Translocation of heme oxygenase-1 contributes to imatinib resistance in chronic myelogenous leukemia

Heme oxygenase-1 (HO-1) degrades heme to bilirubin. In addition, it is upregulated in malignant disease and has been described as an important factor for cancer prognosis and therapy. Under physiological conditions HO-1 is anchored to the endoplasmic reticulum (ER). Under stress conditions HO-1 can be cleaved and subsequently translocates to the cytosol and nucleus. In this study we systematically investigated the influence of HO-1’s catabolic activity and subcellular localization on resistance against the tyrosine kinase inhibitor imatinib in leukemia cells by confocal laser scanning microscopy, hemoglobin synthesis experiments and cell viability assays. We created two types of monoclonal K562 cell lines stably transfected with GFP-tagged HO-1: cell lines expressing ER anchored HO-1 or anchorless HO-1. Since translocation of HO-1 disrupts the association with cytochrome P450 reductase, heme degrading activity was higher for ER anchored versus anchorless HO-1. Cell viability tests with increasing concentrations of imatinib showed IC50-values for all six cell lines with ER localized HO-1 that were similar to control cells. However, out of the seven cell lines with anchorless HO-1, two showed a statistically significant increase in the imatinib IC50 (19.76 μM and 12.35 μM versus 2.35 – 7.57 μM of sensitive cell lines) corresponding to plasma concentrations outside the therapeutic range. We conclude that the presence of translocated HO-1 in the cytosol and nucleus supports imatinib resistance while it is not sufficient to cause imatinib resistance in every cell line. In contrast, an increase in ER anchored HO-1 with high heme degrading activity does not contribute to imatinib resistance

Geometric Algebra Transformers

Problems involving geometric data arise in a variety of fields, including computer vision, robotics, chemistry, and physics. Such data can take numerous forms, such as points, direction vectors, planes, or transformations, but to date there is no single architecture that can be applied to such a wide variety of geometric types while respecting their symmetries. In this paper we introduce the Geometric Algebra Transformer (GATr), a general-purpose architecture for geometric data. GATr represents inputs, outputs, and hidden states in the projective geometric algebra, which offers an efficient 16-dimensional vector space representation of common geometric objects as well as operators acting on them. GATr is equivariant with respect to E(3), the symmetry group of 3D Euclidean space. As a transformer, GATr is scalable, expressive, and versatile. In experiments with n-body modeling and robotic planning, GATr shows strong improvements over non-geometric baselines

Hur kan bilpooler bidra till ett mer hållbart arbetsresande?

Bilpooler används i en begränsad omfattning för arbetsresor. Hinder för en större användning är att bilpoolstjänsterna ofta bedöms som betydligt dyrare än resor med arbetstagarens privata bil samt utformningen av arbetsgivarens parkerings- och resepolicy. Det finns dock en tydlig potential för bilpooler att bidra till ett mer hållbart arbetsresande. För detta krävs det en tydligare reglering av parkering samt en marknadsmässig prissättning, tydliga resepolicies, och en tydlig organisation och ansvar mellan fastighetsägarna och arbetsgivarna

Framtidens varulogistik i städer

Urbaniseringen och ökad e-handel skapar utmaningar när hänsyn till hållbarhet, trängsel och buller samt en levande stadsmiljö ska matchas med boendes krav på leveranstjänster. Kommuner har en avgörande roll för att skapa förutsättningar som främjar implementeringen av systemlösningar för hållbar varulogistik i städer som möter kundernas krav samtidigt som det minskar fragmenteringen av varuflöden och antalet transporter. Kommunen kan vidta åtgärder i alla skeden av planprocessen; detaljplanering, bygglov och driftskedet

Urban freight transport sustainability – assessment and evaluation framework

Research purpose: Various urban freight transport measures have been introduced in order to improve logistics performance while at the same time reducing the negative environmental and socio-economic impacts. The results, however, are disappointing, showing unwanted side effects and/or dependency on government subsidies, which is mainly due to the fact that the measures are planned without taking into account the special characterisation of the city as well as the interests of all urban stakeholders. This paper aims to contribute to improving the effectiveness of urban logistics initiatives. The purpose is to develop an assessment and evaluation framework that reflect first, the characteristics of the city environment, and second, the complexity of urban logistics consisting of many stakeholders. Methodology: The framework is developed based on a literature review on urban freight transport measures and evaluation methods. The practical feasibility of the framework is tested in a multiple case study analysing two pilot projects of consolidated last mile deliveries in two areas representing different spatial urban structures and different transport characteristics. Results: Urban freight transport problems are not standard across cities or within cities and consequently urban freight transport measures need to be adapted to the local conditions. The framework evaluates the appropriateness of urban freight transport measures taking transport chain chara¬cteristics and the spatial constraints of the respective city area into account. The application of the framework on the pilot projects indicates the measures’ implications for all stakeholders, which is key to a successful implementation. Conclusions: The developed framework has both practical and theoretical implications. From a practical perspective, the framework helps local authorities to get a holistic understanding of the implications of urban logistics measures. Furthermore, it helps authorities to assess whether successful measures from elsewhere can be successfully implemented in the local context. In this way, the framework contributes to the transferability of best practice in urban logistics. From a theoretical perspective, the framework is an important contribution to the existing knowledge on the interplay between urban form on the one hand and logistics and transportation on the other hand. In this way, the framework shows the relations between the urban stakeholders and how their integration contributes to sustainable urban freight transport. The framework provides an understanding of the constitutional principles underpinning the functioning of the urban freight transport system and hence can be a reference point for future theory development and empirical research on urban freight transport

The modal shift potential of intermodal line-Trains from a haulier's perspective: Drivers and barriers in the mode choice process

The purpose of this paper is to identify drivers and barriers to the usage of intermodal line-Trains in the hauliers' decision-making process, assuming viable line-Train services exist. In a multiple case study, the operations of four hauliers contracted by two forwarders for the domestic transport of consolidated cargo in Sweden are assessed. The results indicate that hauliers face significant obstacles for outsourcing the long-distance haulage to rail. The main barriers are a vehicle fleet that is not adapted for rail, small transport volumes and congestion on terminal access roads. Hence, in the current industry structure the modal shift potential for consolidated cargo is limited. Alternative business models may be needed to reach transport volumes that allow efficient haulage operations, which in turn may lead to reduced business for road hauliers

The Significance of the Urban Context for the Sustainability Performance of Intermodal Road-rail Transport

The purpose of this paper is to analyse the implications of the urban context for the sustainability performance of intermodal road-rail transport (IRRT). By calculating the external costs of a road transport and an intermodal alternative of consolidated cargo between a freight forwarder's consolidation terminals, the paper shows that the environmental benefits of a modal shift depend on the relative location of the intermodal terminal and shipper and receiver in the spatial structure. A careful integration of the intermodal terminal in the urban spatial structure is therefore a necessity if IRRT is to contribute to the sustainable development of the freight sector