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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 OSTI2022

CHIQUITA1 maintains the temporal transition between proliferation and differentiation in Arabidopsis thaliana

ABSTRACT Body size varies widely among species, populations and individuals, depending on the environment. Transitioning between proliferation and differentiation is a crucial determinant of final organ size, but how the timing of this transition is established and maintained remains unknown. Using cell proliferation markers and genetic analysis, we show that CHIQUITA1 (CHIQ1) is required to maintain the timing of the transition from proliferation to differentiation in Arabidopsis thaliana. Combining kinematic and cell lineage-tracking studies, we found that the number of actively dividing cells in chiquita1-1 plants decreases prematurely compared with wild-type plants, suggesting CHIQ1 maintains the proliferative capacity in dividing cells and ensures that cells divide a specific number of times. CHIQ1 belongs to a plant-specific gene family of unknown molecular function and genetically interacts with three close members of its family to control the timing of proliferation exit. Our work reveals the interdependency between cellular and organ-level processes underlying final organ size determination.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

HPRT promotes proliferation and metastasis in head and neck squamous cell carcinoma through direct interaction with STAT3

Highlights: • The higher expression of HPRT in HNSCC tissue was related to poor prognosis of patients. • Overexpression of HPRT increased the gene expression of epithelial mesenchymal transition markers. • HPRT directly interacted with STAT3. • Knocking down HPRT significantly decreased tumour growth and enhanced the anticancer effect against HNSCC xenografts. Increasing effort has been put into finding novel molecular pathways to improve the efficiency of EGFR inhibitors against head and neck squamous cell cancer (HNSCC). In this study, we performed data mining and bioinformatically analysed RNA-Seq data downloaded from TCGA and confirmed that higher expression of HPRT in HNSCC tissue was related to poor prognosis of patients. Then, we conducted in vitro and in vivo loss- and gain-of-function experiments to demonstrate the role of HPRT in HNSCC cell lines. Overexpression of HPRT increased the gene expression of epithelial mesenchymal transition markers via direct interaction with STAT3. Knocking down HPRT significantly decreased tumour growth and enhanced the anticancer effect of EGFR inhibitors against HNSCC xenografts. In conclusion, HPRT is a binding partner of STAT3 that promotes EMT and proliferation. Our findings support HPRT as a promising prognostic indicator and potential therapeutic target for HNSCC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

FTO regulates myoblast proliferation by controlling CCND1 expression in an m6A-YTHDF2-dependent manner

Highlights: • Silencing FTO delays cell cycle and inhibits cell proliferation. • FTO regulates cell proliferation depending on its m{sup 6}A demethylation activity. • Silencing FTO suppresses CCND1 expression via YTHDF2-mediated mRNA degradation. • Knockdown YTHDF2 eliminates the cell cycle arrest in FTO-deficient cells. N6-Methyladenosine (m{sup 6}A) modification is the most abundant chemical modification in mRNA, and it participates in various biological processes, such as cell differentiation and proliferation. However, little is known about the function of m{sup 6}A demethylase fat mass and obesity-associated (FTO) in myoblast proliferation. Here, we demonstrated that knockdown of FTO can significantly inhibit myoblast proliferation and promote apoptosis. RNA sequencing analysis revealed that a lot of downregulated genes in FTO knockdown cells are associated with cell cycle and apoptosis. Furthermore, silencing FTO drastically decreased cyclin D1 (CCND1) expression through YTHDF2-mediated mRNA degradation, thereby delaying the progression of G1 phase, and leading to impaired myoblast proliferation. These findings unraveled that FTO regulates myoblast proliferation by controlling CCND1 expression in an m{sup 6}A-YTHDF2-dependent manner, which highlights the critical roles of m{sup 6}A modification in myoblast proliferation.

