| 1. |
- Gustafsson, Karin L., 1987, et al.
(författare)
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A tissue-specific role of membrane-initiated ERα signaling for the effects of SERMs
- 2022
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Ingår i: Journal of Endocrinology. - 0022-0795. ; 253:2, s. 75-84
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Tidskriftsartikel (refereegranskat)abstract
- Selective estrogen receptor modulators (SERMs) act as estrogen receptor (ER) agonists or antagonists in a tissue-specific manner. ERs exert effects via nuclear actions but can also utilize membrane-initiated signaling pathways. To dete rmine if membrane-initiated ERα (mERα) signaling affects SERM action in a tissue-specific manner, C451 A mice, lacking mERα signaling due to a mutation at palmitoylation site C451, were treated with Lasofoxifene (Las), Bazedoxifene (Bza), or estradi ol (E2), and various tissues were evaluated. Las and Bza treatment increased uterine weight to a similar extent in C451A and control mice, demonstrating mERα-independent uterine SERM effects, while the E2 effect on the uterus was predominantly mER α-dependent. Las and Bza treatment increased both trabecular and cortical bone mass in controls to a similar degree as E2, while both SERM and E2 treatment effects were abse nt in C451A mice. This demonstrates that SERM effects, similar to E2 effects, in th e skeleton are mERα- dependent. Both Las and E2 treatment decreased thymus weight in controls, while neither treatment affected the thymus in C451A mice, demonstrati ng mERα-dependent SERM and E2 effects in this tissue. Interestingly, both SERM and E2 treatments decreased the total body fat percent in C451A mice, demonstrating the ability of these treatments to affect fat tissue in the absence of functional mER α signaling. In conclusion, mERα signaling can modulate SERM responses in a tissue-specific manne r. This novel knowledge increases the understanding of the mechanisms behind SERM effects and may thereby facilitate the development of new improved SERMs.
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| 2. |
- Gustafsson, Karin L., 1987, et al.
(författare)
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Arginine site 264 in murine estrogen receptor alpha is dispensable for the regulation of the skeleton.
- 2021
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Ingår i: American journal of physiology. Endocrinology and metabolism. - 1522-1555. ; 320:1
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen protects against bone loss, but is not a suitable treatment due to adverse effects in other tissues. Increased knowledge regarding estrogen signaling in estrogen-responsive tissues is therefore warranted to aid the development of bone-specific estrogen treatments. Estrogen receptor alpha (ERα), the main mediator of estrogenic effects in bone, is widely subjected to posttranslational modifications (PTMs). In vitro studies have shown that methylation at site R260 in the human ERα affects receptor localization and intracellular signaling. The corresponding amino acid R264 in murine ERα has been shown to have a functional role in endothelium in vivo; albeit the methylation of R264 in the murine gene is yet to be empirically demonstrated. The aim of this study was to investigate if R264 in ERα is involved in the regulation of the skeleton in vivo. DXA analysis at three, six, nine, and twelve months of age showed no differences in total body areal BMD between R264A and WT in either female or male mice. Furthermore, analyses using CT demonstrated that trabecular bone mass in tibia and vertebra, and cortical thickness in tibia, were similar between R264A and WT mice. In addition, R264A females displayed a normal estrogen treatment response in trabecular bone mass, as well as in cortical thickness. Furthermore, uterus, thymus, and adipose tissue responded similarly in R264A and WT female mice after estrogen treatment. In conclusion, our novel finding that mutation of R264 in ERα does not affect the regulation of the skeleton, together with the known role of R264 for ERα-mediated endothelial effects, supports the concept that R264 determines tissue specificity of ERα.
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| 3. |
- Jiang, Yiwen, et al.
