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At least 199 records · Page 11
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Cadherin 11 Promotes Immunosuppression and Extracellular Matrix Deposition to Support Growth of Pancreatic Tumors and Resistance to Gemcitabine in Mice

Pancreatic ductal adenocarcinomas (PDACs) are characterized by fibrosis and an abundance of cancer-associated fibroblasts (CAFs). Here, we investigated strategies to disrupt interactions among CAFs, the immune system, and cancer cells, focusing on adhesion molecule CDH11, which has been associated with other fibrotic disorders and is expressed by activated fibroblasts. We compared levels of CDH11 messenger RNA in human pancreatitis and pancreatic cancer tissues and cells with normal pancreas, and measured levels of CDH11 protein in human and mouse pancreatic lesions and normal tissues. We crossed p48-Cre;LSL-Kras G12D/+ ;LSL-Trp53 R172H/+ (KPC) mice with CDH11-knockout mice and measured survival times of offspring. Pancreata were collected and analyzed by histology, immunohistochemistry, and (single-cell) RNA sequencing; RNA and proteins were identified by imaging mass cytometry. Some mice were given injections of PD1 antibody or gemcitabine and survival was monitored. Pancreatic cancer cells from KPC mice were subcutaneously injected into Cdh11 +/+ and Cdh11 –/– mice and tumor growth was monitored. Pancreatic cancer cells (mT3) from KPC mice (C57BL/6), were subcutaneously injected into Cdh11 +/+ (C57BL/6J) mice and mice were given injections of antibody against CDH11, gemcitabine, or small molecule inhibitor of CDH11 (SD133) and tumor growth was monitored. Levels of CDH11 messenger RNA and protein were significantly higher in CAFs than in pancreatic cancer epithelial cells, human or mouse pancreatic cancer cell lines, or immune cells. KPC/Cdh11 +/– and KPC/Cdh11 –/– mice survived significantly longer than KPC/Cdh11 +/+ mice. Markers of stromal activation entirely surrounded pancreatic intraepithelial neoplasias in KPC/Cdh11 +/+ mice and incompletely in KPC/Cdh11 +/– and KPC/Cdh11 –/– mice, whose lesions also contained fewer FOXP3 + cells in the tumor center. Compared with pancreatic tumors in KPC/Cdh11 +/+ mice, tumors of KPC/Cdh11 +/– mice had increased markers of antigen processing and presentation; more lymphocytes and associated cytokines; decreased extracellular matrix components; and reductions in markers and cytokines associated with immunosuppression. Administration of the PD1 antibody did not prolong survival of KPC mice with 0, 1, or 2 alleles of Cdh11. Gemcitabine extended survival of KPC/Cdh11 +/– and KPC/Cdh11 –/– mice only or reduced subcutaneous tumor growth in mT3 engrafted Cdh11 +/+ mice when given in combination with the CDH11 antibody. A small molecule inhibitor of CDH11 reduced growth of pre-established mT3 subcutaneous tumors only if T and B cells were present in mice. Knockout or inhibition of CDH11, which is expressed by CAFs in the pancreatic tumor stroma, reduces growth of pancreatic tumors, increases their response to gemcitabine, and significantly extends survival of mice. CDH11 promotes immunosuppression and extracellular matrix deposition, and might be developed as a therapeutic target for pancreatic cancer.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Efficacy of a Short-Term Captive Broodstock Program Compared with Hatchery-Origin Spring Chinook Salmon Derived from the Same Population

Abstract We examined the efficacy of a one-generation (five brood years: 1997–2001) captive broodstock program for spring Chinook Salmon Oncorhynchus tshawytscha by comparing survival rates of captive broodstock progeny (CBP; F2) with that of hatchery-origin fish (HOR) from a conservation hatchery supplementation program in which both groups were derived from the Tucannon River (Washington State) population for the 2000–2006 brood years. Survival rates compared were egg to fry, fry to smolt, egg to smolt, total (ages 3–5) and adult (ages 4+) smolt-to-adult-return (SAR) survival, and total (ages 3–5) and adult (ages 4+) progeny-to-parent (P:P) ratio. Total escapement and adult P:P ratios were also examined to determine if observed demographic benefits to the population continued after the captive broodstock program ended. The CBP group had lower within-hatchery survival than the HOR group, with significant differences in survival at the egg-to-fry and egg-to-smolt stages due to poor egg viability. Mean untransformed total and adult SARs for the CBP were half those of the HOR group; however, SARs did not differ significantly. The CBP also had significantly lower total and adult P:P ratios than the HOR group and were below replacement for six of the seven brood years. While the captive broodstock provided additional fish for release that would not have been available otherwise, overall the CBP performed poorly and below expectations compared with the HOR group, both within the hatchery and after release. The captive broodstock program provided a short-term demographic boost, most notable in the 2008–2010 return years, but the benefit did not carry over after the program ended.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

