| 1. |
- Janelidze, Shorena, et al.
(författare)
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Increased blood-brain barrier permeability is associated with dementia and diabetes but not amyloid pathology or APOE genotype
- 2017
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 51, s. 104-112
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Tidskriftsartikel (refereegranskat)abstract
- Blood-brain barrier (BBB) dysfunction might be an important component of many neurodegenerative disorders. In this study, we investigated its role in dementia using large clinical cohorts. The cerebrospinal fluid (CSF)/plasma albumin ratio (Qalb), an indicator of BBB (and blood-CSF barrier) permeability, was measured in a total of 1015 individuals. The ratio was increased in patients with Alzheimer's disease, dementia with Lewy bodies or Parkinson's disease dementia, subcortical vascular dementia, and frontotemporal dementia compared with controls. However, this measure was not changed during preclinical or prodromal Alzheimer's disease and was not associated with amyloid positron emission tomography or APOE genotype. The Qalb was increased in diabetes mellitus and correlated positively with CSF bio-markers of angiogenesis and endothelial dysfunction (vascular endothelial growth factor, intracellular adhesion molecule 1, and vascular cell adhesion molecule 1). In healthy elderly, high body mass index and waist-hip ratio predicted increased Qalb 20 years later. In summary, BBB permeability is increased in major dementia disorders but does not relate to amyloid pathology or APOE genotype. Instead, BBB impairment may be associated with diabetes and brain microvascular damage. (C) 2016 The Authors. Published by Elsevier Inc.
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| 2. |
- Jespersen, Henrik, et al.
(författare)
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Clinical responses to adoptive T-cell transfer can be modeled in an autologous immune-humanized mouse model.
- 2017
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Immune checkpoint inhibitors and adoptive cell transfer (ACT) of autologous tumor-infiltrating T cells have shown durable responses in patients with melanoma. To study ACT and immunotherapies in a humanized model, we have developed PDXv2.0 -a melanoma PDX model where tumor cells and tumor-infiltrating T cells from the same patient are transplanted sequentially in non-obese diabetic/severe combined immune-deficient/common gamma chain (NOG/NSG) knockout mouse. Key to T-cell survival/effect in this model is the continuous presence of interleukin-2 (IL-2). Tumors that grow in PDXv2.0 are eradicated if the autologous tumor cells and T cells come from a patient that exhibited an objective response to ACT in the clinic. However, T cells from patients that are non-responders to ACT cannot kill tumor cells in PDXv2.0. Taken together, PDXv2.0 provides the potential framework to further model genetically diverse human cancers for assessing the efficacy of immunotherapies as well as combination therapies.Combining different types of immune therapies might benefit certain patients. Here, the authors develop an autologous immune-humanized melanoma mouse model that allows the preclinical assessment of cancer cell-T cell interactions from each individual patient and the benefits of immunotherapies combinations.
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| 3. |
- Nilsson, Anders, et al.
(författare)
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Catalysis in real time using X-ray lasers
- 2017
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Ingår i: Chemical Physics Letters. - : Elsevier BV. - 0009-2614 .- 1873-4448. ; 675, s. 145-173
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Tidskriftsartikel (refereegranskat)abstract
- We describe how the unique temporal and spectral characteristics of X-ray free-electron lasers (XFEL) can be utilized to follow chemical transformations in heterogeneous catalysis in real time. We highlight the systematic study of CO oxidation on Ru(0001), which we initiate either using a femtosecond pulse from an optical laser or by activating only the oxygen atoms using a THz pulse. We find that CO is promoted into an entropy-controlled precursor state prior to desorbing when the surface is heated in the absence of oxygen, whereas in the presence of oxygen, CO desorbs directly into the gas phase. We monitor the activation of atomic oxygen explicitly by the reduced split between bonding and antibonding orbitals as the oxygen comes out of the strongly bound hollow position. Applying these novel XFEL techniques to the full oxidation reaction resulted in the surprising observation of a significant fraction of the reactants at the transition state through the electronic signature of the new bond formation.
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| 4. |
- Ullmark, Tove, et al.
