Separation of metabolic supply and demand: aerobic glycolysis as a normal physiological response to fluctuating energetic demands in the membrane

BACKGROUND: Cancer cells, and a variety of normal cells, exhibit aerobic glycolysis, high rates of glucose fermentation in the presence of normal oxygen concentrations, also known as the Warburg effect. This metabolism is considered abnormal because it violates the standard model of cellular energy production that assumes glucose metabolism is predominantly governed by oxygen concentrations and, therefore, fermentative glycolysis is an emergency back-up for periods of hypoxia. Though several hypotheses have been proposed for the origin of aerobic glycolysis, its biological basis in cancer and normal cells is still not well understood. RESULTS: We examined changes in glucose metabolism following perturbations in membrane activity in different normal and tumor cell lines and found that inhibition or activation of pumps on the cell membrane led to reduction or increase in glycolysis, respectively, while oxidative phosphorylation remained unchanged. Computational simulations demonstrated that these findings are consistent with a new model of normal physiological cellular metabolism in which efficient mitochondrial oxidative phosphorylation supplies chronic energy demand primarily for macromolecule synthesis and glycolysis is necessary to supply rapid energy demands primarily to support membrane pumps. A specific model prediction was that the spatial distribution of ATP-producing enzymes in the glycolytic pathway must be primarily localized adjacent to the cell membrane, while mitochondria should be predominantly peri-nuclear. The predictions were confirmed experimentally. CONCLUSIONS: Our results show that glycolytic metabolism serves a critical physiological function under normoxic conditions by responding to rapid energetic demand, mainly from membrane transport activities, even in the presence of oxygen. This supports a new model for glucose metabolism in which glycolysis and oxidative phosphorylation supply different types of energy demand. Cells use efficient but slow-responding aerobic metabolism to meet baseline, steady energy demand and glycolytic metabolism, which is inefficient but can rapidly increase adenosine triphosphate (ATP) production, to meet short-timescale energy demands, mainly from membrane transport activities. In this model, the origin of the Warburg effect in cancer cells and aerobic glycolysis in general represents a normal physiological function due to enhanced energy demand for membrane transporters activity required for cell division, growth, and migration

Performance optimisation of inertial confinement fusion codes using mini-applications

Despite the recent successes of nuclear energy researchers, the scientific community still remains some distance from being able to create controlled, self-sustaining fusion reactions. Inertial Confinement Fusion (ICF) techniques represent one possible option to surpass this barrier, with scientific simulation playing a leading role in guiding and supporting their development. The simulation of such techniques allows for safe and efficient investigation of laser design and pulse shaping, as well as providing insight into the reaction as a whole. The research presented here focuses on the simulation code EPOCH, a fully relativistic particle-in-cell plasma physics code concerned with faithfully recreating laser-plasma interactions at scale. A significant challenge in developing large codes like EPOCH is maintaining effective scientific delivery on successive generations of high-performance computing architecture. To support this process, we adopt the use of mini-applications -- small code proxies that encapsulate important computational properties of their larger parent counterparts. Through the development of a mini-application for EPOCH (called miniEPOCH), we investigate a variety of the performance features exhibited in EPOCH, expose opportunities for optimisation and increased scientific capability, and offer our conclusions to guide future changes to similar ICF codes

