| 1. |
- Aronsson, Henrik, 1971, et al.
(författare)
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Nucleotide binding and dimerization at the chloroplast pre-protein import receptor, atToc33, are not essential in vivo but do increase import efficiency
- 2010
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Ingår i: PLANT JOURNAL. - 0960-7412. ; 63:2, s. 297-311
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Tidskriftsartikel (refereegranskat)abstract
- P>The atToc33 protein is one of several pre-protein import receptors in the outer envelope of Arabidopsis chloroplasts. It is a GTPase with motifs characteristic of such proteins, and its loss in the plastid protein import 1 (ppi1) mutant interferes with the import of photosynthesis-related pre-proteins, causing a chlorotic phenotype in mutant plants. To assess the significance of GTPase cycling by atToc33, we generated several atToc33 point mutants with predicted effects on GTP binding (K49R, S50N and S50N/S51N), GTP hydrolysis (G45R, G45V, Q68A and N101A), both binding and hydrolysis (G45R/K49N/S50R), and dimerization or the functional interaction between dimeric partners (R125A, R130A and R130K). First, a selection of these mutants was assessed in vitro, or in yeast, to confirm that the mutations have the desired effects: in relation to nucleotide binding and dimerization, the mutants behaved as expected. Then, activities of selected mutants were tested in vivo, by assessing for complementation of ppi1 in transgenic plants. Remarkably, all tested mutants mediated high levels of complementation: complemented plants were similar to the wild type in growth rate, chlorophyll accumulation, photosynthetic performance, and chloroplast ultrastructure. Protein import into mutant chloroplasts was also complemented to > 50% of the wild-type level. Overall, the data indicate that neither nucleotide binding nor dimerization at atToc33 is essential for chloroplast import (in plants that continue to express the other TOC receptors in native form), although both processes do increase import efficiency. Absence of atToc33 GTPase activity might somehow be compensated for by that of the Toc159 receptors. However, overexpression of atToc33 (or its close relative, atToc34) in Toc159-deficient plants did not mediate complementation, indicating that the receptors do not share functional redundancy in the conventional sense.
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| 2. |
- Fearnley, Nils, et al.
(författare)
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Best practices and recommendations on policy packaging
- 2011
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- This report, which is the final deliverable of the Optic project (Optimal Policies for Transport In Combination), summarises two years of collaborative research into the policy process of combining individual measures into policy packages.Six stages of the policy process are identified. This report gives practical and general advice for each of these stages:Define objectives and targetsCreate an inventory of measures, identify potential primary measures and detect causal relationshipsAssess policy packageModify packagePackage implementationEvaluate effects, introduce remedial actionsIn addition, this report explores in further detail indicators and tools for the assessment of policy packages; the management of barriers; and issues of transferability.
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| 3. |
- Givoni, Moshe, et al.
(författare)
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Inventory of measures, typology of non-intentional effects and a framework for policy packaging
- 2010
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- This document represents the conceptual foundations of the EU-FP7 OPTIC project. As such, it seeks to provide a range of theoretical resources with which to develop an informed and pragmatic understanding of the complex causal processes involved in contemporary transport policy-making at the European level. Specifically, this deliverable aims to further methodological advancement with respect to the identification, classification, ex-ante prevention and ex-post mitigation of policies' unintended effects, and the systematic manner in which individual policy measures may be combined so as to improve their effectiveness, acceptability and feasibility. Overall, we argue that policy packaging can offer a far greater potential for achieving policy targets and objectives than single policy measures deployed in isolation. Yet, a careful and relatively well designed process must be undertaken for such packages to be effective.
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| 4. |
- Kehyayan, Aram, et al.
