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All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

Conformational heterogeneity in closed and open states of the KcsA potassium channel in lipid bicelles

The process of ion channel gating—opening and closing—involves local and global structural changes in the channel in response to external stimuli. Conformational changes depend on the energetic landscape that underlies the transition between closed and open states, which plays a key role in ion channel gating. For the prokaryotic, pH-gated potassium channel KcsA, closed and open states have been extensively studied using structural and functional methods, but the dynamics within each of these functional states as well as the transition between them is not as well understood. In this study, we used solution nuclear magnetic resonance (NMR) spectroscopy to investigate the conformational transitions within specific functional states of KcsA. We incorporated KcsA channels into lipid bicelles and stabilized them into a closed state by using either phosphatidylcholine lipids, known to favor the closed channel, or mutations designed to trap the channel shut by disulfide cross-linking. A distinct state, consistent with an open channel, was uncovered by the addition of cardiolipin lipids. Using selective amino acid labeling at locations within the channel that are known to move during gating, we observed at least two different slowly interconverting conformational states for both closed and open channels. The pH dependence of these conformations and the predictable disruptions to this dependence observed in mutant channels with altered pH sensing highlight the importance of conformational heterogeneity for KcsA gating.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Molecular simulations and NMR reveal how lipid fluctuations affect membrane mechanics

Lipid bilayers form the main matrix of functional cell membranes, and their dynamics underlie a host of physical and biological processes. Here we show that elastic membrane properties and collective molecular dynamics (MD) are related by the mean-square amplitudes (order parameters) and relaxation rates (correlation times) of lipid acyl chain motions. We performed all-atom MD simulations of liquid-crystalline bilayers that allow direct comparison with carbon-hydrogen (CH) bond relaxations measured with NMR spectroscopy. Previous computational and theoretical approaches have assumed isotropic relaxation, which yields inaccurate description of lipid chain dynamics and incorrect data interpretation. Instead, the new framework includes a fixed bilayer normal (director axis) and restricted anisotropic motion of the CH bonds in accord with their segmental order parameters, enabling robust validation of lipid force fields. Simulated spectral densities of thermally excited CH bond fluctuations exhibited well-defined spin-lattice (Zeeman) relaxations analogous to those in NMR measurements. Their frequency signature could be fit to a simple power-law function, indicative of nematic-like collective dynamics. Moreover, calculated relaxation rates scaled as the squared order parameters yielding an apparent K C modulus for bilayer bending. Our results show a strong correlation with K C values obtained from solid-state NMR studies of bilayers without and with cholesterol as validated by neutron spin-echo measurements of membrane elasticity. The simulations uncover a critical role of interleaflet coupling in membrane mechanics and thus provide important insights into molecular sites of emerging elastic properties within lipid bilayers.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Biomembrane Structure and Material Properties Studied With Neutron Scattering

Cell membranes and their associated structures are dynamical supramolecular structures where different physiological processes take place. Detailed knowledge of their static and dynamic structures is therefore needed, to better understand membrane biology. The structure–function relationship is a basic tenet in biology and has been pursued using a range of different experimental approaches. In this review, we will discuss one approach, namely the use of neutron scattering techniques as applied, primarily, to model membrane systems composed of lipid bilayers. An advantage of neutron scattering, compared to other scattering techniques, is the differential sensitivity of neutrons to isotopes of hydrogen and, as a result, the relative ease of altering sample contrast by substituting protium for deuterium. This property makes neutrons an ideal probe for the study of hydrogen-rich materials, such as biomembranes. In this review article, we describe isotopic labeling studies of model and viable membranes, and discuss novel applications of neutron contrast variation in order to gain unique insights into the structure, dynamics, and molecular interactions of biological membranes. We specifically focus on how small-angle neutron scattering data is modeled using different contrast data and molecular dynamics simulations. We also briefly discuss neutron reflectometry and present a few recent advances that have taken place in neutron spin echo spectroscopy studies and the unique membrane mechanical data that can be derived from them, primarily due to new models used to fit the data.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2022

Proton transfer reactions in donor site mutants of ESR, a retinal protein from Exiguobacterium sibiricum

Light-driven proton transport by microbial retinal proteins such as archaeal bacteriorhodopsin involves carboxylic residues as internal proton donors to the catalytic center which is a retinal Schiff base (SB). The proton donor, Asp96 in bacteriorhodopsin, supplies a proton to the transiently deprotonated Schiff base during the photochemical cycle. Subsequent proton uptake resets the protonated state of the donor. Here this two step process became a distinctive signature of retinal based proton pumps. Similar steps are observed also in many natural variants of bacterial proteorhodopsins and xanthorhodopsins where glutamic acid residues serve as a proton donor. Recently, however, an exception to this rule was found. A retinal protein from Exiguobacterium sibiricum, ESR, contains a Lys residue in place of Asp or Glu, which facilitates proton transfer from the bulk to the SB. Lys96 can be functionally replaced with the more common donor residues, Asp or Glu. Proton transfer to the SB in the mutants containing these replacements (K96E and K96D/A47T) is much faster than in the proteins lacking the proton donor (K96A and similar mutants), and in the case of K96D/A47T, comparable with that in the wild type, indicating that carboxylic residues can replace Lys96 as proton donors in ESR. We show here that there are important differences in the functioning of these residues in ESR from the way Asp96 functions in bacteriorhodopsin. Reprotonation of the SB and proton uptake from the bulk occur almost simultaneously during the M to N transition (as in the wild type ESR at neutral pH), whereas in bacteriorhodopsin these two steps are well separated in time and occur during the M to N and N to O transitions, respectively.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2012

Crystal structure of a concentrative nucleoside transporter from Vibrio cholerae at 2.4;#8201;Å

