Time-dependent effects of imatinib in human leukaemia cells: a kinetic NMR-profiling study

The goal of this study was to evaluate the time course of metabolic changes in leukaemia cells treated with the Bcr-Abl tyrosine kinase inhibitor imatinib. Human Bcr-Abl+ K562 cells were incubated with imatinib in a dose-escalating manner (starting at 0.1 μM with a weekly increase of 0.1 μM imatinib) for up to 5 weeks. Nuclear magnetic resonance spectroscopy and liquid-chromatography mass spectrometry were performed to assess a global metabolic profile, including glucose metabolism, energy state, lipid metabolism and drug uptake, after incubation with imatinib. Initially, imatinib treatment completely inhibited the activity of Bcr-Abl tyrosine kinase, followed by the inhibition of cell glycolytic activity and glucose uptake. This was accompanied by the increased mitochondrial activity and energy production. With escalating imatinib doses, the process of cell death rapidly progressed. Phosphocreatine and NAD+ concentrations began to decrease, and mitochondrial activity, as well as the glycolysis rate, was further reduced. Subsequently, the synthesis of lipids as necessary membrane precursors for apoptotic bodies was accelerated. The concentrations of the Kennedy pathway intermediates, phosphocholine and phosphatidylcholine, were reduced. After 4 weeks of exposure to imatinib, the secondary necrosis associated with decrease in the mitochondrial and glycolytic activity occurred and was followed by a shutdown of energy production and cell death. In conclusion, monitoring of metabolic changes in cells exposed to novel signal transduction modulators supplements molecular findings and provides further mechanistic insights into longitudinal changes of the mitochondrial and glycolytic pathways of oncogenesis

Citizen scientists discover a new auroral form:dunes provide insight into the upper atmosphere

Abstract Auroral forms are like fingerprints linking optical features to physical phenomena in the near‐Earth space. While discovering new forms is rare, recently, scientists reported of citizens’ observations of STEVE, a pinkish optical manifestation of subauroral ionospheric drifts that were not thought to be visible to the naked eye. Here, we present a new auroral form named “the dunes”. On 7 October 2018, citizen observers took multiple digital photographs of the same dunes simultaneously from different locations in Finland and Sweden. We develop a triangulation method to analyze the photographs and conclude that the dunes are a monochromatic wave field with a wavelength of about 45 km within a thin layer at 100 km altitude. Supporting data suggest that the dunes manifest atmospheric waves, possibly mesospheric bores, which are rarely detected, and have not previously been observed via diffuse aurora nor at auroral latitudes and altitudes. The dunes present a new opportunity to investigate the coupling of the lower/middle atmosphere to the thermosphere and ionosphere. Our paper adds to the growing body of work that illustrates the value of citizen scientist images in carrying out quantitative analysis of optical phenomena, especially at small scales at subauroral latitudes. Further, the dune project presents means to create general interest toward physics, emphasizing that citizens can take part in scientific work by helping to uncover new phenomena

Chondrogenesis and mineralization during in vitro culture of human stem cells on 3D-woven scaffolds

Human mesenchymal stem cells (hMSCs) and three-dimensional (3D) woven poly(ɛ-caprolactone) (PCL) scaffolds are promising tools for skeletal tissue engineering. We hypothesized that in vitro culture duration and medium additives can individually and interactively influence the structure, composition, mechanical, and molecular properties of engineered tissues based on hMSCs and 3D poly(ɛ-caprolactone). Bone marrow hMSCs were suspended in collagen gel, seeded on scaffolds, and cultured for 1, 21, or 45 days under chondrogenic and/or osteogenic conditions. Structure, composition, biomechanics, and gene expression were analyzed. In chondrogenic medium, cartilaginous tissue formed by day 21, and hypertrophic mineralization was observed in the newly formed extracellular matrix at the interface with underlying scaffold by day 45. Glycosaminoglycan, hydroxyproline, and calcium contents, and alkaline phosphatase activity depended on culture duration and medium additives, with significant interactive effects (all p < 0.0001). The 45-day constructs exhibited mechanical properties on the order of magnitude of native articular cartilage (aggregate, Young's, and shear moduli of 0.15, 0.12, and 0.033 MPa, respectively). Gene expression was characteristic of chondrogenesis and endochondral bone formation, with sequential regulation of Sox-9, collagen type II, aggrecan, core binding factor alpha 1 (Cbfα1)/Runx2, bone sialoprotein, bone morphogenetic protein-2, and osteocalcin. In contrast, osteogenic medium produced limited osteogenesis. Long-term culture of hMSC on 3D scaffolds resulted in chondrogenesis and regional mineralization at the interface between soft, newly formed engineered cartilage, and stiffer underlying scaffold. These findings merit consideration when developing grafts for osteochondral defect repair.National Institutes of Health (U.S.) (NIH AR055414)National Institutes of Health (U.S.) (DE016516)National Institutes of Health (U.S.) (NIH AR057600)National Institutes of Health (U.S.) (AR055042)National Institutes of Health (U.S.) (AR050208)United States. National Aeronautics and Space Administration (NNJ04HC72G