| 61. |
- Adler, Jeremy, et al.
(författare)
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Quantifying Colocalization: the Case for Discarding the Manders Overlap Coefficient.
- 2021
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Ingår i: Cytometry. Part A : the journal of the International Society for Analytical Cytology. - : Wiley. - 1552-4930. ; 99:9, s. 910-920
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Tidskriftsartikel (refereegranskat)abstract
- Colocalization measurements aim to characterize the relative distribution of two molecules within a biologically relevant area. It is efficient to measure two distinct features, co-occurrence, the extent to which the molecules appear together, and correlation, how well variations in concentration of the two molecules match. The Manders overlap coefficient (MOC) appears in most colocalization software but the literature contains three interpretations of its measurements: a) co-occurrence, b) correlation or c) a combination of both. This is surprising given the simplicity of the underlying equation. Testing shows that the MOC responds both to changes in co-occurrence and to changes in correlation. Further testing reveals that different distributions of intensity (Gaussian, gamma, uniform, exponential) dramatically alter the balance between the contribution from co-occurrence and correlation. It follows that the MOC's ability to differentiate between different patterns of colocalization is very limited, since any value is compatible with widely differing combinations of co-occurrence, correlation and intensity distribution. To characterize colocalization we recommend reporting both co-occurrence and correlation, using coefficients specific for each attribute. Since the MOC has no clear role in the measurement of colocalization and causes considerable confusion, we conclude that it should be discarded. This article is protected by copyright. All rights reserved.
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| 62. |
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| 63. |
- Adolfsson, Emma, 1977-, et al.
(författare)
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Bone marrow- and adipose tissue-derived mesenchymal stem cells from donors with coronary artery disease : growth, yield, gene expression and the effect of oxygen concentration
- 2020
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Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Taylor & Francis. - 0036-5513 .- 1502-7686. ; 80:4, s. 318-326
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Tidskriftsartikel (refereegranskat)abstract
- Mesenchymal stem cells (MSCs) for cardiovascular cell therapy are procured from different sources including bone marrow and adipose tissue. Differently located MSCs differ in growth potential, differentiation ability and gene expression when cultured in vitro, and studies show different healing abilities for different MSC subgroups. In this study, bone marrow derived MSCs (BMSCs) and adipose tissue derived MSCs (ADSCs) from six human donors with coronary artery disease were compared for growth potential and expression of target genes (Angpt1, LIF, HGF, TGF-β1 and VEGF-A) in response to exposure to 1% and 5% O2, for up to 48 h. We found greater growth of ADSCs compared to BMSCs. ADSCs expressed higher levels of Angpt1, LIF and TGF-β1 and equal levels of VEGF-A and HGF as BMSCs. In BMSCs, exposure to low oxygen resulted in upregulation of TGF-β1, whereas other target genes were unaffected. Upregulation was only present at 1% O2. In ADSCs, LIF was upregulated in both oxygen concentrations, whereas Angpt1 was upregulated only at 1% O2. Different response to reduced oxygen culture conditions is of relevance when expanding cells in vitro prior to administration. These findings indicate ADSCs as better suited for cardiovascular cell therapy compared to BMSCs.
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| 64. |
- Adolfsson, Jörgen
(författare)
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Expression and role of the cytokine tyrosine kinase receptor flt3 in early hematopoiesis
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mature blood cells are crucial for life, but they have a short lifetime and thus have to be replaced. These mature blood cells are produced by lineage restricted progenitors, which themselves are generated by rare multipotent hematopoietic stem cells (HSCs) in a highly dynamic process called hematopoiesis. In addition to the ability of HSCs to generate all blood cell lineages, they possess the unique property of self-renewal, a process in which a HSC, during a cell division generate at least one daughter cell identical to the parental cell. The maintenance and regulation of HSCs and earliest stages of lineage development are partly controlled by soluble and membrane bound regulators called cytokines. The focus in this thesis has been on the cytokine tyrosine kinase receptor flt3 and its ligand and their role in regulating HSCs and the earliest progenitors in adult murine bone marrow (BM). Earlier studies had implicated a role for flt3 and its ligand in the maintenance of HSCs. When studying mice with targeted deletion of the flt3 ligand (FL), we failed to find any role of flt3 and its ligand in HSC regulation. However, the generation of the common lymphoid progenitor (CLP) and earliest stages of B- and T cell development were severely affected, but not myeloid progenitors or later stages of lymphoid development. Based on flt3 