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DOE OSTI2021

Heavy Ion Minibeam Therapy: Side Effects in Normal Brain

The purpose of this work was to investigate whether minibeam therapy with heavy ions might offer improvements of the therapeutic ratio for the treatment of human brain cancers. To assess neurotoxicity, we irradiated normal juvenile rats using 120 MeV lithium-7 ions at an absorbed integral dose of 20 Gy. Beams were configured either as a solid parallel circular beam or as an array of planar parallel minibeams having 300-micron width and 1-mm center-to-center spacing within a circular array. We followed animals for 6 months after treatment and utilized behavioral testing and immunohistochemical studies to investigate the resulting cognitive impairment and chronic pathologic changes. We found both solid-beam therapy and minibeam therapy to result in cognitive impairment compared with sham controls, with no apparent reduction in neurotoxicity using heavy ion minibeams instead of solid beams under the conditions of this study.

60 APPLIED LIFE SCIENCES↗

NASA NTRS2011

Numerical Implementation of a Multiple-ISV Thermodynamically-Based Work Potential Theory for Modeling Progressive Damage and Failure in Fiber-Reinforced Laminates

A thermodynamically-based work potential theory for modeling progressive damage and failure in fiber-reinforced laminates is presented. The current, multiple-internal state variable (ISV) formulation, enhanced Schapery theory (EST), utilizes separate ISVs for modeling the effects of damage and failure. Damage is considered to be the effect of any structural changes in a material that manifest as pre-peak non-linearity in the stress versus strain response. Conversely, failure is taken to be the effect of the evolution of any mechanisms that results in post-peak strain softening. It is assumed that matrix microdamage is the dominant damage mechanism in continuous fiber-reinforced polymer matrix laminates, and its evolution is controlled with a single ISV. Three additional ISVs are introduced to account for failure due to mode I transverse cracking, mode II transverse cracking, and mode I axial failure. Typically, failure evolution (i.e., post-peak strain softening) results in pathologically mesh dependent solutions within a finite element method (FEM) setting. Therefore, consistent character element lengths are introduced into the formulation of the evolution of the three failure ISVs. Using the stationarity of the total work potential with respect to each ISV, a set of thermodynamically consistent evolution equations for the ISVs is derived. The theory is implemented into commercial FEM software. Objectivity of total energy dissipated during the failure process, with regards to refinements in the FEM mesh, is demonstrated. The model is also verified against experimental results from two laminated, T800/3900-2 panels containing a central notch and different fiber-orientation stacking sequences. Global load versus displacement, global load versus local strain gage data, and macroscopic failure paths obtained from the models are compared to the experiments.

Pineda, Evan J.↗

NASA NTRS2012

A Thermodynamically-Based Mesh Objective Work Potential Theory for Predicting Intralaminar Progressive Damage and Failure in Fiber-Reinforced Laminates

Pineda, Evan J.↗

NASA NTRS1999

Late ophthalmological complications after total body irradiation in non-human primates

PURPOSE: To investigate the long-term effects of total body irradiation (TBI) on the incidence and time course of ocular complications. MATERIALS AND METHODS: Rhesus monkeys treated with TBI photon doses up to 8.5 Gy and proton doses up to 7.5 Gy were studied at intervals up to 25 years post-irradiation. They were compared with control groups with a similar age distribution. Cataract formation and ocular fundus lesions were scored according to a standardized protocol. Fluorescein angiography and histopathology was performed in selected animals. RESULTS: Cataract formation occurred after a latent period of 3-5 years. Significant cataract induction was observed for photon-doses of 8 and 8.5 Gy and beyond 20 years after proton irradiation. The severity of the lesions represents significant impairment of vision and would require cataract surgery if similar results occurred in human bone marrow transplant patients. Fluorescein angiography demonstrated a normal pattern of retinal vessels in 13 out of 14 animals (93%) from the irradiated group and in eight out of nine animals (89%) from the control group. No additional lesions apart from age-related degenerative changes could be demonstrated. Histological evaluation revealed no radiation-associated vasculopathy. CONCLUSIONS: Radiation alone for doses up to 8.5 Gy of photons does not carry a potential risk for fundus pathology, whereas clinically important cataract induction should be anticipated within 5 years after photon doses of 8.0 and 8.5 Gy and proton doses in excess of 2.5 Gy.

