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All sourcesNASA NTRSDOE OSTI
DOE OSTI2015

SU-E-T-286: Dose Verification of Spot-Scanning Proton Beam Using GafChromic EBT3 Film

Purpose: Dose verification of spot-scanning proton pencil beam is performed via planar dose measurements at several depths using an ionization-chamber array, requiring repeat irradiations of each field for each depth. Here we investigate film dosimetry which has two advantages: higher resolution and efficiency from one-shot irradiation for multiple depths. Methods: Film calibration was performed using an EBT3 film at 20-cm depth of Plastic Water (CIRS, Norfolk, VA) exposed by a 10-level step wedge on a Proteus Plus proton system (IBA, Belgium). The calibration doses ranged from 25–250 cGy(RBE) for proton energies of 170–200 MeV. A uniform 1000 cm{sup 3} dose cube and a clinical prostate combined with seminal-vesicle and pelvic-nodes plan were used for this study. All treatment plans were generated in the RayStation (RaySearch Lab, Sweden). The planar doses at different depths for both cases were measured with film using triple-channel dosimetry and the MatriXX PT (IBA Dosimetry, Germany). The Gamma passing rates, dose-difference maps, and profiles of 2D planar doses measured with EBT3 film and MatriXX, versus treatment planning system (TPS) calculations were analyzed and compared using the FilmQA Pro (Ashland Inc., Bridgewater, NJ). Results: The EBT3 film measurement results matched well with the TPS calculation data with an average passing rate >95% for 2%/2mm and are comparable with the MatriXX measurements (0.7%, 1.8%, 3.8% mean differences corresponding to 3%/3mm, 3%/2mm, 2%/2mm, respectively). Overall passing rates for EBT3 films appear higher than those with MatriXX detectors. Conclusion: The energy dependence of the film response could be minimized by calibration using proton beam with mixed energies. The greater efficiency of the dose verification using GafChromic EBT3 results in a potential cost trade-off between room capacity and film cost. EBT3 film may offer distinct advantages in highly intensity-modulated fields due to its higher resolution compared to 2D ionization-chamber array detectors. One of the authors has a research grant from Ashland Inc., the manufacturer of GafChromic film.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

SU-E-T-434: Fixed Margin Or Online Adaptation for Intermediate-Risk Prostate Stereotactic Body Radiation Therapy? A Dosimetric Study

Purpose: To investigate the choice of fixed margin or online adaptation when treating intermediate-risk prostate cancer including seminal vesicles (SV) using stereotactic body radiation therapy (SBRT). Methods: 9 prostate SBRT patients were retrospectively studied. All patients were implanted with fiducial markers in the prostate for daily localization and verification. Each patient had 5 pairs of pre-treatment and post-treatment cone-beam CT (CBCT) per protocol. SVs were contoured on planning CT and all CBCTs by one attending physician. Simultaneous integral boost (SIB) IMRT plans were developed to deliver 25Gy/5fx to the SV while delivering 37Gy/5fx to the prostate. A 3mm isotropic margin was added to the prostate while a 5 mm isotropic margin was used for the SV. The planning CT was registered to daily pre-treatment and post-treatment CBCT based on fiducial markers in the prostate to mimic online prostate localization; and the SV on daily CBCT was transferred to the CT structure set after the prostates were aligned. Daily pre-treatment and post-treatment SV dose coverage and the organ-at-risk (OAR) sparing were evaluated for the SIB regimen. At least 95% of the SV need to receive the prescription dose (5Gy per fraction). Results: For the total of 90 daily SVs analyzed (ten CBCTs for each of nine patients), only 45 daily SVs (50%) were able to meet the coverage that 95% of the SV received 25Gy. The OAR sparing performance was acceptable for most of the dosimetric constraints in low-risk prostate SBRT protocol with only two exceptions in bladder V100 (cc). Conclusion: A fixed 5mm margin for SV is not sufficient to provide consistent daily dose coverage due to SV’s substantial inter- and intra-fractional motion relative to the prostate. This finding calls for innovative strategies in margin design as well as online treatment adaptation. This work is partially supported a master research grant from Varian Medical Systems.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

SU-E-T-765: Treatment Planning Comparison of SFUD Proton and 4Ï€ Radiotherapy for Prostate Cases

