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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 1,225 records · Page 68
All sourcesNASA NTRSDOE OSTI
DOE OSTI2016

SU-F-T-374: Dosimetric Effects of Irradiation Through a Bilateral Hip Prosthesis in a MRI Linac

Purpose: To evaluate the interface effects when irradiating through a hip prosthesis in the presence of an orthogonal 1.5 T magnetic field using Monte Carlo simulations. Methods: A 20×20×38 cm virtual phantom with two 5×5×5 cm sections of bilateral titanium hip prosthesis was created in GPU-based Monte Carlo (MC) algorithm (GPUMCD, Elekta AB, Stockholm Sweden). The lateral prosthesis spacing was based on a representative patient CT scan. A treatment SAD of 143.5 cm was chosen, corresponding to the Elekta AB MRI Linac and the beam energy distribution was sampled from a histogram representing the true MRI Linac spectrum. A magnetic field of 1.5 T was applied perpendicular to the plane of irradiation. Dose was calculated, in voxels of side 1 mm, for 2×2, 5×5, and 10×10 cm treatment field sizes with normal beam incidence (gantry at 90° or 270°) and at 5° and 10° from normal, representing the range of incidence through the bilateral prosthesis. Results: With magnetic field ON (B-On) and normal beam incidence the backscatter dose at the interfaces of proximal and distal implants is reduced for all the field sizes compared to the magnetic field OFF (B-Off) case. The absolute reduction in doses at the interface was in the range of 12.93% to 13.16% for the proximal implant and 13.57% to 16.12% for the distal implant. Similarly for the oblique incidences of 5o and 10o the dose in the plane adjacent to the prosthetic implants is lower when the magnetic field is ON. Conclusion: The dosimetric effects of irradiating through a hip prosthesis in the presence of a transverse magnetic field have been determined using MC simulation. The backscatter dose reduction translates into significantly lower hot spots at the prosthetic interfaces, which are otherwise substantially high in the absence of the magnetic field. This project was supported through funding provided by ElektaTM.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-G-201-13: Investigation of Dose Variation Induced by HDR Ir-192 Source Global Shift Within the Varian Ring Applicator Using Monte Carlo Methods

Purpose: The Varian tandem and ring applicators are used to deliver HDR Ir-192 brachytherapy for cervical cancer. The source path within the ring is hard to predict due to the larger interior ring lumen. Some studies showed the source could be several millimeters different from planned positions, while other studies demonstrated minimal dosimetric impact. A global shift can be applied to limit the effect of positioning offsets. The purpose of this study was to assess the necessities of implementing a global source shift using Monte Carlo (MC) simulations. Methods: The MCNP5 radiation transport code was used for all MC simulations. To accommodate TG-186 guidelines and eliminate inter-source attenuation, a BrachyVision plan with 10 dwell positions (0.5cm step sizes) was simulated as the summation of 10 individual sources with equal dwell times for simplification. To simplify the study, the tandem was also excluded from the MC model. Global shifts of ±0.1, ±0.3, ±0.5 cm were then simulated as distal and proximal from the reference positions. Dose was scored in water for all MC simulations and was normalized to 100% at the normalization point 0.5 cm from the cap in the ring plane. For dose comparison, Point A was 2 cm caudal from the buildup cap and 2 cm lateral on either side of the ring axis. With seventy simulations, 108 photon histories gave a statistical uncertainties (k=1) <2% for (0.1 cm)3 voxels. Results: Compared to no global shift, average Point A doses were 0.0%, 0.4%, and 2.2% higher for distal global shifts, and 0.4%, 2.8%, and 5.1% higher for proximal global shifts, respectively. The MC Point A doses differed by < 1% when compared to BrachyVision. Conclusion: Dose variations were not substantial for ±0.3 cm global shifts, which is common in clinical practice.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

WE-AB-207B-03: A Computational Methodology for Determination of CTV-To-PTV Margins with Inter Fractional Shape Variations Based On a Statistical Point Distribution Model for Prostate Cancer Radiation Therapy

