be an effective way to treat mild to moderate depressive symptoms and prevent the emergence or relapse of major depression.Methods/DesignThis study is a currently recruiting multicentre parallel-groups pragmatic randomized-controlled single-blind trial. A total of 1000 participants with mild to moderate symptoms of depression from various settings including in- and outpatient services will be randomized to an online psychological treatment or care as usual (CAU). We hypothesize that the intervention will be superior to CAU in reducing depressive symptoms assessed with the Personal Health Questionnaire (PHQ-9, primary outcome measure) following the intervention (12 wks) and at follow-up (24 and 48 wks). Further outcome parameters include quality of life, use of health care resources and attitude towards online psychological treatments.DiscussionThe study will yield meaningful answers to the question of whether online psychological treatment can contribute to the effective and efficient prevention and treatment of mild to moderate depression on a population level with a low barrier to entry.
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| 3. |
- Lerm, Maria, et al.
(författare)
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Proteasomal degradation of cytotoxic necrotizing factor 1-activated rac
- 2002
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Ingår i: Infection and Immunity. - : American Society for Microbiology. - 0019-9567 .- 1098-5522. ; 70:8, s. 4053-4058
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Tidskriftsartikel (refereegranskat)abstract
- The cytotoxic necrotizing factor 1 (CNF1) from Escherichia coli has been shown to activate members of the Rho family by deamidation of glutamine 63. This amino acid is essential for hydrolysis of GTP, and any substitution results in a constitutively active Rho. Activation of Rho induces the formation of stress fibers, filopodia, and membrane ruffles due to activation of RhoA, Cdc42, and Rac, respectively. Here we show that the level of endogenous Rac decreased in CNF1-treated HEK293 and HeLa cells. The amount of mRNA remained unaffected, leaving the possibility that Rac is subject to proteolytic degradation. Treatment of cells with lactacystin, an inhibitor of the 26S proteasome, protected Rac from degradation. We have previously shown that CNF1 activates the c-Jun N-terminal kinase (JNK) only transiently in HeLa cells (M. Lerm, J. Selzer, A. Hoffmeyer, U. R. Rapp, K. Aktories, and G. Schmidt, Infect. Immun. 67:496-503, 1998). Here we show that CNF1-induced JNK activation is stabilized in the presence of lactacystin. The data indicate that Rac is degraded by a proteasome-dependent pathway in CNF1-treated cells.
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| 4. |
- Löf, David, et al.
(författare)
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Structural Characterization of Nonionic Mixed Micelles Formed by C(12)EO(6) Surfactant and P123 Triblock Copolymer.
- 2009
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Ingår i: The Journal of Physical Chemistry Part B. - : American Chemical Society (ACS). - 1520-5207 .- 1520-6106. ; 113:16, s. 5478-5486
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Tidskriftsartikel (refereegranskat)abstract
- A structural characterization of mixed micelles formed in aqueous solution by the PEO-PPO-PEO triblock copolymer P123 and the nonionic surfactant C(12)EO(6) was carried out using various techniques, including ultralow shear viscosimetry, depolarized dynamic light scattering (VH-DLS), depolarized static light scattering (VH-SLS), and small-angle X-ray scattering (SAXS). The sphere-to-rod transition of the mixed micelles was studied in a diluted regime (P123 concentrations ranging from 0.5 to 10 wt %) at C(12)EO(6)/P123 molar ratios of 2.2, 3.2, 6.0, and 11 as well as for the pure C(12)EO(6). The data from VH-SLS and viscosimetry displayed a sharp increase in the intensity and viscosity, respectively, at the sphere-to-rod transition, and the results from the two methods were in accordance. In both techniques, an increased transition temperature with increasing content of C(12)EO(6) (in the molar ratio regime from 2.2 to 11) was observed. SAXS was used as the main technique, and a thorough structural characterization was performed, where indirect Fourier transformation (IFT) and generalized indirect Fourier transformation (GIFT) were employed in the analysis procedure of the SAXS data. The p(r) functions obtained from the IFT (employed at low P123 concentrations, i.e., 1.0 and 2.0 wt %) and GIFT (employed above 2.0 wt %) analyses revealed increased inhomogeneities in the mixed micelles when the molar ratio was increased. This suggested that the C(12)EO(6) organized themselves at the interface between the PPO core and the PEO corona of the P123 micelles, with the C(12) alkyl chain stretching into the hydrophobic core and the EO(6) part residing in the hydrophilic corona. The structure factor parameters obtained with GIFT for a molar ratio of 2.2 at a P123 concentration of 5.0 wt % showed radius values smaller than what was estimated from the p(r) functions. This was explained by an interpenetration of the PEO chains from one mixed micelle into a neighboring one. VH-DLS was performed on the mixed micelles at a temperature 3 degrees C above the transition temperature and at a molar ratio of 2.2. From the analyzed data, the average length L of the rods was estimated to be 102 nm.