Purpose: Single-Field Uniform Dose (SFUD) proton scanning beams and non-coplanar 4π intensity-modulated radiation therapy (IMRT) represent the most advanced treatment methods based on heavy ion and X-rays, respectively. Here we compare their performance for prostate treatment. Methods: Five prostate patients were planned using 4π radiotherapy and SFUD to an initial dose of 54Gy to a planning target volume (PTV) that encompassed the prostate and seminal vesicles, then a boost prescription dose of 25.2Gy to the prostate for a total dose of 79.2 Gy. 4π plans were created by inversely selecting and optimizing 30 beams from 1162 candidate non-coplanar beams using a greedy column generation algorithm. The SFUD plans utilized two coplanar, parallel-opposing lateral scanning beams. The SFUD plan PTV was modified to account for range uncertainties while keeping an evaluation PTV identical to that of the X-ray plans for comparison. PTV doses, bladder and rectum dose volumes (V40, V45, V60, V70, V75.6, and V80), R50, and PTV homogeneity index (D95/D5) were evaluated. Results: Compared to SFUD, 4π resulted in 6.8% lower high dose spillage as indicated by R50. Bladder and rectum mean doses were 38.3% and 28.2% lower for SFUD, respectively. However, bladder and rectum volumes receiving >70Gy were 13.1% and 12% greater using proton SFUD. Due to the parallel-opposing beam arrangement, SFUD resulted in greater femoral head (87.8%) and penile bulb doses (43.7%). 4π PTV doses were slightly more homogeneous (HI 0.99 vs. 0.98) than the SFUD dose. Conclusion: Proton is physically advantageous to reduce the irradiated normal volume and mean doses to the rectum and bladder but it is also limited in the beam orientations and entrance dose, which resulted in greater doses to the femoral heads and penile bulb, and larger volumes of rectum and bladder exposed to high dose due to the required robust PTV definition. This project is supported by Varian Medical Systems.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

TU-EF-304-05: Anterior Proton Beams for Prostate Treatments Lead to Substantial Elevations in Modeled RBE-Weighted Rectal Dose

Purpose: If a constant RBE of 1.1 is assumed, range-verified anterior oblique (AO) proton beams appear to offer the potential to reduce the mean dose delivered to the rectum, anterior rectal wall and penile bulb by a factor of ∼2 relative to standard bilateral (SB) proton beam arrangements. Additionally, AO proton beams targeted at the prostate avoid the femoral heads and so form a particularly appealing option for patients with hip prostheses. This study investigates LET enhancement at the distal edge of AO SOBPs, applying RBE models to consider the extent to which AO beams lead to hotspots in rectum biological dose. Methods: Eight patients were selected, all treated with passively scattered, SB proton beams to 79.2Gy(E) within the prostate and 50.4Gy(E) within the proximal 5–15mm of seminal vesicles. Additional plans utilizing AO beams (±35°) were created in XiO (Elekta) assuming a fixed RBE of 1.1. Voxelised dose and LET distributions were calculated using Monte Carlo (TOPAS). Three different LET/RBE models were applied (Carabe 2012, Wedenberg 2013, McNamara 2015). Results: Across the eight patients, the mean LET within the rectal wall was found to be 3.5(3.2–4.0)keV/µm for the SB plans compared to 10.5(8.6–13.0)keV/µm for the AO plans. Application of the median LET/RBE model to the AO plans, rather than a fixed RBE of 1.1, resulted in an increase of 13.6(11.9–14.7)GyRBE in maximum rectal wall (1cc) RBEw dose, leading to values of 90.4(90.0–91.3)GyRBE. Conclusion: relative to SB proton beams, AO proton beams exhibit substantially increased mean LET values within the rectal wall. For the passively scattered AO beams, modeling indicates that this enhancement is likely to translate into unacceptable RBEw dose hotspots. Whilst no RBE- LET model has yet been fully validated in-vivo, caution must be applied if AO beams are to be considered for prostate patients.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2015

Dosimetric evaluation of three adaptive strategies for prostate cancer treatment including pelvic lymph nodes irradiation

