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At least 235 records · Page 13

An approach for online evaluations of dose consequences caused by small rotational setup errors in intracranial stereotactic radiation therapy

Purpose: The purpose of this work is to investigate the impact of small rotational errors on the magnitudes and distributions of spatial dose variations for intracranial stereotactic radiotherapy (SRT) treatment setups, and to assess the feasibility of using the original dose map overlaid with rotated contours (ODMORC) method as a fast, online evaluation tool to estimate dose changes (using DVHs) to clinical target volumes (CTVs) and organs-at-risks (OARs) caused by small rotational setup errors. Methods: Fifteen intracranial SRT cases treated with either three-dimensional conformal radiation therapy (3DCRT) or intensity-modulated radiation therapy (IMRT) techniques were chosen for the study. Selected cases have a variety of anatomical dimensions and pathologies. Angles of {+-}3 deg. and {+-}5 deg. in all directions were selected to simulate the rotational errors. Dose variations in different regions of the brain, CTVs, and OARs were evaluated to illustrate the various spatial effects of dose differences before and after rotations. DVHs accounting for rotations that were recomputed by the treatment planning system (TPS) and those generated by the ODMORC method were compared. A framework of a fast algorithm for multicontour rotation implemented by ODMORC is introduced as well. Results: The average values of relative dose variations between original dose and recomputed dose accounting for rotations were greater than 4.0% and 10.0% in absolute mean and in standard deviation, respectively, at the skull and adjacent regions for all cases. They were less than 1.0% and 2.5% in absolute mean and in standard deviation, respectively, for dose points 3 mm away from the skull. The results indicated that spatial dose to any part of the brain organs or tumors separated from the skull or head surface would be relatively stable before and after rotations. Statistical data of CTVs and OARs indicate the lens and cochleas have the large dose variations before and after rotations, whereas the remaining ROIs have insignificant dose differences. DVH comparisons suggest that the ODMORC method is able to estimate the DVH of CTVs fairly accurately (within 1.5% of relative dose differences for evaluation volumes). The results also show that most of the OARs including the brain stem, spinal cord, chiasm, hippocampuses, optic nerves, and retinas, which were relatively distal from the skull and surface, had good agreement (within 2.0% of relative dose differences for 0.1 cc of the volumes ) between the ODMORC method and the recomputation, whereas OARs more proximate to the bone-tissue interface or surface, such as the lenses and cochlea, had larger dose variations (greater than 5.0%) for some cases due to the incapability of the ODMORC to account for scatter contribution variations proximate to interfaces and intrinsic dose calculation uncertainties for ROIs with small volumes. Conclusions: The ODMORC method can be implemented as an online evaluation system for rotation-induced dose changes of CTVs and most OARs and for other related dose consequence analyses.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Gut Microbial Alterations Associated With Protection From Autoimmune Uveitis

The bacteria that live normally in our intestinal tract, or the gut microbiota contribute to the pathogenesis of extra intestinal autoimmune disease via their ability to dynamically educate the immune system. For example, in a mouse model of relapsing, remitting multiple sclerosis (MS), experimental autoimmune encephalomyelitis or EAE, several studies demonstrated that commensal microorganisms are essential in causing clinical disease activity. Interestingly, MS patients have a distinct gut microbiota to healthy controls. Several studies have also illustrated the importance of the gut microbiome in the development of other diseases, including Type 1 diabetes, metabolic syndrome, rheumatoid arthritis, and ankylosing spondylitis. Furthermore, HLA=B27 transgenic rats, which develop spontaneous spondyloarthropathy analogous to patients who have ankylosing spondylitis, associated with uveitis in humans, do not develop intestinal or peripheral join inflammation when raised in a germ-free environment. Our group has shown that HLA-B27 transgenic rats have an altered intestinal microbiota compared to healthy control rats. Given the similarities between the central nervous system (CNS) and the retina, as well as co-expression of potentially immunogenic self-antigens from the CNS and joint in the eye, we hypothesized that modulating the gut microbiome can result in amelioration of autoimmune uveitis. Although uveitis is a heterogeneous collection of diseases, in general immune-mediated, non-infectious, uveitis is thought to be due to a combination of genetic and environmental factors. It arises from an imbalance between the regulatory and effector arms of the immune system, result in an inappropriate immune reaction at an otherwise immune-privileged tissue site, the eye. Th1 and Th17 T lymphocytes are examples of effector immune cell subsets that my contribute to inflammatory disease of the eye, whereas regulatory T cells (Tregs) are an example of a regulatory immune cell subset that is typically required to downregulate an immune response to prevent uncontrolled disease. Experimental autoimmune uveitis (EAU) is a very robust, widely use model of T lymphoocyte mediated uveitis that can be induced in a certain strains of mice (e.g. B10.RIII) by immunizing these animals with a specific retinal antigen, interphotoreceptor binding protein (IRBP), but requires co-administration of an adjuvant containing killed Mycobacterium antigen. Lastly, this model of inducible uveitis is analogous to the EAE model of demyelinating disease mentioned above. EAU is a thought to be predominantly Th1 and Th17 mediated.

