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All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Unveiling the Occupational Exposure to Microbial Contamination in Conservation–Restoration Settings

Assuring a proper environment for the fulfillment of professional activities is one of the Sustainable Development Goals and is contemplated in the One Health approach assumed by the World Health Organization. This particular study is applied to an often neglected sector of our society—the conservators/restorers—despite the many health issues reported by these professionals. Three different specialties (textiles, paintings and wood sculpture) and locations were selected for evaluation by placement of electrostatic dust cloths. After treatment of the samples, bacterial and fungal contamination were assessed, as well as mycotoxin determination, the presence of azole-resistant strains and cytotoxicity of the microorganisms encountered. Bacteria were only present in one of medias used and showed relatively low numbers. The highest level of contamination by fungi was identified in one of the textiles settings. The textile area also showed the highest variability for fungi. Aspergillus sp. are one indicator of possible environmental issues, and A. sections Fumigati and Circumdati were particularly relevant in two of the settings and identified in all of them. No mycotoxins were detected and the large majority of the fungi identified were non-cytotoxic. Overall, these can be considered low-contaminated environments but attention should be given to the Aspergillus sp. contamination. Additional studies are needed not only to make these results more robust, but also to test if the environmental sampling alone is the best approach in a setting where there is very little movement and dust displacement and where professionals are in very close proximity to the artefacts being treated, which may suggest the existence of a micro-atmosphere worth evaluating and comparing to the obtained results.

Viegas, Carla (ORCID:0000000215456479)↗
DOE OSTI2024

Therapeutic efficacy of a potent anti-Venezuelan equine encephalitis virus antibody is contingent on Fc effector function

The development of specific, safe, and potent monoclonal antibodies (Abs) has led to novel therapeutic options for infectious disease. In addition to preventing viral infection through neutralization, Abs can clear infected cells and induce immunomodulatory functions through engagement of their crystallizable fragment (Fc) with complement proteins and Fc receptors on immune cells. Little is known about the role of Fc effector functions of neutralizing Abs in the context of encephalitic alphavirus infection. To determine the role of Fc effector function in therapeutic efficacy against Venezuelan equine encephalitis virus (VEEV), we compared the potently neutralizing anti-VEEV human IgG F5 (hF5) Ab with intact Fc function (hF5-WT) or containing the loss of function Fc mutations L234A and L235A (hF5-LALA) in the context of VEEV infection. We observed significantly reduced binding to complement and Fc receptors, as well as differential in vitro kinetics of Fc-mediated cytotoxicity for hF5-LALA compared to hF5-WT. The in vivo efficacy of hF5-LALA was comparable to hF5-WT at -24 and + 24 h post infection, with both Abs providing high levels of protection. However, when hF5-WT and hF5-LALA were administered + 48 h post infection, there was a significant decrease in the therapeutic efficacy of hF5-LALA. Together these results demonstrate that optimal therapeutic Ab treatment of VEEV, and possibly other encephalitic alphaviruses, requires neutralization paired with engagement of immune effectors via the Fc region.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Dendritic cells focus CTL responses toward highly conserved and topologically important HIV-1 epitopes