Purpose: Our assumption was that interfractional shape variations of target volumes could not be negligible for determination of clinical target volume (CTV)-to-planning target volume (PTV) margins. The aim of this study was to investigate this assumption as a simulation study by developing a computational framework of CTV-to-PTV margins with taking the interfractional shape variations into account based on point distribution model (PDM) Methods: The systematic and random errors for interfractional shape variations and translations of target volumes were evaluated for four types of CTV regions (only a prostate, a prostate plus proximal 1-cm seminal vesicles, a prostate plus proximal 2-cm seminal vesicles, and a prostate plus whole seminal vesicles). The CTV regions were delineated depending on prostate cancer risk groups on planning computed tomography (CT) and cone beam CT (CBCT) images of 73 fractions of 10 patients. The random and systematic errors for shape variations of CTV regions were derived from PDMs of CTV surfaces for all fractions of each patient. Systematic errors of shape variations of CTV regions were derived by comparing PDMs between planning CTV surfaces and average CTV surfaces. Finally, anisotropic CTV-to-PTV margins with shape variations in 6 directions (anterior, posterior, superior, inferior, right, and left) were computed by using a van Herk margin formula. Results: Differences between CTV-to-PTV margins with and without shape variations ranged from 0.7 to 1.7 mm in anterior direction, 1.0 to 2.8 mm in posterior direction, 0.8 to 2.8 mm in superior direction, 0.6 to 1.6 mm in inferior direction, 1.4 to 4.4 mm in right direction, and 1.3 to 5.2 mm in left direction. Conclusion: More than 1.0 mm additional margins were needed at least in 3 directions to guarantee CTV coverage due to shape variations. Therefore, shape variations should be taken into account for the determination of CTV-to-PTV margins.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

TH-CD-209-12: Spatial Mapping of Scanned Proton Biologic Effect Using the High-Throughput Technique, Continued

Purpose: To investigate the biologic effects of scanned protons by evenly sampling dose-averaged LET (LETd) values. Methods: Our previous high-throughput clonogenic study demonstrated a distinct relationship between RBE and LETd. However, our initial experimental design resulted in over-sampling the low LETd values in the plateau region of the Bragg curve while under-sampling in the region proximal to the Bragg peak as well as the high LETd values in the distal edge of the Bragg curve. To further examine the relationship between RBE and LETd, we refined the experimental design to more evenly sample proton LETd values from 1 to 20 keV/µm by optimizing the thicknesses of the irradiation jig steps. We used the clonogenic survival as the biological endpoint for the H460 lung cancer cell line cultured in 96-well plates (12 columns by 8 rows). In the irradiation, the 8 wells in each column received a uniform dose-LETd pair. The dose-LETd pairs of the 12 different columns were sampled along the Bragg curve of 81.4 MeV scanned protons. Five peak dose levels from 1.5 Gy to 7.5 Gy were delivered with an increment of 1.5 Gy in the preliminary test. Two 96-well plates were irradiated simultaneously to decrease the statistical uncertainties. Results: In the proximal region, for LETd = 5 keV/µm and 8 keV/µm, we did not observe any distinct differential biologic effects between the survival curves. At the Bragg peak (LETd = 9.5 keV/µm) and in the distal edge, irradiation with increasing LET values resulted in decreasing cell survival. Conclusion: The survival curves from the new experimental design support our previous findings that below 10 keV/µm, the LET effect in cell kill is obscured, but above 10 keV/µm, the biologic effects increase with LETd. Funding Support: U19 CA021239-35 and R21 CA187484-01.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗
DOE OSTI2020

Absence of evidence for chiral Majorana modes in quantum anomalous Hall-superconductor devices

A quantum anomalous Hall (QAH) insulator coupled to an s-wave superconductor is predicted to harbor chiral Majorana modes. A recent experiment interprets the half-quantized two-terminal conductance plateau as evidence for these modes in a millimeter-size QAH-niobium hybrid device. However, non-Majorana mechanisms can also generate similar signatures, especially in disordered samples. Here, we studied similar hybrid devices with a well-controlled and transparent interface between the superconductor and the QAH insulator. When the devices are in the QAH state with well-aligned magnetization, the two-terminal conductance is always half-quantized. Our experiment provides a comprehensive understanding of the superconducting proximity effect observed in QAH-superconductor hybrid devices and shows that the half-quantized conductance plateau is unlikely to be induced by chiral Majorana fermions in samples with a highly transparent interface.

