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

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At least 19 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2023

RecJ3/4-aRNase J form a Ubl-associated nuclease complex functioning in survival against DNA damage in Haloferax volcanii

Nucleases are strictly regulated and often localized in the cell to avoid the uncontrolled degradation of DNA and RNA. Here, a new type of nuclease complex, composed of RecJ3, RecJ4, and aRNase J, was identified through its ATP-dependent association with the ubiquitin-like SAMP1 and AAA-ATPase Cdc48a. The complex was discovered in Haloferax volcanii , an archaeon lacking an RNA exosome. Genetic analysis revealed aRNase J to be essential and RecJ3, RecJ4, and Cdc48a to function in the recovery from DNA damage including genotoxic agents that generate double-strand breaks. The RecJ3:RecJ4:aRNase J complex (isolated in 2:2:1 stoichiometry) functioned primarily as a 3′−5′ exonuclease in hydrolyzing RNA and ssDNA, with the mechanism non-processive for ssDNA. aRNase J could also be purified as a homodimer that catalyzed endoribonuclease activity and, thus, was not restricted to the 5′−3′ exonuclease activity typical of aRNase J homologs. Moreover, RecJ3 and RecJ4 could be purified as a 560-kDa subcomplex in equimolar subunit ratio with nuclease activities mirroring the full RecJ3/4-aRNase J complex. These findings prompted reconstitution assays that suggested RecJ3/4 could suppress, alter, and/or outcompete the nuclease activities of aRNase J. Based on the phenotypic results, this control mechanism of aRNase J by RecJ3/4 is not necessary for cell growth but instead appears important for DNA repair. IMPORTANCE Nucleases are critical for various cellular processes including DNA replication and repair. Here, a dynamic type of nuclease complex is newly identifiedidentifiedidentifiedin the archaeon Haloferax volcanii , which is missing the canonical RNA exosome. The complex, composed of RecJ3, RecJ4, and aRNase J, functions primarily as a 3′−5′ exonuclease and was discovered through its ATP-dependent association with the ubiquitin-like SAMP1 and Cdc48a. aRNase J alone forms a homodimer that has endonuclease function and, thus, is not restricted to 5′−3′ exonuclease activity typical of other aRNase J enzymes. RecJ3/4 appears to suppress, alter, and/or outcompete the nuclease activities of aRNase J. While aRNase J is essential for growth, RecJ3/4, Cdc48a, and SAMPs are important for recovery against DNA damage. These biological distinctions may correlate with the regulated nuclease activity of aRNase J in the RecJ3/4-aRNaseJ complex.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

HEPA Filter Age Evaluation Report

In 2020, PNNL completed a literature search for high-efficiency particulate air (HEPA) filter age information. HEPA filters are used in many operations to remove particulate matter from effluent exhaust streams. They are thought to degrade over time both during proper storage and during normal operational service; however, the rate at which the filters degrade remains unknown. This brings into question if age is an adequate indicator of HEPA filter performance. Data from six previous reports were obtained from the literature search and combined to create a data set of 1600 operating filters. Filter usage was identified from multiple facilities. The various types of filters (e.g., axial flow, self-contained, and standard 24 x 24 x 11.5 inches; and both separator and separatorless) reported were constructed to the requirements Section FC (HEPA Filters) or Section FK (Special HEPA Filters) of the American Society of Mechanical Engineers AG-1 code. Filters were presumed to have continuously met the operational criteria and in particular passed both annual efficiency tests and annual DP measurements. The environmental conditions within the exhaust system were also assumed adequate for long-term filter operation. The data, by the nature of the reports, excludes rejected filters from quality assurance evaluations, intake, or installation testing. The collective data set shows over half of were operating past the current 10-year Department of Energy (DOE) limit. Data was evaluated for age lifetime using a linear trendline, survival function, probability functions, and failure rate; financial impacts were also addressed. This report supports the notion that HEPA filters can operate safely and efficiently under proper maintenance well past the 10-year lifetime established by DOE. Using the results of the four age evaluation approaches, they collectively point to the reasonableness of an operating HEPA filter lifetime of 20 years. The results are not necessarily definitive, but nevertheless, they are promising. The analysis provides reasonable assurance that when implemented using a graded approach with well-defined performance and operational requirements, extending the service life for HEPA filters beyond 10 years is low risk.