During early HIV-1 infection, immunodominant T cell responses to highly variable epitopes lead to the establishment of immune escape virus variants. Here we assessed a type 1-polarized monocyte-derived dendritic cell (MDC1)-based approach to selectively elicit cytotoxic T lymphocyte (CTL) responses against highly conserved and topologically important HIV-1 epitopes in HIV-1-infected individuals from the Thailand RV254/SEARCH 010 cohort who initiated antiretroviral therapy (ART) during early infection (Fiebig stages I-IV). Autologous MDC1 were used as antigen presenting cells to induce in vitro CTL responses against HIV-1 Gag, Pol, Env, and Nef as determined by flow cytometry and ELISpot assay. Ultra-conserved or topologically important antigens were respectively identified using the Epigraph tool and a structure-based network analysis approach and compared to overlapping peptides spanning the Gag proteome. MDC1 presenting either the overlapping Gag, Epigraph, or Network 14-21mer peptide pools consistently activated and expanded HIV-1-specific T cells to epitopes identified at the 9-13mer peptide level. Interestingly, some CTL responses occurred outside known or expected HLA associations, providing evidence of new HLA-associated CTL epitopes. Comparative analyses demonstrated more sequence conservation among Epigraph antigens but a higher magnitude of CTL responses to Network and Gag peptide groups. Importantly, CTL responses against topologically constrained Gag epitopes contained in both the Network and Gag peptide pools were selectively enhanced in the Network pool-initiated cultures. Our study supports the use of MDC1 as a therapeutic strategy to induce and focus CTL responses toward putative fitness-constrained regions of HIV-1 to prevent immune escape and control HIV-1 infection.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Molecular basis of differential HLA class I-restricted T cell recognition of a highly networked HIV peptide

Cytotoxic-T-lymphocyte (CTL) mediated control of HIV-1 is enhanced by targeting highly networked epitopes in complex with human-leukocyte-antigen-class-I (HLA-I). However, the extent to which the presenting HLA allele contributes to this process is unknown. Here we examine the CTL response to QW9, a highly networked epitope presented by the disease-protective HLA-B57 and disease-neutral HLA-B53. Despite robust targeting of QW9 in persons expressing either allele, T cell receptor (TCR) cross-recognition of the naturally occurring variant QW9_S3T is consistently reduced when presented by HLA-B53 but not by HLA-B57. Crystal structures show substantial conformational changes from QW9-HLA to QW9_S3T-HLA by both alleles. The TCR-QW9-B53 ternary complex structure manifests how the QW9-B53 can elicit effective CTLs and suggests sterically hindered cross-recognition by QW9_S3T-B53. We observe populations of cross-reactive TCRs for B57, but not B53 and also find greater peptide-HLA stability for B57 in comparison to B53. These data demonstrate differential impacts of HLAs on TCR cross-recognition and antigen presentation of a naturally arising variant, with important implications for vaccine design.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Human NCR3 gene variants rs2736191 and rs11575837 alter longitudinal risk for development of pediatric malaria episodes and severe malarial anemia

Background: Plasmodium falciparum malaria is a leading cause of pediatric morbidity and mortality in holoendemic transmission areas. Severe malarial anemia [SMA, hemoglobin (Hb) < 5.0 g/dL in children] is the most common clinical manifestation of severe malaria in such regions. Although innate immune response genes are known to influence the development of SMA, the role of natural killer (NK) cells in malaria pathogenesis remains largely undefined. As such, we examined the impact of genetic variation in the gene encoding a primary NK cell receptor, natural cytotoxicity-triggering receptor 3 (NCR3), on the occurrence of malaria and SMA episodes over time. Methods: Susceptibility to malaria, SMA, and all-cause mortality was determined in carriers of NCR3 genetic variants (i.e., rs2736191:C > G and rs11575837:C > T) and their haplotypes. The prospective observational study was conducted over a 36 mos. follow-up period in a cohort of children (n = 1,515, aged 1.9–40 mos.) residing in a holoendemic P. falciparum transmission region, Siaya, Kenya. Results: Poisson regression modeling, controlling for anemia-promoting covariates, revealed a significantly increased risk of malaria in carriers of the homozygous mutant allele genotype (TT) for rs11575837 after multiple test correction [Incidence rate ratio (IRR) = 1.540, 95% CI = 1.114–2.129, P = 0.009]. Increased risk of SMA was observed for rs2736191 in children who inherited the CG genotype (IRR = 1.269, 95% CI = 1.009–1.597, P = 0.041) and in the additive model (presence of 1 or 2 copies) (IRR = 1.198, 95% CI = 1.030–1.393, P = 0.019), but was not significant after multiple test correction. Modeling of the haplotypes revealed that the CC haplotype had a significant additive effect for protection against SMA (i.e., reduced risk for development of SMA) after multiple test correction (IRR = 0.823, 95% CI = 0.711–0.952, P = 0.009). Although increased susceptibility to SMA was present in carriers of the GC haplotype (IRR = 1.276, 95% CI = 1.030–1.581, P = 0.026) with an additive effect (IRR = 1.182, 95% CI = 1.018–1.372, P = 0.029), the results did not remain significant after multiple test correction. None of the NCR3 genotypes or haplotypes were associated with all-cause mortality. Conclusions: Variation in NCR3 alters susceptibility to malaria and SMA during the acquisition of naturally-acquired malarial immunity. These results highlight the importance of NK cells in the innate immune response to malaria.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Wood combustion nanoparticles emitted by conventional and advanced technology cordwood boilers, and their interactions in vitro with human lung epithelial monolayers

