Engineering Papers⌕ Search

Engineering topics

Fitzgerald, Mark

Publications and source records attributed to Fitzgerald, Mark.

Mechanistic insights into a heterobifunctional degrader-induced PTPN2/N1 complex

PTPN2 (protein tyrosine phosphatase non-receptor type 2, or TC-PTP) and PTPN1 are attractive immuno-oncology targets, with the deletion of Ptpn1 and Ptpn2 improving response to immunotherapy in disease models. Targeted protein degradation has emerged as a promising approach to drug challenging targets including phosphatases. We developed potent PTPN2/N1 dual heterobifunctional degraders (Cmpd-1 and Cmpd-2) which facilitate efficient complex assembly with E3 ubiquitin ligase CRL4 CRBN , and mediate potent PTPN2/N1 degradation in cells and mice. To provide mechanistic insights into the cooperative complex formation introduced by degraders, we employed a combination of structural approaches. Our crystal structure reveals how PTPN2 is recognized by the tri-substituted thiophene moiety of the degrader. We further determined a high-resolution structure of DDB1-CRBN/Cmpd-1/PTPN2 using single-particle cryo-electron microscopy (cryo-EM). This structure reveals that the degrader induces proximity between CRBN and PTPN2, albeit the large conformational heterogeneity of this ternary complex. The molecular dynamic (MD)-simulations constructed based on the cryo-EM structure exhibited a large rigid body movement of PTPN2 and illustrated the dynamic interactions between PTPN2 and CRBN. Together, our study demonstrates the development of PTPN2/N1 heterobifunctional degraders with potential applications in cancer immunotherapy. Furthermore, the developed structural workflow could help to understand the dynamic nature of degrader-induced cooperative ternary complexes.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Advancing Performance Assessment for Disposal of Depleted Uranium at Clive Utah - 12493

A Performance Assessment (PA) for disposal of depleted uranium (DU) waste has recently been completed for a potential disposal facility at Clive in northwestern Utah. For the purposes of this PA, 'DU waste' includes uranium oxides of all naturally-occurring isotopes, though depleted in U-235, varying quantities of other radionuclides introduced to the uranium enrichment process in the form of used nuclear reactor fuel (reactor returns), and decay products of all of these radionuclides. The PA will be used by the State of Utah to inform an approval decision for disposal of DU waste at the facility, and will be available to federal regulators as they revisit rulemaking for the disposal of DU. The specific performance objectives of the Clive DU PA relate to annual individual radiation dose within a 10,000-year performance period, groundwater concentrations of specific radionuclides within a 500-year compliance period, and site stability in the longer term. Fate and transport processes that underlie the PA model include radioactive decay and ingrowth, diffusion in gaseous and water phases, water advection in unsaturated and saturated zones, transport caused by plant and animal activity, cover naturalization, natural and anthropogenic erosion, and air dispersion. Fate and transport models were used to support the dose assessment and the evaluation of groundwater concentrations. Exposure assessment was based on site-specific scenarios, since the traditional human exposure scenarios suggested by DOE and NRC guidance are unrealistic for this site. Because the U-238 in DU waste reaches peak radioactivity (secular equilibrium) after 2 million years (My) following its separation, the PA must also evaluate the impact of climate change cycles, including the return of pluvial lakes such as Lake Bonneville. The first draft of the PA has been submitted to the State of Utah for review. The results of this preliminary analysis indicate that doses are very low for the site-specific receptors for the 10,000-year compliance period. This is primarily because DU waste is not highly radioactive within this time frame, the DU waste is assumed to be buried beneath zones exposed by erosion, groundwater concentrations of DU waste constituents do not exceed groundwater protection limits with in the 500-year compliance period, and the first deep lake occurrence will disperse DU waste across a large area, and will ultimately be covered by lake-derived sediment. A probabilistic PA model was constructed that considered DU waste and decay product doses to site-specific receptors for a 10,000-yr performance period, as well as deep-time effects. The quantitative results are summarized in Table VII. Doses (as TEDE) are always less than 5 mSv in a year, and doses to the offsite receptors are always much less than 0.25 mSv in a year. Groundwater concentrations of Tc-99 are always less than its GWPL except when the Tc-99 contaminated waste is disposed below grade. Even in this case, the median groundwater concentration is only 4.18 Bq/L (113 pCi/L), which is more than one order of magnitude less than the GWPL for Tc-99. The results overall suggest that there are disposal configurations that can be used to dispose of the proposed quantities of DU waste that are adequately protective of human health. (authors)

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗

Algorithm.

Abstract not provided.

Halkjaer-Knudsen, Vibeke↗

An update on the Department of Energy's photovoltaic program

Funding for the terrestrial photovoltaic's program is $78 million in 1994. This is more than double the minimum level reached in 1989 and runs counter to the general trend of decreasing budgets for Department of Energy (DOE) programs. During the past five years, the program has expanded its mission from research and development to also address manufacturing technology and commercialization assistance. These new activities are directed toward revitalizing the market to reinstate the rapid rate of sales growth needed to attract investment. The program is approaching balance among efforts in each of the three areas. This translates to a reduction in some of the R & D activities of most relevance to the space power community. On the other hand, some of the advancements in manufacturing may finally bring thin-film technologies to reality for space arrays. This talk will describe the status and direction of DOE program with an eye toward highlighting its impact on technology of interest for space.

Benner, John P.↗