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Porter, John

Publications and source records attributed to Porter, John.

35 records · Page 2
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

A conformation-selective monoclonal antibody against a small molecule-stabilised signalling-deficient form of TNF

We have recently described the development of a series of small-molecule inhibitors of human tumour necrosis factor (TNF) that stabilise an open, asymmetric, signalling-deficient form of the soluble TNF trimer. Here, we describe the generation, characterisation, and utility of a monoclonal antibody that selectively binds with high affinity to the asymmetric TNF trimer–small molecule complex. The antibody helps to define the molecular dynamics of the apo TNF trimer, reveals the mode of action and specificity of the small molecule inhibitors, acts as a chaperone in solving the human TNF–TNFR1 complex crystal structure, and facilitates the measurement of small molecule target occupancy in complex biological samples. We believe this work defines a role for monoclonal antibodies as tools to facilitate the discovery and development of small-molecule inhibitors of protein–protein interactions.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Structural insights into the disruption of TNF-TNFR1 signalling by small molecules stabilising a distorted TNF

Tumour necrosis factor (TNF) is a trimeric protein which signals through two membrane receptors, TNFR1 and TNFR2. Previously, we identified small molecules that inhibit human TNF by stabilising a distorted trimer and reduce the number of receptors bound to TNF from three to two. Here we present a biochemical and structural characterisation of the small molecule-stabilised TNF-TNFR1 complex, providing insights into how a distorted TNF trimer can alter signalling function. We demonstrate that the inhibitors reduce the binding affinity of TNF to the third TNFR1 molecule. In support of this, we show by X-ray crystallography that the inhibitor-bound, distorted, TNF trimer forms a complex with a dimer of TNFR1 molecules. This observation, along with data from a solution-based network assembly assay, leads us to suggest a model for TNF signalling based on TNF-TNFR1 clusters, which are disrupted by small molecule inhibitors.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Systems and methods for generating slice files from native CAD geometries

A system and method for improving the production of objects with fully defined CAD models by generating CAD slice files from the native CAD geometries for use by AM machines. An electronic processing element receives the CAD model having a native and/or neutral format with metadata, determines a desired resolution, slices the CAD model to create the slice files having a slice format (e.g., point, edge, surface, volume) and retaining the metadata, and evaluates the slice files to determine whether the resolution has been achieved. If so, the slice files are sent to the AM machine. If not, a new desired resolution is determined and the CAD model is re-sliced, which may include combining the slice files to regenerate the CAD model. A support structure for the object may be analyzed, and if distortion is predicted, a modified CAD model may be created and sliced to create modified slice files.

Vernon, Gregory J.↗
DOE OSTI2018

Insight into small molecule binding to the neonatal Fc receptor by X-ray crystallography and 100 kHz magic-angle-spinning NMR

Aiming at the design of an allosteric modulator of the neonatal Fc receptor (FcRn)–Immunoglobulin G (IgG) interaction, we developed a new methodology including NMR fragment screening, X-ray crystallography, and magic-angle-spinning (MAS) NMR at 100 kHz after sedimentation, exploiting very fast spinning of the nondeuterated soluble 42 kDa receptor construct to obtain resolved proton-detected 2D and 3D NMR spectra. FcRn plays a crucial role in regulation of IgG and serum albumin catabolism. It is a clinically validated drug target for the treatment of autoimmune diseases caused by pathogenic antibodies via the inhibition of its interaction with IgG. We herein present the discovery of a small molecule that binds into a conserved cavity of the heterodimeric, extracellular domain composed of an α-chain and β2-microglobulin (β2m) (FcRnECD, 373 residues). X-ray crystallography was used alongside NMR at 100 kHz MAS with sedimented soluble protein to explore possibilities for refining the compound as an allosteric modulator. Proton-detected MAS NMR experiments on fully protonated [ 13 C, 15 N]-labeled FcRnECD yielded ligand-induced chemical-shift perturbations (CSPs) for residues in the binding pocket and allosteric changes close to the interface of the two receptor heterodimers present in the asymmetric unit as well as potentially in the albumin interaction site. X-ray structures with and without ligand suggest the need for an optimized ligand to displace the α-chain with respect to β2m, both of which participate in the FcRn ECD –IgG interaction site. Our investigation establishes a method to characterize structurally small molecule binding to nondeuterated large proteins by NMR, even in their glycosylated form, which may prove highly valuable for structure-based drug discovery campaigns.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

R&D 100, 2016: Ultrafast X-ray Imager

The Ultrafast X-ray Imager is a solid-state camera capable of capturing a sequence of images with user-selectable exposure times as short as 2 billionths of a second. Using 3D semiconductor integration techniques to form a hybrid chip, this camera was developed to enable scientists to study the heating and compression of fusion targets in the quest to harness the energy process that powers the stars.