42 ENGINEERING↗
DOE OSTI2023

Incidence and predictors of tuberculosis among children receiving antiretroviral therapy in the Wolaita Zone: A retrospective cohort study

Tuberculosis is the leading cause of morbidity and mortality among children living with the human immunodeficiency virus (HIV), mainly in sub-Saharan Africa, including Ethiopia. Tuberculosis remains a significant health concern for HIV-positive children in Ethiopia. There is a paucity of data on the incidence and predictors of tuberculosis among children living with HIV on antiretroviral therapy in the Wolaita zone. Hence, this study aimed to assess the incidence and predictors of tuberculosis among children living with HIV on antiretroviral therapy in the Wolaita zone between January 2010 to December 2020. A retrospective cohort study was conducted among 389 children receiving antiretroviral therapy in Wolaita zone health facilities between January 2010 to December 2020. The checklist was adapted from the standardized antiretroviral treatment (ART) follow-up form currently used by the institutions’ ART clinics. The Kaplan-Meier survival function and Log-rank were used to estimate the survival for each categorical variable to compare the survival between different exposure groups. Both bivariable and multivariable parametric survival Gompertz models were fitted to identify predictors of tuberculosis among HIV-positive children. The association was summarized using an adjusted hazard ratio (AHR), and statistical significance was declared at 95% CI and p-value < 0.05. The goodness of the model fit was assessed using a Cox-Snell residual plot. The incidence rate of tuberculosis among children living with HIV was 3.5 (95% CI 2.7–4.5) per 100 child years. World Health Organization clinical stage III or IV (AHR = 2.31, 95% CI [1.26, 4.22]), hemoglobin level <10 g/dL (AHR = 2.87, 95% CI [1.51, 5.45]), fair or poor ART adherence (AHR = 4.4, 95% CI[2.18, 9.05]), underweight (AHR = 2.55, 95% CI [1.45, 4.51]), age >10 years (AHR = 3.62; 95% CI [1.29, 10.0]), and cotrimoxazole preventive therapy (AHR = 0.23; 95% CI [0.08, 0.60]) were among the independent predictors of TB occurrence. The incidence of tuberculosis among children on ART was high. HIV-positive children presenting with advanced disease staging (III and IV), anemia, “fair” and “poor” ART adherence, underweight, age above ten years, and not receiving cotrimoxazole preventive therapy were at higher risk of TB. Therefore, counseling on ART adherence, early diagnosis, and prompt treatment of anemia and malnutrition are recommended to avert tuberculosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Fatigue of laser powder bed fusion processed 17-4 stainless steel using prior process exposed powder feedstock

The rapid pace of development seen in the metal additive manufacturing (AM) process of laser powder-bed fusion (LPBF) requires in-step advances in processes qualification to enable full-scale adoption. This particularly applies to quantifying how powder feedstock conditions impact end-component quality. Here this study examines how in-machine 17-4 stainless steel powder feedstocks are affected by prior LPBF processes, and how these effects impact subsequent builds. Examinations of powder morphology, chemistry, flowability, and rheology were conducted to characterize the powder conditions. The resultant effects of powder feedstock condition on produced component quasi-static tensile and high-cycle fatigue properties were analyzed. Fatigue life was analyzed using a reliability modeling approach that enabled a robust statistical comparison of life. Powder characteristics were found to evolve with powder exposure to prior LPBF processes, particularly in the extremes of powder size distribution and measures of bulk flow. No significant effects of these changes on tensile properties were observed. Reliability modeling methods, including the lognormal and Weibull distributions as well as the empirical survival function, are shown to be effective tools for modeling fatigue variability in LPBF manufactured components. Through these tools, fatigue life was found to be invariant with changes in powder condition.