(författare)
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The effect of a visuospatial interference intervention on posttraumatic intrusions : a cross-over randomized controlled trial
- 2024
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Ingår i: European Journal of Psychotraumatology. - : Taylor & Francis. - 2000-8198 .- 2000-8066. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Intrusive memories form a core symptom of Posttraumatic Stress Disorder (PTSD). Based on concepts of visuospatial interference and memory-updating accounts, technological innovations aim to attenuate such intrusions using visuospatial interventions.Objective: This study aims to test the effect of a visuospatial Tetris-based intervention versus a verbal condition (Wiki) and a never-targeted control (no intervention) on intrusion frequency.Method: A randomized crossover trial was conducted including N = 38 PTSD patients who had at least 3 distinct intrusive memories of trauma. After both 2 weeks (intervention 1) and 4 weeks (intervention 2), one of the three memories was randomly selected and either the visuospatial intervention (memory reminder of a traumatic memory + Tetris) or verbal condition (reading a Wikipedia article + answering questions) was performed on their first memory in randomized order. In the week 4 session, the patient conducted the other intervention condition on their second memory (crossover). The third memory was never targeted (no intervention). Daily occurrence of intrusions over 8 weeks was collected using a diary and analysed using mixed Poisson regression models.Results: Overall, there was no significant reduction in intrusion frequency from either intervention compared to each other, and to no intervention control (relative risk Tetris/Wiki: 0.947; p = .31; relative risk no intervention/Tetris: 1.060; p = .15; relative risk no intervention/Wiki: 1.004; p = .92).Conclusions: There was no effect of either intervention on intrusions when administered in a crossover design where participants received both interventions. Design shortcomings and consequences for future studies are discussed.
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| 5. |
- Kessler, Henrik, et al.
(författare)
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Reducing Intrusive Memories of Trauma Using a Visuospatial Interference Intervention With Inpatients With Posttraumatic Stress Disorder (PTSD)
- 2018
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Ingår i: Journal of Consulting and Clinical Psychology. - : AMER PSYCHOLOGICAL ASSOC. - 0022-006X .- 1939-2117. ; 86:12, s. 1076-1090
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The core clinical feature of posttraumatic stress disorder (PTSD) is recurrent intrusive memories of trauma. This study aimed to test a novel and simple intervention, inspired by the concepts of concurrent task interference and memory reconsolidation, to reduce the occurrence of intrusive memories among inpatients with complex PTSD. Method: In this open-label single case series 20 patients with longstanding complex PTSD in inpatient treatment monitored the occurrence of intrusive trauma memories (intrusions) over the course of their admission (5 to 10 weeks). Patients received study-specific intervention sessions (including a memory reminder for a specific intrusion then 25 min Tetris gameplay) on a weekly basis. A within-subjects multiple baseline AB design was used, in that the length of baseline ("A," preintervention, monitoring only) and postintervention ("B") phases varied within-subjects across individual intrusions. Further, some intrusions were never targeted by the intervention. The study was registered prior to analysis, ISRCTN34320836. Results: Frequency of targeted intrusions reduced by on average 64% from baseline to the postintervention phase. Conversely, never-targeted intrusions reduced in frequency by on average 11% over a comparable time-period. Of the 20 patients, 16 met our criteria for showing "response" to the intervention. Conclusions: Results provide initial evidence that this brief behavioral procedure might reduce the occurrence of intrusive traumatic memories in longstanding and complex PTSD, here delivered in an inpatient setting. The potential of this simple, focused intervention opens up new possibilities for tackling a core clinical symptom of PTSD, warranting further research.
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| 6. |
- Kessler, Henrik, et al.
(författare)
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Visuospatial computer game play after memory reminder delivered three days after a traumatic film reduces the number of intrusive memories of the experimental trauma
- 2020
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Ingår i: Journal of Behavior Therapy and Experimental Psychiatry. - : Elsevier. - 0005-7916 .- 1873-7943. ; 67
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The experience of intrusive memories is a core clinical symptom of posttraumatic stress disorder (PTSD), and can be distressing in its own right. Notions of dual task interference and reconsolidation-update mechanisms suggest novel approaches to target intrusive memories. This study tested the hypothesis that a single-session cognitive intervention (memory reminder task plus Tetris gameplay) would reduce the occurrence of experimental trauma memories even when delivered 3 days post-trauma. Critically, this study tested effects against two control groups: Reminder-only, and reminder plus another computer game (a form of Quiz).METHODS: 86 healthy volunteers (59% female, age M = 24.35, SD = 4.59 years) watched a trauma film and then recorded their intrusive memories in a diary for 3 days (pre-intervention). They then returned to the lab. After presentation of visual reminder cues for the film plus a 10 min wait period (memory reminder task), participants were randomized into one of three task conditions (Tetris game play, Quiz game play, vs. reminder-only). They then kept the diary for a further 3 days (post-intervention).RESULTS: As predicted, after the experimental manipulation, the reminder + Tetris group experienced significantly fewer intrusions than the reminder-only group (d = 1.37). Further, the reminder + Tetris group also experienced significantly fewer intrusions than the reminder + Quiz (d = 0.65) group. Contrary to predictions, the reminder + Quiz group experienced significantly fewer intrusions than the reminder-only group (d = 0.69). Prior to the experimental manipulation, there was no significant difference between groups in number of intrusions. Recognition memory test scores for facts of the trauma film after 6 days were comparable between groups.CONCLUSIONS: We demonstrated that 3 days after experimental trauma (i.e. after memory consolidation) an intervention comprising a reminder task prior to a 15 min cognitive interference task (one of two computer games) led to a reduction in intrusion occurrence compared to reminder only. We interpret and discuss our findings within the framework of supposed reconsolidation-update mechanisms and competition for limited (visuospatial) working memory resources. Should these effects hold true in clinical populations, this type of simple intervention approach could help contribute to reducing intrusive memories of trauma.