(författare)
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Membrane estrogen receptor alpha signaling modulates the sensitivity to estradiol treatment in a dose- and tissue- dependent manner
- 2023
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Ingår i: Scientific Reports. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Estradiol (E2) affects both reproductive and non-reproductive tissues, and the sensitivity to different doses of E2 varies between tissues. Membrane estrogen receptor alpha (mER alpha)-initiated signaling plays a tissue-specific role in mediating E2 effects, however, it is unclear if mER alpha signaling modulates E2 sensitivity. To determine this, we treated ovariectomized C451A females, lacking mER alpha signaling, and wildtype (WT) littermates with physiological (0.05 mu g/mouse/day (low); 0.6 mu g/mouse/day (medium)) or supraphysiological (6 mu g/mouse/day (high)) doses of E2 (17 beta-estradiol-3-benzoate) for three weeks. Low-dose treatment increased uterus weight in WT, but not C451A mice, while non-reproductive tissues (gonadal fat, thymus, trabecular and cortical bone) were unaffected in both genotypes. Medium-dose treatment increased uterus weight and bone mass and decreased thymus and gonadal fat weights in WT mice. Uterus weight was also increased in C451A mice, but the response was significantly attenuated (- 85%) compared to WT mice, and no effects were triggered in non-reproductive tissues. High-dose treatment effects in thymus and trabecular bone were significantly blunted (- 34% and - 64%, respectively) in C451A compared to WT mice, and responses in cortical bone and gonadal fat were similar between genotypes. Interestingly, the high dose effect in uterus was enhanced (+ 26%) in C451A compared to WT mice. In conclusion, loss of mER alpha signaling reduces the sensitivity to physiological E2 treatment in both non-reproductive tissues and uterus. Furthermore, the E2 effect after high-dose treatment in uterus is enhanced in the absence of mER alpha, suggesting a protective effect of mER alpha signaling in this tissue against supraphysiological E2 levels.
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| 6. |
- Desai, S., et al.
(författare)
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A COX-2 Inhibitor Does Not Interfere With the Bone-Protective Effects of Loading in Male Mice With Arthritis
- 2023
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Ingår i: Jbmr Plus. - 2473-4039. ; 7:7
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Tidskriftsartikel (refereegranskat)abstract
- Mechanical loading enhances bone strength and counteracts arthritis-induced inflammation-mediated bone loss in female mice. It is unknown whether nonsteroidal anti-inflammatory drugs (NSAIDs; eg, COX-2 inhibitors) can reduce inflammation without affecting the loading-associated bone formation in male mice. The aim of this study was to investigate if loading combined with a COX-2 inhibitor (NS-398) could prevent arthritis-induced bone loss and inflammation in male mice. Four-month-old male C57BL/6J mice were subjected to axial tibial mechanical loading three times/week for 2 weeks. Local mono-arthritis was induced with a systemic injection of methylated bovine serum albumin on the first day of loading, followed by a local injection in one knee 1 week later. The arthritis induction, knee swelling, bone architecture, and osteoclast number were evaluated in the hind limbs. C-terminal cross-links as a marker for osteoclast activity was measured in serum. Compared with loading and arthritis alone, loading of the arthritic joint enhanced swelling that was partly counteracted by NS-398. Loading of the arthritic joint enhanced synovitis and articular cartilage damage compared with loading alone. Loading increased cortical bone and counteracted the arthritis-induced decrease in epiphyseal bone. NS-398 did not alter the bone-protective effects of loading. C-terminal cross-links, a bone resorption marker, was increased by arthritis but not loading. In conclusion, loading prevented arthritis-induced epiphyseal and metaphyseal bone loss, and NS-398 reduced knee swelling without affecting the bone-protective effects of loading. If our results can be extrapolated to the human situation, specific COX-2 inhibitors could be used in combination with loading exercise to prevent pain and swelling of the joint without influencing the bone-protective effects of loading. (c) 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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| 7. |
- Engdahl, Elin, et al.
