Clostridium thermocellumcellobiohydrolase A X1-module repeat: enhancement through stabilization of the CbhA complex
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Roman, Brunecky↗
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Comparative Genomics of a Plant-Pathogenic Fungus, Pyrenophora tritici-repentis, Reveals Transduplication and the Impact of Repeat Elements on Pathogenicity and Population Divergence
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THE SUCESSFUL APPLICATION OF A REPEATED TEST-TO-FAILURE PROGRAM ON SERGEANT MISSILE ASSEMBLIES. PART I. THE DESIGN, APPLICATION, AND RESULTS OF THE COMBINED OPERATING TEMPERATURE VIBRATION TEST FOR MISSILE ASSEMBLIES RELIABILITY. PART II. STATISTICAL TECHNIQUES APPLIED TO THE SERGEANT REPEATED TEST-TO-FAILURE PROGRAM. PART III. CONCLUSIONS AND RECOMMENDATIONS
Reliability of sergeant missile assemblies - application of test-to-failure program
RELIABILITY↗
Repeatability of Cryogenic Multilayer Insulation
Due to the variety of requirements across aerospace platforms, and one off projects, the repeatability of cryogenic multilayer insulation has never been fully established. The objective of this test program is to provide a more basic understanding of the thermal performance repeatability of MLI systems that are applicable to large scale tanks. There are several different types of repeatability that can be accounted for: these include repeatability between multiple identical blankets, repeatability of installation of the same blanket, and repeatability of a test apparatus. The focus of the work in this report is on the first two types of repeatability. Statistically, repeatability can mean many different things. In simplest form, it refers to the range of performance that a population exhibits and the average of the population. However, as more and more identical components are made (i.e. the population of concern grows), the simple range morphs into a standard deviation from an average performance. Initial repeatability testing on MLI blankets has been completed at Florida State University. Repeatability of five GRC provided coupons with 25 layers was shown to be +/- 8.4 whereas repeatability of repeatedly installing a single coupon was shown to be +/- 8.0. A second group of 10 coupons have been fabricated by Yetispace and tested by Florida State University, through the first 4 tests, the repeatability has been shown to be +/- 16. Based on detailed statistical analysis, the data has been shown to be statistically significant.
multilayer insulation↗
Repeatability of Cryogenic Multilayer Insulation
Due to the variety of requirements across aerospace platforms, and one off projects, the repeatability of cryogenic multilayer insulation has never been fully established. The objective of this test program is to provide a more basic understanding of the thermal performance repeatability of MLI systems that are applicable to large scale tanks. There are several different types of repeatability that can be accounted for: these include repeatability between multiple identical blankets, repeatability of installation of the same blanket, and repeatability of a test apparatus. The focus of the work in this report is on the first two types of repeatability. Statistically, repeatability can mean many different things. In simplest form, it refers to the range of performance that a population exhibits and the average of the population. However, as more and more identical components are made (i.e. the population of concern grows), the simple range morphs into a standard deviation from an average performance. Initial repeatability testing on MLI blankets has been completed at Florida State University. Repeatability of five GRC provided coupons with 25 layers was shown to be +/- 8.4% whereas repeatability of repeatedly installing a single coupon was shown to be +/- 8.0%. A second group of 10 coupons have been fabricated by Yetispace and tested by Florida State University, through the first 4 tests, the repeatability has been shown to be +/- 15-25%. Based on detailed statistical analysis, the data has been shown to be statistically significant.