60 APPLIED LIFE SCIENCES↗
NASA NTRS2002

Dynamics of cell proliferation in the adult dentate gyrus of two inbred strains of mice

The output potential of proliferating populations in either the developing or the adult nervous system is critically dependent on the length of the cell cycle (T(c)) and the size of the proliferating population. We developed a new approach for analyzing the cell cycle, the 'Saturate and Survive Method' (SSM), that also reveals the dynamic behaviors in the proliferative population and estimates of the size of the proliferating population. We used this method to analyze the proliferating population of the adult dentate gyrus in 60 day old mice of two inbred strains, C57BL/6J and BALB/cByJ. The results show that the number of cells labeled by exposure to BUdR changes dramatically with time as a function of the number of proliferating cells in the population, the length of the S-phase, cell division, the length of the cell cycle, dilution of the S-phase label, and cell death. The major difference between C57BL/6J and BALB/cByJ mice is the size of the proliferating population, which differs by a factor of two; the lengths of the cell cycle and the S-phase and the probability that a newly produced cell will die within the first 10 days do not differ in these two strains. This indicates that genetic regulation of the size of the proliferating population is independent of the genetic regulation of cell death among those newly produced cells. The dynamic changes in the number of labeled cells as revealed by the SSM protocol also indicate that neither single nor repeated daily injections of BUdR accurately measure 'proliferation.'.

Non-NASA Center↗
DOE OSTI2021

Protein 4.1R negatively regulates P815 cells proliferation by inhibiting C-Kit-mediated signal transduction

The proliferation of mast cells (MCs) plays a crucial role in either physiological or pathological progression of human physical. C-Kit-mediated signaling pathway has been confirmed to play a key role in MCs proliferation, and the regulatory mechanisms of C-Kit-mediated MCs proliferation need to be further explored. Our previous study found that protein 4.1R could negatively regulate T cell receptor (TCR) mediated signal pathways in CD4{sup +} T cells. Little is known about the function of 4.1R in C-Kit-mediated proliferation of MCs. In this study, P815-4.1R{sup -/-} cells were constructed by using CRISPR/Cas9 technique. Lack of 4.1R significantly enhanced P815 cells proliferation by accelerating the progression of cell cycle. 4.1R could also significantly alleviate the clinical symptoms of systemic mastocytosis (SM) and improve the overall survival of SM mice. Further study showed that 4.1R could interact directly with C-Kit to inhibit the activation of C-Kit-mediated Ras-Raf-MAPKs and PI3K-AKT signal pathways. Taken together, our findings demonstrate that protein 4.1R, a novel negative regulator, negatively regulates MCs proliferation by inhibiting C-Kit-mediated signal transduction, which maybe provide a potential target to the prevention and treatment of abnormal MCs proliferation-related diseases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Workshop Report for Next-Gen AI for Proliferation Detection: Accelerating the Development and Use of Explainability Methods to Design AI Systems Suitable for Nonproliferation Mission Applications

Artificial intelligence (AI) promises powerful new capabilities in an expansive array of applications. One area is proliferation detection, where AI can provide transformative tools to achieve objectives currently inaccessible using conventional methods. In particular, AI affords the opportunity to use new indicators and process massive amounts of heterogeneous data that can increase sensitivity to proliferant activities and push proliferation detection to the earliest possible stages. However, existing AI tools are not ready to achieve such potential, falling short in regard to some important considerations involved in proliferation detection. One crucial aspect that requires improvement is the explainability of the most powerful AI algorithms (i.e., understanding how the algorithms actually arrive at their conclusions)-the lack of which prevents widespread adoption in national security missions. The Data Science and AI portfolio within the National Nuclear Security Administration's Office of Defense Nuclear Nonproliferation Research and Development is driving the development of next-generation AI for proliferation detection through the expertise and work of the national laboratories and partners in academia. The "Next-Gen AI for Proliferation Detection: Accelerating the Development and Use of Explainability Methods to Design AI Systems Suitable for Nonproliferation Mission Applications" workshop aimed to further this objective. The meeting was held virtually on Sept. 15-16, 2020 and included more than 170 participants, primarily from the national laboratories with additional contributions from university researchers and mission partners. Each day included a keynote presentation, four technical presentations about cutting-edge research in explainability, and a panel to explore considerations in applying explainability and developing AI systems that can accelerate the transition of emerging AI technologies among partners and end users to solve critical mission questions. This report summarizes the Next-Gen AI for Proliferation Detection workshop's content and findings.