60 APPLIED LIFE SCIENCES↗

Adhesion Failures Determine the Pattern of Choroidal Neovascularization in the Eye: A Computer Simulation Study

Choroidal neovascularization (CNV) of the macular area of the retina is the major cause of severe vision loss in adults. In CNV, after choriocapillaries initially penetrate Bruch’s membrane (BrM), invading vessels may regress or expand (CNV initiation). Next, during Early and Late CNV, the expanding vasculature usually spreads in one of three distinct patterns: in a layer between BrM and the retinal pigment epithelium (sub-RPE or Type 1 CNV), in a layer between the RPE and the photoreceptors (subretinal or Type 2 CNV) or in both loci simultaneously (combined pattern or Type 3 CNV). While most studies hypothesize that CNV primarily results from growth-factor effects or holes in BrM, our three-dimensional simulations of multi-cell model of the normal and pathological maculae recapitulate the three growth patterns, under the hypothesis that CNV results from combinations of impairment of: 1) RPE-RPE epithelial junctional adhesion, 2) Adhesion of the RPE basement membrane complex to BrM (RPE-BrM adhesion), and 3) Adhesion of the RPE to the photoreceptor outer segments (RPE-POS adhesion). Our key findings are that when an endothelial tip cell penetrates BrM: 1) RPE with normal epithelial junctions, basal attachment to BrM and apical attachment to POS resists CNV. 2) Small holes in BrM do not, by themselves, initiate CNV. 3) RPE with normal epithelial junctions and normal apical RPE-POS adhesion, but weak adhesion to BrM (e.g. due to lipid accumulation in BrM) results in Early sub-RPE CNV. 4) Normal adhesion of RBaM to BrM, but reduced apical RPE-POS or epithelial RPE-RPE adhesion (e.g. due to inflammation) results in Early sub-retinal CNV. 5) Simultaneous reduction in RPE-RPE epithelial binding and RPEBrM adhesion results in either sub-RPE or sub-retinal CNV which often progresses to combined pattern CNV. These findings suggest that defects in adhesion dominate CNV initiation and progression.

59 BASIC BIOLOGICAL SCIENCES↗

Predicting peak spectral sensitivities of vertebrate cone visual pigments using atomistic molecular simulations

Vision is the dominant sensory modality in many organisms for foraging, predator avoidance, and social behaviors including mate selection. Vertebrate visual perception is initiated when light strikes rod and cone photoreceptors within the neural retina of the eye. Sensitivity to individual colors, i.e., peak spectral sensitivities (λ max ) of visual pigments, are a function of the type of chromophore and the amino acid sequence of the associated opsin protein in the photoreceptors. Large differences in peak spectral sensitivities can result from minor differences in amino acid sequence of cone opsins. To determine how minor sequence differences could result in large spectral shifts we selected a spectrally-diverse group of 14 teleost Rh2 cone opsins for which sequences and λ max are experimentally known. Classical molecular dynamics simulations were carried out after embedding chromophore-associated homology structures within explicit bilayers and water. These simulations revealed structural features of visual pigments, particularly within the chromophore, that contributed to diverged spectral sensitivities. Statistical tests performed on all the observed structural parameters associated with the chromophore revealed that a two-term, first-order regression model was sufficient to accurately predict λ max over a range of 452–528 nm. The approach was accurate, efficient and simple in that site-by-site molecular modifications or complex quantum mechanics models were not required to predict λ max . These studies identify structural features associated with the chromophore that may explain diverged spectral sensitivities, and provide a platform for future, functionally predictive opsin modeling.