multilayer insulation↗
WE-H-207A-04: Impact of Lesion Location On the Repeatability of 18F-NaF PET/CT
Purpose: Quantifying the repeatability of imaging biomarkers is critical for assessing therapeutic response. While {sup 18}F-NaF PET/CT has shown to be a repeatable imaging method, research has not shown which factors may influence its repeatability. The purpose of this study was to evaluate whether the location of the lesion impacts the repeatability of quantitative {sup 18}F-NaF PET-derived SUV metrics. Methods: Metastatic castrate-resistant prostate cancer patients with multiple bone lesions received whole-body test-retest NaF PET/CT scans. Malignant bone lesions of PET-defined volume greater than 1.5 cm{sup 3} were identified by a nuclear medicine physician and automatically delineated using a SUV>15 threshold. The maximum (SUVmax), average (SUVmean), and total (SUVtotal) SUV were extracted from each lesion. Atlas-based segmentation was used to divide each patient skeleton into 25 skeletal regions. Test-retest repeatability of each SUV metric was assessed with coefficient of variation (CV). Results: A total of 265 malignant bone lesions from 18 patients were identified by nuclear medicine physician. The largest proportion of bone lesions were localized to the spine (41%), with 41% of those lesions localized to the thoracic spine. One-way ANOVA showed that measurement differences differed significantly for all three metrics across locations (p<0.01 for each metrics). Overall, CV was smallest for SUVmean at 5.3%, followed by SUVmax at 11.5% and SUVtotal at 20.4%. Lesions in the pubis were consistently the most repeatable (CV(SUVmax)= 5.6%, CV(SUVmean)= 0.6%, CV(SUVtotal)= 2.9%). According to SUVmean, repeatability was poorest in the cervical spine (CV = 6.2%), whereas according to SUVmax and SUVtotal, repeatability was poorest in the ribs (CV(SUVmax)= 15.0%, CV(SUVtotal)= 29.8%). Conclusion: Location of the lesion affects the repeatability of {sup 18}F-NaF PET/CT, with the ribs and cervical spine having the lowest repeatability and the pubis having the highest repeatability. These results can be used to establish location-specific response criteria for NaF PET-based treatment response assessment.
60 APPLIED LIFE SCIENCES↗
Effects of repeated Valsalva maneuver straining on cardiac and vasoconstrictive baroreflex responses
INTRODUCTION: We hypothesized that repeated respiratory straining maneuvers (repeated SM) designed to elevate arterial BPs (arterial baroreceptor loading) would acutely increase baroreflex responses. METHODS: We tested this hypothesis by measuring cardiac baroreflex responses to carotid baroreceptor stimulation (neck pressures), and changes in heart rate and diastolic BP after reductions in BP induced by a 15-s Valsalva maneuver in 10 female and 10 male subjects at 1, 3, 6, and 24 h after performing repeated SM. Baroreflex responses were also measured in each subject at 1, 3, 6, and 24 h at the same time on a separate day without repeated SM (control) in a randomized, counter-balanced cross-over experimental design. RESULTS: There was no statistical difference in carotid-cardiac and peripheral vascular baroreflex responses measured across time following repeated SM compared with the control condition. Integrated cardiac baroreflex response (deltaHR/ deltaSBP) measured during performance of a Valsalva maneuver was increased by approximately 50% to 1.1 +/- 0.2 bpm x mm Hg(-1) at 1 h and 1.0 +/- 0.1 bpm x mm Hg(-1) at 3 h following repeated SM compared with the control condition (0.7 +/- 0.1 bpm x mm Hg(-1) at both 1 and 3 h, respectively). However, integrated cardiac baroreflex response after repeated SM returned to control levels at 6 and 24 h after training. These responses did not differ between men and women. CONCLUSIONS: Our results are consistent with the notion that arterial baroreceptor loading induced by repeated SM increased aortic, but not carotid, cardiac baroreflex responses for as long as 3 h after repeated SM. We conclude that repeated SM increases cardiac baroreflex responsiveness which may provide patients, astronauts, and high-performance aircraft pilots with protection from development of orthostatic hypotension.