Science & Technology - Other Topics↗
DOE OSTI2025

Pair wave function symmetry in UTe2 from zero-energy surface state visualization

Although nodal spin-triplet topological superconductivity appears probable in uranium ditelluride (UTe 2 ), its superconductive order parameter Δ k remains unestablished. In theory, a distinctive identifier would be the existence of a superconductive topological surface band, which could facilitate zero-energy Andreev tunneling to an s-wave superconductor and also distinguish a chiral from a nonchiral Δ k through enhanced s-wave proximity. In this study, we used s-wave superconductive scan tips and detected intense zero-energy Andreev conductance at the UTe 2 (0-11) termination surface. Imaging revealed subgap quasiparticle scattering interference signatures with a-axis orientation. The observed zero-energy Andreev peak splitting with enhanced s-wave proximity signifies that Δ k of UTe 2 is a nonchiral state: B 1u , B 2u , or B 3u . However, if the quasiparticle scattering along the a axis is internodal, then a nonchiral B 3u state is the most consistent for UTe 2 .

Gu, Qiangqiang [Cornell Univ., Ithaca, NY (United ↗
DOE OSTI2025

A dynamic protein interactome drives energy conservation and electron flux in Thermococcus kodakarensis

ABSTRACT Life is supported by energy gains fueled by catabolism of a wide range of substrates, each reliant on the selective partitioning of electrons through redox ( red uction and ox idation) reactions. Electron flux through tunable and regulated protein interactions provides dynamic routes for energy conservation, but how electron flux is regulated in vivo , particularly for archaeal metabolisms that support rapid growth at the thermodynamic limits of life, is poorly understood. Identification of bona fide in vivo protein assemblies and how such assemblies dictate the totality of electron flux is critical to our understanding of the regulation imposed on metabolism, energy production, and energy conservation. Here, 25 key proteins in central metabolic redox pathways in the model, genetically accessible, hyperthermophilic archaeon Thermococcus kodakarensis , were purified to reveal an extensive, dynamic, and tightly interconnected network of protein interactions that responds to environmental cues (such as the availability of various reductive sinks) to direct electron flux to maximize energetic gains. Interactions connecting disparate functions suggest many catabolic and anabolic activities occur in spatial proximity in vivo , and while protein complexes have been historically defined under optimal conditions, many of these complexes appear to maintain alternative partnerships in changing conditions. The totality of the results obtained redefines our understanding of in vivo assemblies driving ancient metabolic strategies supporting the growth of modern Archaea. IMPORTANCE Given the potential for rational genetic manipulations of biofuel- and biotech-promising archaea to yield transformative results for major markets, it is a priority to define how the metabolisms of such species are controlled, at least in part, by in vivo protein assemblies, and from such, define routes of energy flux that can be most efficiently altered toward biofuel or biotechnological gains. Proteinaceous electron carriers (PECs, such as ferredoxins) offer the potential for specific protein–protein interactions to coordinate selective reductive flow. Employing the model, genetically accessible, hyperthermophilic archaeon, Thermococcus kodakarensis , we establish the metabolic protein interactome of 25 key redox proteins, revealing that each redox active protein has a dynamic partnership profile, suggesting catabolic and anabolic activities may occur in concert and in temporal and spatial proximity in vivo . These results reveal critical importance in evaluating the newly identified partnerships and their role and utility in providing regulated redox flux in T. kodakarensis .