NASA Discipline Radiation Health↗

NASA NTRS2000

Effect of scanline orientation on ventricular flow propagation: assessment using high frame-rate color Doppler echocardiography

Color M-mode echocardiography has recently been utilized to describe diastolic flow propagation velocity (Vp) in the left ventricle. While increasing temporal resolution from 15 to 200 Hz, this M-mode technique requires the user to select a single scanline, potentially limiting quantification of Vp due to the complex three-dimensional inflow pattern. We previously performed computational fluid dynamics simulations to demonstrate the insignificance of the scanline orientation, however geometric complexity was limited. The purpose of this study was to utilize high frame-rate 2D color Doppler images to investigate the importance of scanline selection in patients for the quantification of Vp. 2D color Doppler images were digitally acquired at 50 frames/s in 6 subjects from the apical 4-chamber window (System 5, GE/Vingmed, Milwaukee, WI). Vp was determined for a set of scanlines positioned through 5 locations across the mitral annulus (from the anterior to posterior mitral annulus). An analysis of variance was performed to examine the differences in Vp as a function of scanline position. Vp was not effected by scanline position in sampled locations from the center of the mitral valve towards the posterior annulus. Although not statistically significant, there was a trend to slower propagation velocities on the anterior side of the valve (60.8 +/- 16.7 vs. 54.4 +/- 13.6 cm/s). This study clinically validates our previous numerical experiment showing that Vp is insensitive to small perturbations of the scanline through the mitral valve. However, further investigation is necessary to examine the impact of ventricular geometry in pathologies including dilated cardiomyopathy.

Non-NASA Center↗

NASA NTRS2004

Solution Preserves Nucleic Acids in Body-Fluid Specimens

A solution has been formulated to preserve deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) in specimens of blood, saliva, and other bodily fluids. Specimens of this type are collected for diagnostic molecular pathology, which is becoming the method of choice for diagnosis of many diseases. The solution makes it possible to store such specimens at room temperature, without risk of decomposition, for subsequent analysis in a laboratory that could be remote from the sampling location. Thus, the solution could be a means to bring the benefits of diagnostic molecular pathology to geographic regions where refrigeration equipment and diagnostic laboratories are not available. The table lists the ingredients of the solution. The functions of the ingredients are the following: EDTA chelates divalent cations that are necessary cofactors for nuclease activity. In so doing, it functionally removes these cations and thereby retards the action of nucleases. EDTA also stabilizes the DNA helix. Tris serves as a buffering agent, which is needed because minor contaminants in an unbuffered solution can exert pronounced effects on pH and thereby cause spontaneous degradation of DNA. SDS is an ionic detergent that inhibits ribonuclease activity. SDS has been used in some lysis buffers and as a storage buffer for RNA after purification. The use of the solution is straightforward. For example, a sample of saliva is collected by placing a cotton roll around in the subject's mouth until it becomes saturated, then the cotton is placed in a collection tube. Next, 1.5 mL of the solution are injected directly into the cotton and the tube is capped for storage at room temperature. The effectiveness of the solution has been demonstrated in tests on specimens of saliva containing herpes simplex virus. In the tests, the viral DNA, as amplified by polymerase chain reaction, was detected even after storage for 120 days.

