Evidence that stimulation of gluconeogenesis by fatty acid is mediated through thermodynamic mechanisms

AbstractWe have studied the stimulatory effects of palmitate on the rate of glucose synthesis from lactate in isolated hepatocytes. Control of the metabolic flow was achieved by modulating the activity of enolase using graded concentrations of fluoride. Unexpectedly, palmitate stimulated gluconeogenesis even when enolase was rate-limiting. This stimulation was also observed when the activities of phosphoenolpyruvate carboxykinase and aspartate aminotransferase were modulated using graded concentrations of quinolinate and aminooxyacetate, respectively. Linear force-flow relationships were found between the rate of gluconeogenesis and indicators of cellular energy status (i.e. mitochondrial membrane and redox potentials and cellular phosphorylation potential). These findings suggest that the fatty acid stimulation of glucose synthesis is in part mediated through thermodynamic mechanisms

Spatial infinity in higher dimensional spacetimes

Motivated by recent studies on the uniqueness or non-uniqueness of higher dimensional black hole spacetime, we investigate the asymptotic structure of spatial infinity in n-dimensional spacetimes($n \geq 4$). It turns out that the geometry of spatial infinity does not have maximal symmetry due to the non-trivial Weyl tensor {}^{(n-1)}C_{abcd} in general. We also address static spacetime and its multipole moments P_{a_1 a_2 ... a_s}. Contrasting with four dimensions, we stress that the local structure of spacetimes cannot be unique under fixed a multipole moments in static vacuum spacetimes. For example, we will consider the generalized Schwarzschild spacetimes which are deformed black hole spacetimes with the same multipole moments as spherical Schwarzschild black holes. To specify the local structure of static vacuum solution we need some additional information, at least, the Weyl tensor {}^{(n-2)}C_{abcd} at spatial infinity.Comment: 6 pages, accepted for publication in Physical Review D, published versio

Alternative Splicing Regulates the Subcellular Localization of a-Kinase Anchoring Protein 18 Isoforms

The cAMP-dependent protein kinase (PKA) is localized to specific subcellular compartments by association with A-kinase anchoring proteins (AKAPs). AKAPs are a family of functionally related proteins that bind the regulatory (R) subunit of PKA with high affinity and target the kinase to specific subcellular organelles. Recently, AKAP18, a low molecular weight plasma membrane AKAP that facilitates PKA-mediated phosphorylation of the L-type Ca2+ channel, was cloned. We now report the cloning of two additional isoforms of AKAP18, which we have designated AKAP18β and AKAP18γ, that arise from alternative mRNA splicing. The AKAP18 isoforms share a common R subunit binding site, but have distinct targeting domains. The original AKAP18 (renamed AKAP18α) and AKAP18β target the plasma membrane when expressed in HEK-293 cells, while AKAP18γ is cytosolic. When expressed in epithelial cells, AKAP18α is targeted to lateral membranes, whereas AKAP18β is accumulated at the apical membrane. A 23-amino acid insert, following the plasma membrane targeting domain, facilitates the association of AKAP18β with the apical membrane. The data suggest that AKAP18 isoforms are differentially targeted to modulate distinct intracellular signaling events. Furthermore, the data suggest that plasma membrane AKAPs may be targeted to subdomains of the cell surface, adding additional specificity in intracellular signaling

Black Holes in Higher-Dimensional Gravity

These lectures review some of the recent progress in uncovering the phase structure of black hole solutions in higher-dimensional vacuum Einstein gravity. The two classes on which we focus are Kaluza-Klein black holes, i.e. static solutions with an event horizon in asymptotically flat spaces with compact directions, and stationary solutions with an event horizon in asymptotically flat space. Highlights include the recently constructed multi-black hole configurations on the cylinder and thin rotating black rings in dimensions higher than five. The phase diagram that is emerging for each of the two classes will be discussed, including an intriguing connection that relates the phase structure of Kaluza-Klein black holes with that of asymptotically flat rotating black holes.Comment: latex, 49 pages, 5 figures. Lectures to appear in the proceedings of the Fourth Aegean Summer School, Mytiline, Lesvos, Greece, September 17-22, 200

HER2-HER3 heterodimer quantification by FRET-FILM and patient subclass analysis of the COIN colorectal trial