Nucleosides are required for DNA and RNA synthesis, and the nucleoside adenosine has a function in a variety of signalling processes. Transport of nucleosides across cell membranes provides the major source of nucleosides in many cell types and is also responsible for the termination of adenosine signalling. As a result of their hydrophilic nature, nucleosides require a specialized class of integral membrane proteins, known as nucleoside transporters (NTs), for specific transport across cell membranes. In addition to nucleosides, NTs are important determinants for the transport of nucleoside-derived drugs across cell membranes. A wide range of nucleoside-derived drugs, including anticancer drugs (such as Ara-C and gemcitabine) and antiviral drugs (such as zidovudine and ribavirin), have been shown to depend, at least in part, on NTs for transport across cell membranes. Concentrative nucleoside transporters, members of the solute carrier transporter superfamily SLC28, use an ion gradient in the active transport of both nucleosides and nucleoside-derived drugs against their chemical gradients. The structural basis for selective ion-coupled nucleoside transport by concentrative nucleoside transporters is unknown. Here we present the crystal structure of a concentrative nucleoside transporter from Vibrio cholerae in complex with uridine at 2.4 {angstrom}. Our functional data show that, like its human orthologues, the transporter uses a sodium-ion gradient for nucleoside transport. The structure reveals the overall architecture of this class of transporter, unravels the molecular determinants for nucleoside and sodium binding, and provides a framework for understanding the mechanism of nucleoside and nucleoside drug transport across cell membranes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

Structures of N-terminally processed KRAS provide insight into the role of N-acetylation

Although post-translational modification of the C-terminus of RAS has been studied extensively, little is known about N-terminal processing. Mass spectrometric characterization of KRAS expressed in mammalian cells showed cleavage of the initiator methionine (iMet) and N-acetylation of the nascent N-terminus. Interestingly, structural studies on GDP- and GMPPNP-bound KRAS lacking the iMet and N-acetylation resulted in Mg 2+ -free structures of KRAS with flexible N-termini. In the Mg 2+ -free KRAS-GDP structure, the flexible N-terminus causes conformational changes in the interswitch region resulting in a fully open conformation of switch I. In the Mg 2+ -free KRAS-GMPPNP structure, the flexible N-terminus causes conformational changes around residue A59 resulting in the loss of Mg 2+ and switch I in the inactive state 1 conformation. Structural studies on N-acetylated KRAS-GDP lacking the iMet revealed the presence of Mg 2+ and a conformation of switch regions also observed in the structure of GDP-bound unprocessed KRAS with the iMet. In the absence of the iMet, the N-acetyl group interacts with the central beta-sheet and stabilizes the N-terminus and the switch regions. These results suggest there is crosstalk between the N-terminus and the Mg 2+ binding site, and that N-acetylation plays an important role by stabilizing the N-terminus of RAS upon excision of the iMet.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1989

Characterization of long-term extension of isolated cell walls from growing cucumber hypocotyls

Walls from frozen-thawed cucumber (Cucumis sativus L.) hypocotyls extend for many hours when placed in tension under acidic conditions. This study examined whether such "creep" is a purely physical process dependent on wall viscoelasticity alone or whether enzymatic activities are needed to maintain wall extension. Chemical denaturants inhibited wall creep, some acting reversibly and others irreversibly. Brief (15 s) boiling in water irreversibly inhibited creep, as did pre-incubation with proteases. Creep exhibited a high Q10 (3.8) between 20 degrees and 30 degrees C, with slow inactivation at higher temperatures, whereas the viscous flow of pectin solutions exhibited a much lower Q10 (1.35). On the basis of its temperature sensitivity, involvement of pectic gel-sol transitions was judged to be of little importance in creep. Pre-incubation of walls in neutral pH irreversibly inactivated their ability to creep, with a half-time of about 40 min. At 1 mM, Cu2+, Hg2+ and Al3+ were strongly inhibitory whereas most other cations, including Ca2+, had little effect. Sulfhydryl-reducing agents strongly stimulated creep, apparently by stabilizing wall enzyme(s). The physical effects of these treatments on polymer interactions were examined by Instron and stress-relaxation analyses. Some treatments, such as pH and Cu2+, had significant effects on wall viscoelasticity, but others had little or no apparent effect, thus implicating an enzymatic creep mechanism. The results indicate that creep depends on relatively rugged enzymes that are firmly attached to or entangled in the wall. The sensitivity of creep to SH-reducing agents indicates that thiol reduction of wall enzymes might provide a control mechanism for endogenous cell growth.

NASA Program Space Biology↗
DOE OSTI2012

The BAH domain of ORC1 links H4K20me2 to DNA replication licensing and Meier-Gorlin syndrome

The recognition of distinctly modified histones by specialized 'effector' proteins constitutes a key mechanism for transducing molecular events at chromatin to biological outcomes. Effector proteins influence DNA-templated processes, including transcription, DNA recombination and DNA repair; however, no effector functions have yet been identified within the mammalian machinery that regulate DNA replication. Here we show that ORC1 - a component of ORC (origin of replication complex), which mediates pre-DNA replication licensing - contains a bromo adjacent homology (BAH) domain that specifically recognizes histone H4 dimethylated at lysine 20 (H4K20me2). Recognition of H4K20me2 is a property common to BAH domains present within diverse metazoan ORC1 proteins. Structural studies reveal that the specificity of the BAH domain for H4K20me2 is mediated by a dynamic aromatic dimethyl-lysine-binding cage and multiple intermolecular contacts involving the bound peptide. H4K20me2 is enriched at replication origins, and abrogating ORC1 recognition of H4K20me2 in cells impairs ORC1 occupancy at replication origins, ORC chromatin loading and cell-cycle progression. Mutation of the ORC1 BAH domain has been implicated in the aetiology of Meier-Gorlin syndrome (MGS), a form of primordial dwarfism, and ORC1 depletion in zebrafish results in an MGS-like phenotype. We find that wild-type human ORC1, but not ORC1-H4K20me2-binding mutants, rescues the growth retardation of orc1 morphants. Moreover, zebrafish depleted of H4K20me2 have diminished body size, mirroring the phenotype of orc1 morphants. Together, our results identify the BAH domain as a novel methyl-lysine-binding module, thereby establishing the first direct link between histone methylation and the metazoan DNA replication machinery, and defining a pivotal aetiological role for the canonical H4K20me2 mark, via ORC1, in primordial dwarfism.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

SU-F-T-681: Does the Biophysical Modeling for Immunological Aspects in Radiotherapy Precisely Predict Tumor and Normal Tissue Responses?