Pierson, Duane L.↗

NASA NTRS2016

Optic Nerve Sheath Mechanics in VIIP Syndrome

Visual Impairment Intracranial Pressure (VIIP) syndrome is a major concern in current space medicine research. While the exact pathology of VIIP is not yet known, it is hypothesized that the microgravity-induced cephalad fluid shift increases intracranial pressure (ICP) and drives remodeling of the optic nerve sheath. To investigate this possibility, we are culturing optic nerve sheath dura mater samples under different pressures and investigating changes in tissue composition. To interpret results from this work, it is essential to first understand the biomechanical response of the optic nerve sheath dura mater to loading. Here, we investigated the effects of mechanical loading on the porcine optic nerve sheath.Porcine optic nerves (number: 6) were obtained immediately after death from a local abattoir. The optic nerve sheath (dura mater) was isolated from the optic nerve proper, leaving a hollow cylinder of connective tissue that was used for biomechanical characterization. We developed a custom mechanical testing system that allowed for unconfined lengthening, twisting, and circumferential distension of the dura mater during inflation and under fixed axial loading. To determine the effects of variations in ICP, the sample was inflated (0-60 millimeters Hg) and circumferential distension was simultaneously recorded. These tests were performed under variable axial loads (0.6 grams - 5.6 grams at increments of 1 gram) by attaching different weights to one end of the dura mater. Results and Conclusions: The samples demonstrated nonlinear behavior, similar to other soft connective tissue (Figure 1). Large increases in diameter were observed at lower transmural pressures (approximately 0 to 5 millimeters Hg), whereas only small diameter changes were observed at higher pressures. Particularly interesting was the existence of a cross-over point at a pressure of approximately 11 millimeters Hg. At this pressure, the same diameter is obtained for all axial loads applied to the tissue; i.e., as the axial load is varied, the diameter of the dura mater remains constant. This cross-over in the pressure-diameter curves occurred in all optic nerve sheaths that were tested, and may correspond with in vivo ICP levels for pigs. These data suggest that diameter of the dura mater of the optic nerve remains nearly constant in vivo despite being stretched axially. This may be a homeostatic mechanism aimed at maintaining target stresses/strains on the cells in the dura mater, and deviations from these stresses may play an important role in optic nerve sheath remodeling. Future studies will involve subjecting the dura mater to varying pressures and axial tensions for extended periods of time, while monitoring changes in the biomechanical properties. The data can then be used to study the effects of changes in ICP on the remodeling of the dura mater.

biomechanics↗

DOE OSTI2022

Short term treatment with a cocktail of rapamycin, acarbose and phenylbutyrate delays aging phenotypes in mice

Pharmaceutical intervention of aging requires targeting multiple pathways, thus there is rationale to test combinations of drugs targeting different but overlapping processes. In order to determine if combining drugs shown to extend lifespan and healthy aging in mice would have greater impact than any individual drug, a cocktail diet containing 14 ppm rapamycin, 1000 ppm acarbose, and 1000 ppm phenylbutyrate was fed to 20-month-old C57BL/6 and HET3 4-way cross mice of both sexes for three months. Mice treated with the cocktail showed a sex and strain-dependent phenotype consistent with healthy aging including decreased body fat, improved cognition, increased strength and endurance, and decreased age-related pathology compared to mice treated with individual drugs or control. The severity of age-related lesions in heart, lungs, liver, and kidney was consistently decreased in mice treated with the cocktail compared to mice treated with individual drugs or control, suggesting an interactive advantage of the three drugs. This study shows that a combination of three drugs, each previously shown to enhance lifespan and health span in mice, is able to delay aging phenotypes in middle-aged mice more effectively than any individual drug in the cocktail over a 3-month treatment period.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2023

New cyclophilin D inhibitor rescues mitochondrial and cognitive function in Alzheimer’s disease

Abstract Mitochondrial dysfunction is an early pathological feature of Alzheimer disease and plays a crucial role in the development and progression of Alzheimer’s disease. Strategies to rescue mitochondrial function and cognition remain to be explored. Cyclophilin D (CypD), the peptidylprolyl isomerase F (PPIase), is a key component in opening the mitochondrial membrane permeability transition pore, leading to mitochondrial dysfunction and cell death. Blocking membrane permeability transition pore opening by inhibiting CypD activity is a promising therapeutic approach for Alzheimer’s disease. However, there is currently no effective CypD inhibitor for Alzheimer’s disease, with previous candidates demonstrating high toxicity, poor ability to cross the blood–brain barrier, compromised biocompatibility and low selectivity. Here, we report a new class of non-toxic and biocompatible CypD inhibitor, ebselen, using a conventional PPIase assay to screen a library of ∼2000 FDA-approved drugs with crystallographic analysis of the CypD-ebselen crystal structure (PDB code: 8EJX). More importantly, we assessed the effects of genetic and pharmacological blockade of CypD on Alzheimer’s disease mitochondrial and glycolytic bioenergetics in Alzheimer’s disease-derived mitochondrial cybrid cells, an ex vivo human sporadic Alzheimer’s disease mitochondrial model, and on synaptic function, inflammatory response and learning and memory in Alzheimer’s disease mouse models. Inhibition of CypD by ebselen protects against sporadic Alzheimer’s disease- and amyloid-β-induced mitochondrial and glycolytic perturbation, synaptic and cognitive dysfunction, together with suppressing neuroinflammation in the brain of Alzheimer’s disease mouse models, which is linked to CypD-related membrane permeability transition pore formation. Thus, CypD inhibitors have the potential to slow the progression of neurodegenerative diseases, including Alzheimer’s disease, by boosting mitochondrial bioenergetics and improving synaptic and cognitive function.