BACKGROUND: The phase 3 MRC COIN trial showed no statistically significant benefit from adding the EGFR-target cetuximab to oxaliplatin-based chemotherapy in first-line treatment of advanced colorectal cancer. This study exploits additional information on HER2-HER3 dimerization to achieve patient stratification and reveal previously hidden subgroups of patients who had differing disease progression and treatment response. METHODS: HER2-HER3 dimerization was quantified by 'FLIM Histology' in primary tumor samples from 550 COIN trial patients receiving oxaliplatin and fluoropyrimidine chemotherapy +/-cetuximab. Bayesian latent class analysis (LCA) and covariate reduction was performed to analyze the effects of HER2-HER3 dimer, RAS mutation and cetuximab on progression-free survival (PFS) and overall survival (OS). All statistical tests were two-sided. RESULTS: LCA on a cohort of 398 patients revealed two patient subclasses with differing prognoses (median OS: 1624 days [95%CI=1466-1816] vs 461 [95%CI=431-504]): Class 1 (15.6%) showed a benefit from cetuximab in OS (HR = 0.43 [95%CI=0.25-0.76]; p = 0.004). Class 2 showed an association of increased HER2-HER3 with better OS (HR = 0.64 [95%CI=0.44-0.94]; p = 0.02). A class prediction signature was formed and tested on an independent validation cohort (N = 152) validating the prognostic utility of the dimer assay. Similar subclasses were also discovered in full trial dataset (N = 1,630) based on 10 baseline clinicopathological and genetic covariates. CONCLUSIONS: Our work suggests that the combined use of HER dimer imaging and conventional mutation analyses will be able to identify a small subclass of patients (>10%) who will have better prognosis following chemotherapy. A larger prospective cohort will be required to confirm its utility in predicting the outcome of anti-EGFR treatment

