| 1. |
- Andersson, Rebecka, et al.
(författare)
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Multi-species multicellular life cycles
- 2022
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Ingår i: The evolution of multicellularity. - Boca Raton : CRC Press. - 9781000542554 - 9780367356965 ; , s. 343-356
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Bokkapitel (refereegranskat)abstract
- Textbook examples of multicellular organisms vary in their scale and complexity but are typically composed of a single species. The prevalence of entities such as lichens, however, suggest that two different species may be capable of forming a type of multi-species multicellularity-though it may not resemble its clonal counterparts. In this chapter, we consider the possibility of multi-species multicellularity and in particular its origins. Drawing upon previous studies of the evolutionary origins of clonal multicellularity, we focus on the emergence of simple reproducing groups that have the capacity to gain adaptations. We present a framework for organizing these initial multi-species group life cycles based on whether the constituent species are unicellular or multicellular and whether the groups reproduce via fragmentation or cycles of dissociation and re-association. We discuss characteristics of each type of multi-species multicellularity and representative examples to assess their likely evolutionary trajectories. Ultimately, we conclude that the multi-species groups that most resemble textbook multicellular organisms are composed of unicellular and multicellular species and reproduce via cycles of dissociation and re-association.
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| 2. |
- Astenvald, Rebecka, et al.
(författare)
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Emotion dysregulation in ADHD and other neurodevelopmental conditions : a co-twin control study
- 2022
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Ingår i: Child and Adolescent Psychiatry and Mental Health. - : Springer Nature. - 1753-2000. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Emotion dysregulation (ED) is common in attention-deficit/hyperactivity disorder (ADHD) and often results in adverse outcomes. However, ED has been suggested as a transdiagnostic construct, why the specific association between ADHD and ED when adjusting for other mental health conditions needs further investigation. It is also important to determine the aetiological basis of the association between ADHD and ED to inform the theoretical conceptualization of ADHD.METHOD: This study used a co-twin control design, including a sample of dizygotic (DZ) and monozygotic (MZ) twins (N = 389; 45.8% females, age = 8-31 years, MZ twin pairs 57.6%). ED was assessed using the dysregulation profile from the parent-rated Child Behaviour Checklist and its adult version. Regression analyses were used across individuals and within the pairs, while adjusting for diagnoses of autism, intellectual disability, other neurodevelopmental conditions and affective conditions.RESULTS: ADHD was significantly associated with ED, even when adjusting for age, sex, attention problems and other mental health conditions, and was the diagnosis most strongly associated with ED. Within-pair analyses revealed that twins with ADHD had higher levels of ED compared to their co-twin without ADHD. This association remained within DZ twins and was non-significant in the MZ subsample, with non-overlapping confidence intervals between the DZ and MZ estimates.CONCLUSION: ADHD is strongly and in part independently linked to ED, stressing the importance of early detection and treatment of emotional difficulties within this group. The findings from the within-pair analyses indicate a genetic influence on the association between ADHD and ED.
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| 3. |
- Handawi, Khalil Al, et al.
(författare)
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Integrating additive manufacturing and repair strategies of aeroengine components in the computational multidisciplinary engineering design process
- 2018
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Ingår i: Proceedings of NordDesign: Design in the Era of Digitalization, NordDesign 2018.
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Konferensbidrag (refereegranskat)abstract
- This paper presents a methodology for integrating failure and lifecycle analysis related to additive manufacturing in a computational multidisciplinary engineering design framework. The specific goal of this framework is to quantify the impact of component design decisions on system-level performance in order to assess alternative manufacturing, re-manufacturing and repair strategies from both technical and business perspectives. The ultimate objective of this research is to enable such considerations in the early product design phases, where sufficient degree of freedom exists to identify component design solutions that can facilitate and accommodate different manufacturing and repair techniques that impact the entire lifecycle. The developed methodology is demonstrated by means of a jet engine component where repair strategies are included as variables in the computational design process. Numerical results confirm that these strategies can be used to trade among design attributes such as lifecycle cost, weight, and performance.
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| 4. |
- Harbottle, David, et al.
(författare)
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Coalescence of particle-laden drops with a planar oil-water interface
- 2011
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Ingår i: Journal of Colloid and Interface Science. - : Elsevier BV. - 0021-9797 .- 1095-7103. ; 362:1, s. 235-241
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Tidskriftsartikel (refereegranskat)abstract
- The coalescence mechanism of a particle-laden drop resting at an oil-water interface has been studied. Two mechanisms for drop coalescence are observed; (i) complete coalescence, in which the drop experiences total coalescence in one event, and (ii) partial coalescence, where a drop is observed to separate during coalescence, producing a smaller secondary drop that rebounds and comes to rest at the planar oil-water interface. For particle-laden drops of approximately 4 mm in diameter, we show the critical condition for partial to complete coalescence to be dependent on the particle concentration, and the interparticle interaction energy. Colloidal silica spheres dispersed in 10(-4) M KNO(3) electrolyte solution are highly charged and remain dispersed in the drop. By increasing the solids concentration, we measure the transition from partial to complete coalescence at 20 wt.%. However, this critical condition can be reduced by increasing the interparticle interaction energy. In 1 M KNO(3) electrolyte solution, the particle surface charge is sufficiently screened such that particle clusters readily form in the water drop. With particle clustering, transition from partial to complete coalescence is measured at 8 wt.% solids.