42 ENGINEERING↗
DOE OSTI2022

All-Electric Nonassociative Learning in Nickel Oxide

Habituation and sensitization represent nonassociative learning mechanisms in both non-neural and neural organisms. They are essential for a range of functions from survival to adaptation in dynamic environments. Design of hardware for neuroinspired computing strives to emulate such features driven by electric bias and can also be incorporated into neural network algorithms. Herein, cellular-like learning in oxygen-deficient NiO x devices is demonstrated. Both habituation learning and sensitization response can be achieved in a single device by simply controlling the magnitude of the electric field. Spontaneous memory relaxations and dynamic redistribution of oxygen vacancies under electric bias enable such learning behavior of NiO x under sequential training. These characteristics in simple device arrays are implemented to learn alphabets as well as demonstrate simulated algorithmic use cases in digit recognition. Transition metal oxides with carefully prepared defect concentrations can be highly sensitive to electronic structure perturbations under moderate electrical stimulus and serve as building blocks for next-generation neuroinspired computing hardware.

36 MATERIALS SCIENCE↗
DOE OSTI2021

Transient Copper Exposure During Embryogenesis and Temperature Affect Developmental Rate, Survival, and Fin Regeneration in Japanese Medaka ( Oryzias latipes )

Combined environmental stressors that an organism experiences can have both immediate and lasting consequences. In this paper we exposed medaka (Oryzias latipes) embryos to sublethal copper sulfate (CuSO 4 ) (0, 10, and 100 ppb) in combination with different rearing temperatures (27, 30, and 33°C) to assess acute and latent effects on development, growth, and regenerative capacity. Embryos exposed to CuSO 4 and/or higher temperatures hatched significantly earlier. At 4 months post-exposure, fish exposed to low levels of CuSO 4 during development had higher survival, while fish exposed to both 100 ppb CuSO 4 and 33°C temperatures had significantly lower survival. Additionally, a sex-specific effect of embryonic CuSO 4 exposure was observed as female mass decreased with increasing copper dose. We also assessed caudal fin regenerative capabilities in both embryo-exposed fish at 4 months of age and adult medaka that were exposed to 0, 10, and 100 ppb CuSO 4 at room temperature during a 14- day trial. Whereas fin regeneration was unaffected by adult exposure to copper, fish transiently exposed during embryogenesis displayed an initial increase in fin growth rate and an increased incidence of abnormal fin morphology following regrowth. Collectively, these data suggest that developmental copper exposure has the potential to exert long lasting impacts to organismal growth, survival, and function.

63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTAN↗
DOE OSTI2022

In Situ Detection of Amino Acids from Bacterial Biofilms and Plant Root Exudates by Liquid Microjunction Surface-Sampling Probe Mass Spectrometry

The plant rhizosphere is a complex and dynamic chemical environment where the exchange of molecular signals between plants, microbes, and fungi drives the development of the entire biological system. Exogenous compounds in the rhizosphere are known to affect plant-microbe organization, interactions between organisms, and ultimately, growth and survivability. The function of exogenous compounds in the rhizosphere is still under much investigation, specifically with respect to their roles in plant growth and development, the assembly of the associated microbial community, and the spatiotemporal distribution of molecular components. A major challenge for spatiotemporal measurements is developing a nondisruptive and nondestructive technique capable of analyzing the exogenous compounds contained within the environment. A methodology using liquid microjunction-surface sampling probe-mass spectrometry (LMJ-SSP-MS) and microfluidic devices with attached microporous membranes was developed for in situ, spatiotemporal measurement of amino acids (AAs) from bacterial biofilms and plant roots. Exuded arginine was measured from a living Pantoea YR 343 biofilm, which resulted in a chemical image indicative of biofilm growth within the device. Spot sampling along the roots of Populus trichocarpa with the LMJ-SSP-MS resulted in the detection of 15 AAs. Of note, variation in AA concentrations across the root system was observed, indicating that exudation is not homogeneous and may be linked to local rhizosphere architecture and different biological processes along the root.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