NASA Discipline Cardiopulmonary↗
SU-F-R-35: Repeatability of Texture Features in T1- and T2-Weighted MR Images
Purpose: To evaluate repeatability of lung tumor texture features from inspiration/expiration MR image pairs for potential use in patient specific care models and applications. Repeatability is a desirable and necessary characteristic of features included in such models. Methods: T1-weighted Volumetric Interpolation Breath-Hold Examination (VIBE) and/or T2-weighted MRI scans were acquired for 15 patients with non-small cell lung cancer before and during radiotherapy for a total of 32 and 34 same session inspiration-expiration breath-hold image pairs respectively. Bias correction was applied to the VIBE (VIBE-BC) and T2-weighted (T2-BC) images. Fifty-nine texture features at five wavelet decomposition ratios were extracted from the delineated primary tumor including: histogram(HIST), gray level co-occurrence matrix(GLCM), gray level run length matrix(GLRLM), gray level size zone matrix(GLSZM), and neighborhood gray tone different matrix (NGTDM) based features. Repeatability of the texture features for VIBE, VIBE-BC, T2-weighted, and T2-BC image pairs was evaluated by the concordance correlation coefficient (CCC) between corresponding image pairs, with a value greater than 0.90 indicating repeatability. Results: For the VIBE image pairs, the percentage of repeatable texture features by wavelet ratio was between 20% and 24% of the 59 extracted features; the T2-weighted image pairs exhibited repeatability in the range of 44–49%. The percentage dropped to 10–20% for the VIBE-BC images, and 12–14% for the T2-BC images. In addition, five texture features were found to be repeatable in all four image sets including two GLRLM, two GLZSM, and one NGTDN features. No single texture feature category was repeatable among all three image types; however, certain categories performed more consistently on a per image type basis. Conclusion: We identified repeatable texture features on T1- and T2-weighted MRI scans. These texture features should be further investigated for use in specific applications such as tissue classification and changes during radiation therapy utilizing a standard imaging protocol. Authors have the following disclosures: a research agreement with Philips Medical systems (Hugo, Weiss), a license agreement with Varian Medical Systems (Hugo, Weiss), research grants from the National Institute of Health (Hugo, Weiss), UpToDate royalties (Weiss), and none(Mahon, Ford, Karki). Authors have no potential conflicts of interest to disclose.
60 APPLIED LIFE SCIENCES↗
Repeatable and reproducible measurements of myocardial oxidative metabolism, blood flow and external efficiency using {sup 11}C-acetate PET
Background: Non-invasive approaches to investigate myocardial efficiency can help track the progression of heart failure (HF). This study evaluates the repeatability and reproducibility of {sup 11}C-acetate positron emission tomography (PET) imaging of oxidative metabolism. Methods and results: Dynamic {sup 11}C-acetate PET scans were performed at baseline and followup (47 ± 22 days apart) in 20 patients with stable HF with reduced ejection fraction. Two observers blinded to patients’ clinical data used FlowQuant{sup ®} to evaluate test–retest repeatability, as well as intra- and inter-observer reproducibility of {sup 11}C-acetate tracer uptake and clearance rates, for the measurement of myocardial oxygen consumption (MVO{sub 2}), myocardial external efficiency (MEE), work metabolic index (WMI), and myocardial blood flow. Reproducibility and repeatability were evaluated using intra-class-correlation (ICC) and Bland–Altman coefficient-of-repeatability (CR). Test–retest correlations and repeatability were better for MEE and WMI compared to MVO{sub 2}. All intra- and inter-observer correlations were excellent (ICC = 0.95-0.99) and the reproducibility values (CR = 3%-6%) were significantly lower than the test–retest repeatability values (22%-54%, P < 0.001). Repeatability was improved for all parameters using a newer PET–computed tomography (CT) scanner compared to older PET-only instrumentation. Conclusion: {sup 11}C-acetate PET measurements of WMI and MEE exhibited excellent test–retest repeatability and operator reproducibility. Newer PET–CT scanners may be preferred for longitudinal tracking of cardiac efficiency. [French] French Abstract: Contexte: Les examens