Biomass-burning boilers and stoves are widely used in many parts of the world, producing combustion emissions linked with health risks. Here, combustion emission nanoparticles (NPs) were collected from four representative wood burning boilers using oak cordwood at specific times in the burn cycle. The morphology and composition of the NPs was characterized using transmission electron microscopy and energy dispersive X-ray analysis. To determine the degree of NP cytotoxicity with human lung tissue, the combustion NPs were introduced to incubated lung bronchial epithelial monolayers (NCI-H292) in vitro at doses of 0.1×10 -6 and 3.0×10 -6 kg/L for 2 and 4 h. Histochemical analysis showed that cell death increased by a factor of 3.5 for both doses after 4 h when compared to the control. Ultrapure NPs prepared by wet chemical methods were also introduced to the epithelial lung cells for similar doses and exposure times and the cultures exhibited significantly reduced mortality. Electron microscopy was used to study the mechanism of cell mortality for the synthesized and combustion-based NPs by examining how the NP byproducts interacted with individual cell organelles. It was found that cell survival was strongly correlated with the absence of contaminants (salts, heavy metals, poly aromatic hydrocarbons) associated with the NPs entering the cells. Synthesized NPs consisting of pure carbon were relatively well tolerated and could be excreted without damaging the cell ultrastructure. Thus, careful removal of extraneous contaminants by controlling the burn cycle with a catalyst is essential to minimize the health and environmental effects of wood biofuel combustion. In better words, optimized advanced technology wood-burning boilers and stoves can provide a CO 2 -neutral energy source and significantly contribute to a future where fossil fuels have a reduced role.

32 ENERGY CONSERVATION, CONSUMPTION, AND UTILIZATI↗
DOE OSTI2022

Microbial Metabolite 3-Indolepropionic Acid Mediates Immunosuppression

The microbial-derived metabolite, 3-indolepropionic acid (3-IPA), has been intensely studied since its origins were discovered in 2009; however, 3-IPA’s role in immunosuppression has had limited attention. Untargeted metabolomic analyses of T-cell exhaustion and immunosuppression, represented by dysfunctional under-responsive CD8+ T cells, reveal a potential role of 3-IPA in these responses. T-cell exhaustion was examined via infection of two genetically related mouse strains, DBA/1J and DBA/2J, with lymphocytic choriomeningitis virus (LCMV) Clone 13 (Cl13). The different mouse strains produced disparate outcomes driven by their T-cell responses. Infected DBA/2J presented with exhausted T cells and persistent infection, and DBA/1J mice died one week after infection from cytotoxic T lymphocytes (CTLs)-mediated pulmonary failure. Metabolomics revealed over 70 metabolites were altered between the DBA/1J and DBA/2J models over the course of the infection, most of them in mice with a fatal outcome. Cognitive-driven prioritization combined with statistical significance and fold change were used to prioritize the metabolites. 3-IPA, a tryptophan-derived metabolite, was identified as a high-priority candidate for testing. To test its activity 3-IPA was added to the drinking water of the mouse models during LCMV Cl13 infection, with the results showing that 3-IPA allowed the mice to survive longer. This negative immune-modulation effect might be of interest for the modulation of CTL responses in events such as autoimmune diseases, type I diabetes or even COVID-19. Moreover, 3-IPA’s bacterial origin raises the possibility of targeting the microbiome to enhance CTL responses in diseases such as cancer and chronic infection.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Potent Antiviral Activity against HSV-1 and SARS-CoV-2 by Antimicrobial Peptoids