Purpose: Recent advances in immunotherapy make possible to combine with radiotherapy. The aim of this study was to assess the TCP/NTCP model with immunological aspects including stochastic distribution as intercellular uncertainties. Methods: In the clinical treatment planning system (Eclipse ver.11.0, Varian medical systems, US), biological parameters such as α/β, D50, γ, n, m, TD50 including repair parameters (bi-exponential repair) can be set as any given values to calculate the TCP/NTCP. Using a prostate cancer patient data with VMAT commissioned as a 6-MV photon beam of Novalis-Tx (BrainLab, US) in clinical use, the fraction schedule were hypothesized as 70–78Gy/35–39fr, 72–81Gy/40–45fr, 52.5–66Gy/16–22fr, 35–40Gy/5fr of 5–7 fractions in a week. By use of stochastic biological model applying for Gaussian distribution, the effects of the TCP/NTCP variation of repair parameters of the immune system as well as the intercellular uncertainty of tumor and normal tissues have been evaluated. Results: As respect to the difference of the α/β, the changes of the TCP/NTCP were increased in hypo-fraction regimens. The difference between the values of n and m affect the variation of the NTCP with the fraction schedules, independently. The elongation of repair half-time (long) increased the TCP/NTCP twice or much higher in the case of hypo-fraction scheme. For tumor, the repopulation parameters such as Tpot and Tstart, which is immunologically working to the tumor, improved TCP. Conclusion: Compared to default fixed value, which has affected by the probability of cell death and cure, hypo-fractionation schemes seemed to have advantages for the variations of the values of m. The possibility of an increase of the α/β or TD50 and repair parameters in tumor and normal tissue by immunological aspects were highly expected. For more precise prediction, treatment planning systems should be incorporated the complicated biological optimization in clinical practice combined with basic experiments data.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Accounting for Training Data Error in Machine Learning Applied to Earth Observations

Remote sensing, or Earth Observation (EO), is increasingly used to understand Earth system dynamics and create continuous and categorical maps of biophysical properties and land cover, especially based on recent advances in machine learning (ML). ML models typically require large, spatially explicit training datasets to make accurate predictions. Training data (TD) are typically generated by digitizing polygons on high spatial-resolution imagery, by collecting in situ data, or by using pre-existing datasets. TD are often assumed to accurately represent the truth, but in practice almost always have error, stemming from (1) sample design, and (2) sample collection errors. The latter is particularly relevant for image-interpreted TD, an increasingly commonly used method due to its practicality and the increasing training sample size requirements of modern ML algorithms. TD errors can cause substantial errors in the maps created using ML algorithms, which may impact map use and interpretation. Despite these potential errors and their real-world consequences for map-based decisions, TD error is often not accounted for or reported in EO research. Here we review the current practices for collecting and handling TD. We identify the sources of TD error, and illustrate their impacts using several case studies representing different EO applications (infrastructure mapping, global surface flux estimates, and agricultural monitoring), and provide guidelines for minimizing and accounting for TD errors. To harmonize terminology, we distinguish TD from three other classes of data that should be used to create and assess ML models: training reference data, used to assess the quality of TD during data generation; validation data, used to iteratively improve models; and map reference data, used only for final accuracy assessment. We focus primarily on TD, but our advice is generally applicable to all four classes, and we ground our review in established best practices for map accuracy assessment literature. EO researchers should start by determining the tolerable levels of map error and appropriate error metrics. Next, TD error should be minimized during sample design by choosing a representative spatio-temporal collection strategy, by using spatially and temporally relevant imagery and ancillary data sources during TD creation, and by selecting a set of legend definitions supported by the data. Furthermore, TD error can be minimized during the collection of individual samples by using consensus-based collection strategies, by directly comparing interpreted training observations against expert-generated training reference data to derive TD error metrics, and by providing image interpreters with thorough application-specific training. We strongly advise that TD error is incorporated in model outputs, either directly in bias and variance estimates or, at a minimum, by documenting the sources and implications of error. TD should be fully documented and made available via an open TD repository, allowing others to replicate and assess its use. To guide researchers in this process, we propose three tiers of TD error accounting standards. Finally, we advise researchers to clearly communicate the magnitude and impacts of TD error on map outputs, with specific consideration given to the likely map audience.