non invasifs de la fonction myocardique aident à suivre la progression de l’insuffisance cardiaque. Dans ce travail, nous avons évalué la répétabilité et la reproductibilité de l’étude du métabolisme oxydatif du myocarde par imagerie tomographique à positrons avec l’acétate marqué au carbone 11. Méthodes et résultats: Une étude de base et un second examen TEP dynamique à l’ acétate marqué au carbone 11 ont été réalisés (47 ± 22 jours) chez 20 patients présentant une insuffisance cardiaque stable avec une fraction d’éjection réduite. Sans aucune connaissance des données cliniques et au moyen du programme FlowQuant®, deux observateurs ont évalué la répétabilité des TEPs de base et de leur suivi, la reproductibilité intra- et inter-observateur, l’absorption et la clearance du traceur, la mesure de la consommation d’oxygène du myocarde (MVO2), l’efficacité contractile du myocarde (MEE), l’index métabolique du travail myocardique (WMI) et le débit sanguin myocardique (MBF). La reproductibilité et la répétabilité ont été évaluées en utilisant la corrélation intra-classe (ICC) et le coefficient de répétabilité Altman (CR). Les corrélations entre les études de base et leur suivi et la répétabilité des données se sont avérées supérieures pour les paramètres MEE et WMI par rapport à MVO2. Toutes les corrélations intra- et inter-observateurs furent excellentes (ICC = 0,95-0,99). Les valeurs de reproductibilité (CR = 3-6%) furent significativement inférieures aux valeurs de répétabilité (22-54%, p <0.001). La répétabilité des paramètres mesurés s’est avérée supérieure avec un scanner TEP-TDM de nouvelle génération par rapport à l’utilisation de la TEP sans TDM Conclusion: Les mesures réalisées dans cette étude TEP 11C-acétate montre une excellent répétabilité et reproductibilité des paramètres WMI et WMI entre les examens de base et leur suivi effectués par des opérateurs différents. Les nouveaux scanners TEP-TDM devraient être préférés pour le suivi longitudinal de la fonction cardiaque. [Spanish] Spanish Abstract: Antecedentes: el abordaje no invasivo para investigar la eficiencia miocárdica puede ayudar en el seguimiento de la progresión de la insuficiencia cardíaca. Este estudio evalúa la repetibilidad y la reproducibilidad del estudio de metabolismo oxidativo con PET 11C-acetato. Métodos y resultados: Se realizaron estudios de PET 11C-acetato dinámicos al inicio y durante el seguimiento (47 ± 22 días de diferencia) en 20 pacientes con insuficiencia cardíaca estable y fracción de eyección reducida. Dos observadores cegados a los datos clínicos de los pacientes utilizaron FlowQuant® para evaluar la repetibilidad de la prueba-reprueba, así como la reproducibilidad intra e interobservador de la captación de radiotrazador 11C-acetato y sus tasas de eliminación, la medición del consumo miocárdico de oxígeno (MVO2), la eficiencia externa miocardica (EEM), el índice trabajo-metabólico (ITM) y flujo sanguíneo miocárdico (FSM). La reproducibilidad y la repetibilidad se evaluaron mediante la correlación intraclase (ICC) y el coeficiente de repetibilidad (CR) de Bland-Altman. Las correlaciones Prueba-Reprueba y la repetibilidad fueron mejores para la EEM y el ITM en comparación con el MVO2. Todas las correlaciones intra e interobservador fueron excelentes (ICC = 0.95-0.99) y los valores de reproducibilidad (CR = 3-6%) fueron significativamente menores que los valores de repetibilidad prueba-reprueba (22-54%, p <0.001). La repetibilidad fue mejor para todos los parámetros utilizando un equipo PET-TC más nuevo en comparación con un equipo PET sin CT. Conclusión: las mediciones del PET con 11C-acetato del ITM y EEM mostraron una excelente repetibilidad prueba-preprueba y reproducibilidad del operador. Los nuevos equipos PET-CT pueden ser elegidos para el seguimiento longitudinal de la eficiencia miocárdica. [Chinese] Chinese Abstract: 背景: 采用非侵入式方法来研究心肌代谢效率可以帮助追踪心力衰竭的过程。本研究评估利用碳-11 醋酸盐为 PET 显影剂行氧化代谢成像的可重复性和可再现性。 方法和结果: 纳入射血分数减低的 20 名稳定性心衰患者,对患者基线和 47±22 天随访都进行碳-11 醋酸盐 PET 扫描。为测量心肌耗氧量(MVO{sub 2}), 心肌外效率(MEE), 工作代谢指标(WMI)和心肌血流量(MBF), 两名观察者按照双盲的方法利用 FlowQuant®对碳-11 醋酸盐的摄取率和清空率进行了重复性测试以及不同观察者之间的可再现性测试。采用组内相关系数(ICC)和 Bland Altman 可重复性系数(CR)分别对可再现性和可重复性进行评估。MEE 和 WMI 的两次试验系数和可重复性优于MVO{sub 2}。所有观察者之间的相关系数都较好(ICC=0.95-0.99),可再现性系数的值(CR=3-6%)明显低于两次试验可重复性的值(22-54%, P<0.001)。相比于旧的只有 PET 的设备, 采用新型 PET-CT 扫描仪能够使所有参数的可再现性都有所提高。 结论: 碳-11醋酸盐 PET 显像测量 WMI 和 MEE 有很好的可重复性和可再现性。新的 PET-CT 扫描仪可能更适合于心脏代谢效率的长期追踪。.