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| 7. |
- Kitazawa, Taro, et al.
(författare)
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A unique bipartite Polycomb signature regulates stimulus-response transcription during development.
- 2021
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 53:3, s. 379-391
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Tidskriftsartikel (refereegranskat)abstract
- Rapid cellular responses to environmental stimuli are fundamental for development and maturation. Immediate early genes can be transcriptionally induced within minutes in response to a variety of signals. How their induction levels are regulated and their untimely activation by spurious signals prevented during development is poorly understood. We found that in developing sensory neurons, before perinatal sensory-activity-dependent induction, immediate early genes are embedded into a unique bipartite Polycomb chromatin signature, carrying active H3K27ac on promoters but repressive Ezh2-dependent H3K27me3 on gene bodies. This bipartite signature is widely present in developing cell types, including embryonic stem cells. Polycomb marking of gene bodies inhibits mRNA elongation, dampening productive transcription, while still allowing for fast stimulus-dependent mark removal and bipartite gene induction. We reveal a developmental epigenetic mechanism regulating the rapidity and amplitude of the transcriptional response to relevant stimuli, while preventing inappropriate activation of stimulus-response genes.
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| 8. |
- Kjallquist, U., et al.
(författare)
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Real World Evaluation of the Prosigna/PAM50 Test in a Node-Negative Postmenopausal Swedish Population: A Multicenter Study
- 2022
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:11
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Tidskriftsartikel (refereegranskat)abstract
- Gene expression signatures can provide important information on the risk of recurrence in patients with hormone receptor positive early breast cancer, and they can guide post-operative treatment. We have investigated how the implementation of gene-expression-based risk signatures with the Prosigna((R)) test impacted patient management in Sweden. The two major conclusions of this study are that prognostic factors derived from routine pathology were poor predictors of the intrinsic subtype and the risk of recurrence score, and that gene-expression-based risk combined with clinicopathological biomarkers (tumor size, Ki67, tumor grade) spared patients from adjuvant chemotherapy, but also identified patients who would potentially benefit from this treatment. Molecular signatures to guide decisions for adjuvant chemotherapy are recommended in early ER-positive, HER2-negative breast cancer. The objective of this study was to assess what impact gene-expression-based risk testing has had following its recommendation by Swedish national guidelines. Postmenopausal women with ER-positive, HER2-negative and node negative breast cancer at intermediate clinical risk and eligible for chemotherapy were identified retrospectively from five Swedish hospitals. Tumor characteristics, results from Prosigna((R)) test and final treatment decision were available for all patients. Treatment recommendations were compared with the last version of regional guidelines before the introduction of routine risk signature testing. Among the 360 included patients, 41% (n = 148) had a change in decision for adjuvant treatment based on Prosigna((R)) test result. Out of the patients with clinical indication for adjuvant chemotherapy, 52% (n = 118) could avoid treatment based on results from Prosigna((R)) test. On the contrary, 23% (n = 30) of the patients with no indication were escalated to receive adjuvant chemotherapy after testing. Ki67 could not distinguish between the Prosigna((R)) risk groups or intrinsic subtypes and did not significantly differ between patients in which decision for adjuvant therapy was changed based on the test results. In conclusion, we report the first real-world data from implementation of gene-expression-based risk assessment in a Swedish context, which may facilitate the optimization of future versions of the national guidelines.