58 GEOSCIENCES↗
NASA NTRS2005

Two-Photon Fluorescence Microscope for Microgravity Research

A two-photon fluorescence microscope has been developed for the study of biophysical phenomena. Two-photon microscopy is a novel form of laser-based scanning microscopy that enables three-dimensional imaging without many of the problems inherent in confocal microscopy. Unlike one-photon optical microscopy, two-photon microscopy utilizes the simultaneous nonlinear absorption of two near-infrared photons. However, the efficiency of two-photon absorption is much lower than that of one-photon absorption, so an ultra-fast pulsed laser source is typically employed. On the other hand, the critical energy threshold for two-photon absorption leads to fluorophore excitation that is intrinsically localized to the focal volume. Consequently, two-photon microscopy enables optical sectioning and confocal performance without the need for a signal-limiting pinhole. In addition, there is a reduction (relative to one-photon optical microscopy) in photon-induced damage because of the longer excitation wavelength. This reduction is especially advantageous for in vivo studies. Relative to confocal microscopy, there is also a reduction in background fluorescence, and, because of a reduction in Rayleigh scattering, there is a 4 increase of penetration depth. The prohibitive cost of a commercial two-photon fluorescence-microscope system, as well as a need for modularity, has led to the construction of a custom-built system (see Figure 1). This system includes a coherent mode-locked titanium: sapphire laser emitting 120-fs-duration pulses at a repetition rate of 80 MHz. The pulsed laser has an average output power of 800 mW and a wavelength tuning range of 700 to 980 nm, enabling the excitation of a variety of targeted fluorophores. The output from the laser is attenuated, spatially filtered, and then directed into a confocal scanning head that has been modified to provide for side entry of the laser beam. The laser output coupler has been replaced with a dichroic filter that reflects the longer-wavelength excitation light and passes the shorter-wavelength fluorescence light. Also, the confocal pinhole has been removed to increase the signal strength. The laser beam is scanned by a twoperpendicular- axis pair of galvanometer mirrors through a pupil transfer lens into the side port of an inverted microscope. Finally, the beam is focused by a 63-magnification, 1.3-numerical- aperture oil-immersion objective lens onto a specimen. The pupil transfer lens serves to match the intermediate image planes of the scanning head and the microscope, and its location is critical. In order to maximize the quality of the image, (that is, the point spread function of the objective lens for all scan positions), the entire system was modeled in optical-design software, and the various free design parameters (the parameters of the spatial-filter components as well as the separations of all of the system components) were determined through an iterative optimization process. A modular design was chosen to facilitate access to the optical train for future fluorescence correlation spectroscopy and fluorescence-lifetime experiments.

Fischer, David G.↗
DOE OSTI2019

Metal Ion Binding to the Amyloid β Monomer Studied by Native Top-Down FTICR Mass Spectrometry

Native top-down mass spectrometry is a fast, robust biophysical technique that can provide molecular-scale information on the interaction between proteins or peptides and ligands, including metal cations. Here we have analyzed complexes of the full-length amyloid β (1-42) monomer with a range of (patho)physiologically relevant metal cations using native Fourier transform ion cyclotron resonance mass spectrometry and three different fragmentation methods—collision-induced dissociation, electron capture dissociation, and infrared multiphoton dissociation—all yielding consistent results. Amyloid β is of particular interest as its oligomerization and aggregation are major events in the etiology of Alzheimer’s disease, and it is known that interactions between the peptide and bioavailable metal cations have the potential to significantly damage neurons. Those metals which exhibited the strongest binding to the peptide (Cu{sup 2+}, Co{sup 2+}, Ni{sup 2+}) all shared a very similar binding region containing two of the histidine residues near the N-terminus (His6, His13). Notably, Fe{sup 3+} bound to the peptide only when stabilized toward hydrolysis, aggregation, and precipitation by a chelating ligand, binding in the region between Ser8 and Gly25. We also identified two additional binding regions near the flexible, hydrophobic C-terminus, where other metals (Mg{sup 2+}, Ca{sup 2+}, Mn{sup 2+}, Na{sup +}, and K{sup +}) bound more weakly—one centered on Leu34, and one on Gly38. Unexpectedly, collisional activation of the complex formed between the peptide and [Co{sup III}(NH{sub 3}){sub 6}]{sup 3+} induced gas-phase reduction of the metal to Co{sup II}, allowing the peptide to fragment via radical-based dissociation pathways. This work demonstrates how native mass spectrometry can provide new insights into the interactions between amyloid β and metal cations. .

74 ATOMIC AND MOLECULAR PHYSICS↗
NASA NTRS1994

Alpha-helical hydrophobic polypeptides form proton-selective channels in lipid bilayers

Proton translocation is important in membrane-mediated processes such as ATP-dependent proton pumps, ATP synthesis, bacteriorhodopsin, and cytochrome oxidase function. The fundamental mechanism, however, is poorly understood. To test the theoretical possibility that bundles of hydrophobic alpha-helices could provide a low energy pathway for ion translocation through the lipid bilayer, polyamino acids were incorporated into extruded liposomes and planar lipid membranes, and proton translocation was measured. Liposomes with incorporated long-chain poly-L-alanine or poly-L-leucine were found to have proton permeability coefficients 5 to 7 times greater than control liposomes, whereas short-chain polyamino acids had relatively little effect. Potassium permeability was not increased markedly by any of the polyamino acids tested. Analytical thin layer chromatography measurements of lipid content and a fluorescamine assay for amino acids showed that there were approximately 135 polyleucine or 65 polyalanine molecules associated with each liposome. Fourier transform infrared spectroscopy indicated that a major fraction of the long-chain hydrophobic peptides existed in an alpha-helical conformation. Single-channel recording in both 0.1 N HCl and 0.1 M KCl was also used to determine whether proton-conducting channels formed in planar lipid membranes (phosphatidylcholine/phosphatidylethanolamine, 1:1). Poly-L-leucine and poly-L-alanine in HCl caused a 10- to 30-fold increase in frequency of conductive events compared to that seen in KCl or by the other polyamino acids in either solution. This finding correlates well with the liposome observations in which these two polyamino acids caused the largest increase in membrane proton permeability but had little effect on potassium permeability. Poly-L-leucine was considerably more conductive than poly-L-alanine due primarily to larger event amplitudes and, to a lesser extent, a higher event frequency. Poly-L-leucine caused two populations of conductive events, one in the 0.1-0.5 pA range, and one in the 1.0-5.0 pA range, whereas nearly all events caused by poly-L-alanine were in the 0.1-0.5 pA range at an applied voltage of +60 mV. The channel-like activity appeared to switch between conductive and nonconductive states, with most open-times in the range of 50-200 ms. We conclude that hydrophobic polyamino acids produce proton-conducting defects in lipid bilayers that may be used to model functional proton channels in biological membranes.