62 RADIOLOGY AND NUCLEAR MEDICINE↗
Repeated Nrf2 stimulation using sulforaphane protects fibroblasts from ionizing radiation
Most of the cytotoxicity induced by ionizing radiation is mediated by radical-induced DNA double-strand breaks. Cellular protection from free radicals can be stimulated several fold by sulforaphane-mediated activation of the transcription factor Nrf2 that regulates more than 50 genes involved in the detoxification of reactive substances and radicals. Here, we report that repeated sulforaphane treatment increases radioresistance in primary human skin fibroblasts. Cells were either treated with sulforaphane for four hours once or with four-hour treatments repeatedly for three consecutive days prior to radiation exposure. Fibroblasts exposed to repeated-sulforaphane treatment showed a more pronounced dose-dependent induction of Nrf2-regulated mRNA and reduced amount of radiation-induced free radicals compared with cells treated once with sulforaphane. In addition, radiation- induced DNA double-strand breaks measured by gamma-H2AX foci were attenuated following repeated sulforaphane treatment. As a result, cellular protection from ionizing radiation measured by the 5-ethynyl-2′-deoxyuridine (EdU) assay was increased, specifically in cells exposed to repeated sulforaphane treatment. Sulforaphane treatment was unable to protect Nrf2 knockout mouse embryonic fibroblasts, indicating that the sulforaphane-induced radioprotection was Nrf2-dependent. Moreover, radioprotection by repeated sulforaphane treatment was dose-dependent with an optimal effect at 10 uM, whereas both lower and higher concentrations resulted in lower levels of radioprotection. Our data indicate that the Nrf2 system can be trained to provide further protection from radical damage. - Highlights: • Repeated treatment with sulforaphane protects fibroblasts from ionizing radiation • Repeated sulforaphane treatment attenuates radiation induced ROS and DNA damage • Sulforaphane mediated protection is Nrf2 dependent.
60 APPLIED LIFE SCIENCES↗
Pathogenic C9ORF72 Antisense Repeat RNA Forms a Double Helix with Tandem C:C Mismatches
Expansion of a GGGGCC/CCCCGG repeat sequence in the first intron of the C9ORF72 gene is a leading cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In this combined disorder, called c9FTD/ALS, the expansion is bidirectionally transcribed into sense and antisense repeat RNA associated with disease. To better understand the role of C9ORF72 repeat RNA in molecular disease pathology, in this work we determined crystal structures of a [(CCCCGG) 3 (CCCC)] model antisense repeat RNA to 1.47 Å resolution. The RNA structure was an A-form-like double helix composed of repeating and regularly spaced tandem C:C mismatch pairs that perturbed helical geometry and surface charge. Solution studies revealed a preference for A-form-like helical conformations as the repeat number increased. Results provide a structural starting point for rationalizing the contribution of repeat RNA to c9FTD/ALS molecular disease mechanisms and for developing molecules to target C9ORF72 repeat RNA as potential therapeutics.
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
O-Glycosylation modulates the stability of epidermal growth factor-like repeats and thereby regulates Notch trafficking
Glycosylation in the endoplasmic reticulum (ER) is closely associated with protein folding and quality control. We recently described a non-canonical ER quality control mechanism for folding of thrombospondin type 1 repeats by protein O-fucosyltransferase 2 (POFUT2). Epidermal growth factor-like (EGF) repeats are also small cysteine-rich protein motifs that can be O-glycosylated by several ER-localized enzymes, including protein O-glucosyltransferase 1 (POGLUT1) and POFUT1. Both POGLUT1 and POFUT1 modify the Notch receptor on multiple EGF repeats and are essential for full Notch function. The fact that POGLUT1 and POFUT1 can distinguish between folded and unfolded EGF repeats raised the possibility that they participate in a quality control pathway for folding of EGF repeats in proteins such as Notch. Here, we demonstrate that cell-surface expression of endogenous Notch1 in HEK293T cells is dependent on the presence of POGLUT1 and POFUT1 in an additive manner. In vitro unfolding assays reveal that addition of O-glucose or O-fucose stabilizes a single EGF repeat and that addition of both O-glucose and O-fucose enhances stability in an additive manner. Finally, we solved the crystal structure of a single EGF repeat covalently modified by a full O-glucose trisaccharide at 2.2 Å resolution. The structure reveals that the glycan fills up a surface groove of the EGF with multiple contacts with the protein, providing a chemical basis for the stabilizing effects of the glycans. Taken together, this work suggests that O-fucose and O-glucose glycans cooperatively stabilize individual EGF repeats through intramolecular interactions, thereby regulating Notch trafficking in cells.