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| 5. |
- Meyer, Björn, et al.
(författare)
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Effects of an Internet intervention (Deprexis) on severe depression symptoms : Randomized controlled trial
- 2015
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Ingår i: Internet Interventions. - : Elsevier. - 2214-7829. ; 2:1, s. 48-59
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundStudies have shown that certain Internet interventions can help alleviate depression. However, many such interventions contain personal support elements, making it difficult to ascertain whether the program or the support drives the effects. Studies are needed to investigate whether Internet interventions contribute to symptom reduction even when they are delivered without personal support, and even among severely depressed individuals who often receive other forms of treatment.ObjectiveThis randomized controlled trial aimed to examine the effect of an Internet intervention that was deployed without personal support (“Deprexis”) among adults with initially severe depression symptoms.MethodsAdults recruited from a range of sources who had exceeded the threshold for severe depression (PHQ-9 ≥ 15) in a pre-screening assessment and met inclusion criteria were randomized (N = 163) to the intervention (3 months program access; n = 78) or care-as-usual/waitlist control (n = 85). A diagnostic screening interview was administered by telephone at baseline to all participants. Online assessments were administered at baseline, 3 months (post-treatment), and 6 months (follow-up). The main outcome was the Patient Health Questionnaire (PHQ-9) between baseline and post-treatment.ResultsEighty-two percent of randomized participants were reached for the post-treatment assessment. Results for the intention-to-treat (ITT) sample showed significant intervention effects on depression reduction between baseline and post-treatment (linear mixed model [MM], F1,155.6 = 9.00, p < .01, for the time by condition interaction), with a medium between-group effect size, Cohen's d = 0.57 (95% CI: 0.22–0.92). Group differences in depression severity at follow-up were marginally significant in the ITT sample, t (119) = 1.83, p = 0.07, and smaller than at post-treatment (PHQ-9, d = 0.33, 95% CI: − 0.03–0.69). The number needed to treat (NNT) at post-treatment was 5, with 38% of participants in the intervention group achieving response (at least 50% PHQ-9 symptom change, plus post-treatment score < 10), compared to 17% in the control group, p < 0.01. Effects on secondary outcomes, including anxiety, health-related quality of life, and somatic symptoms, were not significant, with the exception of significant effects on anxiety reduction in PP analyses. Early ratings of program helpfulness/alliance (after 3 weeks) predicted pre–post depression reduction, controlling for baseline severity and early symptom change.ConclusionsThese results replicate and extend previous findings by showing that Deprexis can facilitate symptomatic improvement over 3 months and, perhaps to a lesser degree, up until 6 months among adults with initially severe depression.
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| 6. |
- Philipp Klein, Jan, et al.
(författare)
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Effects of a Psychological Internet Intervention in the Treatment of Mild to Moderate Depressive Symptoms: Results of the EVIDENT Study, a Randomized Controlled Trial
- 2016
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Ingår i: Psychotherapy and Psychosomatics. - : KARGER. - 0033-3190 .- 1423-0348. ; 85:4, s. 218-228
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Tidskriftsartikel (refereegranskat)abstract
- Background: Mild to moderate depressive symptoms are common but often remain unrecognized and treated inadequately. We hypothesized that an Internet intervention in addition to usual care is superior to care as usual alone (CAU) in the treatment of mild to moderate depressive symptoms in adults. Methods: This trial was controlled, randomized and assessor-blinded. Participants with mild to moderate depressive symptoms (Patient Health Questionnaire, PHQ-9, score 5-14) were recruited from clinical and non-clinical set-tings and randomized to either CAU or a 12-week Internet intervention (Deprexis) adjunctive to usual care. Outcomes were assessed at baseline, 3 months (post-assessment) and 6 months (follow-up). The primary outcome measure was self-rated depression severity (PHQ-9). The main analysis was based on the intention-to-treat principle and used linear mixed models. Results: A total of 1,013 participants were randomized. Changes in PHQ-9 from baseline differed significantly between groups (t(825) = 6.12, p amp;lt; 0.001 for the main effect of group). The post-assessment between-group effect size in favour of the intervention was d = 0.39 (95% CI: 0.13-0.64). It was stable at follow-up, with d = 0.32 (95% CI: 0.06-0.69). The rate of participants experiencing at least minimally clinically important PHQ-9 change at the post-assessment was higher in the intervention group (35.6 vs. 20.2%) with a number needed to treat of 7 (95% CI: 5-10). Conclusions: The Internet intervention examined in this trial was superior to CAU alone in reducing mild to moderate depressive symptoms. The magnitude of the effect is clinically important and has public health implications. (C) 2016 S. Karger AG, Basel
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| 7. |
- Schultheis, M., et al.