Purpose: The movements of the prostate relative to the pelvic lymph nodes during intensity-modulated radiation therapy treatment can limit margin reduction and affect the protection of the organs at risk (OAR). In this study, the authors performed an analysis of three adaptive treatment strategies that combine information from both bony and gold marker registrations. The robustness of those treatments against the interfraction prostate movements was evaluated. Methods: A retrospective study was conducted on five prostate cancer patients with 7–13 daily cone-beam CTs (CBCTs). The clinical target volumes (CTVs) consisting of pelvic lymph nodes, prostate, and seminal vesicles as well as the OARs were delineated on each CBCT and the initial CT. Three adaptive strategies were analyzed. Two of these methods relied on a two-step patient positioning at each fraction. First step: a bony registration was used to deliver the nodal CTV prescription. Second step: a gold marker registration was then used either to (1) complete the dose delivered to the prostate (complement); (2) or give almost the entire prescription to the prostate with a weak dose gradient between the targets to compensate for possible motions (gradient). The third method (COR) used a pool of precalculated plans based on images acquired at previous treatment fractions. At each new fraction, a plan is selected from that pool based on the daily position of prostate center-of-mass. The dosimetric comparison was conducted and results are presented with and without the systematic shift in the prostate position on the CT planning. The adaptive strategies were compared to the current clinical standard where all fractions are treated with the initial nonadaptive plan. Results: The minimum daily prostate D{sub 95%} is improved by 2%, 9%, and 6% for the complement, the gradient, and the COR approaches, respectively, compared to the nonadaptive method. The average nodal CTV D{sub 95%} remains constant across the strategies, except for the gradient approach where a reduction of 7% is observed. However, a correction of the systematic shift reduced the problem, and the adaptive strategies remain robust against the prostate movement across the fraction. The bladder V{sub 55Gy} is reduced by 35% on average for the adaptive strategies. Conclusions: Because they offer increased CTV coverage and OAR sparing, adaptive methods may be suitable candidates for simple and efficient adaptive treatment strategies for prostate cancer. Margin reduction and systematic error correction in the prostate position improve the protection of the OAR and the dose coverage. A cumulative dose to simulate a complete treatment would show real effects and allow a better comparison between each method.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-G-TeP1-05: Development and Clinical Introduction of Automated Radiotherapy Treatment Planning for Prostate Cancer

Purpose: To develop an automated radiotherapy treatment planning and optimization workflow for prostate cancer in order to generate clinical treatment plans. Methods: A fully automated radiotherapy treatment planning and optimization workflow was developed based on the treatment planning system Monaco (Elekta AB, Stockholm, Sweden). To evaluate our method, a retrospective planning study (n=100) was performed on patients treated for prostate cancer with 5 field intensity modulated radiotherapy, receiving a dose of 35×2Gy to the prostate and vesicles and a simultaneous integrated boost of 35×0.2Gy to the prostate only. A comparison was made between the dosimetric values of the automatically and manually generated plans. Operator time to generate a plan and plan efficiency was measured. Results: A comparison of the dosimetric values show that automatically generated plans yield more beneficial dosimetric values. In automatic plans reductions of 43% in the V72Gy of the rectum and 13% in the V72Gy of the bladder are observed when compared to the manually generated plans. Smaller variance in dosimetric values is seen, i.e. the intra- and interplanner variability is decreased. For 97% of the automatically generated plans and 86% of the clinical plans all criteria for target coverage and organs at risk constraints are met. The amount of plan segments and monitor units is reduced by 13% and 9% respectively. Automated planning requires less than one minute of operator time compared to over an hour for manual planning. Conclusion: The automatically generated plans are highly suitable for clinical use. The plans have less variance and a large gain in time efficiency has been achieved. Currently, a pilot study is performed, comparing the preference of the clinician and clinical physicist for the automatic versus manual plan. Future work will include expanding our automated treatment planning method to other tumor sites and develop other automated radiotherapy workflows.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

SU-G-JeP4-09: Impact of Interfractional Motion On Hypofractionated Pencil Beam Scanning Proton Therapy for Prostate Cancer