(författare)
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Increased Serological Response Against Human Herpesvirus 6A Is Associated With Risk for Multiple Sclerosis
- 2019
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Human herpesvirus (HHV)-6A or HHV-6B involvement in multiple sclerosis (MS) etiology has remained controversial mainly due to the lack of serological methods that can distinguish the two viruses. A novel multiplex serological assay measuring IgG reactivity against the immediate-early protein 1 from HHV-6A (IE1A) and HHV-6B (IE1B) was used in a MS cohort (8,742 persons with MS and 7,215 matched controls), and a pre-MS cohort (478 individuals and 476 matched controls) to investigate this further. The IgG response against IE1A was positively associated with MS (OR = 1.55, p = 9 × 10-22), and increased risk of future MS (OR = 2.22, p = 2 × 10-5). An interaction was observed between IE1A and Epstein-Barr virus (EBV) antibody responses for MS risk (attributable proportion = 0.24, p = 6 × 10-6). In contrast, the IgG response against IE1B was negatively associated with MS (OR = 0.74, p = 6 × 10-11). The association did not differ between MS subtypes or vary with severity of disease. The genetic control of HHV-6A/B antibody responses were located to the Human Leukocyte Antigen (HLA) region and the strongest association for IE1A was the DRB1*13:01-DQA1*01:03-DQB1*06:03 haplotype while the main association for IE1B was DRB1*13:02-DQA1*01:02-DQB1*06:04. In conclusion a role for HHV-6A in MS etiology is supported by an increased serological response against HHV-6A IE1 protein, an interaction with EBV, and an association to HLA genes.
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| 8. |
- Engdahl, Ingrid, 1952-, et al.
(författare)
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Writing a Thesis : A Guide for Scientific Reports
- 2012
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- This guide is an introduction to one way to write scientific reports, the way we have been using and taught to our students in Teacher Education Programmes and Child and Youth Studies.It includes how to structure the text, suggested content to go under each heading, some rules about quotes and references, cooperation with the advisor and with fellow students and, finally, guides for the thesis seminar, an agenda for the seminar and advice for the opponent(s) and respondent(s). The references follow the APA-manual.
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| 9. |
- Engdahl, Ingrid, 1952-, et al.
(författare)
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Writing a Thesis : A Guide for Scientific Reports
- 2009
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- This guide is an introduction to one way to write scientific reports, the way we have been using and taught to our students in Teacher Education Programmes and Child and Youth Studies. It includes how to structure the text, suggested content to go under each heading, some rules about quotes and references, cooperation with the advisor and with fellow students and, finally, guides for the thesis seminar, an agenda for the seminar and advice for the opponent(s) and respondent(s).
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| 10. |
- Engdahl, Karin
(författare)
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Analysis of Some Convolutional Coding Constructions
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focuses on different convolutional coding constructions for digital communication systems, and on methods to analyze these constructions. The work presented in the thesis can be divided into three main areas; error probability bounds for convolutional codes, analysis of multilevel modulation, and investigation of low-density parity-check convolutional codes. New bounds are developed for the bit and burst error probabilities of convolutional codes that are used for transmission over a binary symmetric channel or an additive white Gaussian noise channel. The new bounds for the burst error probability are significantly tighter than prevalent bounds. Coded modulation is a technique that can be used when constructing bandwidth efficient systems. One form of coded modulation is multilevel modulation, which offers the opportunity to use a suboptimal multistage decoder. This decoder is less complex than the corresponding maximum likelihood decoder is. In this work, multilevel modulation undergoes an asymptotical ensemble analysis in terms of error exponents, and a comparison to the corresponding conventional coded modulation system. Furthermore, the Chernoff bounding parameter is calculated for a number of signal constellations that can be used in multilevel modulation systems. These calculations are done under the assumption that a suboptimal metric, the nearest neighbor metric, is employed in the multistage decoder. For each of these signal constellations, the effective capacity and cutoff rate are also given. Low-density parity-check codes combined with iterative decoding have proved to have the potential to achieve low bit error rates even when operating close to the channel capacity. In this treatise, low-density parity-check convolutional (LDPCC) codes are defined, and different construction methods are presented. A statistical ensemble analysis of LDPCC codes is performed, and it results in bounds on the free distance and on the error probability. Iterative decoding is discussed, an iterative decoding algorithm is given, and simulations are performed for various LDPCC codes.
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