(författare)
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The nuclear stellar disc of the Milky Way : A dynamically cool and metal-rich component possibly formed from the central molecular zone
- 2021
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 650
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Tidskriftsartikel (refereegranskat)abstract
- Context. The nuclear stellar disc (NSD) is, together with the nuclear star cluster (NSC) and the central massive black hole, one of the main components in the central parts of our Milky Way. However, until recently, only a few studies of the stellar content of the NSD have been obtained owing to extreme extinction and stellar crowding. Aims. We study the kinematics and global metallicities of the NSD based on the observations of K/M giant stars via a dedicated KMOS (VLT, ESO) spectroscopic survey. Methods. We traced radial velocities and metallicities, which were derived based on spectral indices (Na I and CO) along the NSD, and compared those with a Galactic bulge sample of APOGEE (DR16) and data from the NSC. Results. We find that the metallicity distribution function and the fraction of metal-rich and metal-poor stars in the NSD are different from the corresponding distributions and ratios of the NSC and the Galactic bulge. By tracing the velocity dispersion as a function of metallicity, we clearly see that the NSD is kinematically cool and that the velocity dispersion decreases with increasing metallicity contrary to the inner bulge sample of APOGEE (|b|< 4°). Using molecular gas tracers (H2CO, CO(4-3)) of the central molecular zone (CMZ), we find an astonishing agreement between the gas rotation and the rotation of the metal-rich population. This agreement indicates that the metal-rich stars could have formed from gas in the CMZ. On the other hand, the metal-poor stars show a much slower rotation profile with signs of counter-rotation, thereby indicating that these stars have a different origin. Conclusions. Coupling kinematics with global metallicities, our results demonstrate that the NSD is chemically and kinematically distinct with respect to the inner bulge, which indicates a different formation scenario.
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| 8. |
- Sormani, Mattia C., et al.
(författare)
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Self-consistent modelling of the Milky Way's nuclear stellar disc
- 2022
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 512:2, s. 1857-1884
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Tidskriftsartikel (refereegranskat)abstract
- The nuclear stellar disc (NSD) is a flattened high-density stellar structure that dominates the gravitational field of the Milky Way at Galactocentric radius $30\, {\rm pc}\lesssim R\lesssim 300\, {\rm pc}$. We construct axisymmetric self-consistent equilibrium dynamical models of the NSD in which the distribution function is an analytic function of the action variables. We fit the models to the normalized kinematic distributions (line-of-sight velocities + VIRAC2 proper motions) of stars in the NSD survey of Fritz et al., taking the foreground contamination due to the Galactic Bar explicitly into account using an N-body model. The posterior marginalized probability distributions give a total mass of $M{\rm NSD} = 10.5{+1.1}{-1.0} \times 108 \, \, \rm M\odot$, roughly exponential radial and vertical scale lengths of $R{\rm disc} = 88.6{+9.2}{-6.9} \, {\rm pc}$ and $H{\rm disc}=28.4{+5.5}{-5.5} \, {\rm pc}$, respectively, and a velocity dispersion $\sigma \simeq 70\, {\rm km\, s{-1}}$ that decreases with radius. We find that the assumption that the NSD is axisymmetric provides a good representation of the data. We quantify contamination from the Galactic Bar in the sample, which is substantial in most observed fields. Our models provide the full 6D (position + velocity) distribution function of the NSD, which can be used to generate predictions for future surveys. We make the models publicly available as part of the software package agama.
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| 9. |
- Wurst, Friedrich M., et al.
(författare)
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Measurement of direct ethanol metabolites in a case of a former driving under the influence (DUI) of alcohol offender, now claiming abstinence
- 2008
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Ingår i: International Journal of Legal Medicine. - : Springer Science and Business Media LLC. - 0937-9827 .- 1437-1596. ; 122:3, s. 235-239
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Tidskriftsartikel (refereegranskat)abstract
- A 37-year-old female subject had been convicted of driving under the influence of alcohol, and 19 months later, claimed abstinence after supervised disulfiram treatment. Our aim was to elucidate the value of direct ethanol metabolites as measures of abstinence. Ethyl glucuronide (EtG) and fatty acid ethyl esters (FAEE) in hair, phosphatidylethanol in whole blood and EtG and ethyl sulphate in urine were measured. The results were compared with self-report of alcohol consumption and traditional blood biomarkers for chronically elevated alcohol consumption as carbohydrate deficient transferrin (CDT), gamma glutamyl transpeptidase, mean corpuscular erythrocyte volume, aspartate aminotransferase and alanine aminotransferase. EtG was found in distal parts of hair only, whereas the proximal parts were negative. Furthermore, FAEE concentrations were found in the typical distribution over the hair length and showed values typical for either moderate social drinking or abstinence. CDT was above cut-off in 9 out of 16 analyses with a decreasing tendency and the lowest values in the last 2 months before the end of sampling. The data suggest that in addition to traditional markers, a combination of direct ethanol metabolites can be useful in the expert assessment of judging driving ability. A careful individual interpretation of the results for the different markers, however, is an absolute necessity.
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