Viral infections, such as those caused by Herpes Simplex Virus-1 (HSV-1) and SARS-CoV-2, affect millions of people each year. However, there are few antiviral drugs that can effectively treat these infections. The standard approach in the development of antiviral drugs involves the identification of a unique viral target, followed by the design of an agent that addresses that target. Antimicrobial peptides (AMPs) represent a novel source of potential antiviral drugs. AMPs have been shown to inactivate numerous different enveloped viruses through the disruption of their viral envelopes. However, the clinical development of AMPs as antimicrobial therapeutics has been hampered by a number of factors, especially their enzymatically labile structure as peptides. We have examined the antiviral potential of peptoid mimics of AMPs (sequence-specific N-substituted glycine oligomers). These peptoids have the distinct advantage of being insensitive to proteases, and also exhibit increased bioavailability and stability. Our results demonstrate that several peptoids exhibit potent in vitro antiviral activity against both HSV-1 and SARS-CoV-2 when incubated prior to infection. In other words, they have a direct effect on the viral structure, which appears to render the viral particles non-infective. Visualization by cryo-EM shows viral envelope disruption similar to what has been observed with AMP activity against other viruses. Furthermore, we observed no cytotoxicity against primary cultures of oral epithelial cells. These results suggest a common or biomimetic mechanism, possibly due to the differences between the phospholipid head group makeup of viral envelopes and host cell membranes, thus underscoring the potential of this class of molecules as safe and effective broad-spectrum antiviral agents. We discuss how and why differing molecular features between 10 peptoid candidates may affect both antiviral activity and selectivity.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Piperidine CD4-Mimetic Compounds Expose Vulnerable Env Epitopes Sensitizing HIV-1-Infected Cells to ADCC

The ability of the HIV-1 accessory proteins Nef and Vpu to decrease CD4 levels contributes to the protection of infected cells from antibody-dependent cellular cytotoxicity (ADCC) by preventing the exposure of Env vulnerable epitopes. Small-molecule CD4 mimetics (CD4mc) based on the indane and piperidine scaffolds such as (+)-BNM-III-170 and (S)-MCG-IV-210 sensitize HIV-1-infected cells to ADCC by exposing CD4-induced (CD4i) epitopes recognized by non-neutralizing antibodies that are abundantly present in plasma from people living with HIV. Here, we characterize a new family of CD4mc, (S)-MCG-IV-210 derivatives, based on the piperidine scaffold which engages the gp120 within the Phe43 cavity by targeting the highly conserved Asp 368 Env residue. We utilized structure-based approaches and developed a series of piperidine analogs with improved activity to inhibit the infection of difficult-to-neutralize tier-2 viruses and sensitize infected cells to ADCC mediated by HIV+ plasma. Moreover, the new analogs formed an H-bond with the α-carboxylic acid group of Asp 368 , opening a new avenue to enlarge the breadth of this family of anti-Env small molecules. Overall, the new structural and biological attributes of these molecules make them good candidates for strategies aimed at the elimination of HIV-1-infected cells.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

A Synthetic Hydrogel Composite with the Mechanical Behavior and Durability of Cartilage