Purpose: To investigate the impact of anatomy/setup variations on standard vs. hypofractionated anterolateral pencil beam scanning (PBS) proton therapy for prostate cancer. Methods: Six prostate cancer patients treated with double-scattering proton therapy, who underwent weekly verification CT scans were selected. Implanted fiducials were used for localization, and endorectal balloons for immobilization. New PBS plans using combination of lateral and anterior-oblique (AO) (±35 deg) beams were created. AO beams were added to spare the femoral heads during hypofractionation. Lateral beams delivered 50.4 Gy(RBE) to prostate plus 5-15mm of seminal vesicles and AO beams 28.8 Gy(RBE) to prostate, in 44 fractions. PTV was laterally expanded by 2.5% to account for range uncertainty. No range margins were applied for AO beams, assuming delivery with in-vivo range verification. Field-specific apertures with 1.2cm margin were used. Spot size was ∼9.5mm sigma for 172MeV @isocenter in air. Plans were optimized as single-field-uniform-dose with ∼5% maximum non-uniformity. The planned dose was recomputed on each weekly CT after aligning the fiducials with the simulation CT, scaled and accumulated via deformable image registration. Hypofractionated treatments with 12 and 5 fractions were considered. Equivalent doses were calculated for prostate (α/β= 1.5Gy), bladder and rectum (α/β= 3Gy). Results: The biological equivalent prostate dose was 86.2 and 92.9 Gyeq for the hypofractionation scenarios at 4.32 and 7.35 Gy/fx, respectively. The equivalent prostate D98 was degraded by on average 2.7 Gyeq for standard, and 3.1 and 4.0 Gyeq for the hypofractionated plans after accumulation. Differences between accumulated and planned Dmean/D2/EUD were generally reduced when reducing the number of fractions for bladder and rectum. The average Dmean/D2/EUD differences over all patients and organs-at-risk were 0.74/4.0/9.23, 0.49/3.64/5.51, 0.37/3.21/3.49 Gyeq for 44, 12 and 5 fractions. Conclusion: Hypofractionation makes proton therapy of prostate more susceptible to interfractional motion-induced target dose degradation compared to the standard fractionation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2026

Human NLRP3 inflammasome activation leads to formation of condensate at the microtubule organizing center

The NLRP3 inflammasome is a multiprotein molecular machine that drives inflammatory responses in innate immunity. Although its dysregulation is implicated in numerous human diseases, its structural organization in cells remains poorly understood. Here, we used precise fluorescence-guided cryo–focused ion beam (cryo-FIB) milling and cryo–electron tomography (cryo-ET) to visualize NLRP3 inflammasomes in situ within human macrophages at various stages of activation. After priming and activation, we observed expansion and dispersion of Golgi cisternae, along with the emergence of 50-nanometer NLRP3-associated vesicles, which likely transport NLRP3 to the MTOC. Dense NLRP3-containing condensates then formed in and around the MTOC. In later stages, the condensates solidified, coincident with widespread mitochondrial damage, autophagy, and pyroptotic cell death.

Wang, Jue [Division of Chemistry and Chemical Engi↗
DOE OSTI2022

Ultrastructure of Organohalide-Respiring Dehalococcoidia Revealed by Cryo-Electron Tomography

Dehalococcoides mccartyi (Dhc) and Dehalogenimonas spp. (Dhgm) are members of the class Dehalococcoidia, phylum Chloroflexi, characterized by streamlined genomes and a strict requirement for organohalogens as electron acceptors. Here, we used cryo-electron tomography to reveal morphological and ultrastructural features of Dhc strain BAV1 and “Candidatus Dehalogenimonas etheniformans” strain GP cells at unprecedented resolution. Dhc cells were irregularly shaped discs (890 ± 110 nm long, 630 ± 110 nm wide, and 130 ± 15 nm thick) with curved and straight sides that intersected at acute angles, whereas Dhgm cells appeared as slightly flattened cocci (760 ± 85 nm). The cell envelopes were composed of a cytoplasmic membrane (CM), a paracrystalline surface layer (S-layer) with hexagonal symmetry and ~22-nm spacing between repeating units, and a layer of unknown composition separating the CM and the S-layer. Cell surface appendages were only detected in Dhc cells, whereas both cell types had bundled cytoskeletal filaments. Repetitive globular structures, ~5 nm in diameter and ~9 nm apart, were observed associated with the outer leaflet of the CM. We hypothesized that those represent organohalide respiration (OHR) complexes and estimated ~30,000 copies per cell. In Dhgm cultures, extracellular lipid vesicles (20 to 110 nm in diameter) decorated with putative OHR complexes but lacking an S-layer were observed. Furthermore, the new findings expand our understanding of the unique cellular ultrastructure and biology of organohalide-respiring Dehalococcoidia.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