Williams, Sere A. (ORCID:0000000235509590)↗
DOE OSTI2024

The military gear microbiome: risk factors surrounding the warfighter

ABSTRACT Combat extremity wounds are highly susceptible to contamination from surrounding environmental material. This bioburden could be partially transferred from materials in immediate proximity to the wound, including fragments of the uniform and gear. However, the assessment of the microbial bioburden present on military gear during operational conditions of deployment or training is relatively unexplored. Opportunistic pathogens that can survive on gear represent risk factors for infection following injury, especially following combat blasts, where fibers and other materials are embedded in wounded tissue. We utilized 16S rRNA sequencing to assess the microbiome composition of different military gear types (boot, trouser, coat, and canteen) from two operational environments (training in Hawai’i and deployed in Indonesia) across time (days 0 and 14). We found that microbiome diversity, stability, and composition were dependent on gear type, training location, and sampling timepoint. At day 14, species diversity was significantly higher in Hawai’i samples compared to Indonesia samples for boot, coat, and trouser swabs. In addition, we observed the presence of potential microbial risk factors, as opportunistic pathogenic species, such as Acinetobacter , Pseudomonas, and Staphylococcus , were found to be present in all sample types and in both study sites. These study outcomes will be used to guide the design of antimicrobial materials and uniforms and for infection control efforts following combat blasts and other injuries, thereby improving treatment guidance during military training and deployment. IMPORTANCE Combat extremity wounds are vulnerable to contamination from environments of proximity to the warfighter, leading to potential detrimental outcomes such as infection and delayed wound healing. Therefore, microbial surveillance of such environments is necessary to aid the advancement of military safety and preparedness through clinical diagnostics, treatment protocols, and uniform material design.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Molecular Basis of Unusually High Neutralization Resistance in Tier 3 HIV-1 Strain 253-11

Understanding the mechanisms used by HIV-1 to evade antibody neutralization may contribute to the design of a high-coverage vaccine. The tier 3 virus 253-11 is poorly neutralized by subtype-matched and subtype C sera, even compared to other tier 3 viruses, and is also recognized poorly by V3/glycan-targeting monoclonal antibodies (MAbs). We found that sequence polymorphisms in the V3 loop and N-linked glycosylation sites contribute only minimally to the high neutralization resistance of 253-11. Interestingly, the 253-11 membrane-proximal external region (MPER) is rarely recognized by sera in the context of the wild-type virus but is commonly recognized in the context of an HIV-2 chimera, suggesting steric or kinetic hindrance of binding to MPER in the native envelope (Env). Mutations in the 253-11 MPER, which were previously reported to increase the lifetime of the prefusion Env conformation, affected the resistance of 253-11 to antibodies targeting various epitopes on HIV-1 Env, presumably destabilizing its otherwise stable, closed trimer structure. To gain insight into the structure of 253-11, we constructed and crystallized a recombinant 253-11 SOSIP trimer. The resulting structure revealed that the heptad repeat helices in gp41 are drawn in close proximity to the trimer axis and that gp120 protomers also showed a relatively compact disposition around the trimer axis. Furthermore, these observations give substantial insight into the molecular features of an envelope spike from a tier 3 virus and into possible mechanisms that may contribute to its unusually high neutralization resistance.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2012

Cold reaction valleys in the radioactive decay of superheavy {sup 286}112, {sup 292}114, and {sup 296}116 nuclei

Cold reaction valleys in the radioactive decay of superheavy nuclei {sup 286}112, {sup 292}114, and {sup 296}116 are studied taking Coulomb and Proximity Potential as the interacting barrier. It is found that in addition to alpha particle, {sup 8}Be, {sup 14}C, {sup 28}Mg, {sup 34}Si, {sup 50}Ca, etc. are optimal cases of cluster radioactivity since they lie in the cold valleys. Two other regions of deep minima centered on {sup 208}Pb and {sup 132}Sn are also found. Within our Coulomb and Proximity Potential Model half-life times and other characteristics such as barrier penetrability, decay constant for clusters ranging from alpha particle to {sup 68}Ni are calculated. The computed alpha half-lives match with the values calculated using Viola-Seaborg-Sobiczewski systematics. The clusters {sup 8}Be and {sup 14}C are found to be most probable for emission with T{sub 1/2} < 10{sup 30} s. The alpha-decay chains of the three superheavy nuclei are also studied. The computed alpha-decay half-lives are compared with the values predicted by Generalized Liquid Drop Model and they are found to match reasonably well.