(författare)
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Distinct global binding patterns of the Wilms' tumor gene 1 (WT1) -KTS and +KTS isoforms in leukemic cells
- 2017
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 102:2, s. 336-345
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Tidskriftsartikel (refereegranskat)abstract
- The zinc finger transcription factor Wilms' tumor gene 1 (WT1) acts as an oncogene in acute myeloid leukemia. A naturally occurring alternative splice event between zinc fingers three and four, removing or retaining three amino acids (+/-KTS), is believed to change the DNA binding affinity of WT1, although there are conflicting data regarding the binding affinity and motifs of the different isoforms. Increased expression of WT1 -KTS at the expense of WT1 +KTS isoform associates with poor prognosis in acute myeloid leukemia. We determined the genome-wide binding pattern of WT1 -KTS and WT1 +KTS in leukemic K562 cells by chromatin immunoprecipitation and deep sequencing (ChIP-seq). Motif discovery revealed distinct binding motifs for the isoforms, some of which have been previously reported as WT1 binding sites. We discovered that the WT1 -KTS isoform predominantly binds close to transcription start sites and to enhancers, in a similar fashion to other transcription factors, whereas WT1 +KTS binding is rather enriched within gene bodies. We observed a significant overlap between WT1 -KTS and WT1 +KTS target genes, despite the binding sites being distinct. Motif discovery revealed distinct binding motifs for the isoforms, some of which have been previously reported as WT1 binding sites. Additional analyses showed that both WT1 -KTS and WT1 +KTS target genes are more likely to be transcribed than non-targets, and are involved in cell proliferation, cell death, and development. Our study provides evidence that WT1 -KTS and WT1 +KTS share target genes yet still bind distinct locations, indicating isoform-specific regulation in transcription of genes related to cell proliferation and differentiation, consistent with involvement of WT1 in acute myeloid leukemia.
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| 5. |
- Antonelli, Alexandre, 1978, et al.
(författare)
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Toward a Self-Updating Platform for Estimating Rates of Speciation and Migration, Ages, and Relationships of Taxa.
- 2017
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Ingår i: Systematic biology. - : Oxford University Press (OUP). - 1076-836X .- 1063-5157. ; 66:2, s. 152-166
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Tidskriftsartikel (refereegranskat)abstract
- Rapidly growing biological data-including molecular sequences and fossils-hold an unprecedented potential to reveal how evolutionary processes generate and maintain biodiversity. However, researchers often have to develop their own idiosyncratic workflows to integrate and analyze these data for reconstructing time-calibrated phylogenies. In addition, divergence times estimated under different methods and assumptions, and based on data of various quality and reliability, should not be combined without proper correction. Here we introduce a modular framework termed SUPERSMART (Self-Updating Platform for Estimating Rates of Speciation and Migration, Ages, and Relationships of Taxa), and provide a proof of concept for dealing with the moving targets of evolutionary and biogeographical research. This framework assembles comprehensive data sets of molecular and fossil data for any taxa and infers dated phylogenies using robust species tree methods, also allowing for the inclusion of genomic data produced through next-generation sequencing techniques. We exemplify the application of our method by presenting phylogenetic and dating analyses for the mammal order Primates and for the plant family Arecaceae (palms). We believe that this framework will provide a valuable tool for a wide range of hypothesis-driven research questions in systematics, biogeography, and evolution. SUPERSMART will also accelerate the inference of a "Dated Tree of Life" where all node ages are directly comparable. [Bayesian phylogenetics; data mining; divide-and-conquer methods; GenBank; multilocus multispecies coalescent; next-generation sequencing; palms; primates; tree calibration.].
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| 6. |
- Augustinsson, Sören, et al.
(författare)
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How to conceptualize practice as manager in academic education?
- 2017
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Ingår i: Presented at: Educational Governance and Leadership in Transition: Leading and organizing the education for citizenship of the world through technocratic homogenisation or communicative diversity?, Oslo 18-19 oktober 2017.
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Konferensbidrag (refereegranskat)
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| 7. |
- Bergenfeldt, Henrik, et al.