Here, we report the first hydrogel with the strength and modulus of cartilage in both tension and compression, and the first to exhibit cartilage-equivalent tensile fatigue strength at 100 000 cycles. These properties are achieved by infiltrating a bacterial cellulose (BC) nanofiber network with a poly(vinyl alcohol) (PVA)–poly(2-acrylamido-2-methyl-1-propanesulfonic acid sodium salt) (PAMPS) double network hydrogel. The BC provides tensile strength in a manner analogous to collagen in cartilage, while the PAMPS provides a fixed negative charge and osmotic restoring force similar to the role of aggrecan in cartilage. The hydrogel has the same aggregate modulus and permeability as cartilage, resulting in the same time-dependent deformation under confined compression. The hydrogel is not cytotoxic, has a coefficient of friction 45% lower than cartilage, and is 4.4 times more wear-resistant than a PVA hydrogel. The properties of this hydrogel make it an excellent candidate material for replacement of damaged cartilage.

36 MATERIALS SCIENCE↗
DOE OSTI2020

3D Hybrid Nanofiber Aerogels Combining with Nanoparticles Made of a Biocleavable and Targeting Polycation and MiR‐26a for Bone Repair

Abstract The healing of large bone defects represents a clinical challenge, often requiring some form of grafting. 3D nanofiber aerogels could be a promising bone graft due to their biomimetic morphology and controlled porous structures and composition. miR‐26a has been reported to induce the differentiation of bone marrow‐derived mesenchymal stem cells (BMSCs) and facilitate bone formation. Introducing miR‐26a with a suitable polymeric vector targeting BMSCs could improve and enhance the functions of 3D nanofiber aerogels for bone regeneration. Herein, the comb‐shaped polycation (HA–SS–PGEA) is first developed, carrying a targeting component, biocleavable groups, and short ethanolamine (EA)‐decorated poly(glycidyl methacrylate) (PGMA) (abbreviated as PGEA) arms as miR‐26a delivery vector. Thereafter, the cytotoxicity and transfection efficiency of this polycation and cellular response to miR‐26a‐incorporated nanoparticles (NPs) are assessed in vitro. HA–SS–PGEA exhibits a stronger ability to transport miR‐26a and exert its functions than the gold standard polyethyleneimine (PEI) and low‐molecular‐weight linear PGEA. The efficacy of HA–SS–PGEA/miR‐26a NPs loaded 3D hybrid nanofiber aerogels showing a positive effect on the cranial bone defect healing is finally examined. Together, the combination of 3D nanofiber aerogels and functional NPs consisting of a biodegradable and targeting polycation and therapeutic miRNA could be a promising approach for bone regeneration.

Li, Ruiquan↗
DOE OSTI2021

Codelivery of Paclitaxel and Parthenolide in Discoidal Bicelles for a Synergistic Anticancer Effect: Structure Matters

Nanotechnology has long been used to improve the tumor targeting of chemotherapeutics. The structure of these nanocarriers greatly affects their efficacy and toxicity. Herein, structurally stable nanodiscoidal phospholipid bicelles, which are capable of encapsulating anticancer drugs, paclitaxel (PTX) and parthenolide (PTL), are designed. This nanodiscoidal bicelle structure is shown previously to exhibit longer blood circulation, deeper tumor penetration, and increased tumor cell uptake compared with spherical particles of similar compositions. Structural characterization and loading capacity of the PTX‐ and PTL‐ loaded nanodiscs are conducted along with an investigation into the cytotoxicity of the bicelles based on the drug‐to‐lipid ratios of both drugs loaded separately and in combination. A significant synergistic effect between both loaded drugs is also observed in A549 lung cancer and drug‐resistant MDA‐MB‐231 cell lines. An in vivo study using mice bearing subcutaneous A549 tumors shows a long circulation time of the intravenously injected DiR‐loaded bicelles and significant antitumor efficacy of the PTX‐ and PTL‐loaded bicelles. This efficacious self‐assembled nanoparticle system displays great potential as a nanoplatform to codeliver multiple therapeutics or diagnostics for improving cancer therapy.

