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| 2. |
- Pass, Jesper, et al.
(författare)
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Murine monoclonal antibodies against murine uPA receptor produced in gene-deficient mice: inhibitory effects on receptor-mediated uPA activity in vitro and in vivo
- 2007
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Ingår i: Thrombosis and Haemostasis. - 0340-6245. ; 97:6, s. 1013-1022
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Tidskriftsartikel (refereegranskat)abstract
- Binding of urokinase plasminogen activator (uPA) to its cellular receptor, uPAR, potentiates plasminogen activation and localizes it to the cell surface. Focal plasminogen activation is involved in both normal and pathological tissue remodeling processes including cancer invasion. The interaction between uPA and uPAR therefore represents a potential target for anti-invasive cancer therapy. Inhibitors of the human uPA-uPAR interaction have no effect in the murine system. To enable in-vivo studies in murine cancer models we have now generated murine monoclonal antibodies (mAbs) against murine uPAR (muPAR) by immunizing uPAR-deficient mice with recombinant muPAR and screened for antibodies, which inhibit the muPA-muPAR interaction. Two of the twelve mAbs obtained, mR1 and mR2, interfered with the interaction between muPAR and the amino-terminal fragment of muPA (mATF) when analyzed by surface plasmon resonance. The epitope for mR1 is located on domain I of muPAR, while that of mR2 is on domains (II-III). In cell binding experiments using radiolabelled mATF, the maximal inhibition obtained with mR1 was 85% while that obtained with mR2 was 50%. The IC(50) value for mR1 was 0.67 nM compared to 0.14 nM for mATF. In an assay based on modified anthrax toxins, requiring cell-bound muPA activity for its cytotoxity, an approximately 50% rescue of the cells could be obtained by addition of mR1. Importantly, in-vivo efficacy of mR1 was demonstrated by the ability of mR1 to rescue mice treated with a lethal dose of uPA-activatable anthrax toxins.
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| 3. |
- Hatem, Gad, et al.
(författare)
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Mapping the cord blood transcriptome of pregnancies affected by early maternal anemia to identify signatures of fetal programming
- 2022
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 107:5, s. 1303-1316
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Anemia during early pregnancy (EP) is common in developing countries and is associated with adverse health consequences for both mother and children. Offspring of women with EP anemia often have low birth-weight, the latter being a risk factor for cardiometabolic diseases including type 2 diabetes (T2D) later in life. Mechanisms underlying developmental programming of adult cardiometabolic disease include epigenetic and transcriptional alterations potentially detectable in umbilical cord blood (UCB) at time of birth.METHODS: We leveraged global transcriptome- and accompanying epigenome-wide changes in 48 UCB from newborns of EP-anemic Tanzanian mothers and 50 controls to identify differentially expressed genes (DEG) in UCB exposed to maternal EP-anemia. DEGs were assessed for association with neonatal anthropometry and cord insulin levels. These genes were further studied in expression data from human fetal pancreas and adult islets to understand their role in beta-cell development and/or function.RESULTS: The expression of 137 genes was altered in UCB of newborns exposed to maternal EP anemia. These putative signatures of fetal programming which included the birth-weight locus LCORL, were potentially mediated by epigenetic changes in 27 genes and associated with neonatal anthropometry. Among the DEGs were P2RX7, PIK3C2B, and NUMBL which potentially influence beta-cell development. Insulin levels were lower in EP anemia exposed UCB, supporting the notion of developmental programming of pancreatic beta-cell dysfunction and subsequently increased risk of T2D in offspring of EP anemic mothers.CONCLUSIONS: Our data provide proof-of-concept on distinct transcriptional and epigenetic changes detectable in UCB from newborns exposed to maternal EP anemia.
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| 4. |
- Liu, Kui, et al.
(författare)
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Successful ovulation in plasminogen-deficient mice treated with the broad-spectrum matrix metalloproteinase inhibitor galardin.