NASA Discipline Exobiology↗
DOE OSTI2011

3D modeling of effects of increased oxygenation and activity concentration in tumors treated with radionuclides and antiangiogenic drugs

Purpose: Formation of new blood vessels (angiogenesis) in response to hypoxia is a fundamental event in the process of tumor growth and metastatic dissemination. However, abnormalities in tumor neovasculature often induce increased interstitial pressure (IP) and further reduce oxygenation (pO{sub 2}) of tumor cells. In radiotherapy, well-oxygenated tumors favor treatment. Antiangiogenic drugs may lower IP in the tumor, improving perfusion, pO{sub 2} and drug uptake, by reducing the number of malfunctioning vessels in the tissue. This study aims to create a model for quantifying the effects of altered pO{sub 2}-distribution due to antiangiogenic treatment in combination with radionuclide therapy. Methods: Based on experimental data, describing the effects of antiangiogenic agents on oxygenation of GlioblastomaMultiforme (GBM), a single cell based 3D model, including 10{sup 10} tumor cells, was developed, showing how radionuclide therapy response improves as tumor oxygenation approaches normal tissue levels. The nuclides studied were {sup 90}Y, {sup 131}I, {sup 177}Lu, and {sup 211}At. The absorbed dose levels required for a tumor control probability (TCP) of 0.990 are compared for three different log-normal pO{sub 2}-distributions: {mu}{sub 1} = 2.483, {sigma}{sub 1} = 0.711; {mu}{sub 2} = 2.946, {sigma}{sub 2} = 0.689; {mu}{sub 3} = 3.689, and {sigma}{sub 3} = 0.330. The normal tissue absorbed doses will, in turn, depend on this. These distributions were chosen to represent the expected oxygen levels in an untreated hypoxic tumor, a hypoxic tumor treated with an anti-VEGF agent, and in normal, fully-oxygenated tissue, respectively. The former two are fitted to experimental data. The geometric oxygen distributions are simulated using two different patterns: one Monte Carlo based and one radially increasing, while keeping the log-normal volumetric distributions intact. Oxygen and activity are distributed, according to the same pattern. Results: As tumor pO{sub 2} approaches normal tissue levels, the therapeutic effect is improved so that the normal tissue absorbed doses can be decreased by more than 95%, while retaining TCP, in the most favorable scenario and by up to about 80% with oxygen levels previously achieved in vivo, when the least favourable oxygenation case is used as starting point. The major difference occurs in poorly oxygenated cells. This is also where the pO{sub 2}-dependence of the oxygen enhancement ratio is maximal. Conclusions: Improved tumor oxygenation together with increased radionuclide uptake show great potential for optimising treatment strategies, leaving room for successive treatments, or lowering absorbed dose to normal tissues, due to increased tumor response. Further studies of the concomitant use of antiangiogenic drugs and radionuclide therapy therefore appear merited.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2015