Rad, Armin Tahmasbi↗
DOE OSTI2022

Determination of the Structures of Lignin Subunits and Nanoparticles in Solution by Small‐Angle Neutron Scattering: Towards Improving Lignin Valorization

Abstract Lignin nanoparticles (LNPs) are usually produced from lignin solution through supersaturation. The structure of the lignin in solution is still poorly understood due to structural variability of isolated lignins. Here, lignins were extracted from different plants to establish a general pattern of their structure in several lignin solvents. Lignin molecules (lignin subunits) and larger aggregates were observed in dimethyl sulfoxide (DMSO), ethylene glycol (EG) and 0.1 N NaOD solutions by small‐angle neutron scattering (SANS). It was proposed that the aggregates were composed of lignin subunits with a higher molecular weight and a higher ratio of the aliphatic to phenolic hydroxyl groups. The size, shape, and compactness are important factors that affect the uses of the LNPs, which were obtained from the SANS data for the first time. A discrepancy in the radius between SANS and DLS was discovered, pointing to a large hydration shell around the LNPs in aqueous solutions. The cytotoxicity of the corncob lignin, kraft lignin, and their LNPs were measured and compared.

Zhang, Xin↗
DOE OSTI2019

Synthesis of dehydro-α-lapachones, α- and β-lapachones, and screening against cancer cell lines

14 new naphthoquinones were prepared and tested against human cancer cell lines PC-3 (prostate), HCT-116 (colon carcinoma), SNB-19 (glioblastoma), HL-60 (leukemia) and MCF-7 (breast), and a nontumor cell line L929 (murine fibroblasts) to determine cytotoxicity with the MTT assay. 8-OH-β-lapachones (14a, 14c, 14d) presented best results, showing low IC{sub 50} values and high selectivity for HCT-116 and HL-60 tumor cells.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Synthesis of novel benzimidazole–oxadiazole derivatives as potent anticancer activity

DNA topoisomerase I regulates DNA topological structure in many cellular metabolic processes and is a validated target for the development of antitumor agents. In this work, a series of novel 2-[(5-(4-(5(6)-substituted-1H-benzimidazol-2-yl)phenyl)-1,3,4-oxadiazol-2-yl)thio]-1-(4-substitutedphenyl)ethan-1-ones (4a–4s) derivatives have been synthesized and evaluated for DNA Topo I inhibition and cytotoxicity. The structures of the compounds (4a–4s) were confirmed by IR, {sup 1}H-NMR, {sup 13}C-NMR, 2D NMR, and mass spectroscopy. Anticancer activity of these compounds was assessed against two different human cancer cell lines A549 (human lung adenocarcinoma) and HepG2 (human liver cancer cell line), as well as normal mouse embryonic fibroblast cells (NIH3T3). IC{sub 50} values of compounds 4a, 4c, and 4f were highest than those exhibited for the reference drug cisplatin. Then, the inhibitory effect of 4a, 4c, and 4f compounds on topoisomerase I enzyme with the relaxation assay was investigated on supercoiled DNA using agarose gel electrophoresis. The Annexin V-FITC assay demonstrated that these compounds induce cell death by apoptosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

Structural characterization and biological activity of an α-glucan from the mollusk Marcia hiantina (Lamarck, 1818)

Marcia hiantina (Mollusca, Bivalvia) (Lamarck, 1818), is an edible clam mainly distributed along the tropical coastal regions. Recent researches have demonstrated that clams can possess compounds, including polysaccharides, with a wide range of biological actions including antioxidant, immunomodulatory and antitumor activities. Here an α-glucan was isolated from M. hiantina by hot water, purified by anion exchange chromatography, and its structure was characterized by a combination of multiple nuclear magnetic resonance (NMR) methods (1D 1 H, 1 H- 1 H COSY, 1 H- 1 H TOCSY, 1 H- 1 H NOESY, 1 H- 13 C HSQC and 1 H- 13 C HSQC-NOESY spectra), gas chromatography-mass spectrometry, and high performance size exclusion chromatography (HPSEC). The analysis from NMR, monosaccharide composition, methylation analyses and HPSEC combined with multi angle light scattering (MALS) of M. hiantina-derived α-glycan confirmed a branched polysaccharide exclusively composed of glucose (Glc), mostly 4-linked in its backbone, branched occasionally at 6-positions, and having a molecular weight of ~ 570 kDa. The mollusk α-glucan was subjected to four cell-based assays: (i) viability of three cell lines (RAW264.7, HaCaT, and HT-29), (ii) activity on lipopolysaccharide (LPS)-induced prostaglandin production in RAW264.7 cells, (iii) inhibitory activities of in H 2 O 2 - and LPS-induced reactive oxygen species (ROS) production in HMC3 cells, and (iv) HaCaT cell proliferation. Furthermore, results have indicated no cytotoxicity, potent inhibition of both H 2 O 2 - and LPS-induced ROS, and potent cell proliferative activity.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Multiple pathways mediate chloroplast singlet oxygen stress signaling