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| 9. |
- Kornalijnslijper-Altena, Renske, et al.
(författare)
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PREDIX II HER2 : Improving pre-operative systemic therapy for human epidermal growth factor receptor 2 (HER2) amplified breast cancer (BC)
- 2020
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Ingår i: Journal of Clinical Oncology. - : American Society of Clinical Oncology. - 0732-183X .- 1527-7755. ; 38:15 Suppl.
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Neo-adjuvant systemic therapy (NAT) is the standard of care for most patients with early HER2-amplified and triple negative breast cancer (BC). Increasing the rate of pathological complete response (pCR) is highly meaningful for those patients, as pCR is strongly predictive for improved long-term disease-related outcomes. Clinical and preclinical evidence support the hypothesis that pCR-rates may be augmented by the addition of checkpoint inhibitors, such as monoclonal antibodies targeting the Programmed Death Ligand receptor 1 (PD-L1), to standard systemic NAT. Studies in different BC patient cohorts (e.g., IMPassion130, PANACEA, KATE2) have indicated that PD-L1 protein expression on tumor-infiltrating lymphocytes (TIL’s) is a predictive marker for checkpoint inhibitor efficacy.Methods: We have initiated a phase II open-label, 2:1 randomized clinical trial where women with early HER2-amplified, PD-L1+ BC (cT2-3 and/or cN+) are treated with standard NAT (composed of anti-HER2 antibodies with a chemotherapy backbone of sequentially taxanes + carboplatin and epirubicin + cyclophosphamide [EC]) +/- atezolizumab during EC. N = 190 patients will be accrued in nine centers in Sweden to be able to demonstrate a 20% increase in pCR-rate, with a power of 80% and a two-sided alpha of 10%. Firstly, a prescreening is performed to select patients with a PD-L1 expression of > 1% on TIL’s. Important exclusion criteria are significant organ dysfunction and (with some exceptions) active auto-immune diseases. Extensive translational side-studies are performed to explore predictive markers for treatment efficacy, including clinicopathologic studies, molecular imaging and microbiome analyses, as well as monitoring of acute and chronic treatment-related toxicity, objective cognitive function and quality of life. As of February 11th, 4 patients have been prescreened and 1 enrolled in the trial. The clinical trial registry number is NCT03894007.
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| 10. |
- O´brien, Nathan, et al.
(författare)
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In Situ Activation of an Indium(III) Triazenide Precursor for Epitaxial Growth of Indium Nitride by Atomic Layer Deposition
- 2020
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Ingår i: Chemistry of Materials. - : AMER CHEMICAL SOC. - 0897-4756 .- 1520-5002. ; 32:11, s. 4481-4489
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Tidskriftsartikel (refereegranskat)abstract
- Indium nitride (InN) is characterized by its high electron mobility, making it a ground-breaking material for high frequency electronics. The difficulty of depositing high-quality crystalline InN currently impedes its broad implementation in electronic devices. Herein, we report a new highly volatile In(III) triazenide precursor and demonstrate its ability to deposit high-quality epitaxial hexagonal InN by atomic layer deposition (ALD). The new In(III) precursor, the first example of a homoleptic triazenide used in a vapor deposition process, was easily synthesized and purified by sublimation. Thermogravimetric analysis showed single step volatilization with an onset temperature of 145 degrees C and negligible residual mass. Strikingly, two temperature intervals with self-limiting growth were observed when depositing InN films. In the high-temperature interval, the precursor underwent a gas-phase thermal decomposition inside the ALD reaction chamber to produce a more reactive In(III) compound while retaining self-limiting growth behavior. Density functional theory calculations revealed a unique two-step decomposition process, which liberates three molecules of each propene and N-2 to give a smaller tricoordinated In(III) species. Stoichiometric InN films with very low levels of impurities were grown epitaxially on 4H-SiC. The InN films deposited at 325 degrees C had a sheet resistivity of 920 Omega/sq. This new triazenide precursor enables ALD of InN for semiconductor applications and provides a new family of M-N bonded precursors for future deposition processes.
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