Karolinska Institutet

About: Karolinska Institutet is a education organization based out in Stockholm, Sweden. It is known for research contribution in the topics: Population & Poison control. The organization has 46212 authors who have published 121142 publications receiving 6008130 citations.

Structure of the Ligand-Binding Domain of Oestrogen Receptor Beta in the Presence of a Partial Agonist and a Full Antagonist

Abstract: Oestrogens exert their physiological effects through two receptor subtypes. Here we report the three-dimensional structure of the oestrogen receptor beta isoform (ERbeta) ligand-binding domain (LBD) in the presence of the phyto-oestrogen genistein and the antagonist raloxifene. The overall structure of ERbeta-LBD is very similar to that previously reported for ERalpha. Each ligand interacts with a unique set of residues within the hormone-binding cavity and induces a distinct orientation in the AF-2 helix (H12). The bulky side chain of raloxifene protrudes from the cavity and physically prevents the alignment of H12 over the bound ligand. In contrast, genistein is completely buried within the hydrophobic core of the protein and binds in a manner similar to that observed for ER's endogenous hormone, 17beta-oestradiol. However, in the ERbeta-genistein complex, H12 does not adopt the distinctive 'agonist' position but, instead, lies in a similar orientation to that induced by ER antagonists. Such a sub-optimal alignment of the transactivation helix is consistent with genistein's partial agonist character in ERbeta and demonstrates how ER's transcriptional response to certain bound ligands is attenuated.

Pooled Analysis of Prospective Cohort Studies on Height, Weight, and Breast Cancer Risk

Abstract: The association between anthropometric indices and the risk of breast cancer was analyzed using pooled data from seven prospective cohort studies. Together, these cohorts comprise 337,819 women and 4,385 incident invasive breast cancer cases. In multivariate analyses controlling for reproductive, dietary, and other risk factors, the pooled relative risk (RR) of breast cancer per height increment of 5 cm was 1.02 (95% confidence interval (Cl): 0.96, 1.10) in premenopausal women and 1.07 (95% Cl: 1.03, 1.12) in postmenopausal women. Body mass index (BMI) showed significant inverse and positive associations with breast cancer among pre- and postmenopausal women, respectively; these associations were nonlinear. Compared with premenopausal women with a BMI of less than 21 kg/m2, women with a BMI exceeding 31 kg/m2 had an RR of 0.54 (95% Cl: 0.34, 0.85). In postmenopausal women, the RRs did not increase further when BMI exceeded 28 kg/m2; the RR for these women was 1.26 (95% Cl: 1.09, 1.46). The authors found little evidence for interaction with other breast cancer risk factors. Their data indicate that height is an independent risk factor for postmenopausal breast cancer; in premenopausal women, this relation is less clear. The association between BMI and breast cancer varies by menopausal status. Weight control may reduce the risk among postmenopausal women.

Natural regulatory T cells control the development of atherosclerosis in mice.

Abstract: Atherosclerosis is an immunoinflammatory disease elicited by accumulation of lipids in the artery wall and leads to myocardial infarction and stroke. Here, we show that naturally arising CD4(+)CD25(+) regulatory T cells, which actively maintain immunological tolerance to self and nonself antigens, are powerful inhibitors of atherosclerosis in several mouse models. These results provide new insights into the immunopathogenesis of atherosclerosis and could lead to new therapeutic approaches that involve immune modulation using regulatory T cells.

Antidiabetogenic effect of glucagon-like peptide-1 (7-36)amide in normal subjects and patients with diabetes mellitus.

Abstract: Glucagon-like peptide-1 (7–36)amide (glucagon-like insulinotropic peptide, or GLIP) is a gastrointestinal peptide that potentiates the release of insulin in physiologic concentrations. Its effects in patients with diabetes mellitus are not known. Methods. We compared the effect of an Infusion of GLIP that raised plasma concentrations of GLIP twofold with the effect of an infusion of saline, on the meal-related release of insulin, glucagon, and somatostatin in eight normal subjects, nine obese patients with non-insulin-dependent diabetes mellitus (NIDDM), and eight patients with insulin-dependent diabetes mellitus (IDDM). The blood glucose concentrations in the patients with diabetes were controlled by a closed-loop insulin-infusion system (artificial pancreas) during the Infusion of each agent, allowing measurement of the meal-related requirement for exogenous insulin. In the patients with IDDM, normoglycemic-clamp studies were performed during the infusions of GLIP and saline to determine the ef...

Training and transfer effects of executive functions in preschool children.

Abstract: Executive functions, including working memory and inhibition, are of central importance to much of human behavior. Interventions intended to improve executive functions might therefore serve an important purpose. Previous studies show that working memory can be improved by training, but it is unknown if this also holds for inhibition, and whether it is possible to train executive functions in preschoolers. In the present study, preschool children received computerized training of either visuo-spatial working memory or inhibition for 5 weeks. An active control group played commercially available computer games, and a passive control group took part in only pre- and posttesting. Children trained on working memory improved significantly on trained tasks; they showed training effects on non-trained tests of spatial and verbal working memory, as well as transfer effects to attention. Children trained on inhibition showed a significant improvement over time on two out of three trained task paradigms, but no significant improvements relative to the control groups on tasks measuring working memory or attention. In neither of the two interventions were there effects on non-trained inhibitory tasks. The results suggest that working memory training can have significant effects also among preschool children. The finding that inhibition could not be improved by either one of the two training programs might be due to the particular training program used in the present study or possibly indicate that executive functions differ in how easily they can be improved by training, which in turn might relate to differences in their underlying psychological and neural processes.