Neurosciences & Neurology↗

NASA NTRS1997

Neocytolysis Contributes to the Anemia of Renal Disease

Neocytolysis is a recently described physiologic process effecting selective hemolysis of young red blood cells in circumstances of plethora. Erythropoietin depression appears to initiate the process, providing rationale to investigate its contributions to the anemia of renal disease. When erythropoietin therapy was withheld, four of five stable hemodialysis patients demonstrated Cr-51 red cell survival patterns indicative of neocytolysis; red cell survival was short in the first 9 days, then normalized. Two of these patients received oral (13)C-glycine and (15)N-glycine and showed pathologic enrichment of stool porphyrins by the most recently ingested isotope when EPO therapy was held. This confirms selective hemolysis of newly-released red cells. (One patient had chronic hemolysis by isotope studies of blood and stool.) Thus, neocytolysis can contribute to the anemia of renal disease and explains some unresolved issues about such anemia. One implication is the prediction that intravenous bolus erythropoietin therapy is metabolically and economically inefficient compared to lower doses given more frequently subcutaneously.

Rice, Lawrence↗

NASA NTRSDate not supplied

Comparison of Multispectral Imaging and Traditional Fundoscopy in the Detection of Terrestrial Retinal and Optic Nerve Pathologies like those Encountered During and/or Immediately Following Long-Duration Spaceflight

INTRODUCTION: The purpose of this investigation was to evaluate if MultiColor Imaging (MCI) can replace color fundus photography (CFP) as a diagnostic screening tool during spaceflight. MCI significantly reduces crew time (approx. 115 minutes/session, 36 hours/year) by eliminating nominal on-orbit fundoscopy sessions, while also providing the option to capture a larger field of view (55 vs. 35). METHODS: A comprehensive PubMed literature search was conducted using the following key words: multicolor, multispectral, imaging, retina, choroid, optic nerve, optic disc, and papilledema. Publications were filtered based on optic nerve and chorioretinal pathologies matching those seen during or immediately after spaceflight: optic disc edema (ODE), cotton wool spots (CWS), retinal hemorrhage, pigment epithelial detachment (PED), and serous chorioretinopathy (SCR). In a separate effort, 44 multicolor images (30 abnormal) of terrestrial patients were graded and compared to corresponding color fundus images acquired at the Doheny Eye Centers and UCLA. RESULTS: The search identified 340 articles; 9 describing MCI in relevant pathologies, 6 comparing MCI to CFP. MCI is superior in detecting CWS (1 paper), PED (2 papers), retinal hemorrhages (2 papers), and choroidal folds (1 paper), and can better delineate extent or boundaries of subretinal fluid and identify areas of RPE damage in SCR (2 papers). On MCI, ODE was described as a hyperreflective ring with a green shift and indistinct disc margins, with equaldetectability as using CFP (3 papers). Grading at Doheny Eye Institute confirmed these findings. DISCUSSION: MCI can effectively detect all retinal and optic nerve findings detectable by CFP during and immediately post-spaceflight and represents a suitable replacement as an on-orbit diagnostic screening tool. Additionally, by eliminating the nominal on-orbit fundoscopy sessions, dozens of crew hours are spared per year by utilizing MCI.