CpoS-Inc interactions facilitate host cell modulation during Chlamydia trachomatis infection

ABSTRACT Chlamydia trachomatis ( C.t .), the leading bacterial cause of sexually transmitted infections, replicates within a unique intracellular compartment called the inclusion, which is modified by secreted proteins known as inclusion membrane (Inc) proteins. Here, we further characterize CpoS, an Inc protein previously shown to be critical for bacterial replication and inclusion development. We demonstrate that CpoS directly binds multiple coiled-coil region-containing Incs and engages Rab GTPases at a separate site. Notably, CpoS-InaC interactions facilitate the recruitment of select Arf GTPases to the inclusion membrane, while Rab recruitment occurs independently of these interactions. Biochemical and biophysical analyses revealed that Incs self-oligomerize to form higher-ordered structures, with CpoS adopting a tetrameric conformation resembling that of eukaryotic SNARE proteins. We propose that these assemblies serve as scaffolds to orchestrate vesicle docking, tethering, and fusion. Our findings highlight the intricate interplay between bacterial and host factors, revealing how C.t . leverages both Inc-Inc interactions and host protein engagement to manipulate vesicular trafficking and sustain infection.

Tijerina, Xavier [Department of Microbiology and I↗
DOE OSTI2016

Functional Role of MrpA in the MrpABCDEFG Na + /H + Antiporter Complex from the Archaeon Methanosarcina acetivorans

The multisubunit cation/proton antiporter 3 family, also called Mrp, is widely distributed in all three phylogenetic domains ( Eukarya, Bacteria, and Archaea ). Investigations have focused on Mrp complexes from the domain Bacteria to the exclusion of Archaea , with a consensus emerging that all seven subunits are required for Na + /H + antiport activity. The MrpA subunit from the MrpABCDEFG Na + /H + antiporter complex of the archaeon Methanosarcina acetivorans was produced in antiporter-deficient Escherichia coli strains EP432 and KNabc and biochemically characterized to determine the role of MrpA in the complex. Both strains containing MrpA grew in the presence of up to 500 mM NaCl and pH values up to 11.0 with no added NaCl. Everted vesicles from the strains containing MrpA were able to generate a NADH-dependent pH gradient (ΔpH), which was abated by the addition of monovalent cations. The apparent K m values for Na + and Li + were similar and ranged from 31 to 63 mM, whereas activity was too low to determine the apparent K m for K + . Optimum activity was obtained between pH 7.0 and 8.0. Homology molecular modeling identified two half-closed symmetry-related ion translocation channels that are linked, forming a continuous path from the cytoplasm to the periplasm, analogous to the NuoL subunit of complex I. Bioinformatics analyses revealed genes encoding homologs of MrpABCDEFG in metabolically diverse methane-producing species. In conclusion, the results advance the biochemical, evolutionary, and physiological understanding of Mrp complexes that extends to the domain Archaea .

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2025

Dual function of Candida auris mannosyltransferase, MNT5, in biofilm community protection from antifungal therapy and the host

Screen of mutants from a mannosyltransferase family identified the importance of MNT5 for C. auris biofilm drug resistance and neutrophil evasion. Biochemical analysis of the mnt5∆ mutant matrix and cell wall identified alterations in the mannan structures. Resistance and matrix for mnt5∆ were restored with delivery of wild-type matrix via extracellular vesicles. Analysis of the mnt5∆ cell wall revealed a reduction in mannan and compensatory increase in cell surface glucan and chitin, suggesting a role for MNT5 in mannan masking of pathogen-associated molecular patterns.

Candida auris↗
DOE OSTI2024

Cryogenic electron tomography reveals novel structures in the apical complex of Plasmodium falciparum

