An alle gedacht?!: Frauen, Gender, Mobilität - Wie kommen wir aus der Debatte in die Umsetzung?

Frauenbelange in der Mobilität zu berücksichtigen, ist scheinbar das Thema der Stunde. Dabei wird dazu schon seit 40 Jahren geforscht und gearbeitet. In der Planungspraxis werden die Ergebnisse dieser Forschung hingegen bislang nur in wenigen Fällen umgesetzt. Dieses Papier stellt die Frage, wie wir den neuen Schwung in der Debatte nutzen können und was geschehen muss, damit nicht nur diskutiert wird, sondern auch in der Umsetzung Veränderungen bewirkt werden. Dazu wird in einem ersten Teil der Verlauf der Debatte um Frauen, Gender und Mobilität über die letzten Jahrzehnte nachgezeichnet und die oft verschwimmenden Begrifflichkeiten definiert. Darauf aufbauend wird die Frage diskutiert, ob wir es mit einer Wissens- oder einer Umsetzungslücke zu tun haben. Im dritten Teil werden Thesen vorgestellt, wie die identifizierten Wissens- und Umsetzungslücken behoben werden können. Die Arbeit versteht sich als Anstoß für eine Debatte zur Frage, wie das Thema gendersensibler und Nutzer:innen-zentrierter Verkehrsplanung dauerhaft und qualitativ hochwertig in der Umsetzung verankert werden kann

An alle gedacht?!: Frauen, Gender, Mobilität - Wie kommen wir aus der Debatte in die Umsetzung?

Frauenbelange in der Mobilität zu berücksichtigen, ist scheinbar das Thema der Stunde. Dabei wird dazu schon seit 40 Jahren geforscht und gearbeitet. In der Planungspraxis werden die Ergebnisse dieser Forschung hingegen bislang nur in wenigen Fällen umgesetzt. Dieses Papier stellt die Frage, wie wir den neuen Schwung in der Debatte nutzen können und was geschehen muss, damit nicht nur diskutiert wird, sondern auch in der Umsetzung Veränderungen bewirkt werden. Dazu wird in einem ersten Teil der Verlauf der Debatte um Frauen, Gender und Mobilität über die letzten Jahrzehnte nachgezeichnet und die oft verschwimmenden Begrifflichkeiten definiert. Darauf aufbauend wird die Frage diskutiert, ob wir es mit einer Wissens- oder einer Umsetzungslücke zu tun haben. Im dritten Teil werden Thesen vorgestellt, wie die identifizierten Wissens- und Umsetzungslücken behoben werden können. Die Arbeit versteht sich als Anstoß für eine Debatte zur Frage, wie das Thema gendersensibler und Nutzer:innen-zentrierter Verkehrsplanung dauerhaft und qualitativ hochwertig in der Umsetzung verankert werden kann

An alle gedacht?!: Frauen, Gender, Mobilität - Wie kommen wir aus der Debatte in die Umsetzung?

Frauenbelange in der Mobilität zu berücksichtigen, ist scheinbar das Thema der Stunde. Dabei wird dazu schon seit 40 Jahren geforscht und gearbeitet. In der Planungspraxis werden die Ergebnisse dieser Forschung hingegen bislang nur in wenigen Fällen umgesetzt. Dieses Papier stellt die Frage, wie wir den neuen Schwung in der Debatte nutzen können und was geschehen muss, damit nicht nur diskutiert wird, sondern auch in der Umsetzung Veränderungen bewirkt werden. Dazu wird in einem ersten Teil der Verlauf der Debatte um Frauen, Gender und Mobilität über die letzten Jahrzehnte nachgezeichnet und die oft verschwimmenden Begrifflichkeiten definiert. Darauf aufbauend wird die Frage diskutiert, ob wir es mit einer Wissens- oder einer Umsetzungslücke zu tun haben. Im dritten Teil werden Thesen vorgestellt, wie die identifizierten Wissens- und Umsetzungslücken behoben werden können. Die Arbeit versteht sich als Anstoß für eine Debatte zur Frage, wie das Thema gendersensibler und Nutzer:innen-zentrierter Verkehrsplanung dauerhaft und qualitativ hochwertig in der Umsetzung verankert werden kann