Jorge Nagel↗

NASA NTRS1994

Transitory endolymph leakage induced hearing loss and tinnitus: depolarization, biphasic shortening and loss of electromotility of outer hair cells

There are types of deafness and tinnitus in which ruptures or massive changes in the ionic permeability of the membranes lining the endolymphatic space [e.g., of the reticular lamina (RL)] are believed to allow potassium-rich endolymph to deluge the low [K+] perilymphatic fluid (e.g., in the small spaces of Nuel). This would result in a K+ intoxication of sensory and neural structures. Acute attacks of Meniere's disease have been suggested to be an important example for this event. The present study investigated the effects of transiently elevated [K+] due to the addition of artificial endolymph to the basolateral cell surface of outer hair cells (OHC) in replicating endolymph-induced K+ intoxication of the perilymph in the small spaces of Nuel. The influence of K+ intoxication of the basolateral OHC cell surface on the transduction was then examined. Intoxication resulted in an inhibition of the physiological repolarizing K+ efflux from hair cells. This induced unwanted depolarizations of the hair cells, interfering with mechanoelectrical transduction. A pathological longitudinal OHC shortening was also found, with subsequent compression of the organ of Corti possibly influencing the micromechanics of the mechanically active OHC. Both micromechanical and electrophysiological alterations are proposed to contribute to endolymph leakage induced attacks of deafness and possibly also to tinnitus. Moreover, repeated or long-lasting K+ intoxications of OHC resulted in a chronic and complete loss of OHC motility. This is suggested to be a pathophysiological basis in some patients with chronic hearing loss resulting from Meniere's syndrome.

Non-NASA Center↗

NASA NTRS2010

Impact of CO2 on Intracranial Hypertension in Spaceflight. Visual Impairment and Intracranial Hypertension: An Emerging Spaceflight Risk [Part 1 and 2]

A. CO2 - Acute: Given the history of uneven removal of CO2 from spacecraft areas, there is a history of acute illness that impacts short-term health and performance. 1) Acute CO2 symptoms occur in space flight due to a combination of CO2 scrubbing limitations, microgravity-related lack of convection, and possibly interaction with microgravity-related physiological changes. 2) Reported symptoms mainly include headaches, malaise, and lethargy. Symptoms are treatable with analgesics, rest, temporarily increasing scrubbing capability, and breathing oxygen. This does not treat the underlying pathology. 3)ld prevent occurrence of symptoms. B. CO2 - Chronic: Given prolonged exposure to elevated CO2 levels, there is a history that the long-term health of the crew is impacted. 1) Chronic CO2 exposures occur in space flight due to a combination of CO2 scrubbing limitations and microgravity-related lack of convection, with possible contribution from microgravity-related physiological changes. 2) Since acute symptoms are experienced at levels significantly lower than expected, there are unidentified long-term effects from prolonged exposure to elevated CO2 levels on orbit. There have been long term effects seen terrestrially and research needed to further elucidate long term effects on orbit. 3) Recommended disposition: Research required to further elucidate long term effects. In particular, elucidation of the role of elevated CO2 on various levels of CO2 vasodilatation of intracranial blood vessels and its potential contribution to elevation of intracranial pressure.