expression, we subfractionated the Lin(-)Sca-1(+)c-kit(+) (LSK) stem cell pool in mouse bone marrow. In contrast to LSKflt3- cells, which sustained multilineage long-term reconstitution, LSKflt3+ cells generated only short-term lymphoid dominated reconstitution when injected into lethally ablated recipients. We also demonstrated the hierarchical relationship at the earliest stages of hematopoiesis, in that LSKflt3- HSCs generate LSKflt3+ cells, which generate the CLP but not the LSKflt3- cells. In the classical model of the hematopoietic hierarchy, the first lineage commitment step of HSCs results in a strict separation into distinct lymphoid and myeloid pathways, generating the recently identified CLP and the common myeloid progenitor (CMP). However, in sharp contrast to LSKflt3-, cells which could generate all blood cell lineages, LSK cells expressing flt3 could not generate megakaryocytes or erythroid cells. Thus, these finding together with the above mentioned relationship between the LSKflt3-, LSKflt3+ and CLP do not support the classical hematopoietic hierarchy model depicting the first lineage commitment generating a strict separation of lymphoid and myeloid pathways. The LSK population contains all LT-HSC activity. However, this population is not homogenous neither in phenotype or function and it has been proposed to contain at least two populations, one with long-term reconstitution (LTR) potential and one with short-term reconstitution potential. Based on the expression of CD34 and flt3 within the adult LSK stem cell pool we were able to subfractionate short-term hematopoietic stem cells (ST-HSC) from the LT-HSCs. In contrast to the LSKCD34-flt3- and LSKCD34+flt3+ cells, the LSKCD34+flt3- is highly enriched for CFU-S activity and capable of rescuing lethally irradiated recipients, fulfilling the criteria of ST-HSCs.
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| 65. |
- Adolfsson, Jörgen, et al.
(författare)
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Identification of Flt3(+) lympho-myeloid stem cells lacking erythro-megakaryocytic potential: A revised road map for adult blood lineage commitment
- 2005
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Ingår i: Cell. - : Elsevier (Cell Press). - 0092-8674 .- 1097-4172. ; 121:2, s. 295-306
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Tidskriftsartikel (refereegranskat)abstract
- All blood cell lineages derive from a common hematopoietic stem cell (HSC). The current model implicates that the first lineage commitment step of adult pluripotent HSCs results in a strict separation into common lymphoid and common myeloid precursors. We present evidence for a population of cells which, although sustaining a high proliferative and combined lympho-myeloid differentiation potential, have lost the ability to adopt erythroid and megakaryocyte lineage fates. Cells in the Lin-Sca-1+c-kit+ HSC compartment coexpressing high levels of the tyrosine kinase receptor Flt3 sustain granulocyte, monocyte, and B and T cell potentials but in contrast to Lin-Sca-1(+)ckit(+)Flt3(-) HSCs fail to produce significant erythroid and megakaryocytic progeny. This distinct lineage restriction site is accompanied by downregulation of genes for regulators of erythroid and megakaryocyte development. In agreement with representing a lymphoid primed progenitor, Lin(-)Sca-l(+)c-kit(+)CD34(+)Flt3(+) cells display upregulated IL-7 receptor gene expression. Based on these observations, we propose a revised road map for adult blood lineage development.
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| 66. |
- Adolfsson, Per I, et al.
(författare)
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Zinc Induces a Bell-shaped Proliferative Dose-response Effect in Cultured Smooth Muscle Cells From Benign Prostatic Hyperplasia.
- 2015
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Ingår i: Urology. - : Elsevier BV. - 0090-4295 .- 1527-9995. ; 85:3, s. 704.e15-704.e19
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate the effects of zinc (Zn(2+)) concentrations on cultured benign prostatic hyperplasia (BPH) smooth muscle cell (SMC) proliferation.METHODS: The effects of Zn(2+) were studied in primary cultures of human BPH SMC, stimulated with either 10-μM lysophosphatidic acid (LPA) or LPA in combination with 100-nM testosterone. Deoxyribonucleic acid replication and protein synthesis using [(3)H]-thymidine and [(35)S]-methionine incorporation were measured. Furthermore, studies were performed to evaluate if Zn(2+) could potentiate the inhibitory effect of phosphodiesterase-5 blockers, on BPH SMC proliferation.RESULTS: Zn(2+) generated a bell-shaped concentration response, both regarding deoxyribonucleic acid replication and protein synthesis in cultured BPH SMC. Below a threshold value (approximately 200 μM), a significant mitogenic effect was seen, whereas higher concentrations inhibited SMC proliferation after stimulation with LPA. This effect was even more pronounced after stimulation of LPA in combination with testosterone. Moreover, phosphodiesterase-5 inhibitors, that is, sildenafil blocked LPA-stimulated BPH SMC proliferation. This antiproliferative effect, was significantly potentiated by coincubation with Zn(2+) in an additative manner.CONCLUSION: The bell-shaped concentration response of Zn(2+) on cultured BPH SMC proliferation suggests that changes in prostate Zn(2+) concentrations, during aging, diet, or inflammatory conditions, may be of importance in the pathogenesis of BPH.