Intracellular infectious agents, like the malaria parasite, Plasmodium falciparum, face the daunting challenge of how to invade a host cell. This problem may be even harder when the host cell in question is the enucleated red blood cell, which lacks the host machinery co-opted by many pathogens for internalization. Evolution has provided P. falciparum and related single-celled parasites within the phylum Apicomplexa with a collection of organelles at their apical end that mediate invasion. This apical complex includes at least two sets of secretory organelles, micronemes and rhoptries, and several structural features like apical rings and a putative pore through which proteins may be introduced into the host cell during invasion. We perform cryogenic electron tomography (cryo-ET) equipped with Volta Phase Plate on isolated and vitrified merozoites to visualize the apical machinery. Through tomographic reconstruction of cellular compartments, we see new details of known structures like the rhoptry tip interacting directly with a rosette resembling the recently described rhoptry secretory apparatus (RSA), or with an apical vesicle docked beneath the RSA. Subtomogram averaging reveals that the apical rings have a fixed number of repeating units, each of which is similar in overall size and shape to the units in the apical rings of tachyzoites of Toxoplasma gondii. Comparison of these polar rings in Plasmodium and Toxoplasma parasites also reveals them to have a structurally conserved assembly pattern. These results provide new insight into the essential and structurally conserved features of this remarkable machinery used by apicomplexan parasites to invade their respective host cells.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Campylobacter jejuni resistance to human milk involves the acyl carrier protein AcpP

Campylobacter jejuni is a common foodborne pathogen worldwide that is associated with high rates of morbidity and mortality among infants in low- to middle-income countries (LMICs). Human milk provides infants with an important source of nutrients and contains antimicrobial components for protection against infection. However, recent studies, including our own, have found significantly higher levels of Campylobacter in diarrheal stool samples collected from breastfed infants compared to non-breastfed infants in LMICs. We hypothesized that C. jejuni has unique strategies to resist the antimicrobial properties of human milk. Transcriptional profiling found human milk exposure induces genes associated with ribosomal function, iron acquisition, and amino acid utilization in C. jejuni strains 81–176 and 11168. However, unidentified proteinaceous components of human milk prevent bacterial growth. Evolving both C. jejuni isolates to survive in human milk resulted in mutations in genes encoding the acyl carrier protein (AcpP) and the major outer membrane porin (PorA). Introduction of the PorA/AcpP amino acid changes into the parental backgrounds followed by electron microscopy showed distinct membrane architectures, and the AcpP changes not only significantly improved growth in human milk, but also yielded cells surrounded with outer membrane vesicles. Analyses of the phospholipid and lipooligosaccharide (LOS) compositions suggest an imbalance in acyl chain distributions. For strain 11168, these changes protect both evolved and 11168ΔacpP G33R strains from bacteriophage infection and polymyxin killing. Taken together, this study provides insights into how C. jejuni may evolve to resist the bactericidal activity of human milk and flourish in the hostile environment of the gastrointestinal tract.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2018

Contact Challenge of Cattle with Foot-and-Mouth Disease Virus Validates the Role of the Nasopharyngeal Epithelium as the Site of Primary and Persistent Infection

The pathogenesis of foot-and-mouth disease virus (FMDV) in cattle was investigated through early and late stages of infection by use of an optimized experimental model for controlled contact exposure. Time-limited exposure of cattle to FMDV-infected pigs led to primary FMDV infection of the nasopharyngeal mucosa in both vaccinated and nonvaccinated cattle. In nonvaccinated cattle, the infection generalized rapidly to cause clinical disease, without apparent virus amplification in the lungs prior to establishment of viremia. Vaccinated cattle were protected against clinical disease and viremia; however, all vaccinated cattle were subclinically infected, and persistent infection occurred at similarly high prevalences in both animal cohorts. Infection dynamics in cattle were consistent and synchronous and comparable to those of simulated natural and needle inoculation systems. However, the current experimental model utilizes a natural route of virus exposure and is therefore superior for investigations of disease pathogenesis and host response. Deep sequencing of viruses obtained during early infection of pigs and cattle indicated that virus populations sampled from sites of primary infection were markedly more diverse than viruses from vesicular lesions of cattle, suggesting the occurrence of substantial bottlenecks associated with vesicle formation. These data expand previous knowledge of FMDV pathogenesis in cattle and provide novel insights for validation of inoculation models of bovine FMD studies. IMPORTANCE: Foot-and-mouth disease virus (FMDV) is an important livestock pathogen that is often described as the greatest constraint to global trade in animal products. The present study utilized a standardized pig-to-cow contact exposure model to demonstrate that FMDV infection of cattle initiates in the nasopharyngeal mucosa following natural virus exposure. Furthermore, this work confirmed the role of the bovine nasopharyngeal mucosa as the site of persistent FMDV infection in vaccinated and nonvaccinated cattle. The critical output of this study validates previous studies that have used simulated natural inoculation models to characterize FMDV pathogenesis in cattle and emphasizes the importance of continued research of the unique virus-host interactions that occur within the bovine nasopharynx. Specifically, vaccines and biotherapeutic countermeasures designed to prevent nasopharyngeal infection of vaccinated animals could contribute to substantially improved control of FMDV.