PSInet: a new global water potential network

Abstract Given the pressing challenges posed by climate change, it is crucial to develop a deeper understanding of the impacts of escalating drought and heat stress on terrestrial ecosystems and the vital services they offer. Soil and plant water potential play a pivotal role in governing the dynamics of water within ecosystems and exert direct control over plant function and mortality risk during periods of ecological stress. However, existing observations of water potential suffer from significant limitations, including their sporadic and discontinuous nature, inconsistent representation of relevant spatio-temporal scales and numerous methodological challenges. These limitations hinder the comprehensive and synthetic research needed to enhance our conceptual understanding and predictive models of plant function and survival under limited moisture availability. In this article, we present PSInet (PSI—for the Greek letter Ψ used to denote water potential), a novel collaborative network of researchers and data, designed to bridge the current critical information gap in water potential data. The primary objectives of PSInet are as follows. (i) Establishing the first openly accessible global database for time series of plant and soil water potential measurements, while providing important linkages with other relevant observation networks. (ii) Fostering an inclusive and diverse collaborative environment for all scientists studying water potential in various stages of their careers. (iii) Standardizing methodologies, processing and interpretation of water potential data through the engagement of a global community of scientists, facilitated by the dissemination of standardized protocols, best practices and early career training opportunities. (iv) Facilitating the use of the PSInet database for synthesizing knowledge and addressing prominent gaps in our understanding of plants’ physiological responses to various environmental stressors. The PSInet initiative is integral to meeting the fundamental research challenge of discerning which plant species will thrive and which will be vulnerable in a world undergoing rapid warming and increasing aridification.

Forestry↗
DOE OSTI2024

Steroid responsiveness in alcohol-associated hepatitis is linked to glucocorticoid metabolism, mitochondrial repair, and heat shock proteins

Alcohol-associated hepatitis (AH) is one of the clinical presentations of alcohol-associated liver disease. AH has poor prognosis, and corticosteroids remain the mainstay of drug therapy. However, ~40% of patients do not respond to this treatment, and the mechanisms underlying the altered response to corticosteroids are not understood. The current study aimed to identify changes in hepatic protein expression associated with responsiveness to corticosteroids and prognosis in patients with AH. Patients with AH were enrolled based on the National Institute on Alcohol Abuse and Alcoholism inclusion criteria for acute AH and further confirmed by a diagnostic liver biopsy. Proteomic analysis was conducted on liver samples acquired from patients with AH grouped as nonresponders (AH-NR, n = 7) and responders (AH-R, n = 14) to corticosteroids, and nonalcohol-associated liver disease controls (n = 10). The definition of responders was based on the clinical prognostic model, the Lille Score, where a score < 0.45 classified patients as AH-R and a score > 0.45 as AH-NR. Primary outcomes used to assess steroid response were Lille Score (eg, improved liver function) and survival at 24 weeks. Reduced levels of the glucocorticoid receptor and its transcriptional co-activator, glucocorticoid modulatory element-binding protein 2, were observed in the hepatic proteome of AH-NR versus AH-R. The corticosteroid metabolizing enzyme, 11-beta-hydroxysteroid dehydrogenase 1, was increased in AH-NR versus AH-R along with elevated mitochondrial DNA repair enzymes, while several proteins of the heat shock pathway were reduced. Analysis of differentially expressed proteins in AH-NR who survived 24 weeks relative to AH-NR nonsurvivors revealed several protein expression changes, including increased levels of acute phase proteins, elevated coagulation factors, and reduced mast cell markers. This study identified hepatic proteomic changes that may predict responsiveness to corticosteroids and mortality in patients with AH.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Microcystin-LR aerosol induces inflammatory responses in healthy human primary airway epithelium