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
A Single Whole-Body Low Dose X-Irradiation Does Not Affect L1, B1 and IAP Repeat Element DNA Methylation Longitudinally
The low dose radioadaptive response has been shown to be protective against high doses of radiation as well as aging-induced genomic instability. We hypothesised that a single whole-body exposure of low dose radiation would induce a radioadaptive response thereby reducing or abrogating aging-related changes in repeat element DNA methylation in mice. Following sham or 10 mGy X-irradiation, serial peripheral blood sampling was performed and differences in Long Interspersed Nucleic Element 1 (L1), B1 and Intracisternal-A-Particle (IAP) repeat element methylation between samples were assessed using high resolution melt analysis of PCR amplicons. By 420 days post-irradiation, neither radiation- or aging-related changes in the methylation of peripheral blood, spleen or liver L1, B1 and IAP elements were observed. Analysis of the spleen and liver tissues of cohorts of untreated aging mice showed that the 17–19 month age group exhibited higher repeat element methylation than younger or older mice, with no overall decline in methylation detected with age. This is the first temporal analysis of the effect of low dose radiation on repeat element methylation in mouse peripheral blood and the first to examine the long term effect of this dose on repeat element methylation in a radiosensitive tissue (spleen) and a tissue fundamental to the aging process (liver). Our data indicate that the methylation of murine DNA repeat elements can fluctuate with age, but unlike human studies, do not demonstrate an overall aging-related decline. Furthermore, our results indicate that a low dose of ionising radiation does not induce detectable changes to murine repeat element DNA methylation in the tissues and at the time-points examined in this study. This radiation dose is relevant to human diagnostic radiation exposures and suggests that a dose of 10 mGy X-rays, unlike high dose radiation, does not cause significant short or long term changes to repeat element or global DNA methylation.
59 BASIC BIOLOGICAL SCIENCES↗
Demonstration of repeatability in a high-energy-density planar shear mixing layer experiment
On laser-driven platforms the assumption of experiment repeatability is particularly important due to a typically low data acquisition rate that doesn’t often allow for data redundancy. If the platform is repeatable, then measurements of the repeatable dynamics from multiple experiments can be treated as measurements of the same system. In high-energy-density hydrodynamic instability experiments the interface growth is assumed to be one of the repeatable aspects of the system. In this paper we demonstrate the repeatability of the instability growth in the counter-propagating shear experiment at the OMEGA laser facility, where the instability growth is characterized by the tracer layer thickness or mix-width evolution. Furthermore, in our previous experiment campaigns we have assumed the instability growth was repeatable enough to identify trends, but in this work we explicitly show that the mix-width measurements for nominally identical experiments are repeatable within the measurement error bars.
70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗
GT-repeat polymorphism in the heme oxygenase-1 gene promoter is associated with cardiovascular mortality risk in an arsenic-exposed population in northeastern Taiwan
Inorganic arsenic has been associated with increased risk of atherosclerotic vascular disease and mortality in humans. A functional GT-repeat polymorphism in the heme oxygenase-1 (HO-1) gene promoter is inversely correlated with the development of coronary artery disease and restenosis after clinical angioplasty. The relationship of HO-1 genotype with arsenic-associated cardiovascular disease has not been studied. In this study, we evaluated the relationship between the HO-1 GT-repeat polymorphism and cardiovascular mortality in an arsenic-exposed population. A total of 504 study participants were followed up for a median of 10.7 years for occurrence of cardiovascular deaths (coronary heart disease, cerebrovascular disease, and peripheral arterial disease). Cardiovascular risk factors and DNA samples for determination of HO-1 GT repeats were obtained at recruitment. GT repeats variants were grouped into the S (< 27 repeats) or L allele ({>=} 27 repeats). Relative mortality risk was estimated using Cox regression analysis, adjusted for competing risk of cancer and other causes. For the L/L, L/S, and S/S genotype groups, the crude mortalities for cardiovascular disease were 8.42, 3.10, and 2.85 cases/1000 person-years, respectively. After adjusting for conventional cardiovascular risk factors and competing risk of cancer and other causes, carriers with class S allele (L/S or S/S genotypes) had a significantly reduced risk of cardiovascular mortality compared to non-carriers (L/L genotype) [OR, 0.38; 95% CI, 0.16-0.90]. In contrast, no significant association was observed between HO-1 genotype and cancer mortality or mortality from other causes. Shorter (GT)n repeats in the HO-1 gene promoter may confer protective effects against cardiovascular mortality related to arsenic exposure.