59 BASIC BIOLOGICAL SCIENCES↗

Short-wavelength-sensitive 2 (Sws2) visual photopigment models combined with atomistic molecular simulations to predict spectral peaks of absorbance

For many species, vision is one of the most important sensory modalities for mediating essential tasks that include navigation, predation and foraging, predator avoidance, and numerous social behaviors. The vertebrate visual process begins when photons of the light interact with rod and cone photoreceptors that are present in the neural retina. Vertebrate visual photopigments are housed within these photoreceptor cells and are sensitive to a wide range of wavelengths that peak within the light spectrum, the latter of which is a function of the type of chromophore used and how it interacts with specific amino acid residues found within the opsin protein sequence. Minor differences in the amino acid sequences of the opsins are known to lead to large differences in the spectral peak of absorbance (i.e. the λ max value). In our prior studies, we developed a new approach that combined homology modeling and molecular dynamics simulations to gather structural information associated with chromophore conformation, then used it to generate statistical models for the accurate prediction of λ max values for photopigments derived from Rh1 and Rh2 amino acid sequences. In the present study, we test our novel approach to predict the λ max of phylogenetically distant Sws2 cone opsins. To build a model that can predict the λ max using our approach presented in our prior studies, we selected a spectrally-diverse set of 11 teleost Sws2 photopigments for which both amino acid sequence information and experimentally measured λ max values are known. The final first-order regression model, consisting of three terms associated with chromophore conformation, was sufficient to predict the λ max of Sws2 photopigments with high accuracy. This study further highlights the breadth of our approach in reliably predicting λ max values of Sws2 cone photopigments, evolutionary-more distant from template bovine RH1, and provided mechanistic insights into the role of known spectral tuning sites.

59 BASIC BIOLOGICAL SCIENCES↗

Laser Incident Lessons Learned and Action List

On Thursday November 19, 2015, LANL postdoc received an eye injury from a reflected, nonvisible laser beam (Class 4, pulsed, wavelength 800 nanometer). The setup is configured to split the laser output into two work areas in which qualified operators conduct research experiments. During this incident, the laser output beam was being projected to both experimental work areas, although only one experimental area was actively being used. The second laser beam directed to the second work area was blocked by an inappropriate device (Plexiglas, reflective, non-normal incidence) that reflected substantial portion of the beam toward the first setup. In preparation for the measurements, worker stepped on the stepstool and decided to remove the laser goggles to better see the micrometer readings which were difficult to see due to insufficient lighting. Immediately, he noticed a flash of light in his eye. The operator quickly replaced the laser eye-wear and then, using an infrared viewer, located a stray laser beam being reflected from the plexiglas beam block. The operator did not think he had sustained any injury and continued working. Later that day, however, he noticed a blurry spot in the vision of his left eye. He notified his supervisor on Friday morning, November 20, 2015, and was taken by CINT management to Sandia National Laboratories (SNL) medical facility for evaluation. SNL Medical did not find any abnormalities, but referred the operator to a local ophthalmologist for further evaluation. Further evaluations by the ophthalmologist on November 21 and November 23 identified a small spot of inflammation near the fovea on the retina in his left eye. The ophthalmologist stated that this spot would most likely heal on its own and that the blurry spot on the operator's vision would go away. A follow-up visit was scheduled. The employee was released back to work without restrictions.

99 GENERAL AND MISCELLANEOUS↗

Implementing Neural Adaptive Filtering in Engineered Detection Systems

The retina plays an important role in animal vision --- namely to pre-process visual information before sending it to the brain. The goal of this LDRD was to develop models of motion-sensitive retinal cells for the purpose of developing retinal-inspired algorithms to be applied to real-world data specific to Sandia's national security missions. We specifically focus on detection of small, dim moving targets amidst varying types of clutter or distractor signals. We compare a classic motion-sensitive model, the Hassenstein-Reichardt model, to a model of the OMS (object motion- sensitive) cell, and find that the Reichardt model performs better under continuous clutter (e.g. white noise) but is very sensitive to particular stimulus conditions (e.g. target velocity). We also demonstrate that lateral inhibition, a ubiquitous characteristic of neural circuitry, can effect target-size tuning, improving detection specifically of small targets.

47 OTHER INSTRUMENTATION↗

Centriole and transition zone structures in photoreceptor cilia revealed by cryo-electron tomography

Primary cilia mediate sensory signaling in multiple organisms and cell types but have structures adapted for specific roles. Structural defects in them lead to devastating diseases known as ciliopathies in humans. Key to their functions are structures at their base: the basal body, the transition zone, the “Y-shaped links,” and the “ciliary necklace.” We have used cryo-electron tomography with subtomogram averaging and conventional transmission electron microscopy to elucidate the structures associated with the basal region of the “connecting cilia” of rod outer segments in mouse retina. The longitudinal variations in microtubule (MT) structures and the lumenal scaffold complexes connecting them have been determined, as well as membrane-associated transition zone structures: Y-shaped links connecting MT to the membrane, and ciliary beads connected to them that protrude from the cell surface and form a necklace-like structure. These results represent a clearer structural scaffold onto which molecules identified by genetics, proteomics, and superresolution fluorescence can be placed in our emerging model of photoreceptor sensory cilia.