Harmful algal blooms plague bodies of freshwater globally. These blooms are often composed of outgrowths of cyanobacteria capable of producing the heptapeptide Microcystin-LR (MC-LR) which is a well-known hepatotoxin. Recently, MC-LR has been detected in aerosols generated from lake water. However, the risk for human health effects due to MC-LR inhalation exposure have not been extensively investigated. In this study, we exposed a fully differentiated 3D human airway epithelium derived from 14 healthy donors to MC-LR-containing aerosol for 3 minutes per day for 3 days. Concentrations of MC-LR ranged from 100 pM to 1 µM. Although there were little to no detrimental alterations in measures of the airway epithelial function (i.e. cell survival, tissue integrity, mucociliary clearance, or cilia beating frequency), a distinct shift in the transcriptional activity was found. Genes related to inflammation were found to be upregulated such as C-C motif chemokine 5 (CCL5; log2FC = 0.56 , p = 0.02) and C-C chemokine receptor type 7 (CCR7; log2FC = 0.83, p = 0.03). Functionally, conditioned media from MC-LR exposed airway epithelium was also found to have significant chemo-attractive properties for primary human neutrophils. Additionally, increases were found in the concentration of secreted chemokine proteins in the conditioned media such as CCL1 (log2FC = 5.07 , p = 0.0001) and CCL5 (log2FC = 1.02, p = 0.046). These results suggest that MC-LR exposure to the human airway epithelium is capable of inducing an inflammatory response that may potentiate acute or chronic disease.

3D human airway epithelium↗
DOE OSTI2023

Effects of head-starting on multi-year space use and survival of an at-risk tortoise

A major challenge in the recovery of long-lived at-risk taxa like turtles is low juvenile recruitment. Head-starting—the raising of juveniles to larger sizes to improve survival—is one tool that can be used in circumstances where juvenile recruitment is limited. Due to declining populations and difficulty detecting juveniles, however, lack of knowledge of the ecology of juveniles can hinder efforts to develop and evaluate head-starting programs for many turtle species. We sought to inform recovery efforts of Mojave desert tortoises by quantifying multi-year space use and survival of head-started juveniles after release. We radio-tracked tortoises head-started under three different husbandry treatments that varied in rearing duration (from two to over six years) and whether head-starting included an indoor rearing component the first year. We compared postrelease space use and survival as a function of treatment, release size, and time since release. We found that space use, including home range size and site fidelity, varied by husbandry treatment, with smaller and younger tortoises having smaller home ranges and higher site fidelity. Additionally, home range size decreased and site fidelity increased with time since release across treatments. Tortoises with an indoor-rearing component experiencing increased risk of mortality as movement increased compared to tortoises reared solely outdoors. Nevertheless, survival did not differ among treatments or with tortoise age or size. Regardless of husbandry treatment, head-started tortoises exhibited similar space-use and survival overall. Our study provides insight into juvenile tortoise behavior and head-starting as a tool for tortoise conservation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Ensuring planetary survival: the centrality of organic carbon in balancing the multifunctional nature of soils

Not only do soils provide 98.7% of the calories consumed by humans, they also provide numerous other functions upon which planetary survivability closely depends. However, our continuously increasing focus on soils for biomass provision (food, fiber, and energy) through intensive agriculture is rapidly degrading soils and diminishing their capacity to deliver other vital functions. These tradeoffs in soil functionality – the increased provision of one function at the expense of other critical planetary functions – are the focus of this review. Here, we examine how land-use change for biomass provision has decreased the ability of soils to regulate the carbon pool and thereby contribute profoundly to climate change, to cycle the nutrients that sustain plant growth and ecosystem health, to protect the soil biodiversity upon which many other functions depend, and to cycle the Earth’s freshwater supplies. We also examine how this decreasing ability of soil to provide these other functions can be halted and reversed. Despite the complexity and the interconnectedness of soil functions, we show that soil organic carbon plays a central role and is a master indicator for soil functioning and that we require a better understanding of the factors controlling the behavior and persistence of C in soils. Given the threats facing humanity and their economies, it is imperative that we recognize that Soil Security is itself an existential challenge and that we need to increase our focus on the multiple functions of soils for long-term human welfare and survivability of the planet.