WE-G-213-01: Roentgen and the Birth of Modern Medical Physics

Roentgen and the Birth of Modern Medical Physics – Perry Sprawls Wilhelm Roentgen is well known for his discovery of x-radiation. What is less known and appreciated is his intensive research following the discovery to determine the characteristics of the “new kind of radiation” and demonstrate its great value for medical purposes. In this presentation we will imagine ourselves in Roentgen’s mind and follow his thinking, including questions and doubts, as he designs and conducts a series of innovative experiments that provided the foundation for the rapid growth of medical physics. Learning Objectives: Become familiar with the personal characteristics and work of Prof. Roentgen that establishes him as an inspiring model for the medical physics profession. Observe the thought process and experiments that determined and demonstrated the comprehensive characteristics of x-radiation. The AAPM Award Eponyms: William D. Coolidge, Edith H. Quimby, and Marvin M.D. Williams - Who were they and what did they do? – Lawrence N. Rothenberg William David Coolidge (1873–1975) William Coolidge was born in Hudson, NY in 1873. He obtained his BS at the Massacusetts Institute of Technology in 1896. Coolidge then went to the University of Leipzig, Germany for graduate study with physicists Paul Drude and Gustave Wiedemann and received a Ph.D. in 1899. While in Germany he met Wilhelm Roentgen. Coolidge returned to the US to teach at MIT where he was associated with Arthur A. Noyes of the Chemistry Department, working on the electrical conductivity of aqueous solutions. Willis R. Whitney, under whom Coolidge had worked before going to Germany, became head of the newly formed General Electric Research Laboratory and he invited Coolidge to work with him. In 1905, Coolidge joined the staff of the GE laboratory and was associated with it for the remainder of his life. He developed ductile tungsten filaments to replace fragile carbon filaments as the material for electric light bulb filaments. Until that innovation light bulbs had a notoriously short life. He later incorporated the ductile tungsten as a filament material for a hot cathode, fully evacuated x-ray tube, first described in 1912, which allowed higher current and x-ray output, and greater reliability than had previously been possible. These “Coolidge x-ray tubes” were far superior to the cold cathode, partial pressure gas x-ray tubes that had been in use since Roentgen’s discovery of x-rays in 1895. The Coolidge tube with incremental developments is now the key component for x-ray production in all of our modern x-ray imaging devices, such as CT scanners, interventional radiology systems, and mammography units. Coolidge was also involved in the development of sectional x-ray tubes for research and treatment that were initially designed to reach 800 kV. Additional improvements led to 1 MV and 2 MV devices. In 1932 Coolidge became director of the General Electric Research Laboratory, and in 1940, was made Vice-President and Director of Research. In 1945 he retired and was named Director Emeritus of the laboratory. Coolidge held 83 patents and was recognized for these and many other achievements by election to the National Academy of Engineers, a place in the Engineering Hall of Fame and the National Inventor’s Hall of Fame. The AAPM’s highest honor, the Coolidge Award, was named after him. He accepted Honorary Membership in the AAPM and was the first recipient of the AAPM Coolidge Award, which was presented to him in a special ceremony in Schenectady, NY in 1972 when he was 100 years old. Edith Hinckley Quimby (1891–1982) Edith Quimby was born in Rockford, IL in 1891. She graduated from Whitman College in Walla Walla, WA with a B.S. in 1913, and then obtained a masters degree from the University of California at Berkeley. Later in her career, after many significant achievements, Quimby was awarded honorary doctorates by Whitman College and Rutgers University. Edith Quimby was hired by Giacchino Failla as a radiation physicist at Memorial Hospital for Cancer in New York City. Failla had studied with Madame Curie and obtained his doctoral degree in her laboratory. After many groundbreaking medical physics studies from 1919 until 1942, they both moved to Columbia University. Dr. Quimby developed a widely employed dosimetry system for single plane implants with radium and radon seeds, and a dosimetry methodology for internal radionuclides. She was author of more than 75 scientific publications, and of significant textbooks including the first comprehensive physics textbook for radiologists “Physical Foundations of Radiology”, which was co-authored with Otto Glasser, Lauriston Taylor and James Weatherwax in the first edition, with Russell Morgan added for the second edition and Paul Goodwin for the fourth edition. With Sergei Feitelberg, M.D. she published two editions of “Radioactive Isotopes in Medicine and Biology: Basic Physics and Instrumentation”. Quimby became a renowned examiner for the American Board of Radiology when the third ABR examination, given in 1936, added physics. She served as President of the American Radium Society, received the RSNA Gold Medal, and also numerous prestigious awards given to women in science. Edith Quimby was a Charter Member of AAPM. The AAPM Lifetime Achievement Award was renamed the Edith H. Quimby Lifetime Achievement Award in her honor in 2011. Marvin Martin Dixon Williams (1902–1981) Marvin Williams was born in Walla Walla, WA in 1902, and attended the same college as Edith Quimby, graduating from Whitman College in 1926. He was greatly influenced to go into medical physics by her accomplishments. During his early career, Williams worked with James Weatherwax in Philadelphia while he was working toward an M.S. from the University of Pennsylvania. In 1931 Williams was awarded a Ph.D. in Biophysics from the University of Minnesota, with the work actually performed at the Mayo Clinic Graduate School of the University. While completing his Ph.D. studies, Marvin met Dr. Paul Hodges who had returned from the Peiping Union Medical College in Peiping (now Beijing), China. Hodges suggested that a physicist be sent to Peiping to install x-ray therapy equipment and a radon plant. Williams accepted the position and, in 1931, he and his wife Orpha left for China. Before going to China, Williams had spent time with the physics group at Memorial Hospital to learn about the operation of a radon plant. In China, he constructed the radon plant, employing 0.25 g of radium, and also installed the x-ray therapy unit. Williams and his wife returned to the US in 1935, and he accepted a research position at the Mayo Clinic. In 1950, he became Professor of Biophysics at Mayo, where he taught physics and biophysics until his retirement in 1967. Williams was also very active in the American Board of Radiology where, from 1944 through 1977, he examined over 3000 radiologists and 250 physicists. Marvin Williams was a Charter member of AAPM, served as the fourth President of AAPM in 1963, and was the fourth recipient the AAPM Coolidge Award in 1975. The Marvin Williams Award was originally established as the highest award of the American College of Medical Physics. When various functions of the ACMP were absorbed into the AAPM in 2012, the Marvin M D Williams Professional Achievement Award became one of the AAPM’s highest honors. Learning Objectives: Become familiar with the persons in whose honor the three major AAPM Award are named Learn about the achievements and activities which influenced the AAPM to name these awards in their honor.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

WE-G-213-00: History Symposium: Radiological Physics Pioneers: Roentgen and the AAPM Award Eponyms - William Coolidge, Edith Quimby, and Marvin Williams - Who Were They and What Did They Do?