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| 5. |
- Isaksson, Johan, et al.
(författare)
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Predictors of long-term survival and recurrence patterns after definitive chemoradiotherapy in stage III NSCLC – a multicenter cohort study from Mid Sweden
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Stage III NSCLC is heterogeneous but often recurs despite intensive treatment with curative intent. Clinical tools to predict the risk and pattern of recurrence and long-term survival in individual patients are largely lacking. Methods: NSCLC stage III patients (N=193) treated 2009-2018 with definitive, curatively intended chemoradiotherapy (CRT, 60Gy+) were retrospectively identified from three healthcare regions in Mid Sweden. Outcome variables included overall survival (OS), progression-free survival (PFS) and recurrence patterns. Results: Median follow-up of patients alive was 52 months. 1, 2 and 5-year OS was 80%, 63% and 34% with a mOS of 32 months. Pre-treatment serum inflammatory markers were associated with inferior OS, including leukocyte count > 10 (HR 1.58, 95% CI 1.08-2.31, p=0.018) and CRP > 5 (HR 1.81, 95% CI 1.16-2.83, p=0.009). CRP remained independently associated with OS in multivariable analysis, HR 1.67 (1.05-2.65, p=0.029). No other pre-treatment variable was significantly associated with OS. Progressive disease (PD) was documented in 65% of patients after a median time of 9.5 months, 96% within 3 years from CRT, and was typically either distant or locoregional (12% mixed). Distant PD developed earlier (6.3 months) than locoregional PD (11.5 months; p=0.052). N3 disease (OR 2.7, 95% CI 1.2-6.3,; p=0.022) and presence of driver mutations (OR 4.6, 95% CI 1.5-14.0; p=0.0076) increased the risk of distant PD, while ≥2 concurrent chemotherapy courses was protective of locoregional PD (OR 0.38, 9% CI 0.1-1.0; p=0.049). Brain metastases were the first indication of PD in 22 patients (12%) and were in all cases isolated without synchronous extracranial PD. A post-CRT 18F-FDG-PET SUVmax of ≥7 was associated with a shorter time to PD (HR 0.41, 95% CI 0.21-0.79, p=0.008). Conclusions: The study reinforces the prognostic role of systemic inflammation in stage III NSCLC and provides clinically useful indicators of relapse pattern as a basis for rational disease monitoring following CRT.
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| 6. |
- Isaksson, Rebecka, et al.
(författare)
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A Series of Analogues to the AT2R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode
- 2019
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Ingår i: ChemistryOpen. - : Wiley. - 2191-1363. ; 8:1, s. 114-125
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Tidskriftsartikel (refereegranskat)abstract
- We here report on our continued studies of ligands binding tothe promising drug target angiotensin II type 2 receptor (AT2R). Two series of compounds were synthesized and investigated. The first series explored the effects of adding small substituents to the phenyl ring of the known selective nonpeptide AT2R antagonist C38, generating small but significant shifts in AT2R affinity. One compound in the first series was equipotent to C38 and showed similar kinetic solubility, and stability in both human and mouse liver microsomes. The second series was comprised of new bicyclic derivatives, amongst which one ligand exhibited a five-fold improved affinity to AT2R ascompared to C38. The majority of the compounds in the second series, including the most potent ligand, were inferior to C38 with regard to stability in both human and mouse microsomes. In contrast to our previously reported findings, ligands with shorter carbamate alkyl chains only demonstrated slightly improved stability in microsomes. Based on data presented herein, a more adequate, tentative model of the binding modes of ligand analogues to the prototype AT2R antagonist C38 is proposed, as deduced from docking redefined by molecular dynamic simulations.
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| 7. |
- Isaksson, Rebecka, et al.
(författare)
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Direct stimulation of angiotensin II type 2 receptor reduces nitric oxide production in lipopolysaccharide treated mouse macrophages
- 2020
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Ingår i: European Journal of Pharmacology. - : Elsevier. - 0014-2999 .- 1879-0712. ; 868
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Tidskriftsartikel (refereegranskat)abstract
- The angiotensin II type 2 receptor (AT2) is upregulated after tissue damage and mediates protective functions in the renin-angiotensin-aldosterone system (RAAS). One of these is to inhibit inducible nitric oxide synthase (iNOS) in activated macrophages. In the present study, we assessed the effect of AT2 receptor ligands on nitric oxide production in murine macrophages as a potential assay to determine the functional activity of an AT2 receptor ligand. Mouse macrophage J744.2 and RAW264.7 were cultivated in lipopolysaccharide (LPS) to induce M1 differentiation and increase iNOS expression. Using Griess reagent and spectrophotometric analysis, the nitric oxide levels were determined, while employing Western blot and immunocytochemistry to determine basal protein expression.Using the first reported selective non-peptide AT2 receptor agonist, compound C21, we conclude that activation of AT2 receptor reduces nitric oxide production in M1 macrophages. Furthermore, the AT2 receptor selective ligand compound C38, a regioisomer of C21, reported as a selective AT2 receptor antagonist exhibits a similar effect on nitric oxide production. Thus, we propose C38 acts as a partial agonist in the macrophage system. Monitoring nitric oxide attenuation in M1 J744.1 and RAW264.7 macrophages provides a new method for characterizing functional activity of AT2 receptor ligands, foreseen to be valuable in future drug discovery programs.