Transparent Gradient-Index Lens for Underwater Sound Based on Phase Advance

Spatial gradients in a refractive index are used extensively in acoustic metamaterial applications to control wave propagation through phase delay. This study reports the design and experimental realization of an acoustic gradient-index lens using a sonic crystal lattice that is impedance matched to water over a broad bandwidth. In contrast to previous designs, the underlying lattice features refractive indices that are lower than the water background, which facilitates propagation control based on a phase advance as opposed to a delay. The index gradient is achieved by varying the filling fraction of hollow, air-filled aluminum tubes that individually exhibit a higher sound speed than water and matched impedance. Acoustic focusing is observed over a broad bandwidth of frequencies in the homogenization limit of the lattice, with intensity magnifications in excess of 7 dB. An anisotropic lattice design facilitates a flat-faceted geometry with low backscattering at 18 dB below the incident sound-pressure level. A three-dimensional Rayleigh-Sommerfeld integration that accounts for the anisotropic refraction is used to accurately predict the experimentally measured focal patterns.This work is supported by the Office of Naval Research.Martin, TP.; Naify, C.; Skerritt, E.; Layman, C.; Nicholas, M.; Calvo, D.; Orris, GJ.... (2015). Transparent Gradient-Index Lens for Underwater Sound Based on Phase Advance. Physical Review Applied. 4(3):034003-1-034003-8. doi:10.1103/PhysRevApplied.4.034003S034003-1034003-843Naify, C. J., Martin, T. P., Layman, C. N., Nicholas, M., Thangawng, A. L., Calvo, D. C., & Orris, G. J. (2014). Underwater acoustic omnidirectional absorber. Applied Physics Letters, 104(7), 073505. doi:10.1063/1.4865480Li, R.-Q., Zhu, X.-F., Liang, B., Li, Y., Zou, X.-Y., & Cheng, J.-C. (2011). A broadband acoustic omnidirectional absorber comprising positive-index materials. Applied Physics Letters, 99(19), 193507. doi:10.1063/1.3659690Climente, A., Torrent, D., & Sánchez-Dehesa, J. (2012). Omnidirectional broadband acoustic absorber based on metamaterials. Applied Physics Letters, 100(14), 144103. doi:10.1063/1.3701611Martin, T. P., Layman, C. N., Moore, K. M., & Orris, G. J. (2012). Elastic shells with high-contrast material properties as acoustic metamaterial components. Physical Review B, 85(16). doi:10.1103/physrevb.85.161103Titovich, A. S., & Norris, A. N. (2014). Tunable cylindrical shell as an element in acoustic metamaterial. The Journal of the Acoustical Society of America, 136(4), 1601-1609. doi:10.1121/1.4894723Zhang, B., Chan, T., & Wu, B.-I. (2010). Lateral Shift Makes a Ground-Plane Cloak Detectable. Physical Review Letters, 104(23). doi:10.1103/physrevlett.104.233903Yin, M., Yong Tian, X., Xue Han, H., & Chen Li, D. (2012). Free-space carpet-cloak based on gradient index photonic crystals in metamaterial regime. Applied Physics Letters, 100(12), 124101. doi:10.1063/1.3696040Torrent, D., & Sánchez-Dehesa, J. (2007). Acoustic metamaterials for new two-dimensional sonic devices. New Journal of Physics, 9(9), 323-323. doi:10.1088/1367-2630/9/9/323Climente, A., Torrent, D., & Sánchez-Dehesa, J. (2010). Sound focusing by gradient index sonic lenses. Applied Physics Letters, 97(10), 104103. doi:10.1063/1.3488349Martin, T. P., Nicholas, M., Orris, G. J., Cai, L.-W., Torrent, D., & Sánchez-Dehesa, J. (2010). Sonic gradient index lens for aqueous applications. Applied Physics Letters, 97(11), 113503. doi:10.1063/1.3489373Peng, S., He, Z., Jia, H., Zhang, A., Qiu, C., Ke, M., & Liu, Z. (2010). Acoustic far-field focusing effect for two-dimensional graded negative refractive-index sonic crystals. Applied Physics Letters, 96(26), 263502. doi:10.1063/1.3457447Sanchis, L., Yánez, A., Galindo, P. L., Pizarro, J., & Pastor, J. M. (2010). Three-dimensional acoustic lenses with axial symmetry. Applied Physics Letters, 97(5), 054103. doi:10.1063/1.3474616Zigoneanu, L., Popa, B.-I., & Cummer, S. A. (2011). Design and measurements of a broadband two-dimensional acoustic lens. Physical Review B, 84(2). doi:10.1103/physrevb.84.024305Lin, S.-C. S., Tittmann, B. R., & Huang, T. J. (2012). Design of acoustic beam aperture modifier using gradient-index phononic crystals. Journal of Applied Physics, 111(12), 123510. doi:10.1063/1.4729803Chang, T. M., Dupont, G., Enoch, S., & Guenneau, S. (2012). Enhanced control of light and sound trajectories with three-dimensional gradient index lenses. New Journal of Physics, 14(3), 035011. doi:10.1088/1367-2630/14/3/035011Hladky-Hennion, A.