73 NUCLEAR PHYSICS AND RADIATION PHYSICS↗
DOE OSTI2017

Phase transitions in hybrid SFS structures with thin superconducting layers

Calculations of critical temperature T{sub c} of the phase transition to superconducting state of a superconductor/ ferromagnet/superconductor (SFS) hybrid structure with proximity effect is performed on the base of linearized Usadel equations. It is shown that the proximity effect between S and F metals and the exchange interaction can induce an inhomogeneous superconducting state with longitudinal to layers Δ {sub ∝} exp(ipz) modulation of the superconductivity order parameter, which is characterized by nonzero value of the wave number p, describing the Larkin–Ovchinnikov–Fulde–Ferrell instability. Influence of this instability on transitions between 0- and π-states of the SFS structure is studied. It is shown that the 0–π transition is accompanied by a nonmonotonic dependence of both the critical temperature T{sub c} and the effective penetration depth Λ of the magnetic field into the hybrid structure on the characteristic size of the ferromagnetic region.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗
DOE OSTI2018

Probing Electrode-Electrolyte Interfaces Using Nano-Gap Surface-Enhanced Raman Spectroscopy and Imaging

Performance of portable electronic devices and electric vehicles is currently limited by the energy density, lifetime and safety of lithium rechargeable batteries. Overcoming those limitations requires in-depth understanding of the electrode-electrolyte interfaces. Surface-enhanced Raman spectroscopy (SERS) can provide a critical component to this effort as an in situ technique with ultrahigh surface sensitivity that provides quantitative molecular specificity. SERS relies on local electromagnetic field amplification generated by surface plasmon resonance (SPR) at the surface of metal nanoparticles (NPs) with sub-wavelength dimensions. The most significant Raman enhancements have been observed when the local SPRs of multiple NPs interact. This occurs when the NPs are in close proximity (less than 10 nm), which could be achieved in ordered NP monolayers if they could be assembled reproducibly. Methods to assemble gold NPs into large area (cm2) monolayers will be presented. The interparticle gap can be tuned between 1 and 4 nm by using surface ligands of different sizes. The Au NP monolayers exhibit high SERS sensitivity (enhancement factor greater than 107). This allows for the measurement of electrolyte components across a broad range of concentrations. Components include lithium hexafluorophosphate (LiPF6), fluoroethylene carbonate (FEC), ethylene carbonate (EC) and diethyl carbonate (DEC). The investigation of solutions of LiPF6 in EC + DEC binary solvents using SERS allows for the determination of the solvent coordination numbers, which range from 2 to 5. This result is in sharp contrast to the bulk values calculated from infrared spectroscopy, which range from 3 to 7. Numerical simulations show that the electromagnetic field is concentrated in the nanogap, indicating the information of the aprotic electrolyte solution structures is obtained from the immediately adjacent area of the solid substrate. Our findings facilitate a better understanding of the structure of solvated ions in close proximity to the electrode surface.

Yang, Guang↗
DOE OSTI2014

Analysis of a Destructive Wind Storm on 16 November 2008 in Brisbane, Australia

During the late afternoon on 16 November 2008 the Brisbane (Australia) suburb of “The Gap” experienced extensive wind damage caused by an intense local thunderstorm. The CP2 research radar nearby detected near-surface radial velocities exceeding 44 m s -1 above The Gap while hail size reports did not exceed golf ball size, and no tornadoes were reported. This study shows that the storm environment was characterized by a layer of very moist (mixing ratios exceeding 12 g kg -1 ) near-surface air embedded in strong storm-relative low-level flow, whereas the storm-relative winds aloft were significantly weaker. And while the thermodynamic storm environment contained a range of downdraft promoting ingredients such as a ~4 km high melting level above a ~2 km deep layer with nearly dry adiabatic lapse rates mostly collocated with dry ambient air, a ~1 km deep stable layer near the ground would generally lower expectations of destructive surface winds based on the downburst mechanism. We also found that once observed reflectivities exceed 70 dBZ that downdraft cooling due to hail melting and downdraft acceleration based on hail loading are likely to become non-negligible forcing mechanisms for a strong downdraft. The study found a close proximity of the hydrostatically and dynamically driven mesohigh at the base of the downdraft to a dynamically driven mesolow associated with a radar-observed low-level circulation. This proximity is hypothesized to have been instrumental in the observed anisotropic horizontal acceleration of the near-ground outflow and the ultimate strength of the Gap storm surface winds. Finally, we speculate that the 44 weak storm-relative midlevel winds allowed the downdraft to descend close to the low45 level circulation which set up this strong horizontal perturbation pressure gradient.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2024