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| 67. |
- Adori, Csaba, et al.
(författare)
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Disorganization and degeneration of liver sympathetic innervations in nonalcoholic fatty liver disease revealed by 3D imaging
- 2021
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:30
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Tidskriftsartikel (refereegranskat)abstract
- Hepatic nerves have a complex role in synchronizing liver metabolism. Here, we used three-dimensional (3D) immunoimaging to explore the integrity of the hepatic nervous system in experimental and human nonalcoholic fatty liver disease (NAFLD). We demonstrate parallel signs of mild degeneration and axonal sprouting of sympathetic innervations in early stages of experimental NAFLD and a collapse of sympathetic arborization in steatohepatitis. Human fatty livers display a similar pattern of sympathetic nerve degeneration, correlating with the severity of NAFLD pathology. We show that chronic sympathetic hyperexcitation is a key factor in the axonal degeneration, here genetically phenocopied in mice deficient of the Rac-1 activator Vav3. In experimental steatohepatitis, 3D imaging reveals a severe portal vein contraction, spatially correlated with the extension of the remaining nerves around the portal vein, enlightening a potential intrahepatic neuronal mechanism of portal hypertension. These fundamental alterations in liver innervation and vasculature uncover previously unidentified neuronal components in NAFLD pathomechanisms.
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| 68. |
- Adori, Monika, et al.
(författare)
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Hepatic Innervations and Nonalcoholic Fatty Liver Disease
- 2023
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Ingår i: Seminars in liver disease (Print). - : Thieme Medical Publishers, Inc.. - 0272-8087 .- 1098-8971. ; 43:02, s. 149-162
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Forskningsöversikt (refereegranskat)abstract
- Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder. Increased sympathetic (noradrenergic) nerve tone has a complex role in the etiopathomechanism of NAFLD, affecting the development/progression of steatosis, inflammation, fibrosis, and liver hemodynamical alterations. Also, lipid sensing by vagal afferent fibers is an important player in the development of hepatic steatosis. Moreover, disorganization and progressive degeneration of liver sympathetic nerves were recently described in human and experimental NAFLD. These structural alterations likely come along with impaired liver sympathetic nerve functionality and lack of adequate hepatic noradrenergic signaling. Here, we first overview the anatomy and physiology of liver nerves. Then, we discuss the nerve impairments in NAFLD and their pathophysiological consequences in hepatic metabolism, inflammation, fibrosis, and hemodynamics. We conclude that further studies considering the spatial-temporal dynamics of structural and functional changes in the hepatic nervous system may lead to more targeted pharmacotherapeutic advances in NAFLD.
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| 69. |
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| 70. |
- Afanasyeva, Elena A., et al.
(författare)
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Kalirin-RAC controls nucleokinetic migration in ADRN-type neuroblastoma
- 2021
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Ingår i: Life Science Alliance. - : Life Science Alliance, LLC. - 2575-1077. ; 4:5
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Tidskriftsartikel (refereegranskat)abstract
- The migrational propensity of neuroblastoma is affected by cell identity, but the mechanisms behind the divergence remain unknown. Using RNAi and time-lapse imaging, we show that ADRN-type NB cells exhibit RAC1- and kalirin-dependent nucleokinetic (NUC) migration that relies on several integral components of neuronal migration. Inhibition of NUC migration by RAC1 and kalirin-GEF1 inhibitors occurs without hampering cell proliferation and ADRN identity. Using three clinically relevant expression dichotomies, we reveal that most of up-regulated mRNAs in RAC1- and kalirin-GEF1-suppressed ADRN-type NB cells are associated with low-risk characteristics. The computational analysis shows that, in a context of overall gene set poverty, the upregulomes in RAC1- and kalirin-GEF1-suppressed ADRN-type cells are a batch of AU-rich element-containing mRNAs, which suggests a link between NUC migration and mRNA stability. Gene set enrichment analysis-based search for vulnerabilities reveals prospective weak points in RAC1- and kalirin-GEF1-suppressed ADRN-type NB cells, including activities of H3K27- and DNA methyltransferases. Altogether, these data support the introduction of NUC inhibitors into cancer treatment research.
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