59 BASIC BIOLOGICAL SCIENCES↗

An EvoDevo Study of Salmonid Visual Opsin Dynamics and Photopigment Spectral Sensitivity

Salmonids are ideal models as many species follow a distinct developmental program from demersal eggs and a large yolk sac to hatching at an advanced developmental stage. Further, these economically important teleosts inhabit both marine- and freshwaters and experience diverse light environments during their life histories. At a genome level, salmonids have undergone a salmonid-specific fourth whole genome duplication event (Ss4R) compared to other teleosts that are already more genetically diverse compared to many non-teleost vertebrates. Thus, salmonids display phenotypically plastic visual systems that appear to be closely related to their anadromous migration patterns. This is most likely due to a complex interplay between their larger, more gene-rich genomes and broad spectrally enriched habitats; however, the molecular basis and functional consequences for such diversity is not fully understood. This study used advances in genome sequencing to identify the repertoire and genome organization of visual opsin genes (those primarily expressed in retinal photoreceptors) from six different salmonids [Atlantic salmon ( Salmo salar ), brown trout ( Salmo trutta ), Chinook salmon ( Oncorhynchus tshawytcha ), coho salmon ( Oncorhynchus kisutch ), rainbow trout ( Oncorhynchus mykiss ), and sockeye salmon ( Oncorhynchus nerka )] compared to the northern pike ( Esox lucius ), a closely related non-salmonid species. Results identified multiple orthologues for all five visual opsin classes, except for presence of a single short-wavelength-sensitive-2 opsin gene. Several visual opsin genes were not retained after the Ss4R duplication event, which is consistent with the concept of salmonid rediploidization. Developmentally, transcriptomic analyzes of Atlantic salmon revealed differential expression within each opsin class, with two of the long-wavelength-sensitive opsins not being expressed before first feeding. Also, early opsin expression in the retina was located centrally, expanding dorsally and ventrally as eye development progressed, with rod opsin being the dominant visual opsin post-hatching. Modeling by spectral tuning analysis and atomistic molecular simulation, predicted the greatest variation in the spectral peak of absorbance to be within the Rh2 class, with a ∼40 nm difference in λ max values between the four medium-wavelength-sensitive photopigments. Overall, it appears that opsin duplication and expression, and their respective spectral tuning profiles, evolved to maximize specialist color vision throughout an anadromous lifecycle, with some visual opsin genes being lost to tailor marine-based vision.

59 BASIC BIOLOGICAL SCIENCES↗

Deep Learning Approaches to Surrogates for Solving the Diffusion Equation for Mechanistic Real-World Simulations

In many mechanistic medical, biological, physical, and engineered spatiotemporal dynamic models the numerical solution of partial differential equations (PDEs), especially for diffusion, fluid flow and mechanical relaxation, can make simulations impractically slow. Biological models of tissues and organs often require the simultaneous calculation of the spatial variation of concentration of dozens of diffusing chemical species. One clinical example where rapid calculation of a diffusing field is of use is the estimation of oxygen gradients in the retina, based on imaging of the retinal vasculature, to guide surgical interventions in diabetic retinopathy. Furthermore, the ability to predict blood perfusion and oxygenation may one day guide clinical interventions in diverse settings, i.e., from stent placement in treating heart disease to BOLD fMRI interpretation in evaluating cognitive function (Xie et al., 2019; Lee et al., 2020). Since the quasi-steady-state solutions required for fast-diffusing chemical species like oxygen are particularly computationally costly, we consider the use of a neural network to provide an approximate solution to the steady-state diffusion equation. Machine learning surrogates, neural networks trained to provide approximate solutions to such complicated numerical problems, can often provide speed-ups of several orders of magnitude compared to direct calculation. Surrogates of PDEs could enable use of larger and more detailed models than are possible with direct calculation and can make including such simulations in real-time or near-real time workflows practical. Creating a surrogate requires running the direct calculation tens of thousands of times to generate training data and then training the neural network, both of which are computationally expensive. Often the practical applications of such models require thousands to millions of replica simulations, for example for parameter identification and uncertainty quantification, each of which gains speed from surrogate use and rapidly recovers the up-front costs of surrogate generation. We use a Convolutional Neural Network to approximate the stationary solution to the diffusion equation in the case of two equal-diameter, circular, constant-value sources located at random positions in a two-dimensional square domain with absorbing boundary conditions. Such a configuration caricatures the chemical concentration field of a fast-diffusing species like oxygen in a tissue with two parallel blood vessels in a cross section perpendicular to the two blood vessels. To improve convergence during training, we apply a training approach that uses roll-back to reject stochastic changes to the network that increase the loss function. The trained neural network approximation is about 1000 times faster than the direct calculation for individual replicas. Because different applications will have different criteria for acceptable approximation accuracy, we discuss a variety of loss functions and accuracy estimators that can help select the best network for a particular application. We briefly discuss some of the issues we encountered with overfitting, mismapping of the field values and the geometrical conditions that lead to large absolute and relative errors in the approximate solution.