98 NUCLEAR DISARMAMENT, SAFEGUARDS, AND PHYSICAL P↗
DOE OSTI2021

Report on Next-Gen AI for Proliferation Detection Workshop: Domain-Aware Methods

The emergence of artificial intelligence (AI) and machine learning (ML) in the modern world has impacted nearly every application imaginable. This includes nuclear proliferation detection, which offers the potential to improve existing capabilities as well as create new ones. Proliferation detection seeks to detect and characterize attempts by state and non-state actors to acquire nuclear weapons or associated technology, materials, or knowledge. Such a mission is vitally important for global stability and security but is notoriously difficult. By leveraging advances in AI, exciting opportunities exist to enhance the proliferation detection regime. The Data Science and AI portfolio within the National Nuclear Security Administration’s Office of Defense Nuclear Nonproliferation Research and Development (DNN R&D) seeks to leverage the capabilities of the Department of Energy’s (DOE’s) national laboratories and other partners to develop AI systems that can accomplish otherwise impossible tasks in support of proliferation detection. As part of its efforts, the portfolio has created a series of workshops on Next-Gen AI for Proliferation Detection to help define the requirements for suitable AI systems, share successful research and best practices, and foster connection and understanding between the relevant parties including researchers and end-users. Each workshop in the series focuses on a specific and critical aspect of AI to enable it to accomplish proliferation detection objectives. The first workshop focused on explainability techniques; the second workshop and the topic of this report, covers methods for incorporating domain awareness into AI. The Next-Gen AI for Proliferation Detection Workshop: Domain-Aware Methods took place virtually over two days in February 2021 and included four keynote presentations, 22 technical presentations, and a concluding panel. The presentations, discussions, and workshop findings are summarized in this report.

97 MATHEMATICS AND COMPUTING↗
NASA NTRS1997

Strain activation of bovine aortic smooth muscle cell proliferation and alignment: study of strain dependency and the role of protein kinase A and C signaling pathways

Smooth muscle cell (SMC) phenotype can be altered by physical forces as demonstrated by cyclic strain-induced changes in proliferation, orientation, and secretion of macromolecules. However, the magnitude of strain required and the intracellular coupling pathways remain ill defined. To examine the strain requirements for SMC proliferation, we selectively seeded bovine aortic SMC either on the center or periphery of silastic membranes which were deformed with 150 mm Hg vacuum (0-7% center; 7-24% periphery). SMC located in either the center or peripheral regions showed enhanced proliferation compared to cells grown under the absence of cyclic strain. Moreover, SMC located in the center region demonstrated significantly (P < 0.005) greater proliferation as compared to those in the periphery. In contrast, SMC exposed to high strain (7-24%) demonstrated alignment perpendicular to the strain gradient, whereas SMC in the center (0-7%) remained aligned randomly. To determine the mechanisms of these phenomena, we examined the effect of cyclic strain on bovine aortic SMC signaling pathways. We observed strain-induced stimulation of the cyclic AMP pathway including adenylate cyclase activity and cyclic AMP accumulation. In addition, exposure of SMC to cyclic strain caused a significant increase in protein kinase C (PKC) activity and enzyme translocation from the cytosol to a particulate fraction. Further study was conducted to examine the effect of strain magnitude on signaling, particularly protein kinase A (PKA) activity as well as cAMP response element (CRE) binding protein levels. We observed significantly (P < 0.05) greater PKA activity and CRE binding protein levels in SMC located in the center as compared to the peripheral region. However, inhibition of PKA (with 10 microM Rp-cAMP) or PKC (with 5-20 ng/ml staurosporine) failed to alter either the strain-induced increase in SMC proliferation or alignment. These data characterize the strain determinants for activation of SMC proliferation and alignment. Although strain activated both the AC/cAMP/PKA and the PKC pathways in SMC, singular inhibition of PKA and PKC failed to prevent strain-induced alignment and proliferation, suggesting either their lack of involvement or the multifactorial nature of these responses.

Non-NASA Center↗
DOE OSTI2021

RNA methyltransferase NSUN2 promotes hypopharyngeal squamous cell carcinoma proliferation and migration by enhancing TEAD1 expression in an m5C-dependent manner

Highlights: • NSUN2 is highly expressed in hypopharyngeal squamous cell carcinoma. • NSUN2 knockdown in vitro and in vivo decreased cell proliferation and invasion. • NSUN2 promotes tumor proliferation and invasion through TEAD1. RNA methyltransferase NSUN2 is involved in cell proliferation and invasion in a variety of tumors. However, the expression, function, and mechanism of NSUN2 in hypopharyngeal squamous cell carcinoma (HPSCC) remains unknown. We used a bioinformatics database, polymerase chain reaction, cell culture and transfection, immunohistochemistry, cell proliferation assay, wound healing experiments, transwell assays, western blotting, RNA-seq detection, dual-luciferase reporter assay, in vivo experiments, and a dot blot assay to evaluate the role of NSUN2 in HPSCC. NSUN2 mRNA and protein were highly expressed in HPSCC; NSUN2 knockdown in vitro and in vivo decreased cell proliferation and invasion. Studies have shown that TEAD1, a transcription factor, may act downstream of NSUN2 in HPSCC. NSUN2 was found to promote the proliferation and invasion of HPSCC by upregulating TEAD1 in an 5-methylcytosine-dependent manner, thereby representing an oncogene and potential new target for treating HPSCC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Potential applications of microbial genomics in nuclear non-proliferation