A Fish Out of Basin: Increased Stress Physiology and Reduced Performance of Salmon River Hatchery Chinook Salmon

Abstract Variation in rearing conditions across hatcheries and basins can affect the performance of hatchery salmonids in the wild. In 2008, the Shoshone-Bannock Tribes began planning an out-of-basin hatchery facility on the eastern Snake River Plain for rearing threatened Chinook Salmon Oncorhynchus tshawytscha for release in tributaries of the upper Salmon River, Idaho, USA. To help determine the viability of the planned out-of-basin hatchery, we reared 100,000 juvenile Chinook Salmon from the same genetic stock at one in-basin (Sawtooth Fish Hatchery on the Salmon River) and one out-of-basin (Springfield Fish Hatchery on the Snake River Plain) site in Idaho that are characterized by significant differences in water hardness and temperature regime. In October 2018 and April 2019, we tested whether fish condition, stress physiology, acute mortality, and downstream survival differed between the two groups at the parr and smolt life stages upon release in the Yankee Fork Salmon River, which is characterized by low water hardness. For both release groups, parr experienced low acute mortality during the 48 h after release; however, the out-of-basin group had a downstream survival rate through an unimpounded portion of the migration corridor that was an order of magnitude lower than that for the in-basin group. During the smolt release, the out-of-basin group showed signs of extreme physiological stress, acute mortality rates of 40–80%, and low survival in the unimpounded portion of the migratory corridor. The in-basin group recovered from the stress of transport and release, had no acute mortality, and survived through the unimpounded migratory corridor at a rate comparable to that of previous years’ releases. Based on the results of this comparative study, comanagers are evaluating alternatives to the proposed out-of-basin hatchery program. This case study highlights the effects of differences between rearing and release conditions on salmon physiology and survival as well as the value of conducting preliminary evaluations prior to implementing large-scale hatchery supplementation programs.

Ebel, Jonathan D.↗
DOE OSTI2024

Labile assembly of a tardigrade protein induces biostasis

Abstract Tardigrades are microscopic animals that survive desiccation by inducing biostasis. To survive drying tardigrades rely on intrinsically disordered CAHS proteins, which also function to prevent perturbations induced by drying in vitro and in heterologous systems. CAHS proteins have been shown to form gels both in vitro and in vivo, which has been speculated to be linked to their protective capacity. However, the sequence features and mechanisms underlying gel formation and the necessity of gelation for protection have not been demonstrated. Here we report a mechanism of fibrillization and gelation for CAHS D similar to that of intermediate filament assembly. We show that in vitro, gelation restricts molecular motion, immobilizing and protecting labile material from the harmful effects of drying. In vivo, we observe that CAHS D forms fibrillar networks during osmotic stress. Fibrillar networking of CAHS D improves survival of osmotically shocked cells. We observe two emergent properties associated with fibrillization; (i) prevention of cell volume change and (ii) reduction of metabolic activity during osmotic shock. We find that there is no significant correlation between maintenance of cell volume and survival, while there is a significant correlation between reduced metabolism and survival. Importantly, CAHS D's fibrillar network formation is reversible and metabolic rates return to control levels after CAHS fibers are resolved. This work provides insights into how tardigrades induce reversible biostasis through the self‐assembly of labile CAHS gels.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Stannous chloride as a tool for mercury stripping in contaminated streams: Experimental assessment of toxicity in an invertebrate model species

