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This document contains supplemental figures 1-7 and detailed supplemental methods

Supplemental tables 1-10.

Hepatic fat accumulation is associated with diabetes and hepatocellular carcinoma (HCC). Here, we characterize the metabolic response that high-fat availability elicits in livers before disease development. After a short term on a high-fat diet (HFD), otherwise healthy mice showed elevated hepatic glucose uptake and increased glucose contribution to serine and pyruvate carboxylase activity compared with control diet (CD) mice. This glucose phenotype occurred independently from transcriptional or proteomic programming, which identifies increased peroxisomal and lipid metabolism pathways. HFD-fed mice exhibited increased lactate production when challenged with glucose. Consistently, administration of an oral glucose bolus to healthy individuals revealed a correlation between waist circumference and lactate secretion in a human cohort. In vitro, palmitate exposure stimulated production of reactive oxygen species and subsequent glucose uptake and lactate secretion in hepatocytes and liver cancer cells. Furthermore, HFD enhanced the formation of HCC compared with CD in mice exposed to a hepatic carcinogen. Regardless of the dietary background, all murine tumors showed similar alterations in glucose metabolism to those identified in fat exposed nontransformed mouse livers, however, particular lipid species were elevated in HFD tumor and nontumor-bearing HFD liver tissue. These findings suggest that fat can induce glucose-mediated metabolic changes in nontransformed liver cells similar to those found in HCC.Significance:With obesity-induced hepatocellular carcinoma on a rising trend, this study shows in normal, nontransformed livers that fat induces glucose metabolism similar to an oncogenic transformation.

Cancer cells outgrowing in distant organs of metastasis rewire their metabolism to fuel on the available nutrients. While this is often considered an adaptive pressure limiting metastasis formation, some nutrients available at the metastatic site naturally or through changes in organ physiology may inherently promote metastatic growth. We find that the lung, a frequent site of metastasis, is a lipid-rich environment. Moreover, we observe that pathological conditions such as pre-metastatic niche formation and obesity further increase the availability of the fatty acid palmitate in the lung. We find that targeting palmitate processing inhibits spheroid growthin vitroand metastasis formation in lean and obese mice. Mechanistically, we discover that breast cancer cells use palmitate to synthesize acetyl-CoA in a carnitine palmitoyltransferase 1a (CPT1a)-dependent manner. Lysine acetyltransferase 2a (KAT2a), whose expression is promoted by palmitate availability, relies on the available acetyl-CoA to acetylate the NF-κB subunit p65. This favors nuclear location of p65 and activates a pro-metastatic transcriptional program. Accordingly, deletion of KAT2a phenocopies CPT1a silencingin vitroas well asin vivoand patients with breast cancer show co-expression of both proteins in metastases across palmitate-rich metastatic sites. In conclusion, we find that palmitate-rich environments foster metastasis growth by increasing p65 acetylation resulting in elevated NF-κB signaling.

The validity of the Stokes-Millikan equation is examined in light of mass and mobility measurements of clusters of the ionic liquid 1-ethyl-3-methyl-imidazolium tetrafluoroborate (EMI-BF4) in ambient air. The mobility diameter dZ based on the measured mobility and the Stokes-Millikan law is compared with the volume diameter dv , which generalizes the mass diameter for binary substances such as salts. dv is based on the sum of anion and cation volumes in the cluster corrected for the void fraction of the bulk ionic liquid. For dv > 1.5 nm, d Z is within 1.4% of dv + 0.3 nm. For smaller clusters 3.84 and 14.3% deviations are observed at dv = 1.21 nm and 0.68 nm, respectively. These differences are smaller than expected due to a cancellation of competing effects. The increasing difference seen for dv < 1.5 nm is due primarily to the interaction between the cluster and the dipole it induces in the gas molecules. Other potential sources of disagreement are non-globular cluster geometries, and departures of the...

The Open Innovation and Open Business Model Innovation (OBMI) approach (Chesbrough 2005, 2008) has been one of the most discussed innovation frameworks in the 2000s, and probably one of the most important contributions to business model innovations (BMIs) since 2005. Managers in the healthcare sector responsible for innovations have also tried to adapt the OBMI approach as a tool among the numerous other innovation tools. The aim of the paper is to present an initial study of the implementation of the framework of OBMI in the European healthcare sector. The study is naturally inspired by Chesbrough’s work on OBMI but also Michael Porters work on healthcare sector (Porter 2010) and shared values (Porter 2011). The study includes four European Hospitals (University Hospital Oslo, HSDJ Barcelona, University Hospital Aarhus and University Hospital Aalborg). Data is supplemented with experience from the European and US healthcare sectors. The paper focuses on the following research questions: • How can OBMI be defined? • How is OBMI used in the healthcare sector? The paper concludes by proposing a definition of open and close business models, and open and close business model innovations.

Electrospray propulsion (ESP) offers the possibility to change widely the specific impulse Isp (from hundreds to thousands of seconds and at fixed power) at higher propulsion efficiency than most electrostic thrusters operating at fixed Isp. This critical advantage is offset by the sub-N thrust level offered by single ESP emitters, that is much too low for most missions other than those requiring extremely precise thrust control. Accordingly, here we aim at: a) multiplexing the electrospray source using silicon-based microfabrication and b) identifying a suitable propellant offering wide Isp control. We demonstrated continuous operation of a multiplexed electrospray (MES) microfabricated device consisting of an array of 7 identical cylindrical nozzles, each measuring 10 m in inner dimater and 30 m in outer dimater, with nozzle-to-nozzle distance of one mm, resulting in a packing density of 150 emitters per square centimeter. The propellant was a solution of methylammonium formate dissolved in formamide at a concentration of 21.5% by volume, with a high electric conductivity K=1.8 S/m. Total propellant flow rate was varied in the 0.0024-4.9 L/h range, yielding a specific impulse in the 1300-130 s range, a thrust T in the 1-2000 nN range, and an efficiency of 70-97%. Post-acceleration to 10 kV would quadruple T and Isp. The MES was successfully tested in a vacuum system for nearly 7 hours without any noticeable electrode degradation, while propulsive parameters were measured by the “time of flight” technique. The success of the demonstration relied on two critical design features: a) the realization of a microfabricated multi-hole extractor electrode carefully positioned and aligned with respect to the nozzle array; and b) an increase in the device hydraulic impedance through the insertion of 2 m silica microbeads in the nozzles to ensure uniform electrospray dispersion from all nozzles at the smallest propellant flow rates. Further scaleup by multiplexing is being pursued to fulfill mission requirements.