As nuclear technology evolves in response to increased demand for diversification and decarbonization of the energy sector, new and innovative approaches are needed to effectively identify and deter the proliferation of nuclear arms, while ensuring safe development of global nuclear energy resources. Preventing the use of nuclear material and technology for unsanctioned development of nuclear weapons has been a long-standing challenge for the International Atomic Energy Agency and signatories of the Treaty on the Non-Proliferation of Nuclear Weapons. Environmental swipe sampling has proven to be an effective technique for characterizing clandestine proliferation activities within and around known locations of nuclear facilities and sites. However, limited tools and techniques exist for detecting nuclear proliferation in unknown locations beyond the boundaries of declared nuclear fuel cycle facilities, representing a critical gap in non-proliferation safeguards. Microbiomes, defined as “characteristic communities of microorganisms” found in specific habitats with distinct physical and chemical properties, can provide valuable information about the conditions and activities occurring in the surrounding environment. Microorganisms are known to inhabit radionuclide-contaminated sites, spent nuclear fuel storage pools, and cooling systems of water-cooled nuclear reactors, where they can cause radionuclide migration and corrosion of critical structures. Microbial transformation of radionuclides is a well-established process that has been documented in numerous field and laboratory studies. These studies helped to identify key bacterial taxa and microbially-mediated processes that directly and indirectly control the transformation, mobility, and fate of radionuclides in the environment. Expanding on this work, other studies have used microbial genomics integrated with machine learning models to successfully monitor and predict the occurrence of heavy metals, radionuclides, and other process wastes in the environment, indicating the potential role of nuclear activities in shaping microbial community structure and function. Results of this previous body of work suggest fundamental geochemical-microbial interactions occurring at nuclear fuel cycle facilities could give rise to microbiomes that are characteristic of nuclear activities. These microbiomes could provide valuable information for monitoring nuclear fuel cycle facilities, planning environmental sampling campaigns, and developing biosensor technology for the detection of undisclosed fuel cycle activities and proliferation concerns.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

MSR Proliferation Resistance and Physical Protection White Paper

This document represents the status of Proliferation Resistance and Physical Protection (PR&PP) characteristics for the Molten Salt Reactor designs selected by the Generation IV International Forum (GIF) Molten Salt Reactor (MSR) provisional System Steering Committee (pSSC) as representatives of three broad classes of MSRs. The three classes of MSRs are: (1) Liquid-fueled with integrated salt processing, (2) Liquid-fueled without integrated salt processing, (3) Solid-fueled with salt coolant. The intent is to generate preliminary information about the PR&PP merits of the MSR Reactor Technology and to provide insights for optimizing their PR&PP performance for the benefit of MSR system designers. It updates the MSR analysis published in the 2011 report “Proliferation Resistance and Physical Protection of the Six Generation IV Nuclear Energy Systems”, prepared Jointly by the Proliferation Resistance and Physical Protection Working Group (PRPPWG) and the System Steering Committees of the Generation IV International Forum, taking into account the evolution of both the systems and the GIF R&D activities since its publication. The document, prepared jointly by the GIF PRPPWG and the GIF MSR pSSC, follows the high-level paradigm of the GIF Proliferation Resistance and Physical Protection Evaluation Methodology to investigate the Proliferation Resistance and Physical Protection features of the GIF MSR representative designs. For PR, the document analyses and discusses the proliferation resistance aspects in terms of robustness against State-based threats associated with diversion of materials, misuse of facilities, breakout scenarios, and production in clandestine facilities. Similarly, for physical protection, the document discusses the robustness against theft of material and sabotage by non-State actors.