-C., Vasseur, J. O., Haw, G., Croënne, C., Haumesser, L., & Norris, A. N. (2013). Negative refraction of acoustic waves using a foam-like metallic structure. Applied Physics Letters, 102(14), 144103. doi:10.1063/1.4801642Ren, C., Xiang, Z., & Cen, Z. (2010). Design of acoustic devices with isotropic material via conformal transformation. Applied Physics Letters, 97(4), 044101. doi:10.1063/1.3467852Layman, C. N., Martin, T. P., Moore, K. M., Calvo, D. C., & Orris, G. J. (2011). Designing acoustic transformation devices using fluid homogenization of an elastic substructure. Applied Physics Letters, 99(16), 163503. doi:10.1063/1.3652914Maldovan, M. (2013). Sound and heat revolutions in phononics. Nature, 503(7475), 209-217. doi:10.1038/nature12608Kadic, M., Bückmann, T., Schittny, R., & Wegener, M. (2013). Metamaterials beyond electromagnetism. Reports on Progress in Physics, 76(12), 126501. doi:10.1088/0034-4885/76/12/126501Torrent, D., & Sánchez-Dehesa, J. (2008). Anisotropic mass density by two-dimensional acoustic metamaterials. New Journal of Physics, 10(2), 023004. doi:10.1088/1367-2630/10/2/023004Parazzoli, C. G., Koltenbah, B. E. C., Greegor, R. B., Lam, T. A., & Tanielian, M. H. (2006). Eikonal equation for a general anisotropic or chiral medium: application to a negative-graded index-of-refraction lens with an anisotropic material. Journal of the Optical Society of America B, 23(3), 439. doi:10.1364/josab.23.000439Ward, G. P., Lovelock, R. K., Murray, A. R. J., Hibbins, A. P., Sambles, J. R., & Smith, J. D. (2015). Boundary-Layer Effects on Acoustic Transmission Through Narrow Slit Cavities. Physical Review Letters, 115(4). doi:10.1103/physrevlett.115.044302Guild, M. D., García-Chocano, V. M., Kan, W., & Sánchez-Dehesa, J. (2015). Acoustic metamaterial absorbers based on multilayered sonic crystals. Journal of Applied Physics, 117(11), 114902. doi:10.1063/1.4915346Reyes-Ayona, E., Torrent, D., & Sánchez-Dehesa, J. (2012). Homogenization theory for periodic distributions of elastic cylinders embedded in a viscous fluid. The Journal of the Acoustical Society of America, 132(4), 2896-2908. doi:10.1121/1.4744933Molerón, M., Serra-Garcia, M., & Daraio, C. (2014). Acoustic Fresnel lenses with extraordinary transmission. Applied Physics Letters, 105(11), 114109. doi:10.1063/1.4896276Li, Y., Yu, G., Liang, B., Zou, X., Li, G., Cheng, S., & Cheng, J. (2014). Three-dimensional Ultrathin Planar Lenses by Acoustic Metamaterials. Scientific Reports, 4(1). doi:10.1038/srep06830Gao, Y., Liu, J., Zhang, X., Wang, Y., Song, Y., Liu, S., & Zhang, Y. (2012). Analysis of focal-shift effect in planar metallic nanoslit lenses. Optics Express, 20(2), 1320. doi:10.1364/oe.20.001320Born, M., Wolf, E., Bhatia, A. B., Clemmow, P. C., Gabor, D., Stokes, A. R., … Wilcock, W. L. (1999). Principles of Optics. doi:10.1017/cbo9781139644181Shen, C., Xu, J., Fang, N. X., & Jing, Y. (2014). Anisotropic Complementary Acoustic Metamaterial for Canceling out Aberrating Layers. Physical Review X, 4(4). doi:10.1103/physrevx.4.041033Dubois, M., Farhat, M., Bossy, E., Enoch, S., Guenneau, S., & Sebbah, P. (2013). Flat lens for pulse focusing of elastic waves in thin plates. Applied Physics Letters, 103(7), 071915. doi:10.1063/1.4818716Dubois, M., Bossy, E., Enoch, S., Guenneau, S., Lerosey, G., & Sebbah, P. (2015). Time-Driven Superoscillations with Negative Refraction. Physical Review Letters, 114(1). doi:10.1103/physrevlett.114.013902Kock, W. E., & Harvey, F. K. (1949). Refracting Sound Waves. The Journal of the Acoustical Society of America, 21(5), 471-481. doi:10.1121/1.1906536Liang, Z., & Li, J. (2012). Extreme Acoustic Metamaterial by Coiling Up Space. Physical Review Letters, 108(11). doi:10.1103/physrevlett.108.114301Xie, Y., Konneker, A., Popa, B.-I., & Cummer, S. A. (2013). Tapered labyrinthine acoustic metamaterials for broadband impedance matching. Applied Physics Letters, 103(20), 201906. doi:10.1063/1.4831770Frenzel, T., David Brehm, J., Bückmann, T., Schittny, R., Kadic, M., & Wegener, M. (2013). Three-dimensional labyrinthine acoustic metamaterials. Applied Physics Letters, 103(6), 061907. doi:10.1063/1.4817934Bozhko, A., García-Chocano, V. M., Sánchez-Dehesa, J., & Krokhin, A. (2015). Redirection of sound in straight fluid channel with elastic boundaries. Physical Review B, 91(9). doi:10.1103/physrevb.91.094303García-Meca, C., Carloni, S., Barceló, C., Jannes, G., Sánchez-Dehesa, J., & Martínez, A. (2014). Transformational acoustic metamaterials based on pressure gradients. Physical Review B, 90(2). doi:10.1103/physrevb.90.024310Cummer, S. A., & Schurig, D. (2007). One path to acoustic cloaking. New Journal of Physics, 9(3), 45-45. doi:10.1088/1367-2630/9/3/045Chen, H., & Chan, C. T. (2007). Acoustic cloaking in three dimensions using acoustic metamaterials. 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CD4+ T cell surface alpha enolase is lower in older adults