Tornadoes in Southeast South America: Mesoscale to Planetary-Scale Environments

Abstract A multiscale analysis of the environment supporting tornadoes in southeast South America (SESA) was conducted based on a self-constructed database of 74 reports. Composites of environmental and convective parameters from ERA5 were generated relative to tornado events. The distribution of the reported tornadoes maximizes over the Argentine plains, while events are rare close to the Andes and south of Sierras de Córdoba. Events are relatively common in all seasons except in winter. Proximity environment evolution shows enhanced instability, deep-layer vertical wind shear, storm-relative helicity, reduced convective inhibition, and a lowered lifting condensation level before or during the development of tornadic storms in SESA. No consistent signal in low-level wind shear is seen during tornado occurrence. However, a curved hodograph with counterclockwise rotation is present. The Significant Tornado Parameter (STP) is also maximized prior to tornadogenesis, most strongly associated with enhanced CAPE. Differences in the convective environment between tornadoes in SESA and the U.S. Great Plains are discussed. On the synoptic scale, tornado events are associated with a strong anomalous trough crossing the southern Andes that triggers lee cyclogenesis, subsequently enhancing the South American low-level jet (SALLJ) that increases moisture advection to support deep convection. This synoptic trough also enhances vertical shear that, along with enhanced instability, sustains organized convection capable of producing tornadic storms. At planetary scales, the tornadic environment is modulated by Rossby wave trains that appear to be forced by convection near northern Australia. Madden–Julian oscillation phase 3 preferentially occurs 1–2 weeks ahead of tornado occurrence. Significance Statement The main goal of this study is to describe what atmospheric conditions (from local to global scales) are present prior to and during tornadic storms impacting southeast South America (SESA). Increasing potential for deep convection, wind shear, and potential for rotating updrafts, as well as reducing convective inhibition and cloud-base height, are predominant a few hours before and during the events in connection to low-level northerly winds enhancing moisture transport to the region. Remote convective activity near northern Australia appears to influence large-scale atmospheric circulation that subsequently triggers convective storms supporting tornadogenesis 1–2 weeks later in SESA. Our findings highlight the importance of accounting for atmospheric processes occurring at different scales to understand and predict tornado occurrences.

Meteorology & Atmospheric Sciences↗
DOE OSTI2020

A terminology for in situ visualization and analysis systems

The term "in situ processing" has evolved over the last decade to mean both a specific strategy for visualizing and analyzing data and an umbrella term for a processing paradigm. The resulting confusion makes it difficult for visualization and analysis scientists to communicate with each other and with their stakeholders. To address this problem, a group of over 50 experts convened with the goal of standardizing terminology. This paper summarizes their findings and proposes a new terminology for describing in situ systems. An important finding from this group was that in situ systems are best described via multiple, distinct axes: integration type, proximity, access, division of execution, operation controls, and output type. This paper discusses these axes, evaluates existing systems within the axes, and explores how currently used terms relate to the axes.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2015

Association mapping in sunflower ( Helianthus annuus L.) reveals independent control of apical vs. basal branching

Background - Shoot branching is an important determinant of plant architecture and influences various aspects of growth and development. Selection on branching has also played an important role in the domestication of crop plants, including sunflower ( Helianthus annuus L.). Here, we describe an investigation of the genetic basis of variation in branching in sunflower via association mapping in a diverse collection of cultivated sunflower lines. Results - Detailed phenotypic analyses revealed extensive variation in the extent and type of branching within the focal population. After correcting for population structure and kinship, association analyses were performed using a genome-wide collection of SNPs to identify genomic regions that influence a variety of branching-related traits. This work resulted in the identification of multiple previously unidentified genomic regions that contribute to variation in branching. Genomic regions that were associated with apical and mid-apical branching were generally distinct from those associated with basal and mid-basal branching. Homologs of known branching genes from other study systems (i.e., Arabidopsis , rice, pea, and petunia) were also identified from the draft assembly of the sunflower genome and their map positions were compared to those of associations identified herein. Numerous candidate branching genes were found to map in close proximity to significant branching associations. Conclusions - In sunflower, variation in branching is genetically complex and overall branching patterns (i.e., apical vs. basal) were found to be influenced by distinct genomic regions. Moreover, numerous candidate branching genes mapped in close proximity to significant branching associations. Although the sunflower genome exhibits localized islands of elevated linkage disequilibrium (LD), these non-random associations are known to decay rapidly elsewhere. The subset of candidate genes that co-localized with significant associations in regions of low LD represents the most promising target for future functional analyses.