Oncogenic Kras G12D causes myeloproliferation via NLRP3 inflammasome activation

Oncogenic Ras mutations occur in various leukemias. It was unclear if, besides the direct transforming effect via constant RAS/MEK/ERK signaling, an inflammation-related effect of KRAS contributes to the disease. Here, we identify a functional link between oncogenic KrasG12D and NLRP3 inflammasome activation in murine and human cells. Mice expressing active KrasG12D in the hematopoietic system developed myeloproliferation and cytopenia, which is reversed in KrasG12D mice lacking NLRP3 in the hematopoietic system. Therapeutic IL-1-receptor blockade or NLRP3-inhibition reduces myeloproliferation and improves hematopoiesis. Mechanistically, KrasG12D-RAC1 activation induces reactive oxygen species (ROS) production causing NLRP3 inflammasome-activation. In agreement with our observations in mice, patient-derived myeloid leukemia cells exhibit KRAS/RAC1/ROS/NLRP3/IL-1β axis activity. Our findings indicate that oncogenic KRAS not only act via its canonical oncogenic driver function, but also enhances the activation of the pro-inflammatory RAC1/ROS/NLRP3/IL-1β axis. This paves the way for a therapeutic approach based on immune modulation via NLRP3 blockade in KRAS-mutant myeloid malignancies

Use of confocal microscopy to follow the development of penetrative hyphae during growth of Rhizopus oligosporus in an artificial solid-state fermentation system

Two methods were compared for determining the concentration of penetrative biomass during growth of Rhizopus oligosporus on an artificial solid substrate consisting of an inert gel and starch as the sole source of carbon and energy. The first method was based on the use of a hand microtome to make sections of approximately 0.2- to 0.4-mm thickness parallel to the substrate surface and the determination of the glucosamine content in each slice. Use of glucosamine measurements to estimate biomass concentrations was shown to be problematic due to the large variations in glucosamine content with mycelial age. The second method was a novel method based on the use of confocal scanning laser microscopy to estimate the fractional volume occupied by the biomass. Although it is not simple to translate fractional volumes into dry weights of hyphae due to the lack of experimentally determined conversion factors, measurement of the fractional volumes in themselves is useful for characterizing fungal penetration into the substrate. Growth of penetrative biomass in the artificial model substrate showed two forms of growth with an indistinct mass in the region close to the substrate surface and a few hyphae penetrating perpendicularly to the surface in regions further away from the substrate surface. The biomass profiles against depth obtained from the confocal microscopy showed two linear regions on log-linear plots, which are possibly related to different oxygen availability at different depths within the substrate. Confocal microscopy has the potential to be a powerful tool in the investigation of fungal growth mechanisms in solid-state fermentation. (C) 2003 Wiley Periodicals, Inc

Predictions of in vivo prolactin levels from in vitro k I values of d 2 receptor antagonists using an agonist-antagonist interaction model

Item does not contain fulltextProlactin elevation is a side effect of all currently available D2 receptor antagonists used in the treatment of schizophrenia. Prolactin elevation is the result of a direct antagonistic D2 effect blocking the tonic inhibition of prolactin release by dopamine. The aims of this work were to assess the correlation between in vitro estimates of D2 receptor affinity and pharmacokinetic-pharmacodynamic model-based estimates obtained from analysis of clinical data using an agonist-antagonist interaction (AAI) model and to assess the value of such a correlation in early prediction of full prolactin time profiles. A population model describing longitudinal prolactin data was fitted to clinical data from 16 clinical phases 1 and 3 trials including five different compounds. Pharmacokinetic data were modeled for each compound and the prolactin model was both fitted in per-compound fits as well as simultaneously to all prolactin data. Estimates of prolactin elevating potency were compared to corresponding in vitro values and their predictability was evaluated through model-based simulations. The model successfully described the prolactin time course for all compounds. Estimates derived from experimental preclinical data and the model fit of the clinical data were strongly correlated (p < 0.001), and simulations adequately predicted the prolactin elevation in five out of six compounds. The AAI model has the potential to be used in drug development to predict prolactin response for a given exposure of D2 antagonists using routinely produced preclinical data

Non‐invasive evaluation of new‐onset atrial fibrillation after cardiac surgery: a protocol for the BigMap study