In this work, the chronic toxicity of an innovative Hg water treatment system using tin (Sn) (II) chloride (SnCl 2 ) followed by air stripping was assessed through measurements of survival, growth, and reproduction rate in the freshwater cladoceran Ceriodaphnia dubia, a model species for toxicity testing. We first calculated the concentrations of Hg causing 25% reduction in survival and reproduction (Lethal or Inhibition Concentrations, or LC 25 and IC 25 , for survival and reproduction, respectively) through exposure to aqueous Hg at concentrations ranging from 0 to 25,000 ng L -1 . Then, we treated media (DMW and natural stream water) contaminated with Hg at LC 25 and IC 25 concentrations with SnCl 2 at a Sn:Hg stoichiometric ratio of 8:1 and air stripping and exposed C. dubia to this Sn-amended media. Our results showed that Hg significantly affected survival, reproduction rates and impaired growth. SnCl 2 -treatment removed 100% of the Hg from the media at all concentrations tested with no deleterious effects on survival, growth and reproduction. Our results confirmed the efficacy of SnCl 2 in removing aqueous Hg from stream water and showed that the added Sn did not impact C. dubia at the concentrations tested, supporting the suitability of SnCl 2 -based treatments in appropriate Hg-contaminated environments.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2026

Identification of drug repurposing candidates for amyotrophic lateral sclerosis using electronic health records: a retrospective cohort study

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease with a life expectancy of only 3–5 years and few approved treatments. To identify drug repurposing candidates for the treatment of ALS, we analysed the electronic health records (EHRs) of a large cohort of military veterans with ALS. We analysed the EHRs of individuals in the US Veterans Health Administration (VHA) database who were diagnosed with ALS between Jan 1, 2009 and Dec 31, 2019 to assess medication effects. Individuals without recorded prescriptions after the date of diagnosis were excluded. Two sets of criteria were applied to ascertain exposure. Exposure criteria A were met if the dispense date or the end date of the medication was within 12 months of ALS diagnosis and the end date was at least 6 months after the dispense date. Exposure criteria B were met if there were at least two dispenses within 6 months before diagnosis and 12 months after diagnosis. Propensity score-matched control groups were generated on the basis of confounders included in the EHR, with methodology of potential outcomes used to infer treatment effects. The primary outcome was death. A standard Cox proportional hazards analysis was done to assess association with survival. Survival was defined as the time from diagnosis date recorded in the EHR to death reported in the Department for Veterans Affairs Vital Status File. Follow-up survival time was censored on Dec 31, 2020, for those alive on this date. Downstream protein targets of drugs with clinically significant effects were analysed using the protein–protein interaction networks-based algorithm PathFX. The EHRs of 11 003 individuals with ALS in the VHA database were appropriate for analysis. 162 medications with treatment groups of 30 or more individuals were identified. Among these 162 medications, 27 were associated with statistically significant changes (≥0·1) in the hazard ratio (HR) for death. 18 of the medications were associated with a reduced HR for death (prolonged survival), and nine were associated with an increased HR for death (reduced survival). Drugs associated with reduced HR included HMG-CoA reductase inhibitors (simvastatin, pravastatin, lovastatin, and atorvastatin), PDE5 inhibitors (vardenafil and sildenafil), and α-adrenergic antagonists (tamsulosin and terazosin). The medications associated with an increased HR were drugs used either in the management of clinical features of ALS associated with poor outcomes or in end-of-life care. PathFx analysis identified a complex of proteins interacting with several of the identified drugs. To our knowledge, this analysis is the largest EHR-based study for identifying drug repurposing candidates for ALS. We identified several drugs that warrant further assessment as therapeutic options in ALS, as well as a protein network complex that might serve as a therapeutic target for ALS.

Reimer, Richard J. [Stanford Univ., CA (United Sta↗
DOE OSTI2021

Is a Prescribed Fire Sufficient to Slow the Spread of Woody Plants in an Infrequently Burned Grassland? A Case Study in Tallgrass Prairie

In many mesic grasslands, such as the central Great Plains in North America, frequent fire is a key regulator of ecological processes. Long periods of infrequent fire facilitate the conversion of herbaceous-dominated grassland to woody-dominated shrubland or woodland. At the Konza Prairie Biological Station in northeast Kansas, one infrequently burned portion of the landscape has undergone transformation from grassland to woodland after nearly 30 yr without fire. In Spring 2017, a prescribed burn was implemented to assess fire effectiveness on woody plant mortality. A postfire census of 3 000+ individual woody plants identified the distribution of species by size (height), topographic position, and slope on the landscape. Mortality and canopy fire damage were calculated for each individual. In lowland locations with near-continuous shrub cover (30.7% of the landscape), woody plants were unaffected by fire. However, in upland and slope locations, where shrubs and trees were sparser, survival probability varied by topographic position and species. In these locations 68% of all woody individuals experienced 90% or greater fire damage to the canopy, with 56% of these individuals exhibiting new canopy regrowth within 2 mo after the fire. Here, the two most abundant woody shrubs, Cornus drummondii and Rhus aromatica, showed high survival at all height classes and landscape positions. The two abundant tree species, Gleditsia triacanthos and Juniperus virginiana, showed increased survival probability with tree height that varied by landscape position. Survival of J. virginiana also varied according to proximity and size of neighboring clonal shrubs, providing a mechanism for persistence of this fire-sensitive tree species even at small height classes. The probability survival curves developed here are useful for managers assessing when to prescribe fire to maximize mortality for J. virginiana and provide insight relevant for broader ecological understanding of woody encroachment within grasslands throughout the world.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2021