22 GENERAL STUDIES OF NUCLEAR REACTORS↗
DOE OSTI2022

GIF Supercritical Water Cooled Reactor: Proliferation Resistance and Physical Protection White Paper

This report is part of a series of six white papers, prepared jointly by the Proliferation Resistance and Physical Protection Working Group (PRPPWG) and the six System Steering Committees (SSCs) and provisional System Steering Committees (pSSCs). This publication is an update to a similar series published in 2011 presenting the status of Proliferation Resistance & Physical Protection (PR&PP) characteristics for each of the six systems selected by the Generation IV International Forum (GIF) for further research and development, namely: the Sodium-cooled fast Reactor (SFR), the Very high temperature reactor (VHTR), the gas-cooled fast reactor (GFR), the Molten salt reactor (MSR) and the Supercritical water–cooled reactor (SCWR). This white paper represents the status of Proliferation Resistance and Physical Protection (PR&PP) characteristics for the Supercritical Water-cooled Fast reactor (SCFR) reference designs selected by the Generation IV International Forum (GIF) SCWR System Steering Committee (SSC). The intent is to generate preliminary information about the PR&PP features of the SCWR reactor technology and to provide insights for optimizing their PR&PP performance for the benefit of SCWR system designers. It updates the SCWR analysis published in the 2011 report “Proliferation Resistance and Physical Protection of the Six Generation IV Nuclear Energy Systems”, prepared Jointly by the Proliferation Resistance and Physical Protection Working Group (PRPPWG) and the System Steering Committees and provisional System Steering Committees of the Generation IV International Forum, taking into account the evolution of both the systems, the GIF R&D activities, and an increased understanding of the PR&PP features. The white paper, prepared jointly by the GIF PRPPWG and the GIF SCWR SSC, follows the highlevel paradigm of the GIF PR&PP Evaluation Methodology to investigate the PR&PP features of the eight proposed GIF SCWR designs. Two small modular reactors, the Canadian SSR and the Canada/China/Europe ECC-SMART are also mentioned. An overview of the fuel cycles for the GIF designs are provided. For PR, the document analyses and discusses the proliferation resistance aspects in terms of robustness against State-based threats associated with diversion of materials, misuse of facilities, breakout scenarios, and production in clandestine facilities. Similarly, for PP, the document discusses the robustness against theft of material and sabotage by non-State actors. The document follows a common template adopted by all the white papers in the updated series.

11 NUCLEAR FUEL CYCLE AND FUEL MATERIALS↗
DOE OSTI2022

GIF Very High Temperature Reactor: Proliferation Resistance and Physical Protection White Paper

This report is part of a series of six white papers, prepared jointly by the Proliferation Resistance and Physical Protection Working Group (PRPPWG) and the six System Steering Committees (SSCs) and provisional System Steering Committees (pSSCs). This publication is an update to a similar series published in 2011 presenting the status of Proliferation Resistance & Physical Protection (PR&PP) characteristics for each of the six systems selected by the Generation IV International Forum (GIF) for further research and development, namely: the Sodium-cooled fast Reactor (SFR), the Very high temperature reactor (VHTR), the gas-cooled fast reactor (GFR), the Molten salt reactor (MSR) and the Supercritical water–cooled reactor (SCWR). This white paper represents the status of Proliferation Resistance and Physical Protection (PR&PP) characteristics for the Very-High-Temperature Reactor (VHTR) reference designs selected by the Generation IV International Forum (GIF) VHTR System Steering Committee (SSC). The intent is to generate preliminary information about the PR&PP features of the VHTR reactor technology and to provide insights for optimizing their PR&PP performance for the benefit of VHTR system designers. It updates the VHTR analysis published in the 2011 report “Proliferation Resistance and Physical Protection of the Six Generation IV Nuclear Energy Systems”, prepared Jointly by the Proliferation Resistance and Physical Protection Working Group (PRPPWG) and the System Steering Committees and provisional System Steering Committees of the Generation IV International Forum, taking into account the evolution of both the systems, the GIF R&D activities, and an increased understanding of the PR&PP features. The white paper, prepared jointly by the GIF PRPPWG and the GIF VHTR SSC, follows the high-level paradigm of the GIF PR&PP Evaluation Methodology to investigate the key points of PR&PP features extracted from the reference designs of VHTRs under consideration in various countries. A major update from the 2011 report is an explicit distinction between prismatic block-type VHTRs and pebble-bed VHTRs. The white paper also provides an overview of the TRISO fuel and fuel cycle. For PR, the document analyses and discusses the proliferation resistance aspects in terms of robustness against State-based threats associated with diversion of materials, misuse of facilities, breakout scenarios, and production in clandestine facilities. Similarly, for PP, the document discusses the robustness against theft of material and sabotage by non-State actors. The document follows a common template adopted by all the white papers in the updated series.