- 2006
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Ingår i: Developmental Biology. - New York : Academic P.. - 0012-1606 .- 1095-564X. ; 295:2, s. 615-622
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Tidskriftsartikel (refereegranskat)abstract
- Many studies have suggested the hypothesis that the plasminogen activator (PA) system and the matrix metalloproteinase (MMP) system, either separately or in combination, may provide the proteolytic activity that is required for rupture of the follicular wall at the time of ovulation. Our recent studies on ovulation in plasminogen (plg)-deficient mice have, however, shown that plasmin is not required for normal ovulation, leading us to the hypothesis that MMPs may be a more important source of proteolysis for this process. To investigate the role of MMPs and also the possibility of a functional overlap or synergy between the MMP and PA systems during ovulation, we have studied ovulation efficiency in wild-type and plg-deficient mice treated with the broad-spectrum MMP inhibitor galardin. We found that in both wild-type mice and heterozygous plg-deficient (plg(+/-)) mice that had been treated with galardin prior to ovulation, there was a mild (18-20%) reduction in ovulation efficiency. Surprisingly, galardin treatment of plg-deficient (plg(-/-)) mice only caused an additional 14% reduction in ovulation efficiency as compared to vehicle-treated plg(-/-) mice. Our data therefore suggest that although MMPs may play a role in degradation of the follicular wall, they may not be obligatory for ovulation. In contrast to previous studies on tissue remodeling during wound heating and placental development, we have demonstrated that there is no obvious functional overlap or synergy between the PA and MMP systems, which has previously been thought to be essential for the ovulatory process.
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| 5. |
- Otero, Jaime, et al.
(författare)
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Basin-scale phenology and effects of climate variability on global timing of initial seaward migration of Atlantic salmon (Salmo salar)
- 2014
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Ingår i: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 20:1, s. 61-75
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Tidskriftsartikel (refereegranskat)abstract
- Migrations between different habitats are key events in the lives of many organisms. Such movements involve annually recurring travel over long distances usually triggered by seasonal changes in the environment. Often, the migration is associated with travel to or from reproduction areas to regions of growth. Young anadromous Atlantic salmon (Salmo salar) emigrate from freshwater nursery areas during spring and early summer to feed and grow in the North Atlantic Ocean. The transition from the freshwater ('parr') stage to the migratory stage where they descend streams and enter salt water ('smolt') is characterized by morphological, physiological and behavioural changes where the timing of this parr-smolt transition is cued by photoperiod and water temperature. Environmental conditions in the freshwater habitat control the downstream migration and contribute to within- and among-river variation in migratory timing. Moreover, the timing of the freshwater emigration has likely evolved to meet environmental conditions in the ocean as these affect growth and survival of the post-smolts. Using generalized additive mixed-effects modelling, we analysed spatio-temporal variations in the dates of downstream smolt migration in 67 rivers throughout the North Atlantic during the last five decades and found that migrations were earlier in populations in the east than the west. After accounting for this spatial effect, the initiation of the downstream migration among rivers was positively associated with freshwater temperatures, up to about 10 °C and levelling off at higher values, and with sea-surface temperatures. Earlier migration occurred when river discharge levels were low but increasing. On average, the initiation of the smolt seaward migration has occurred 2.5 days earlier per decade throughout the basin of the North Atlantic. This shift in phenology matches changes in air, river, and ocean temperatures, suggesting that Atlantic salmon emigration is responding to the current global climate changes.
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| 6. |
- Påhlman, Sven, et al.
(författare)
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Differential HIF-1α and HIF-2α Expression in Mammary Epithelial Cells during Fat Pad Invasion, Lactation, and Involution.
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:5
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Tidskriftsartikel (refereegranskat)abstract
- The development and functional cycle of the mammary gland involves a number of processes that are caricatured by breast cancer cells during invasion and metastasis. Expression of the hypoxia-inducible transcription factors HIF-1 and HIF-2 has been associated with metastatic, poor prognosis, and high-grade breast cancers. Since hypoxia affects normal epithelial differentiation, we hypothesise that HIFs are important for normal breast epithelial development and regeneration as well as cancer initiation and progression. Here, we investigated the expression of the oxygen-sensitive HIF-alpha subunits during mouse mammary gland development, lactation, and involution. In breast epithelial cells, HIF-1α was expressed during early development, prior to cell polarisation. In contrast, expression of HIF-2α occurred later and was restricted to a subpopulation of luminal epithelial cells in the lactating gland. Mammary gland involution is a developmental stage that involves extensive tissue remodelling with cell death but survival of tissue stem/progenitor cells. At this stage, HIF-2α, but little HIF-1α, was expressed in CK14-positive epithelial cells. The temporal but differential expression of the HIF-alpha subunits during the mammary gland life cycle indicates that their expression is controlled by additional factors to hypoxia. Further functional studies of the roles of these proteins in the mammary gland and breast cancer are warranted.