New Particle Formation and Growth to Climate-Relevant Aerosols at a Background Remote Site in the Western Himalaya

New particle formation (NPF) can influence the Earth’s radiative budget when the newly formed particles grow to climate-relevant sizes. Here, we present analysis of 21-months of continuous aerosol size distribution measurements at a background remote site in the western Himalaya and provide observational evidence that newly formed particles grow to cloud condensation nuclei (CCN)-active sizes (i.e. >20-100 nm in diameter). Out of total 55 NPF events, 38 (66%) events occurred in the pre-monsoon season (March-May). NPF events were classified into those with and without pollution influence as polluted and cleaner, respectively, using black carbon data. The analysis of air mass age, based on the ratio of number concentration of Aitken to accumulation mode aerosols, indicated that NPF occurred in the relatively cleaner air masses reaching to the site. The median formation rate of 10 nm particles and particle growth rates for cleaner events were three-fold and two-fold, respectively, higher than polluted events. We present the first estimates of the survival probability of newly formed particles to 50 nm and 100 nm size, which was not attempted in an Indian environment previously. The survival probability to 50 nm particles ranged from 44 to 98%, with a mean and standard deviation of 82 ± 18%. On average, ~60% of the particles surviving to 50 nm survived to 100 nm, making the overall survival probability of 100 nm to 53 ± 31%. This indicates that the probability of nucleated particles growing to CCN-active sizes under a large source of condensing vapor (transported from nearby lower-altitude regions) and low pre-existing particle concentrations (background mountain site) is high compared to the previous studies. These findings highlight the importance of the efficiency of nucleation events for producing CCN, which is a critical basis of aerosol indirect effects.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2023

Tripogon loliiformis tolerates rapid desiccation after metabolic and transcriptional priming during initial drying

Abstract Crop plants and undomesticated resilient species employ different strategies to regulate their energy resources and growth. Most crop species are sensitive to stress and prioritise rapid growth to maximise yield or biomass production. In contrast, resilient plants grow slowly, are small, and allocate their resources for survival in challenging environments. One small group of plants, termed resurrection plants, survive desiccation of their vegetative tissue and regain full metabolic activity upon watering. However, the precise molecular mechanisms underlying this extreme tolerance remain unknown. In this study, we employed a transcriptomics and metabolomics approach, to investigate the mechanisms of desiccation tolerance in Tripogon loliiformis , a modified desiccation-tolerant plant, that survives gradual but not rapid drying. We show that T. loliiformis can survive rapid desiccation if it is gradually dried to 60% relative water content (RWC). Furthermore, the gene expression data showed that T. loliiformis is genetically predisposed for desiccation in the hydrated state, as evidenced by the accumulation of MYB, NAC, bZIP, WRKY transcription factors along with the phytohormones, abscisic acid, salicylic acid, amino acids (e.g., proline) and TCA cycle sugars during initial drying. Through network analysis of co-expressed genes, we observed differential responses to desiccation between T. loliiformis shoots and roots. Dehydrating shoots displayed global transcriptional changes across broad functional categories, although no enrichment was observed during drying. In contrast, dehydrating roots showed distinct network changes with the most significant differences occurring at 40% RWC. The cumulative effects of the early stress responses may indicate the minimum requirements of desiccation tolerance and enable T. loliiformis to survive rapid drying. These findings potentially hold promise for identifying biotechnological solutions aimed at developing drought-tolerant crops without growth and yield penalties.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Handling and Tagging Techniques for Implanting Juvenile American Shad with a New Acoustic Microtransmitter