60 APPLIED LIFE SCIENCES↗
Exploring the repeat protein universe through computational protein design
A central question in protein evolution is the extent to which naturally occurring proteins sample the space of folded structures accessible to the polypeptide chain. Repeat proteins composed of multiple tandem copies of a modular structure unit are widespread in nature and have critical roles in molecular recognition, signalling, and other essential biological processes. Naturally occurring repeat proteins have been re-engineered for molecular recognition and modular scaffolding applications. In this paper, we use computational protein design to investigate the space of folded structures that can be generated by tandem repeating a simple helix–loop–helix–loop structural motif. Eighty-three designs with sequences unrelated to known repeat proteins were experimentally characterized. Of these, 53 are monomeric and stable at 95 °C, and 43 have solution X-ray scattering spectra consistent with the design models. Crystal structures of 15 designs spanning a broad range of curvatures are in close agreement with the design models with root mean square deviations ranging from 0.7 to 2.5 Å. Finally, our results show that existing repeat proteins occupy only a small fraction of the possible repeat protein sequence and structure space and that it is possible to design novel repeat proteins with precisely specified geometries, opening up a wide array of new possibilities for biomolecular engineering.
59 BASIC BIOLOGICAL SCIENCES↗
TU-AB-BRA-05: Repeatability of [F-18]-NaF PET Imaging Biomarkers for Bone Lesions: A Multicenter Study
Purpose: Quantifying the repeatability of imaging biomarkers is critical for assessing therapeutic response. While therapeutic efficacy has been traditionally quantified by SUV metrics, imaging texture features have shown potential for use as quantitative biomarkers. In this study we evaluated the repeatability of quantitative {sup 18}F-NaF PET-derived SUV metrics and texture features in bone lesions from patients in a multicenter study. Methods: Twenty-nine metastatic castrate-resistant prostate cancer patients received whole-body test-retest NaF PET/CT scans from one of three harmonized imaging centers. Bone lesions of volume greater than 1.5 cm{sup 3} were identified and automatically segmented using a SUV>15 threshold. From each lesion, 55 NaF PET-derived texture features (including first-order, co-occurrence, grey-level run-length, neighbor gray-level, and neighbor gray-tone difference matrix) were extracted. The test-retest repeatability of each SUV metric and texture feature was assessed with Bland-Altman analysis. Results: A total of 315 bone lesions were evaluated. Of the traditional SUV metrics, the repeatability coefficient (RC) was 12.6 SUV for SUVmax, 2.5 SUV for SUVmean, and 4.3 cm{sup 3} for volume. Their respective intralesion coefficients of variation (COVs) were 12%, 17%, and 6%. Of the texture features, COV was lowest for entropy (0.03%) and highest for kurtosis (105%). Lesion intraclass correlation coefficient (ICC) was lowest for maximum correlation coefficient (ICC=0.848), and highest for entropy (ICC=0.985). Across imaging centers, repeatability of texture features and SUV varied. For example, across imaging centers, COV for SUVmax ranged between 11–23%. Conclusion: Many NaF PET-derived SUV metrics and texture features for bone lesions demonstrated high repeatability, such as SUVmax, entropy, and volume. Several imaging texture features demonstrated poor repeatability, such as SUVtotal and SUVstd. These results can be used to establish response criteria for NaF PET-based treatment response assessment. Prostate Cancer Foundation (PCF)
60 APPLIED LIFE SCIENCES↗