21 SPECIFIC NUCLEAR REACTORS AND ASSOCIATED PLANTS↗
NASA NTRS2003

Hypergravity Stimulates Osteoblast Proliferation Via Matrix-Integrin-Signaling Pathways

Extensive characterizations of the physiologic consequences of microgravity and gravity indicate that lack of weight-bearing may cause tissue atrophy through cellular and subcellular level mechanisms. We hypothesize that gravity is needed for the efficient transduction of cell growth and survival signals from the extra-cellular matrix (ECM) in mechanosensitive tissues. Recent work from our laboratory and from others shows that an increase of gravity increases bone cell growth and survival. We found that 50-g hypergravity stimulation increased osteoblast proliferation for cells grown on Collagen Type I and Fibronectin, but not on Laminin or uncoated plastic. This may be a tissue-specific response, because 50-g hypergravity stimulation caused no increase in proliferation for primary rat fibroblasts. These results combined with RT-PCR for all possible integrins indicate that beta1 integrin subunit may be involved. The osteoblast proliferation response on Collagen Type I was greater at 25-g than at 10-g or 50-g; 24-h duration of hypergravity was necessary to see an increase in proliferation. Survival was enhanced during hypergravity stimulation by the presence of matrix. Flow cytometry analysis indicated that cell cycle may be altered; BrdU incorporation in proliferating cells showed an increase in the number of actively dividing cells from about 60% at 1-g to over 90% at 25-g. To further investigate the molecular components involved, we applied fluorescence labeling of cytoskeletal and signaling molecules to cells after 2 to 30 minutes of hypergravity stimulation. While structural components did not appear to be altered, phosphorylation increased, indicating that signaling pathways may be activated. These data indicate that gravity mechanostimulation of osteoblast proliferation involves specific matrix-integrin signaling pathways which are sensitive to duration and g-level.

Vercoutere, W.↗
NASA NTRS1997

Synchrony of clonal cell proliferation and contiguity of clonally related cells: production of mosaicism in the ventricular zone of developing mouse neocortex

We have analyzed clonal cell proliferation in the ventricular zone (VZ) of the early developing mouse neocortex with a replication-incompetent retrovirus encoding human placental alkaline phosphatase (AP). The retrovirus was injected into the lateral ventricles on embryonic day 11 (E11), i.e., at the onset of neuronogenesis. Three days postinjection, on E14, a total of 259 AP-labeled clones of various sizes were found in 7 fetal brains. There are approximately 7 cell cycles between E11 and E14 (), and there is a 1-2 cell cycle delay between retroviral injection and the production of a retrovirally labeled "founder" cell; thus, we estimate that the "age" of the clones was about 5-6 cell cycles. Almost one-half of the clones (48.3%) identified were pure proliferating clones containing cells only in the VZ. Another 18.5% contained both proliferating and postproliferative cells, and 33.2% contained only postproliferative cells. It was striking that over 90% of the clonally related proliferating cells occurred in clusters of two or more apparently contiguous cells, and about 73% of the proliferating cells occurred in clusters of three or more cells. Regardless of the number of cells in the clone, these clusters were tightly packed and confined to a single level of the VZ. This clustering of proliferating cells indicates that clonally related cells maintain neighbor-neighbor relationships as they undergo interkinetic nuclear migration and progress through several cell cycles, and, as a result, the ventricular zone is a mosaic of small clusters of clonally related and synchronously cycling cells. In addition, cells in the intermediate zone and the cortical plate were also frequently clustered, indicating that they became postproliferative at a similar time and that the output of the VZ is influenced by its mosaic structure.