Roentgen and the Birth of Modern Medical Physics – Perry Sprawls Wilhelm Roentgen is well known for his discovery of x-radiation. What is less known and appreciated is his intensive research following the discovery to determine the characteristics of the “new kind of radiation” and demonstrate its great value for medical purposes. In this presentation we will imagine ourselves in Roentgen’s mind and follow his thinking, including questions and doubts, as he designs and conducts a series of innovative experiments that provided the foundation for the rapid growth of medical physics. Learning Objectives: Become familiar with the personal characteristics and work of Prof. Roentgen that establishes him as an inspiring model for the medical physics profession. Observe the thought process and experiments that determined and demonstrated the comprehensive characteristics of x-radiation. The AAPM Award Eponyms: William D. Coolidge, Edith H. Quimby, and Marvin M.D. Williams - Who were they and what did they do? – Lawrence N. Rothenberg William David Coolidge (1873–1975) William Coolidge was born in Hudson, NY in 1873. He obtained his BS at the Massacusetts Institute of Technology in 1896. Coolidge then went to the University of Leipzig, Germany for graduate study with physicists Paul Drude and Gustave Wiedemann and received a Ph.D. in 1899. While in Germany he met Wilhelm Roentgen. Coolidge returned to the US to teach at MIT where he was associated with Arthur A. Noyes of the Chemistry Department, working on the electrical conductivity of aqueous solutions. Willis R. Whitney, under whom Coolidge had worked before going to Germany, became head of the newly formed General Electric Research Laboratory and he invited Coolidge to work with him. In 1905, Coolidge joined the staff of the GE laboratory and was associated with it for the remainder of his life. He developed ductile tungsten filaments to replace fragile carbon filaments as the material for electric light bulb filaments. Until that innovation light bulbs had a notoriously short life. He later incorporated the ductile tungsten as a filament material for a hot cathode, fully evacuated x-ray tube, first described in 1912, which allowed higher current and x-ray output, and greater reliability than had previously been possible. These “Coolidge x-ray tubes” were far superior to the cold cathode, partial pressure gas x-ray tubes that had been in use since Roentgen’s discovery of x-rays in 1895. The Coolidge tube with incremental developments is now the key component for x-ray production in all of our modern x-ray imaging devices, such as CT scanners, interventional radiology systems, and mammography units. Coolidge was also involved in the development of sectional x-ray tubes for research and treatment that were initially designed to reach 800 kV. Additional improvements led to 1 MV and 2 MV devices. In 1932 Coolidge became director of the General Electric Research Laboratory, and in 1940, was made Vice-President and Director of Research. In 1945 he retired and was named Director Emeritus of the laboratory. Coolidge held 83 patents and was recognized for these and many other achievements by election to the National Academy of Engineers, a place in the Engineering Hall of Fame and the National Inventor’s Hall of Fame. The AAPM’s highest honor, the Coolidge Award, was named after him. He accepted Honorary Membership in the AAPM and was the first recipient of the AAPM Coolidge Award, which was presented to him in a special ceremony in Schenectady, NY in 1972 when he was 100 years old. Edith Hinckley Quimby (1891–1982) Edith Quimby was born in Rockford, IL in 1891. She graduated from Whitman College in Walla Walla, WA with a B.S. in 1913, and then obtained a masters degree from the University of California at Berkeley. Later in her career, after many significant achievements, Quimby was awarded honorary doctorates by Whitman College and Rutgers University. Edith Quimby was hired by Giacchino Failla as a radiation physicist at Memorial Hospital for Cancer in New York City. Failla had studied with Madame Curie and obtained his doctoral degree in her laboratory. After many groundbreaking medical physics studies from 1919 until 1942, they both moved to Columbia University. Dr. Quimby developed a widely employed dosimetry system for single plane implants with radium and radon seeds, and a dosimetry methodology for internal radionuclides. She was author of more than 75 scientific publications, and of significant textbooks including the first comprehensive physics textbook for radiologists “Physical Foundations of Radiology”, which was co-authored with Otto Glasser, Lauriston Taylor and James Weatherwax in the first edition, with Russell Morgan added for the second edition and Paul Goodwin for the fourth edition. With Sergei Feitelberg, M.D. she published two editions of “Radioactive Isotopes in Medicine and Biology: Basic Physics and Instrumentation”. Quimby became a renowned examiner for the American Board of Radiology when the third ABR examination, given in 1936, added physics. She served as President of the American Radium Society, received the RSNA Gold Medal, and also numerous prestigious awards given to women in science. Edith Quimby was a Charter Member of AAPM. The AAPM Lifetime Achievement Award was renamed the Edith H. Quimby Lifetime Achievement Award in her honor in 2011. Marvin Martin Dixon Williams (1902–1981) Marvin Williams was born in Walla Walla, WA in 1902, and attended the same college as Edith Quimby, graduating from Whitman College in 1926. He was greatly influenced to go into medical physics by her accomplishments. During his early career, Williams worked with James Weatherwax in Philadelphia while he was working toward an M.S. from the University of Pennsylvania. In 1931 Williams was awarded a Ph.D. in Biophysics from the University of Minnesota, with the work actually performed at the Mayo Clinic Graduate School of the University. While completing his Ph.D. studies, Marvin met Dr. Paul Hodges who had returned from the Peiping Union Medical College in Peiping (now Beijing), China. Hodges suggested that a physicist be sent to Peiping to install x-ray therapy equipment and a radon plant. Williams accepted the position and, in 1931, he and his wife Orpha left for China. Before going to China, Williams had spent time with the physics group at Memorial Hospital to learn about the operation of a radon plant. In China, he constructed the radon plant, employing 0.25 g of radium, and also installed the x-ray therapy unit. Williams and his wife returned to the US in 1935, and he accepted a research position at the Mayo Clinic. In 1950, he became Professor of Biophysics at Mayo, where he taught physics and biophysics until his retirement in 1967. Williams was also very active in the American Board of Radiology where, from 1944 through 1977, he examined over 3000 radiologists and 250 physicists. Marvin Williams was a Charter member of AAPM, served as the fourth President of AAPM in 1963, and was the fourth recipient the AAPM Coolidge Award in 1975. The Marvin Williams Award was originally established as the highest award of the American College of Medical Physics. When various functions of the ACMP were absorbed into the AAPM in 2012, the Marvin M D Williams Professional Achievement Award became one of the AAPM’s highest honors. Learning Objectives: Become familiar with the persons in whose honor the three major AAPM Award are named Learn about the achievements and activities which influenced the AAPM to name these awards in their honor.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

WE-G-213-02: The AAPM Award Eponyms: William D. Coolidge, Edith H. Quimby, and Marvin M.D. Williams - Who Were They and What Did They Do?