Chloroplasts can respond to stress and changes in the environment by producing reactive oxygen species (ROS). Aside from being cytotoxic, ROS also have signaling capabilities. For example, the ROS singlet oxygen ( 1 O 2 ) can initiate nuclear gene expression, chloroplast degradation, and cell death. Here to unveil the signaling mechanisms involved, researchers have used several 1 O 2 -producing Arabidopsis thaliana mutants as genetic model systems, including plastid ferrochelatase two (fc2), fluorescent in blue light (flu), chlorina 1 (ch1), and accelerated cell death 2 (acd2). Here, we compare these 1 O 2 -producing mutants to elucidate if they utilize one or more signaling pathways to control cell death and nuclear gene expression. Using publicly available transcriptomic data, we demonstrate fc2, flu, and ch1 share a core response to 1 O 2 accumulation, but maintain unique responses, potentially tailored to respond to their specific stresses. Subsequently, we used a genetic approach to determine if these mutants share 1 O 2 signaling pathways by testing the ability of genetic suppressors of one 1 O 2 producing mutant to suppress signaling in a different 1 O 2 producing mutant. Our genetic analyses revealed at least two different chloroplast 1 O 2 signaling pathways control cellular degradation: one specific to the flu mutant and one shared by fc2, ch1, and acd2 mutants, but with life-stage-specific (seedling vs. adult) features. Overall, this work reveals chloroplast stress signaling involving 1 O 2 is complex and may allow cells to finely tune their physiology to environmental inputs.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

Cancer Treatment-Associated Pericardial Disease: Epidemiology, Clinical Presentation, Diagnosis, and Management

Purpose of Review: Cancer therapeutics have seen tremendous growth in the last decade and have been effective in the treatment of several cancer types. However, with advanced therapies like kinase inhibitors and immunotherapies, there have been unintended consequences of cardiotoxicities. While traditional chemotherapy and radiation-induced cardiotoxicity have been well studied, further research is needed to understand the adverse effects of newer regimens. Recent Findings: Both immune-mediated and non-immune-medicated cytotoxicity have been noted with targeted therapies such as tyrosine kinase inhibitors and immune checkpoint inhibitors. In this manuscript, we describe the pericardial syndromes associated with cancer therapies and propose management strategies. Pericardial effusion and pericarditis are common presentations in cancer patients and often difficult to diagnose. Concomitant myocarditis may also present with pericardial toxicity, especially with immunotherapies. In addition to proper history and physical, additional testing such as cardiovascular imaging and tissue histology need to be obtained as appropriate. Holding the offending oncology drug, and institution of anti-inflammatory medications, and immunosuppressants such as steroids are indicated. Summary: A high index of suspicion, use of standardized definitions, and comprehensive evaluation are needed for early identification, appropriate treatment, and better outcomes for patients with cancer treatment-associated pericardial disease. Further research is needed to understand the pathophysiology and to evaluate how the management of pericardial conditions in these patients differ from traditional management and also evaluate new therapies.

62 RADIOLOGY AND NUCLEAR MEDICINE↗