Mini-app driven optimisation of inertial confinement fusion codes

In September 2013, the large laser-based inertial confinement fusion device housed in the National Ignition Facility at Lawrence Livermore National Laboratory, was widely acclaimed to have achieved a milestone in controlled fusion – successfully initiating a reaction that resulted in the release of more energy than the fuel absorbed. Despite this success, we remain some distance from being able to create controlled, self-sustaining fusion reactions. Inertial Confinement Fusion (ICF) represents one leading design for the generation of energy by nuclear fusion. Since the 1950s, ICF has been supported by computing simulations, providing the mathematical foundations for pulse shaping, lasers, and material shells needed to ensure effective and efficient implosion. The research presented here focuses on one such simulation code, EPOCH, a fully relativistic particle-in-cell plasma physics code, developed by a leading network of over 30 UK researchers. A significant challenge in developing large codes like EPOCH is maintaining effective scientific delivery on successive generations of high-performance computing architecture. To support this process, we adopt the use of mini-applications – small code proxies that encapsulate important computational properties of their larger parent counterparts. Through the development of a miniapp for EPOCH (called miniEPOCH), we investigate known timestep scaling issues within EPOCH and explore possible optimisations: (i) Employing loop fission to increase levels of vectorisation; (ii) Enforcing particle ordering to allow the exploitation of domain specific knowledge and, (iii) Changing underlying data storage to improve memory locality. When applied to EPOCH, these improvements represent a 2.02× speed-up in the core algorithm and a 1.55× speed-up to the overall application runtime, when executed on EPCC’s Cray XC30 ARCHER platform

Increasing water cycle extremes in California and in relation to ENSO cycle under global warming

Since the winter of 2013–2014, California has experienced its most severe drought in recorded history, causing statewide water stress, severe economic loss and an extraordinary increase in wildfires. Identifying the effects of global warming on regional water cycle extremes, such as the ongoing drought in California, remains a challenge. Here we analyse large-ensemble and multi-model simulations that project the future of water cycle extremes in California as well as to understand those associations that pertain to changing climate oscillations under global warming. Both intense drought and excessive flooding are projected to increase by at least 50% towards the end of the twenty-first century; this projected increase in water cycle extremes is associated with a strengthened relation to El Niño and the Southern Oscillation (ENSO)—in particular, extreme El Niño and La Niña events that modulate California’s climate not only through its warm and cold phases but also its precursor patterns

A mathematical model of tumour & blood pHe regulation: The HCO-3/CO2 buffering system

Malignant tumours are characterised by a low, acidic extracellular pH (pHe) which facilitates invasion and metastasis. Previous research has proposed the potential benefits of manipulating systemic pHe, and recent experiments have highlighted the potential for buffer therapy to raise tumour pHe, prevent metastases, and prolong survival in laboratory mice. To examine the physiological regulation of tumour buffering and investigate how perturbations of the buffering system (via metabolic/respiratory disorders or changes in parameters) can alter tumour and blood pHe, we develop a simple compartmentalised ordinary differential equation model of pHe regulation by the View the MathML source buffering system. An approximate analytical solution is constructed and used to carry out a sensitivity analysis, where we identify key parameters that regulate tumour pHe in both humans and mice. From this analysis, we suggest promising alternative and combination therapies, and identify specific patient groups which may show an enhanced response to buffer therapy. In addition, numerical simulations are performed, validating the model against well-known metabolic/respiratory disorders and predicting how these disorders could change tumour pHe

Cancer-associated mesenchymal stroma fosters the stemness of osteosarcoma cells in response to intratumoral acidosis via NF-κB activation

The role of mesenchymal stem cells (MSC) in osteosarcoma (OS), the most common primary tumor of bone, has not been extensively elucidated. We have recently shown that OS is characterized by interstitial acidosis, a microenvironmental condition that is similar to a wound setting, in which mesenchymal reactive cells are activated to release mitogenic and chemotactic factors. We therefore intended to test the hypothesis that, in OS, acid-activated MSC influence tumor cell behavior. Conditioned media or co-culture with normal MSC previously incubated with short-term acidosis (pH 6.8 for 10 hr, H+-MSC) enhanced OS clonogenicity and invasion. This effect was mediated by NF-κB pathway activation. In fact, deep-sequencing analysis, confirmed by Real-Time PCR and ELISA, demonstrated that H+-MSC differentially induced a tissue remodeling phenotype with increased expression of RelA, RelB and NF-κB1, and downstream, of CSF2/GM-CSF, CSF3/G-CSF and BMP2 colony-promoting factors, and of chemokines (CCL5, CXCL5 and CXCL1), and cytokines (IL6 and IL8), with an increased expression of CXCR4. An increased expression of IL6 and IL8 were found only in normal stromal cells, but not in OS cells, and this was confirmed in tumor-associated stromal cells isolated from OS tissue. Finally, H+-MSC conditioned medium differentially promoted OS stemness (sarcosphere number, stem-associated gene expression), and chemoresistance also via IL6 secretion. Our data support the hypothesis that the acidic OS microenvironment is a key factor for MSC activation, in turn promoting the secretion of paracrine factors that influence tumor behavior, a mechanism that holds the potential for future therapeutic interventions aimed to target OS