Apical dominance↗
DOE OSTI2016

Improved safety and efficacy of 213 Bi-DOTATATE-targeted alpha therapy of somatostatin receptor-expressing neuroendocrine tumors in mice pre-treated with l-lysine

Background: Targeted alpha therapy (TAT) offers advantages over current β-emitting conjugates for peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors. PRRT with 177 Lu-DOTATATE or 90 Y-DOTATOC has shown dose-limiting nephrotoxicity due to radiopeptide retention in the proximal tubules. Pharmacological protection can reduce renal uptake of radiopeptides, e.g., positively charged amino acids, to saturate in the proximal tubules, thereby enabling higher radioactivity to be safely administered. The aim of this preclinical study was to evaluate the therapeutic effect of 213 Bi-DOTATATE with and without renal protection using L-lysine in mice. Tumor uptake and kinetics as a function of injected mass of peptide (range 0.03–3 nmol) were investigated using 111In-DOTATATE. These results allowed estimation of the mean radiation absorbed tumor dose for 213Bi-DOTATATE. Pharmacokinetics and dosimetry of 213Bi-DOTATATE was determined in mice, in combination with renal protection. A dose escalation study with 213 Bi-DOTATATE was performed to determine the maximum tolerated dose (MTD) with and without pre-administration of L-lysine as for renal protection. Neutrophil gelatinase-associated lipocalin (NGAL) served as renal biomarker to determine kidney injury. Results: The maximum mean radiation absorbed tumor dose occurred at 0.03 nmol and the minimum at 3 nmol. Similar mean radiation absorbed tumor doses were determined for 0.1 and 0.3 nmol with a mean radiation absorbed dose of approximately 0.5 Gy/MBq 213 Bi-DOTATATE. The optimal mass of injected peptide was found to be 0.3 nmol. Tumor uptake was similar for 111 In-DOTATATE and 213 Bi-DOTATATE at 0.3 nmol peptide. Lysine reduced the renal uptake of 213 Bi-DOTATATE by 50% with no effect on the tumor uptake. The MTD was <13.0 ± 1.6 MBq in absence of L-lysine and 21.7 ± 1.9 MBq with L-lysine renal protection, both imparting an LD 50 mean renal radiation absorbed dose of 20 Gy. A correlation was found between the amount of injected radioactivity and NGAL levels. Conclusions: The therapeutic potential of 213 Bi-DOTATATE was illustrated by significantly decreased tumor burden and improved overall survival. Renal protection with L-lysine immediately prior to TAT with 213 Bi-DOTATATE prolonged survival providing substantial evidence for pharmacological nephron blockade to mitigate nephrotoxicity.

213Bi-DOTATATE↗
DOE OSTI2016

A unique stylopod patterning mechanism by Shox2 -controlled osteogenesis

Vertebrate appendage patterning is programmed by Hox-TALE factor-bound regulatory elements. However, it remains unclear which cell lineages are commissioned by Hox-TALE factors to generate regional specific patterns and whether other Hox-TALE co-factors exist. In this study, we investigated the transcriptional mechanisms controlled by the Shox2 transcriptional regulator in limb patterning. Harnessing an osteogenic lineage-specific Shox2 inactivation approach we show that despite widespread Shox2 expression in multiple cell lineages, lack of the stylopod observed upon Shox2 deficiency is a specific result of Shox2 loss of function in the osteogenic lineage. ChIP-Seq revealed robust interaction of Shox2 with cis-regulatory enhancers clustering around skeletogenic genes that are also bound by Hox-TALE factors, supporting a lineage autonomous function of Shox2 in osteogenic lineage fate determination and skeleton patterning. Pbx ChIP-Seq further allowed the genome-wide identification of cis-regulatory modules exhibiting co-occupancy of Pbx, Meis and Shox2 transcriptional regulators. Integrative analysis of ChIP-Seq and RNA-Seq data and transgenic enhancer assays indicate that Shox2 patterns the stylopod as a repressor via interaction with enhancers active in the proximal limb mesenchyme and antagonizes the repressive function of TALE factors in osteogenesis.

Ye, Wenduo↗