60 APPLIED LIFE SCIENCES↗

Saccadic suppression.

Stiles-Crawford effect measurements before and following eye movements to determine retina shearing during eye movements

Richards, W.↗

Frequency of light-flashes induced by Cerenkov radiation from heavy cosmic-ray nuclei

The expected frequency was calculated for light flashes induced in the dark-adapted eye by Cerenkov radiation from the flux of heavy nuclei that exists in space beyond the geomagnetic field. The expected frequency of light flashes depends on the threshold number of photons that must be absorbed in a rod cluster. The results of the calculation are presented as a curve of the mean frequency of light flashes versus the threshold number of absorbed photons. The results are not sensitive to variations in the path length from 5 to 15 grams per square centimeter of water-equivalent before the nucleus reaches the retina. Calculations were based on the fluxes and energy spectra of galactic cosmic ray nuclei of helium to iron, measured at a time of minimum solar modulation. The expected light flash frequencies induced by Cerenkov radiation are consistent with the frequencies reported by the astronauts on Apollo missions 11 through 14.

Madey, R.↗

Experimental study of visual accommodation

A summary report of a research effort related to the human visual accommodation system is presented. A theoretical study of the accommodation system was made. Subsequent effort was aimed at the development of specialized instrumentation for experiments designed to lead to understanding the nature of the control system in human accommodation. The necessary instrumentation consisted primarily of: (1) an automatic optometer to measure the state of eye focus, (2) a focus stimulator device to control the apparent optical distance to any target, and (3) a two-dimensional eye tracker. The concepts and designs of the first two instruments have been published in the open literature, but this report contains the first detailed treatment of the Purkinje eye tracker developed under this program. The report also discusses an accommodation lag model to explain the ability of the eye to apparently know the polarity of focus error even though the blur on the retina is to a first-approximation an even function. The interaction of the accommodation and eye movement systems is also discussed, as is the ability to train the visual accommodation system to a surprisingly responsive condition in only a few hours of training.

Cornsweet, T. N.↗

Star magnitude and manual navigation sighting accuracy using the Apollo T2 sextant.

This laboratory study investigated the effect of four star magnitudes (0, +1, +2, +3) upon the angular sighting accuracy attainable between a star and a lunar limb using a space-rated sextant with an 8-power telescope. Four males were tested. The results indicated that over a series of daily sightings sighting accuracy increases as star magnitude decreases; i.e., the angle between the actual lunar limb and the perceived lunar limb decreases as the intensity of the star increases. The significant subject and day main effects that were found indicate that each individual must be calibrated against himself and that extreme care must be taken to center the various images correctly within the sextant's field of view each time the instrument is set up. These findings are discussed in relation to further refinement of a graphic model of the distribution of energy on the retina. A discussion is also presented on the differences between sextant sighting research conducted in the laboratory and in the real, high-altitude or space environment.

Haines, R. F.↗

Effect of bedrest and positive radial acceleration upon peripheral visual response time.

Attempt to determine if peripheral visual response time (RT) could be used as a reliable advanced predictor of +G sub z-related blackout or grayout. The relatively high luminance of the peripheral stimuli used in the experiments may account for the finding that peripheral RT was not sensitive to impending blackout or grayout. The relatively consistent mean RTs within subjects across test days in bed is probably due to the relatively constant response characteristics of the retina and to the high repeatability of the stimuli.

Haines, R. F.↗