NASA Discipline Neuroscience↗
DOE OSTI2021

BST-2/Tetherin is involved in BAFF-enhanced proliferation and survival via canonical NF-κB signaling in neoplastic B-lymphoid cells

Highlights: • BST-2 doze dependently responded to BAFF in neoplastic B cells. • BST-2 inhibition defected the proliferation and survival of neoplastic B cells. • BST-2 facilitated BAFF-induced NF-κB signaling in neoplastic B-lymphoid cells. • BAFF-induced NF-κB signaling is required for the proliferation and survival of neoplastic B cells. The development of Sjögren's syndrome (SS) is accompanied by B cell hyperproliferation and mutation. Our previous study identified aberrant expression of BST-2 (also known as Tetherin/CD317) in B cells from either the peripheral blood or infiltrated salivary glands. However, the roles of BST-2 in the regulation of B cell activation remain unknown. In this study, we identified that BST-2 can respond to BAFF simulation but not to other B cell simulators in neoplastic B cell lines. A CCK-8 assay, an EdU assay and Annexin V/PI staining indicated that BST-2 inhibition attenuated BAFF-enhanced proliferation and survival in both Raji cells and Daudi cells. Screening of BAFF-related signaling in neoplastic B-lymphoid cells indicated that BST-2 was involved in the regulation of NF-κB signaling upon BAFF simulation. However, inhibition of NF-κB by JSH-23 significantly reduced the proliferation and survival of Raji and Daudi cells under both normal and BAFF-simulated conditions. Collectively, our results indicate that BST-2/Tetherin is a BAFF-responsive membrane factor involved in the regulation of NF-κB signaling, thereby assisting in the proliferation and survival of neoplastic B-lymphoid cells. Our study provides a potential molecular mechanism underlying aberrant overactivation of B cells upon SS development.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Cancer/testis antigen LDHC promotes proliferation and metastasis by activating the PI3K/Akt/GSK-3β-signaling pathway and the in lung adenocarcinoma

The cancer/testis antigen lactate dehydrogenase-C4 (LDHC) is a specific isoenzyme of the LDH family that regulates invasion and metastasis in some malignancies; however, little is known regarding its role in progression of lung adenocarcinoma (LUAD). Thus, we investigated LDHC expression by immunohistochemistry, and analyzed its clinical significance in 88 LUAD specimens. The role and molecular mechanisms subserving LDHC in cellular proliferation, migration, and invasion were explored both in vitro and in vivo. As a result, we found that high LDHC expression was significantly correlated with clinicopathological features of aggressive LUAD and a poor prognosis. Overexpression of LDHC induced LUAD cells to produce lactate and ATP, increased their metastatic and invasive potential—, and accelerated xenograft tumor growth. We further demonstrated that overexpression of LDHC affected the expression of cell proliferation-related proteins (cyclin D1 and c-Myc) and epithelial-mesenchymal transition (EMT)-related proteins (MMP-2, MMP-9, E-cadherin, Vimentin, Twist, Slug, and Snail) both in vitro and in vivo. Finally, excessive activation of LDHC enhanced the phosphorylation levels of AKT and GSK-3β, revealing activation of the PI3K/Akt/GSK-3β oncogenic-signaling pathways. Treatment with a PI3K inhibitor reversed the effects of LDHC overexpression by inhibiting cellular proliferation, migration, and invasion, with diminished levels of p-Akt and p-GSK3β. PI3K inhibition also reversed cell proliferation-related and EMT-related proteins in LDHC-overexpressing A549 cells. In conclusion, LDHC promotes proliferation, migration, invasion, and EMT in LUAD cells via activation of the PI3K/Akt/GSK-3β pathway.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Learning Global Proliferation Expertise Evolution Using AI-Driven Analytics and Public Information

Detecting and anticipating global proliferation expertise and capability evolution from unstructured, noisy, and incomplete public data streams is a highly desired, but extremely challenging task. Here, in this article, we present our pioneering data-driven approach to support the non-proliferation mission to detect and explain the evolution of proliferation expertise and capability development globally from terabytes of publicly available information (PAI), focusing on our knowledge extraction pipeline and descriptive analytics. We first discuss how we fuse nine open-source data streams, including multilingual data, to convert 4 TB of unstructured data to structured knowledge and encode dynamically evolving proliferation expertise representations—content and context graphs. For this, we rely on natural language processing (NLP) and deep learning (DL) models to perform information extraction, topic modeling, and distributed text representation (aka embedding) learning. We then present interactive, usable, and explainable descriptive analytics to refine domain knowledge and present it in a human-understandable form. Finally, we introduce future work avenues that will leverage our dynamic knowledge representations and descriptive analytics to enable predictive and prescriptive inferences to achieve real-time domain understanding and contextual reasoning about global proliferation expertise and capability evolution.

98 NUCLEAR DISARMAMENT, SAFEGUARDS, AND PHYSICAL P↗