Melanocortin 1 receptor ligands and methods of use

The subject invention pertains to a modified MC1R peptide ligand comprising a peptide that is a melanocortin 1 receptor (MC1R) ligand and a functionality or linker, such as a click functionality, for conjugation to a surface or agent. The modified MC1R peptide ligand can be coupled, e.g., via a click reaction with a complementary click functionality attached, to a moiety to form an MC1R-targeted agent. Drugs, contrast agents, polymers, particles, micelles, surfaces of larger structures, or other moieties can be targeted to the MC1R. The subject invention also pertains to a MC1R peptide ligand-micelle complex comprising a peptide that is a melanocortin 1 receptor ligand connected via a click reaction product to a micelle. The micelle is stable in vivo and can target melanoma tumor cells by association of the peptide ligand with the MC1R or the tumor and selectively provide a detectable and/or therapeutic agent (such as an imageable contrast agent and/or anti-cancer agent) selectively to the tumor cell.Board of Regents, University of Texas Syste

A semiautomatic CT-based ensemble segmentation of lung tumors: Comparison with oncologists’ delineations and with the surgical specimen

AbstractPurposeTo assess the clinical relevance of a semiautomatic CT-based ensemble segmentation method, by comparing it to pathology and to CT/PET manual delineations by five independent radiation oncologists in non-small cell lung cancer (NSCLC).Materials and methodsFor 20 NSCLC patients (stages Ib–IIIb) the primary tumor was delineated manually on CT/PET scans by five independent radiation oncologists and segmented using a CT based semi-automatic tool. Tumor volume and overlap fractions between manual and semiautomatic-segmented volumes were compared. All measurements were correlated with the maximal diameter on macroscopic examination of the surgical specimen. Imaging data are available on www.cancerdata.org.ResultsHigh overlap fractions were observed between the semi-automatically segmented volumes and the intersection (92.5±9.0, mean±SD) and union (94.2±6.8) of the manual delineations. No statistically significant differences in tumor volume were observed between the semiautomatic segmentation (71.4±83.2cm3, mean±SD) and manual delineations (81.9±94.1cm3; p=0.57). The maximal tumor diameter of the semiautomatic-segmented tumor correlated strongly with the macroscopic diameter of the primary tumor (r=0.96).ConclusionsSemiautomatic segmentation of the primary tumor on CT demonstrated high agreement with CT/PET manual delineations and strongly correlated with the macroscopic diameter considered as the “gold standard”. This method may be used routinely in clinical practice and could be employed as a starting point for treatment planning, target definition in multi-center clinical trials or for high throughput data mining research. This method is particularly suitable for peripherally located tumors

The Uncertainty in Newton's Constant and Precision Predictions of the Primordial Helium Abundance

The current uncertainty in Newton's constant, G_N, is of the order of 0.15%. For values of the baryon to photon ratio consistent with both cosmic microwave background observations and the primordial deuterium abundance, this uncertainty in G_N corresponds to an uncertainty in the primordial 4He mass fraction, Y_P, of +-1.3 x 10^{-4}. This uncertainty in Y_P is comparable to the effect from the current uncertainty in the neutron lifetime, which is often treated as the dominant uncertainty in calculations of Y_P. Recent measurements of G_N seem to be converging within a smaller range; a reduction in the estimated error on G_N by a factor of 10 would essentially eliminate it as a source of uncertainty in the calculation of the primordial 4He abundance.Comment: 3 pages, no figures, fixed typos, to appear in Phys. Rev.