47 OTHER INSTRUMENTATION↗
DOE OSTI2016

Recent laser upgrades at Sandia’s Z-backlighter facility in order to accommodate new requirements for magnetized liner inertial fusion on the Z-machine

The Z-backlighter laser facility primarily consists of two high energy, high-power laser systems. Z-Beamlet laser (ZBL) (Rambo et al., Appl. Opt. 44, 2421 (2005)) is a multi-kJ-class, nanosecond laser operating at 1054 nm which is frequency doubled to 527 nm in order to provide x-ray backlighting of high energy density events on the Z-machine. Z-Petawatt (ZPW) (Schwarz et al., J. Phys.: Conf. Ser. 112, 032020 (2008)) is a petawatt-class system operating at 1054 nm delivering up to 500 J in 500 fs for backlighting and various short-pulse laser experiments (see also Figure 10 for a facility overview). With the development of the magnetized liner inertial fusion (MagLIF) concept on the Z-machine, the primary backlighting missions of ZBL and ZPW have been adjusted accordingly. As a result, we have focused our recent efforts on increasing the output energy of ZBL from 2 to 4 kJ at 527 nm by modifying the fiber front end to now include extra bandwidth (for stimulated Brillouin scattering suppression). The MagLIF concept requires a well-defined/behaved beam for interaction with the pressurized fuel. Hence we have made great efforts to implement an adaptive optics system on ZBL and have explored the use of phase plates. We are also exploring concepts to use ZPW as a backlighter for ZBL driven MagLIF experiments. Alternatively, ZPW could be used as an additional fusion fuel pre-heater or as a temporally flexible high energy pre-pulse. All of these concepts require the ability to operate the ZPW in a nanosecond long-pulse mode, in which the beam can co-propagate with ZBL. Finally, some of the proposed modifications are complete and most of them are well on their way.

47 OTHER INSTRUMENTATION↗
DOE OSTI2015

Stress and Strain Modeling of Low Temperature Cofired Ceramic (LTCC) Seal Frame and Lid

Low temperature cofired ceramic (LTCC) is established as an excellent packaging technology for high reliability, high density microelectronics. LTCC multichip modules (MCMs) comprising both ‘surface mount’ and ‘chip and wire’ technologies provide additional customization for performance. Long term robustness of the packages is impacted by the selection of seal frame and lid materials used to enclose the components inside distinct rooms in LTCC MCMs. An LTCC seal frame and lid combination has been developed that is capable of meeting the sealing and electromagnetic shielding requirements of MCMs. Here, we analyze the stress and strain performance of various seal frame and lid materials, sealing materials, and configurations. The application for the MCM will affect selection of the seal frame, lid, and sealing materials based on this analysis.

36 MATERIALS SCIENCE↗
NASA NTRS2001

Sun and Sky Radiance Measurements and Data Analysis Protocols

This chapter is concerned with two types of radiometric measurements essential to verify atmospheric correction algorithms and to calibrate vicariously satellite ocean color sensors. The first type is a photometric measurement of the direct solar beam to determine the optical thickness of the atmosphere. The intensity of the solar beam can be measured directly, or obtained indirectly from measurements of diffuse global upper hemispheric irradiance. The second type is a measurement of the solar aureole and sky radiance distribution using a CCD camera, or a scanning radiometer viewing in and perpendicular to the solar principal plane. From the two types of measurements, the optical properties of aerosols, highly variable in space and time, can be derived. Because of the high variability, the aerosol properties should be known at the time of satellite overpass. Atmospheric optics measurements, however, are not easy to perform at sea, from a ship or any platform. This complicates the measurement protocols and data analysis. Some instrumentation cannot be deployed at sea, and is limited to island and coastal sites. In the following, measurement protocols are described for radiometers commonly used to measure direct atmospheric transmittance and sky radiance, namely standard sun photometers, fast-rotating shadow-band radiometers, automated sky scanning systems, and CCD cameras. Methods and procedures to analyze and quality control the data are discussed, as well as proper measurement strategies for evaluation of atmospheric correction algorithms and satellite-derived ocean color.

Frouin, Robert↗
NASA NTRS1993

Clustered engine study

Several topics are presented in viewgraph form which together encompass the preliminary assessment of nuclear thermal rocket engine clustering. The study objectives, schedule, flow, and groundrules are covered. This is followed by the NASA groundrules mission and our interpretation of the associated operational scenario. The NASA reference vehicle is illustrated, then the four propulsion system options are examined. Each propulsion system's preliminary design, fluid systems, operating characteristics, thrust structure, dimensions, and mass properties are detailed as well as the associated key propulsion system/vehicle interfaces. A brief series of systems analysis is also covered including: thrust vector control requirements, engine out possibilities, propulsion system failure modes, surviving system requirements, and technology requirements. An assessment of vehicle/propulsion system impacts due to the lessons learned are presented.

Shepard, Kyle↗
NASA NTRS1991

Comparison of CO2 backscatter using Mie theory from aerosol measurements over Pacific Basin with lidar data

Results of a comparison of aerosol backscatter with measurements over the Pacific Basin obtained from the CW CO2 lidars are presented. Both the Laser Optical Particle Counter (POPC) and CW CO2 lidars performed measurements at the flight level close to the aircraft and measured the same air mass. From the number distributions measured during a flight over Tokyo in June 1990, the backscatter coefficient for each component is calculated by integrating the differential backscatter. Fifteen sets of number distributions measured by the LOPC during the flight are used to predict aerosol backscatter. The backscatter from microphysics of the aerosols obtained from the LOPC and from the lidar measurements are in good agreement. It is concluded that the size distribution and composition of the aerosols can change dramatically as a function of altitude and location. The magnitude of the aerosol backscatter can vary by over three orders of magnitude from clear air to an aerosol layer.

Srivastava, Vandana↗