Fogarty, Jennifer A.↗

NASA NTRS2016

Colonoscopy Screening in the US Astronaut Corps

BACKGROUND: Historically, colonoscopy screenings for astronauts have been conducted to ensure that astronauts are in good health for space missions. Recently this historical data has been identified as being useful for developing an occupational surveillance requirement. It can be used to assess overall colon health and to have a point of reference for future tests in current and former astronauts, as well as to follow-up and track rates of colorectal cancer and polyps. These rates can be compared to military and other terrestrial populations. In 2003, the active astronaut colonoscopy requirements changed to require less frequent colonoscopies. Since polyp removal during a colonoscopy is an intervention that prevents the polyp from potentially developing into cancer, the procedure decreases the individual's risk for colon cancer. The objective of this study is to evaluate the possible effect of increased follow-up times between colonoscopies on the number and severity of polyps identified during the procedures among both current and former NASA astronauts. Initial results and forward work regarding astronaut colonoscopy screenings will be presented. METHODS: A retrospective study of all colonoscopy procedures performed on NASA astronauts between 1962 and 2015 (both during active career and retirement) was conducted by review of the JSC Clinic Electronic Medical Record and Lifetime Surveillance of Astronaut Health (LSAH) database for colonoscopy screening procedures and pathology reports. The timeframe of interest was from the time of selection into the Astronaut Corps through May 2015 or death. For each colonoscopy report, the following data were captured: date of procedure, age at time of procedure, reason for procedure, quality of bowel prep, completion of procedure and/or reason for termination of procedure, findings of procedure, subsequent treatment (if any), recommended follow-up interval, actual follow up interval, family history of polyps or colon cancer, and other significant items or discrepancies. The population consisted of 338 astronauts: 52 females, 286 males. Of these, 56 were deceased, and 11 astronauts had no record of any colonoscopies. Because of a screening requirement change in 2003, analyses were conducted to determine if there were differences between the two time periods. One-sided Wilcoxon rank sum tests were used to identify statistically significant differences between the two time periods. RESULTS: There was a combined total of 1,964 colonoscopy screenings identified. The average follow-up intervals between colonoscopies were indeed longer after the screening requirement change than before the change. The mean follow-up interval pre -2003 was 3.59 years, while post-2003 it increased to 4.35 years. The statistical significance of this difference was confirmed using a one sided Wilcoxon rank sum test which yielded p<.001. Colonoscopies performed after the requirement change tended to have a higher incidence and greater severity of polyps. From pre-2003 to post-2003 the percentage of colonoscopy procedures yielding no polyps decreased from 83.77% to 74.70%. Not only did post-2003 procedures yield more polyp findings, but the polyps recorded were more often of severe pathology. Before 2003 3.62% of colonoscopy findings were polyps of the hyperplastic type (the least severe polyp type) and only 3.35% were of greater severity. Post-2003, 4.21% of findings were hyperplastic polyps while 11.44% were of greater severity. Upon the investigation of other possible contributing factors to these results, we also found that mean age post-2003 was 54.55 years which was significantly higher than during the pre-2003 timeframe (47.32 years). This was observed with a one-sided Wilcoxon rank sum test, resulting in a p<0.001. The increased average age of astronauts could also be a contributing factor to the greater number of polyps found since the risk of developing polyps increases with age. Further work is needed to better understand the increased incidence and greater severity of polyps found in astronaut colonoscopy outcomes.

Masterova, K.↗

NASA NTRS2006

Effects of Walking Speed and Visual-Target Distance on Toe Trajectory During Swing Phase

After spaceflight, astronauts experience disturbances in their ability to walk and maintain postural stability (Bloomberg, et al., 1997). One of the post-flight neurovestibular assessments requires that the astronaut walk on a treadmill at 1.8 m/sec (4.0 mph), while performing a visual acuity test, set at two different distances ( far and near ). For the first few days after landing, some crewmembers can not maintain the required pace, so a lower speed may be used. The slower velocity must be considered in the kinematic analysis, because Andriacchi, et al. (1977) showed that in clinical populations, changes in gait parameters may be attributable more to slower gait speed than pathology. Studying toe trajectory gives a global view of control of the leg, since it involves coordination of muscles and joints in both the swing and stance legs (Karst, et al., 1999). Winter (1992) and Murray, et al. (1984) reported that toe clearance during overground walking increased slightly as speed increased, but not significantly. Also, toe vertical peaks in both early and late swing phase did increase significantly with increasing speed. During conventional testing of overground locomotion, subjects are usually asked to fix their gaze on the end of the walkway a far target. But target (i.e., visual fixation) distance has been shown to affect head and trunk motion during treadmill walking (Bloomberg, et al., 1992; Peters, et al., in review). Since the head and trunk can not maintain stable gaze without proper coordination with the lower body (Mulavara & Bloomberg, 2003), it would stand to reason that lower body kinematics may be altered as well when target distance is modified. The purpose of this study was to determine changes in toe vertical trajectory during treadmill walking due to changes in walking speed and target distance.