To identify novel cell ageing markers in order to gain insight into ageing mechanisms, we adopted membrane enrichment and comparison of the CD4+ T cell membrane proteome (purified by cell surface labelling using Sulfo-NHS-SS-Biotin reagent) between healthy young (n=9, 20-25y) and older (n=10; 50-70y) male adults. Following two-dimensional gel electrophoresis (2DE) to separate pooled membrane proteins in triplicates, the identity of protein spots with age-dependent differences (p1.4 fold difference) was determined using liquid chromatography-mass spectrometry (LC-MS/MS). Seventeen protein spot density differences (ten increased and seven decreased in the older adult group) were observed between young and older adults. From spot intensity analysis, CD4+ T cell surface α-enolase was decreased in expression by 1.5 fold in the older age group; this was verified by flow cytometry (n=22) and qPCR with significantly lower expression of cellular α-enolase mRNA and protein compared to young adult CD4+ T cells (p<0.05). In an independent age-matched case-control study, lower CD4+ T cell surface α-enolase expression was observed in age-matched patients with cardiovascular disease (p<0.05). An immune-modulatory role has been proposed for surface α-enolase and our findings of decreased expression suggest that deficits in surface α-enolase merit investigation in the context of immune dysfunction during ageing and vascular disease

Heavy quarkonium: progress, puzzles, and opportunities

A golden age for heavy quarkonium physics dawned a decade ago, initiated by the confluence of exciting advances in quantum chromodynamics (QCD) and an explosion of related experimental activity. The early years of this period were chronicled in the Quarkonium Working Group (QWG) CERN Yellow Report (YR) in 2004, which presented a comprehensive review of the status of the field at that time and provided specific recommendations for further progress. However, the broad spectrum of subsequent breakthroughs, surprises, and continuing puzzles could only be partially anticipated. Since the release of the YR, the BESII program concluded only to give birth to BESIII; the $B$-factories and CLEO-c flourished; quarkonium production and polarization measurements at HERA and the Tevatron matured; and heavy-ion collisions at RHIC have opened a window on the deconfinement regime. All these experiments leave legacies of quality, precision, and unsolved mysteries for quarkonium physics, and therefore beg for continuing investigations. The plethora of newly-found quarkonium-like states unleashed a flood of theoretical investigations into new forms of matter such as quark-gluon hybrids, mesonic molecules, and tetraquarks. Measurements of the spectroscopy, decays, production, and in-medium behavior of c\bar{c}, b\bar{b}, and b\bar{c} bound states have been shown to validate some theoretical approaches to QCD and highlight lack of quantitative success for others. The intriguing details of quarkonium suppression in heavy-ion collisions that have emerged from RHIC have elevated the importance of separating hot- and cold-nuclear-matter effects in quark-gluon plasma studies. This review systematically addresses all these matters and concludes by prioritizing directions for ongoing and future efforts.Comment: 182 pages, 112 figures. Editors: N. Brambilla, S. Eidelman, B. K. Heltsley, R. Vogt. Section Coordinators: G. T. Bodwin, E. Eichten, A. D. Frawley, A. B. Meyer, R. E. Mitchell, V. Papadimitriou, P. Petreczky, A. A. Petrov, P. Robbe, A. Vair

Size Doesn't Matter: Towards a More Inclusive Philosophy of Biology

notes: As the primary author, O’Malley drafted the paper, and gathered and analysed data (scientific papers and talks). Conceptual analysis was conducted by both authors.publication-status: Publishedtypes: ArticlePhilosophers of biology, along with everyone else, generally perceive life to fall into two broad categories, the microbes and macrobes, and then pay most of their attention to the latter. ‘Macrobe’ is the word we propose for larger life forms, and we use it as part of an argument for microbial equality. We suggest that taking more notice of microbes – the dominant life form on the planet, both now and throughout evolutionary history – will transform some of the philosophy of biology’s standard ideas on ontology, evolution, taxonomy and biodiversity. We set out a number of recent developments in microbiology – including biofilm formation, chemotaxis, quorum sensing and gene transfer – that highlight microbial capacities for cooperation and communication and break down conventional thinking that microbes are solely or primarily single-celled organisms. These insights also bring new perspectives to the levels of selection debate, as well as to discussions of the evolution and nature of multicellularity, and to neo-Darwinian understandings of evolutionary mechanisms. We show how these revisions lead to further complications for microbial classification and the philosophies of systematics and biodiversity. Incorporating microbial insights into the philosophy of biology will challenge many of its assumptions, but also give greater scope and depth to its investigations