Carboncarbon sequestration↗
DOE OSTI2022

Self-powered Through-wall communication for dry cask storage monitoring

Many nuclear facilities, such as spent fuel storage dry casks and nuclear reactor pressure vessels, are entirely sealed by metal layers to prevent harmful radiation. For safety and security operations, the temperature, pressure, radiation, and humidity inside the vessel needs to be closely monitored. However, no practical technology is currently available to realize the through-wall data communication and monitoring for these vessels due to the inside harsh environment of high temperature and nuclear radiation. In this paper, an innovative self-powered wireless through-wall data communication system for the nuclear environment is presented, which demonstrates a successful solution to such challenges. The presented system is composed of four modules, i.e., energy harvester with power management circuits, ultrasound wireless communication using high-temperature piezoelectric transducers, electronic circuits for sensing and data transmission, and radiation shielding for electronics. Here, constitutive functions of each module were firstly designed and followed by the system integration. Experiments were conducted subsequently to validate the designed functions and evaluate the performance of the integrated system. Results showed that the average power of over 40 mW was harvested from the thermal flow inside the nuclear spent fuel canisters which could provide enough energy to operate the sensing and data communication systems. The gamma radiation test results showed that the thermoelectric energy harvester and ultrasound transceivers can withstand radiation dosing over 100 Mrad. Furthermore, temperature shock tests demonstrated that the entire system including the shielded electronics can survive and maintain their functionalities at temperatures as high as 195°C. Under the in-lab mocked-up high temperature conditions and radiation shielding, the proposed system is foreseen to survive and operate stably for fifty years inside a nuclear spent fuel canister, and send the frequency modulated data out of the canister for 3 s in every 10 min.

11 NUCLEAR FUEL CYCLE AND FUEL MATERIALS↗
DOE OSTI2021

Evolution of eggshell structure in relation to nesting ecology in non-avian reptiles

Amniotic eggs are multifunctional structures that enabled early tetrapods to colonize the land millions of years ago, and are now the reproductive mode of over 70% of all terrestrial amniotes. Eggshell morphology is at the core of animal survival, mediating the interactions between embryos and their environment, and has evolved into a massive diversity of forms and functions in modern reptiles. These functions are critical to embryonic survival and may serve as models for new antimicrobial and/or breathable membranes. However, we still lack critical data on the basic structural and functional properties of eggs, particularly of reptiles. Here, we first characterized egg shape, shell thickness, porosity, and mineralization of eggs from 91 reptile species using optical images, scanning electron microscopy, and micro computed tomography, and collected data on nesting ecology from the literature. We then used comparative analyses to test hypotheses on the selective pressures driving their evolution. We hypothesized that eggshell morphology has evolved to protect shells from physical damage and desiccation, and, in support, found a positive relationship between thickness and precipitation, and a negative relationship between porosity and temperature. Although mineralization varied extensively, it was not correlated with nesting ecology variables. Ancestral state reconstructions show thinning and increased porosity over evolutionary time in squamates, but the opposite in turtles and crocodilians. Egg shape, size, porosity and calcification were correlated, suggesting potential structural or developmental tradeoffs. This study provides new data and insights into the morphology and evolution of reptile eggs, and raises numerous questions for additional research.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Tree water uptake patterns across the globe

Plant water uptake from the soil is a crucial element of the global hydrological cycle and essential for vegetation drought resilience. Yet, knowledge of how the distribution of water uptake depth (WUD) varies across species, climates, and seasons is scarce relative to our knowledge of aboveground plant functions. With a global literature review, we found that average WUD varied more among biomes than plant functional types (i.e. deciduous/evergreen broadleaves and conifers), illustrating the importance of the hydroclimate, especially precipitation seasonality, on WUD. By combining records of rooting depth with WUD, we observed a consistently deeper maximum rooting depth than WUD with the largest differences in arid regions – indicating that deep taproots act as lifelines while not contributing to the majority of water uptake. The most ubiquitous observation across the literature was that woody plants switch water sources to soil layers with the highest water availability within short timescales. Hence, seasonal shifts to deep soil layers occur across the globe when shallow soils are drying out, allowing continued transpiration and hydraulic safety. While there are still significant gaps in our understanding of WUD, the consistency across global ecosystems allows integration of existing knowledge into the next generation of vegetation process models.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2021