(författare)
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Donor-recipient size matching and mortality in heart transplantation : Influence of body mass index and gender
- 2017
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Ingår i: Journal of Heart and Lung Transplantation. - : Elsevier BV. - 1053-2498. ; 36:9, s. 940-947
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Tidskriftsartikel (refereegranskat)abstract
- Background: The International Society for Heart and Lung Transplantation (ISHLT) guidelines advise against inappropriate weight match (IWM) for heart transplant, defined as donor weight <70% of recipient's weight. Few studies have explored in detail this size-matching recommendation, especially with regard to body mass index (BMI) and gender matching. We aimed to determine whether any difference could be observed between size-matching in obese and non-obese recipients with regard to mortality after cardiac transplantation. Methods: Data from 52,455 adult heart transplants (recipients ≥18 years of age) between 1994 and 2013 were obtained from the ISHLT Registry. We defined the following subgroups of patients based on BMI: underweight, BMI <18.5; non-obese, BMI 18.5 to 30; and obese, BMI >30. The end-points were all-cause 30-day mortality and cumulative mortality. Results: IWM was associated with increased 30-day mortality (odds ratio [OR] = 1.20, 95% confidence interval [CI] 1.01 to 1.43, p = 0.041) and cumulative mortality (hazard ratio [HR] = 1.14, 95% CI 1.07 to 1.22, p < 0.001). In non-obese recipients, IWM was associated with increased 30-day mortality (OR = 1.89, 95% CI 1.48 to 2.41, p < 0.001) as well as cumulative mortality (HR = 1.27, 95% CI 1.15 to 1.41, p < 0.001), whereas, for obese recipients, IWM was not associated with 30-day or cumulative mortality. Male recipients of female allografts (HR = 1.08, 95% CI 1.04 to 1.12, p < 0.001) as well as female recipients of male allografts (HR = 1.07, 95% CI 1.02 to 1.13, p = 0.003) had increased cumulative mortality compared with gender-matched transplants. There was no interaction between IWM and gender mismatch. Conclusions: Our results indicate that donor weight <70% of recipient weight increases mortality in non-obese heart transplant recipients, but not in obese transplant recipients. Gender mismatch increases mortality independently of weight match.
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| 8. |
- Berggren, Peter, 1971-, et al.
(författare)
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The importance of using the designated duty officers when assessing the medical response organization
- 2017
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundAn important aspect of disaster medicine is to be proactive and respond quickly when disaster strikes. In Sweden, the role responsible for swift medical response on the regional level is the designated duty officer.MethodsA large exercise to assess national medical response ability was conducted. Seven medical regional staffs (a total of 93 individuals participated as tested participants) were involved in handling a large train accident scenario. The exercise was run for 5 hours, where the different regional staffs were located at their regular command posts. The exercise was organized using Emergo Train Systems.ResultsSeveral capabilities were identified during the exercise as important for the organization to maintain the ability to handle a similar event: documentation and operational picture, communication and terminology, command of resources, strategy for distribution of resources, national co-ordination, and exercise development.The designated duty officers were central to the exercise in several aspects: 1) in developing and verifying a realistic scenario and preparing background information, 2) as participants in the exercise, 3) assessors of the staffs’ behaviors, and 4) as domain experts when interpreting the exercise outcome.ConclusionsUsing subject matter experts is central to many research domains. However, the more complex a situation is the larger the demand of expertise is. The technical platform allows for coordinating complex exercises, whereas the subject matter expert in terms of the designated duty officer is required to guarantee validity and reliability in these large-scale exercises.Key messages:Running complex scenarios to train and test abilities requires subject matter experts in both planning, preparation, implementation, and assessment.Sophisticated simulator and training platforms, such as Emergo Train Systems, facilitates while the designated duty officers are necessary to guarantee validity and reliability in the exercise.
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| 9. |
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| 10. |
- Chen, Gefei, et al.
(författare)
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Bri2 BRICHOS client specificity and chaperone activity are governed by assembly state
- 2017
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- . Protein misfolding and aggregation is increasingly being recognized as a cause of disease. In Alzheimer's disease the amyloid-beta peptide (A beta) misfolds into neurotoxic oligomers and assembles into amyloid fibrils. The Bri2 protein associated with Familial British and Danish dementias contains a BRICHOS domain, which reduces A beta fibrillization as well as neurotoxicity in vitro and in a Drosophila model, but also rescues proteins from irreversible nonfibrillar aggregation. How these different activities are mediated is not known. Here we show that Bri2 BRICHOS monomers potently prevent neuronal network toxicity of A beta, while dimers strongly suppress A beta fibril formation. The dimers assemble into high-molecular-weight oligomers with an apparent two-fold symmetry, which are efficient inhibitors of non-fibrillar protein aggregation. These results indicate that Bri2 BRICHOS affects qualitatively different aspects of protein misfolding and toxicity via different quaternary structures, suggesting a means to generate molecular chaperone diversity.
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