Miller, Chris↗

NASA NTRS1966

Progress in Development of Methods in Bone Densitometry

The effects of weightlessness and decreased activity on the astronaut's musculoskeletal system during prolonged space flight, missions are of concern to NASA. This problem was anticipated from the knowledge that human subjects lose significant quantities of calcium from the skeleton during periods of bedrest, immobilization, and water immersion. An accurate method of measurement of the changes in mineral content of the skeleton is required not only in the space program but also in the biological, medical, and dental fields for mineral metabolism studies and for studying various pathological conditions of the skeleton and teeth. This method is a difficult one requiring the coordinated efforts of physiologists, biophysicists, radiologists, and clinicians. The densitometry methods reported in this conference which have been used or are being developed include X-ray, beta excited X-rays, radioisotopes, sonic vibration, and neutron activation analysis Studies in the Gemini, Biosatellite, and Apollo flights use the X-ray bone densitometry method which requires making X-rays before and after the flights. An in-flight method of bone densitometry would be valuable, and use of radioisotope sources has been suggested. Many advances in bone densitometry have been made in the last five years, and the urgency of the requirement makes this working conference timely and valuable. In such a rapidly developing field with investigators working independently in a variety of scientific disciplines, a working conference is of great value in exchanging information and ideas, critically evaluating approaches and methods, and pointing out new research pathways.

DENSITOMETER↗

DOE OSTI2021

Roles of miR-204 in retinal development and maintenance

Highlights: • miR-204 plays an important role in the development, maintenance, and diseases of the retina. • Various layers of the retina including RPE express miR-204. • Retinoblastoma, age-related macular degeneration, glaucoma and optic nerve injury are among the most common retinopathies caused by miR-204 dysfunction. • miR-204 target genes are involved in diverse signaling pathways crucial for retinal physiology. The retina is the innermost part of the eye of most vertebrates and it is essential for vision. The development, maintenance, and function of this laminated structure is tightly regulated by numerous genes. Deficiencies in the expression of these genes as well as deregulation of various molecular mechanisms can cause retinopathies and blindness. MicroRNAs (miRNAs) are one of the most important and effective molecular regulatory mechanisms that underlie the biology of the retina. miRNAs have specific functional roles in the development and maintenance of different retinal layers and retinal cell types. While previous studies have reported a large number of miRNAs linked to development, maintenance and diseases of the retina, no comprehensive study has properly discussed and integrated data from these studies. Given the particular importance of miR-204 in retinal biology, we intend to critically discuss the expression and functional significance of this miRNA in the development, maintenance, and pathologies of the retina. Moreover, we explore biological processes through which miR-204 influences retinal pathophysiology. This review highlights the crucial functions of miR-204 in the retina and suggests the putative mechanism of miR-204 action in retinal biology.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2020

TDCOSMO. I. An exploration of systematic uncertainties in the inference of $H_0$ from time-delay cosmography

Time-delay cosmography of lensed quasars has achieved 2.4% precision on the measurement of the Hubble constant, H0. As part of an ongoing effort to uncover and control systematic uncertainties, we investigate three potential sources: 1- stellar kinematics, 2- line-of-sight effects, and 3- the deflector mass model. To meet this goal in a quantitative way, we reproduced the H0LiCOW/SHARP/STRIDES (hereafter TDCOSMO) procedures on a set of real and simulated data, and we find the following. First, stellar kinematics cannot be a dominant source of error or bias since we find that a systematic change of 10% of measured velocity dispersion leads to only a 0.7% shift on H0 from the seven lenses analyzed by TDCOSMO. Second, we find no bias to arise from incorrect estimation of the line-of-sight effects. Third, we show that elliptical composite (stars + dark matter halo), power-law, and cored power-law mass profiles have the flexibility to yield a broad range in H0 values. However, the TDCOSMO procedures that model the data with both composite and power-law mass profiles are informative. If the models agree, as we observe in real systems owing to the “bulge-halo” conspiracy, H0 is recovered precisely and accurately by both models. If the two models disagree, as in the case of some pathological models illustrated here, the TDCOSMO procedure either discriminates between them through the goodness of fit, or it accounts for the discrepancy in the final error bars provided by the analysis. This conclusion is consistent with a reanalysis of six of the TDCOSMO (real) lenses: the composite model yields H0 = 74.0−1.8+1.7 km s−1 Mpc−1, while the power-law model yields 74.2−1.6+1.6 km s−1 Mpc−1. In conclusion, we find no evidence of bias or errors larger than the current statistical uncertainties reported by TDCOSMO.

79 ASTRONOMY AND ASTROPHYSICS↗