cattle↗
DOE OSTI2018

Dark Conductivity and Photoconductivity of Nonaqueous Liposomes: a New Method for Measuring the Phase-Transition Temperatures of Lipid Membranes

A new method is developed to measure the phase-transition temperatures in artificial phospholipid membranes. This method is based on studying the temperature dependence of dark conductivity and photoconductivity in a symmetric cell with current-conducting indium–tin oxide (ITO) electrodes. Internal electron photoemission into a thin liposome layer is induced by visible and near IR light from the ITO electrodes. This method is applied to study the lyotropic phases in 1,2-dipalmitoyl-rac-glycero-3-phosphocholine (DPPC) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) with ethylene glycol (EG) and glycerol (G). The results of time-of-flight measurements are used to calculate the carrier mobilities in liposome vesicles. The measurement results are compared with the results obtained by dc conductometry. We are the first to detect the effect of a positive temperature coefficient of resistivity in a liquid-crystal phase. The proposed method makes it possible to detect the phase transitions in lyotropic liquid-crystal systems and, hence, can be used to create biocompatible drug carriers based on thermosensitive liposomes.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗
DOE OSTI2016

Direct comparison of elastic incoherent neutron scattering experiments with molecular dynamics simulations of DMPC phase transitions

Neutron scattering techniques have been employed to investigate 1,2-dimyristoyl-sn-glycero-3- phosphocholine (DMPC) membranes in the form of multilamellar vesicles (MLVs) and deposited, stacked multilamellar-bilayers (MLBs), covering transitions from the gel to the liquid phase. Neutron diffraction was used to characterise the samples in terms of transition temperatures, whereas elastic incoherent neutron scattering (EINS) demonstrates that the dynamics on the sub-macromolecular length-scale and pico- to nano-second time-scale are correlated with the structural transitions through a discontinuity in the observed elastic intensities and the derived mean square displacements. Molecular dynamics simulations have been performed in parallel focussing on the length-, time- and temperature-scales of the neutron experiments. They correctly reproduce the structural features of the main gel-liquid phase transition. Particular emphasis is placed on the dynamical amplitudes derived from experiment and simulations. Two methods are used to analyse the experimental data and mean square displacements. They agree within a factor of 2 irrespective of the probed time-scale, i.e. the instrument utilized. Mean square displacements computed from simulations show a comparable level of agreement with the experimental values, albeit, the best match with the two methods varies for the two instruments. Consequently, experiments and simulations together give a consistent picture of the structural and dynamical aspects of the main lipid transition and provide a basis for future, theoretical modelling of dynamics and phase behaviour in membranes. The need for more detailed analytical models is pointed out by the remaining variation of the dynamical amplitudes derived in two different ways from experiments on the one hand and simulations on the other.

Aoun, Bachir↗
DOE OSTI2017

Efficient Simulation of Nested Hollow Sphere Intersections: for Dynamically Nested Compartmental Models in Cell Biology

In the particle-based simulation of cell-biological systems in continuous space, a key performance bottleneck is the computation of all possible intersections between particles. These typically rely for collision detection on solid sphere approaches. The behavior of cell biological systems is influenced by dynamic hierarchical nesting, such as the forming of, the transport within, and the merging of vesicles. Existing collision detection algorithms are found not to be designed for these types of spatial cell-biological models, because nearly all existing high performance parallel algorithms are focusing on solid sphere interactions. The known algorithms for solid sphere intersections return more intersections than actually occur with nested hollow spheres. Here we define a new problem of computing the intersections among arbitrarily nested hollow spheres of possibly different sizes, thicknesses, positions, and nesting levels. We describe a new algorithm designed to solve this nested hollow sphere intersection problem and implement it for parallel execution on graphical processing units (GPUs). We present first results about the runtime performance and scaling to hundreds of thousands of spheres, and compare the performance with that from a leading solid object intersection package also running on GPUs.

Koester, Till↗