Abstract Aims New‐onset atrial fibrillation (NOAF) is the most common complication after cardiac surgery, occurring in 25–50% of patients. It is associated with post‐operative stroke, increased mortality, prolonged hospital length of stay, and higher treatment costs. Previous small observational studies have identified the left atrium as a source of the electrical rotors and foci maintaining NOAF, but confirmation by a large prospective clinical study is still missing. The aim of the proposed study is to investigate whether the source of NOAF lies in the left atrium. The correct identification of NOAF‐maintaining structures in cardiac surgical patients might offer potential therapeutic targets for prophylactic perioperative ablation strategies. Methods and results This is a prospective single‐centre observational study of patients developing NOAF after cardiac surgery. The primary outcome is the description of NOAF‐maintaining structures within the atria. Key secondary outcomes include overall mortality, intensive care unit length of stay, hospital–ventilator‐free days, and proportion of persistent NOAF. In NOAF patients, the non‐invasive electrophysiological mapping will be conducted using a 252‐electrode electrocardiogram vest. After mapping, a low‐dose computed tomography scan of the chest will be performed to integrate the electrophysiological mapping results into a 3D picture of the heart. The study will include approximately 570 patients, of whom 30% (n = 170) are expected to develop NOAF. Sample size calculation revealed that 157 NOAF patients are necessary to assess the primary outcome. Patients will be tracked for a total of 5 years. Conclusions This is the largest prospective study to date describing the electrophysiological mechanisms of NOAF using non‐invasive mapping

Oncogenic KrasG12D causes myeloproliferation via NLRP3 inflammasome activation

Oncogenic Ras mutations occur in various leukemias. It was unclear if, besides the direct transforming effect via constant RAS/MEK/ERK signaling, an inflammation-related effect of KRAS contributes to the disease. Here, we identify a functional link between oncogenic Kras and NLRP3 inflammasome activation in murine and human cells. Mice expressing active Kras in the hematopoietic system developed myeloproliferation and cytopenia, which is reversed in Kras mice lacking NLRP3 in the hematopoietic system. Therapeutic IL-1-receptor blockade or NLRP3-inhibition reduces myeloproliferation and improves hematopoiesis. Mechanistically, Kras-RAC1 activation induces\ua0reactive oxygen species (ROS) production causing NLRP3 inflammasome-activation. In agreement with our observations in mice, patient-derived myeloid leukemia cells exhibit KRAS/RAC1/ROS/NLRP3/IL-1β axis activity. Our findings indicate that oncogenic KRAS not only act via its canonical oncogenic driver function, but also enhances\ua0the activation of the pro-inflammatory RAC1/ROS/NLRP3/IL-1β axis. This paves the way for a therapeutic approach based on immune modulation via NLRP3 blockade in KRAS-mutant myeloid malignancies

Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells

Individuals with acute myeloid leukemia (AML) harboring an internal tandem duplication (ITD) in the gene encoding Fms-related tyrosine kinase 3 (FLT3) who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) have a 1-year survival rate below 20%. We observed that sorafenib, a multitargeted tyrosine kinase inhibitor, increased IL-15 production by FLT3-ITD + leukemia cells. This synergized with the allogeneic CD8 + T cell response, leading to long-term survival in six mouse models of FLT3-ITD + AML. Sorafenib-related IL-15 production caused an increase in CD8 + CD107a + IFN-3 + T cells with features of longevity (high levels of Bcl-2 and reduced PD-1 levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced expression of the transcription factor ATF4, thereby blocking negative regulation of interferon regulatory factor 7 (IRF7) activation, which enhanced IL-15 transcription. Both IRF7 knockdown and ATF4 overexpression in leukemia cells antagonized sorafenib-induced IL-15 production in vitro. Human FLT3-ITD + AML cells obtained from sorafenib responders following sorafenib therapy showed increased levels of IL-15, phosphorylated IRF7, and a transcriptionally active IRF7 chromatin state. The mitochondrial spare respiratory capacity and glycolytic capacity of CD8 + T cells increased upon sorafenib treatment in sorafenib responders but not in nonresponders. Our findings indicate that the synergism of T cells and sorafenib is mediated via reduced ATF4 expression, causing activation of the IRF7-IL-15 axis in leukemia cells and thereby leading to metabolic reprogramming of leukemia-reactive T cells in humans. Therefore, sorafenib treatment has the potential to contribute to an immune-mediated cure of FLT3-ITD-mutant AML relapse, an otherwise fatal complication after allo-HCT

Erratum: Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD-mutant leukemia cells

This corrects the article DOI: 10.1038/nm.4484