Proton Radiotherapy to Preserve Fertility and Endocrine Function: A Translational Investigation

Photon radiation therapy (x-ray radiation therapy [XRT] and gamma-ray radiation therapy [GRT]) of tumors close to ovaries causes reproductive and endocrine sequelae due to ovarian primordial follicle depletion. Given its finite range, proton radiation therapy (PRT) can preserve ovarian function when ovaries are positioned distal to the spread-out Bragg peak (SOBP) in tumors of the abdominopelvic region. This study compared anti-Müllerian hormone (AMH) levels (a biomarker of ovarian function) and primordial follicle survival after in vivo mouse pelvic GRT versus PRT.

62 RADIOLOGY AND NUCLEAR MEDICINE↗
DOE OSTI2020

Uncovering DNA-PKcs ancient phylogeny, unique sequence motifs and insights for human disease

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a key member of the phosphatidylinositol-3 kinase-like (PIKK) family of protein kinases with critical roles in DNA-double strand break repair, transcription, metastasis, mitosis, RNA processing, and innate and adaptive immunity. The absence of DNA-PKcs from many model organisms has led to the assumption that DNA-PKcs is a vertebrate-specific PIKK. Here, we find that DNA-PKcs is widely distributed in invertebrates, fungi, plants, and protists, and that threonines 2609, 2638, and 2647 of the ABCDE cluster of phosphorylation sites are highly conserved amongst most Eukaryotes. Furthermore, we identify highly conserved amino acid sequence motifs and domains that are characteristic of DNA-PKcs relative to other PIKKs. These include residues in the Forehead domain and a novel motif we have termed YRPD, located in an α helix C-terminal to the ABCDE phosphorylation site loop. Combining sequence with biochemistry plus structural data on human DNA-PKcs unveils conserved sequence and conformational features with functional insights and implications. The defined generally progressive DNA-PKcs sequence diversification uncovers conserved functionality supported by Evolutionary Trace analysis, suggesting that for many organisms both functional sites and evolutionary pressures remain identical due to fundamental cell biology. The mining of cancer genomic data and germline mutations causing human inherited disease reveal that robust DNA-PKcs activity in tumors is detrimental to patient survival, whereas germline mutations compromising function are linked to severe immunodeficiency and neuronal degeneration. We anticipate that these collective results will enable ongoing DNA-PKcs functional analyses with biological and medical implications.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

The Association Between Baseline Hepatic or Renal Function and Clinical Outcomes for Patients With Non–Small Cell Lung Cancer Treated With a PD –1/PD– L1 Blocking Antibody Using Real–World and Trial Data

Clinical trials have demonstrated the benefit of PD-1/PD-L1 blocking antibodies for the treatment of patients with advanced non-small cell lung cancer (NSCLC) in defined patient populations that often exclude patients with moderate or severe hepatic or renal impairment. We assessed the association between overall survival (OS) and baseline organ function in patients with advanced NSCLC treated with PD-1/PD-L1 blocking antibodies in real-world data (RWD; patient-level data from electronic health records) and pooled clinical trial data submitted to the US Food and Drug Administration (FDA). The Kaplan–Meier estimator was used to estimate OS in different subgroups based on organ function. Unadjusted and adjusted Cox proportional hazards models were used to estimate the association between OS and organ function. In this hypothesis-generating study, baseline renal impairment did not appear to be associated with OS, while patients with baseline liver impairment had shorter OS. RWD provided information on a broader range of renal and hepatic function than was evaluated in clinical trials and hold promise to complement trial data in better understanding populations not represented in clinical trials.

60 APPLIED LIFE SCIENCES↗