Roentgen and the Birth of Modern Medical Physics – Perry Sprawls Wilhelm Roentgen is well known for his discovery of x-radiation. What is less known and appreciated is his intensive research following the discovery to determine the characteristics of the “new kind of radiation” and demonstrate its great value for medical purposes. In this presentation we will imagine ourselves in Roentgen’s mind and follow his thinking, including questions and doubts, as he designs and conducts a series of innovative experiments that provided the foundation for the rapid growth of medical physics. Learning Objectives: Become familiar with the personal characteristics and work of Prof. Roentgen that establishes him as an inspiring model for the medical physics profession. Observe the thought process and experiments that determined and demonstrated the comprehensive characteristics of x-radiation. The AAPM Award Eponyms: William D. Coolidge, Edith H. Quimby, and Marvin M.D. Williams - Who were they and what did they do? – Lawrence N. Rothenberg William David Coolidge (1873–1975) William Coolidge was born in Hudson, NY in 1873. He obtained his BS at the Massacusetts Institute of Technology in 1896. Coolidge then went to the University of Leipzig, Germany for graduate study with physicists Paul Drude and Gustave Wiedemann and received a Ph.D. in 1899. While in Germany he met Wilhelm Roentgen. Coolidge returned to the US to teach at MIT where he was associated with Arthur A. Noyes of the Chemistry Department, working on the electrical conductivity of aqueous solutions. Willis R. Whitney, under whom Coolidge had worked before going to Germany, became head of the newly formed General Electric Research Laboratory and he invited Coolidge to work with him. In 1905, Coolidge joined the staff of the GE laboratory and was associated with it for the remainder of his life. He developed ductile tungsten filaments to replace fragile carbon filaments as the material for electric light bulb filaments. Until that innovation light bulbs had a notoriously short life. He later incorporated the ductile tungsten as a filament material for a hot cathode, fully evacuated x-ray tube, first described in 1912, which allowed higher current and x-ray output, and greater reliability than had previously been possible. These “Coolidge x-ray tubes” were far superior to the cold cathode, partial pressure gas x-ray tubes that had been in use since Roentgen’s discovery of x-rays in 1895. The Coolidge tube with incremental developments is now the key component for x-ray production in all of our modern x-ray imaging devices, such as CT scanners, interventional radiology systems, and mammography units. Coolidge was also involved in the development of sectional x-ray tubes for research and treatment that were initially designed to reach 800 kV. Additional improvements led to 1 MV and 2 MV devices. In 1932 Coolidge became director of the General Electric Research Laboratory, and in 1940, was made Vice-President and Director of Research. In 1945 he retired and was named Director Emeritus of the laboratory. Coolidge held 83 patents and was recognized for these and many other achievements by election to the National Academy of Engineers, a place in the Engineering Hall of Fame and the National Inventor’s Hall of Fame. The AAPM’s highest honor, the Coolidge Award, was named after him. He accepted Honorary Membership in the AAPM and was the first recipient of the AAPM Coolidge Award, which was presented to him in a special ceremony in Schenectady, NY in 1972 when he was 100 years old. Edith Hinckley Quimby (1891–1982) Edith Quimby was born in Rockford, IL in 1891. She graduated from Whitman College in Walla Walla, WA with a B.S. in 1913, and then obtained a masters degree from the University of California at Berkeley. Later in her career, after many significant achievements, Quimby was awarded honorary doctorates by Whitman College and Rutgers University. Edith Quimby was hired by Giacchino Failla as a radiation physicist at Memorial Hospital for Cancer in New York City. Failla had studied with Madame Curie and obtained his doctoral degree in her laboratory. After many groundbreaking medical physics studies from 1919 until 1942, they both moved to Columbia University. Dr. Quimby developed a widely employed dosimetry system for single plane implants with radium and radon seeds, and a dosimetry methodology for internal radionuclides. She was author of more than 75 scientific publications, and of significant textbooks including the first comprehensive physics textbook for radiologists “Physical Foundations of Radiology”, which was co-authored with Otto Glasser, Lauriston Taylor and James Weatherwax in the first edition, with Russell Morgan added for the second edition and Paul Goodwin for the fourth edition. With Sergei Feitelberg, M.D. she published two editions of “Radioactive Isotopes in Medicine and Biology: Basic Physics and Instrumentation”. Quimby became a renowned examiner for the American Board of Radiology when the third ABR examination, given in 1936, added physics. She served as President of the American Radium Society, received the RSNA Gold Medal, and also numerous prestigious awards given to women in science. Edith Quimby was a Charter Member of AAPM. The AAPM Lifetime Achievement Award was renamed the Edith H. Quimby Lifetime Achievement Award in her honor in 2011. Marvin Martin Dixon Williams (1902–1981) Marvin Williams was born in Walla Walla, WA in 1902, and attended the same college as Edith Quimby, graduating from Whitman College in 1926. He was greatly influenced to go into medical physics by her accomplishments. During his early career, Williams worked with James Weatherwax in Philadelphia while he was working toward an M.S. from the University of Pennsylvania. In 1931 Williams was awarded a Ph.D. in Biophysics from the University of Minnesota, with the work actually performed at the Mayo Clinic Graduate School of the University. While completing his Ph.D. studies, Marvin met Dr. Paul Hodges who had returned from the Peiping Union Medical College in Peiping (now Beijing), China. Hodges suggested that a physicist be sent to Peiping to install x-ray therapy equipment and a radon plant. Williams accepted the position and, in 1931, he and his wife Orpha left for China. Before going to China, Williams had spent time with the physics group at Memorial Hospital to learn about the operation of a radon plant. In China, he constructed the radon plant, employing 0.25 g of radium, and also installed the x-ray therapy unit. Williams and his wife returned to the US in 1935, and he accepted a research position at the Mayo Clinic. In 1950, he became Professor of Biophysics at Mayo, where he taught physics and biophysics until his retirement in 1967. Williams was also very active in the American Board of Radiology where, from 1944 through 1977, he examined over 3000 radiologists and 250 physicists. Marvin Williams was a Charter member of AAPM, served as the fourth President of AAPM in 1963, and was the fourth recipient the AAPM Coolidge Award in 1975. The Marvin Williams Award was originally established as the highest award of the American College of Medical Physics. When various functions of the ACMP were absorbed into the AAPM in 2012, the Marvin M D Williams Professional Achievement Award became one of the AAPM’s highest honors. Learning Objectives: Become familiar with the persons in whose honor the three major AAPM Award are named Learn about the achievements and activities which influenced the AAPM to name these awards in their honor.

60 APPLIED LIFE SCIENCES↗