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| 7. |
- von Bothmer, Roland, et al.
(författare)
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Jord : mylla, mark och makt
- 2017
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Bok (populärvet., debatt m.m.)abstract
- Våra jordar är basen för en hållbar matproduktion. Vi har tagit jorden och jordarna för självklara men jordens hälsa är en garanti för framtiden. Jorden vi trampar på är av största vikt för allt levande på land. Med tanke på den alarmerande hastighet med vilken världens jordar håller på att förstöras är det viktigt att fästa uppmärksamheten på jord som en värdefull resurs som måste bevaras och utnyttjas skonsamt.Människans historia har varit beroende av hur vi skött eller misskött våra jordar. Våra jordar är dock så mycket mer än den geologiska och biologiska sfären. Jord är också ett laddat begrepp. Jorden bevarar spåren efter tidens flöde och berättar med sina på många ställen tjocka kulturlager. Den är ett arkiv över människans historia och utveckling.Jordens bördighet har varit grunden för alla stora kulturer på vår planet, och krig har utkämpats för att mätta hungern efter bördig jord. Under millennierna har jorden haft en stor symbolisk betydelse, Av jord är du kommen och fosterjorden är uttryck som visar det laddade värdet som jorden och myllan har. Att äga och bruka sin egen jord har under alla tider varit en drivkraft hos människan.Vi lever i människans tidevarv, Antropocen, och i dag är det vi som styr jordens naturgeografi. Är det en slump att rädda våra själar, Save Our Souls (S.O.S.), låter så lika rädda våra jordar, Save our Soils? Ande och materia är nära förbundna och att rädda den värdefulla jorden bidrar också till att rädda oss själva. Är det också en slump att den jorden vi odlar i är homonym till planeten Jorden vi bor på när den astronomiskt korrekta termen egentligen är planeten Tellus?Med denna essäantologi vill vi belysa komplexiteten i begreppet jord och hur dess betydelse genomsyrar hela vår tillvaro. Den är ett möte mellan humaniora, naturvetenskap och agrikultur och syftar till att öka kunskapen och förståelsen om vår sköna och sköra jord.
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| 8. |
- Wahlberg, Patrik, et al.
(författare)
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Functional corpora lutea are formed in matrix metalloproteinase inhibitor-treated plasminogen-deficient mice.
- 2007
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Ingår i: Endocrinology. - 0013-7227. ; 148:3, s. 1226-34
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Tidskriftsartikel (refereegranskat)abstract
- The extended Förster theory (EFT) is for the first time applied to the quantitative determination of the intramolecular distances in proteins. It is shown how the EFT (J. Chem. Phys., 1996, 105, 10896) can be adapted to the analyses of fluorescence depolarisation experiments based on the time-correlated single photon counting technique (TCSPC). The protein system studied was the latent form of plasminogen activator inhibitor type I (PAI-1), which was mutated and labelled by the thiol reactive BODIPY® derivative {N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-yl)methyl iodoacetamide}. The energy migration occurs within pairs of photophysically identical donor groups that undergo reorientational motions on the timescales of energy migration and fluorescence relaxation. Unlike all models currently used for analysing fluorescence TCSPC data, the EFT explicitly accounts for the time-dependent reorientations that influence the rate of electronic energy transfer/migration in a complex manner. The complexity is related to the 2 problem, which has been discussed for years. The EFT brings the analyses of DDEM data to the same level of molecular description as in ESR and NMR spectroscopy, i.e. it yields microscopic information about the reorientation correlation times, the order parameters, as well as inter-chromophoric distances.
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