Biochemical adaptations of the retina and retinal pigment epithelium support a metabolic ecosystem in the vertebrate eye

Here we report multiple lines of evidence for a comprehensive model of energy metabolism in the vertebrate eye. Metabolic flux, locations of key enzymes, and our finding that glucose enters mouse and zebrafish retinas mostly through photoreceptors support a conceptually new model for retinal metabolism. In this model, glucose from the choroidal blood passes through the retinal pigment epithelium to the retina where photoreceptors convert it to lactate. Photoreceptors then export the lactate as fuel for the retinal pigment epithelium and for neighboring Mu ̈ ller glial cells. We used human retinal epithelial cells to show that lactate can suppress consumption of glucose by the retinal pigment epithelium. Suppression of glucose consumption in the retinal pigment epithelium can increase the amount of glucose that reaches the retina. This framework for understanding metabolic relationships in the vertebrate retina provides new insights into the underlying causes of retinal disease and age-related vision loss

The SUrvey for Pulsars and Extragalactic Radio Bursts - III. Polarization properties of FRBs 160102 and 151230

We report on the polarization properties of two fast radio bursts (FRBs): 151230 and 160102 discovered in the SUrvey for Pulsars and Extragalactic Radio Bursts (SUPERB) at the Parkes Radio Telescope. FRB 151230 is observed to be 6 ± 11 per cent circularly polarized and 35 ± 13 per cent linearly polarized with a rotation measure (RM) consistent with zero. Conversely, FRB160102 is observed to have a circular polarization fraction of 30±11 per cent, linear polarization fraction of 84 ± 15 per cent for RM = -221(6) radm-2, and the highest measured dispersion measure (2596.1±0.3 pc cm-3) for an FRB to date.We examine possible progenitor models for FRB 160102 in extragalactic, non-cosmological and cosmological scenarios. After accounting for the Galactic foreground contribution, we estimate the intrinsic RM to be -256(9) rad m-2in the low-redshift case and ~-2.4×102rad m-2in the highredshift case. We assess the relative likeliness of these scenarios and how each can be tested. We also place constraints on the scattering measure and study the impact of scattering on the signal's polarization position angle

Metabolism in Cancer and Aging

Metabolism is one of the most fundamental processes in living systems: the conversion of nutrients to energy and cellular building blocks and the disposal of wastes and toxins enables organisms to live and grow. The essential nature of metabolism renders animals sensitive to conditions and factors that disrupt ordinary metabolism, such as cancer and aging. Understanding the features of metabolism that dysfunction in such states is thus instrumental in developing strategies to counteract these pathologies. In this thesis, I discuss the use of untargeted metabolomic profiling by liquid chromatography coupled to mass spectrometry (LC- MS) in addition to more targeted analyses using stable isotope tracers in studies of cancer and aging. First, I discuss metabolic profiling to interrogate the pro-oxidant activity of pharmacologic ascorbate as an anti-cancer treatment, leading to the discovery that dietary selenium restriction can sensitize cancer to ascorbate in vivo. I then discuss the application of metabolomics and stable isotope tracing for flux studies in aging mice in two distinct analyses. The first of these analyses entails a highly detailed analysis of whole-body NAD+ metabolism in aging mice, and the second encompasses a much broader, yet highly comprehensive, analysis of metabolic changes associated with aging and how they differ from those that present in obesity. Collectively, my work demonstrates the power of metabolic analyses in establishing biochemical mechanisms and to differentiate confounding factors that present in pathological states and establish an exhaustive resource for future studies on metabolism in the context of mammalian aging

Acidic Methanol Treatment Facilitates Matrix-Assisted Laser Desorption Ionization-Mass Spectrometry Imaging of Energy Metabolism.

Detection of small molecule metabolites (SMM), particularly those involved in energy metabolism using MALDI-mass spectrometry imaging (MSI), is challenging due to factors including ion suppression from other analytes present (e.g., proteins and lipids). One potential solution to enhance SMM detection is to remove analytes that cause ion suppression from tissue sections before matrix deposition through solvent washes. Here, we systematically investigated solvent treatment conditions to improve SMM signal and preserve metabolite localization. Washing with acidic methanol significantly enhances the detection of phosphate-containing metabolites involved in energy metabolism. The improved detection is due to removing lipids and highly polar metabolites that cause ion suppression and denaturing proteins that release bound phosphate-containing metabolites. Stable isotope infusions of [13C6]nicotinamide coupled to MALDI-MSI (Iso-imaging) in the kidney reveal patterns that indicate blood vessels, medulla, outer stripe, and cortex. We also observed different ATP:ADP raw signals across mouse kidney regions, consistent with regional differences in glucose metabolism favoring either gluconeogenesis or glycolysis. In mouse muscle, Iso-imaging using [13C6]glucose shows high glycolytic flux from infused circulating glucose in type 1 and 2a fibers (soleus) and relatively lower glycolytic flux in type 2b fiber type (gastrocnemius). Thus, improved detection of phosphate-containing metabolites due to acidic methanol treatment combined with isotope tracing provides an improved way to probe energy metabolism with spatial resolution in vivo