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| 8. |
- Isaksson, Rebecka, 1988-
(författare)
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Ligands of the Angiotensin II Type 2 Receptor : Exploring structure and function of the AT2R ligand C38
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The renin-angiotensin-aldosterone-system (RAAS) control blood-pressure regulation, exerted by the main effector peptide angiotensin II (AngII) binding the angiotensin II type 1 receptor (AT1R). While hypertension is the most known disease caused by over-activity in RAAS, several proteins in the system exhibit protective functions.One of these protective proteins is the GPCR angiotensin II type 2 receptor (AT2R). After decades of research its biological role remain to be fully elucidated, exemplified by the two AT2R ligands currently in clinical trials; agonist C21 for treatment of idiopathic pulmonary fibrosis, and antagonist EMA401 for treatment of peripheral neuropathic pain. Making a minor structural change in C21 shifted the pharmacological profile, generating the regioisomer antagonist C38. The renewed interest in AT2R antagonists as potential drugs to treat neuropathic pain make continued studies of antagonist C38 highly interesting. The aim of this thesis was to continue exploring the structure-activity relationship of antagonist C38 by investigating three chemical motifs to identify compounds with better drug-like properties. Developing a new chemical method, transesterification of sulfonyl carbamates, allowed quick modification of one of the motifs. Reducing the length of the sulfonyl carbamate chain significantly increased metabolic stability in liver microsomes without losing affinity for AT2R. Using a model substrate, the transesterification reaction was applied in a microwave heated continuous-flow system.Adding small substituents to the central phenyl ring generated a second library of ligands with retained affinity, but with no observed increase in metabolic stability. Docking studies with this library and a recently presented crystal structure of AT2R, resulted in a proposed binding mode of C38. Replacing the imidazole head group with bicyclic amides slightly improved affinity. While metabolic stability improved compared to previously published amide analogs, the bicyclic ligands were inferior to C38. Developing an assay based on RAW264.7 macrophages allowed a new evaluation of the functional activity exhibited by C38. In contrast to previous research, C21 and C38 both display agonistic functional activity in the macrophage assay.In summary, the work presented in this thesis expand the structure-activity relationship of C38 and its pharmacological profile. Two new ligands were identified that could serve as tools in murine models of neuropathic pain.
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| 9. |
- Isaksson, Rebecka, et al.
(författare)
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Rapid and straightforward transesterification of sulfonyl carbamates
- 2016
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Ingår i: Tetrahedron Letters. - : Elsevier BV. - 0040-4039 .- 1359-8562. ; 57:13, s. 1476-1478
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Tidskriftsartikel (refereegranskat)abstract
- A fast and convenient method for the alkoxy exchange of sulfonyl carbamates by simply heating in a chosen alkyl alcohol is described. No catalysts or additives are required. Microwave heating at 100-120 degrees C for 20-60 min resulted in good to excellent yields (53-93%) of alkyl (arylsulfonyl)carbamates where the alkyl part originates from the alcohol solvent. The developed protocol was applied to the synthesis of an angiotensin II type 2 receptor (AT2R) ligand.
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| 10. |
- Kjellström, Rebecka, et al.
(författare)
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Social hållbarhet i regional kollektivtrafikplanering : perspektiv och processer för att stärka den sociala hållbarhetens position i planeringssammanhang
- 2021
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Syftet med denna studie har varit att fördjupa förståelsen av hur sociala hållbarhetsfrågor kan integreras och operationaliseras i strategisk regional kollektivtrafikplanering. Empiriskt fokus har riktats mot region Stockholms trafikförsörjningsprogram och processen med att ta fram det. Specifikt undersöks hur den regionala trafikförsörjningsplaneringen i nuläget förhåller sig till, och inkluderar social hållbarhet. Mot denna bakgrund diskuteras möjliga sätt att vidareutveckla dagens ansatser och praktik. Studien har genomförts utifrån en kvalitativ metodansats, och grundas dels i semistrukturerade intervjuer med planerare och analytiker som arbetar med strategisk samhälls- och kollektivtrafikplanering samt hållbarhetsfrågor vid Region Stockholm, dels i analyser av centrala dokument från aktuell regional planering och kollektivtrafikplanering.
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