In this article, the use of telemetry techniques to better understand the behavior and survival of juvenile American shad (Alosa sapidissima), as they migrate through hydropower systems, has been challenging because shad are widely known to be particularly sensitive to handling. The goal of this study was to develop a tagging protocol using a new, acoustic micro transmitter that minimizes the detrimental effects of the tagging process and maximizes post-tagging survival of juvenile American shad. Limiting out-of-water handling and the use of brackish saltwater (7.5 parts per thousand) before and after tagging improved survival for shad tagged using a simple pectoral implantation method. This protocol provides a detailed, step-by-step procedure for tagging juvenile shad with acoustic transmitters. Fish tagged using this procedure and held in the laboratory for 60 days had an 81.5% survival rate, compared to 70% for their untagged counterparts. The successful tagging and handling practices developed in this study could be applied to field telemetry studies of juvenile shad and other sensitive species.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Development of a prediction model for radiotherapy response among patients with head and neck squamous cell carcinoma based on the tumor immune microenvironment and hypoxia signature

Abstract Introduction The immune system and hypoxia are major factors influencing radiosensitivity in patients with different cancer types. This study aimed at developing a model to predict radiotherapy response in patients with head and neck squamous cell carcinoma (HNSCC) based on the tumor immune microenvironment and hypoxia signature. Materials and Methods We first evaluated the hypoxia status and tumor immune microenvironment in the Cancer Genome Atlas (TCGA) cohort by using transcriptomic data. Differentially expressed genes (DEGs) were identified between the “high immunity and low hypoxia” and “low immunity and high hypoxia” groups and those DEGs significantly associated with disease‐specific survival in the univariate Cox regression analysis were selected as the prognostic DEGs. We selected the immune hypoxia–related genes (IHRGs) by intersecting prognostic DEGs with immune and hypoxia gene sets. We used the IHRGs to train a multivariate Cox regression model in the TCGA cohort, based on which we calculated the IHRG prognostic index (IHRGPI) for each patient and validated its efficacy in predicting radiotherapy response in the Gene Expression Omnibus cohorts. Furthermore, we explored potential mechanisms and effective combinational treatment strategies for different IHRGPI groups. Results Five IHRGs were used to construct the IHRGPI, which was used to dichotomize the cohorts. The patients with lower IHRGPI showed a better radiotherapy response across different cohorts and endpoints, including overall survival, progression‐free survival, and recurrence‐free survival ( p < 0.05). Patients with higher IHRGPI showed greater hypoxia and lesser immune cell infiltration. A lower IHRGPI indicated a better immunotherapy response, while a higher IHRGPI indicated a better chemotherapy response. Conclusions IHRGPI is promising for predicting radiotherapy response and guiding combinational treatment strategies in patients with HNSCC.

Zhu, Guang‐Li↗
DOE OSTI2023

Reciprocal transplants reveal asymmetric local adaptation of Himalayan Rhododendron approaching elevational range limit

Abstract As plant species expand their upper limits of distribution under current warming, some retain both traditional climate space and biotic environment while others encounter novel conditions. The latter is the case for Rhododendron campanulatum , a woody shrub that grows both above and below treeline at our study site in the Eastern Himalayas where a very conspicuous, stable treeline was defined by a nearly contiguous canopy of tall Abies spectabilis trees, many of which are over a century old. Prior work showed that treeline had remained static in this region while R. campanulatum expanded its elevational range limit. We tested local adaptation of R. campanulatum by performing reciprocal transplants between the species' current elevational range limit (4023 m above sea level [asl]) and just above treeline (3876 m asl). Contrary to expectation, the coldest temperatures of late winter and early mid‐spring were experienced by plants at the lower elevation: R. campanulatum at species' limit (upper site) were covered by snow for a longer period (40 more days) and escaped the coldest temperatures suffered by conspecifics at treeline (lower site). The harsher spring conditions at treeline likely explain why leaves were smaller at treeline (15.3 cm 2 ) than at species limit (21.3 cm 2 ). Contrary to results from equivalent studies in other regions, survival was reduced more by downslope than by upslope movement, again potentially due to extreme cold temperatures observed at treeline in spring. Upslope transplantation had no effect on mortality, but mortality of species limit saplings transplanted downslope was three times higher than that of residents at both sites. A general expectation is that locals should survive better than foreign transplants, but survival of locals and immigrants at our species limit site was identical. However, those species limit saplings that survived the transplant to treeline grew faster than both locals at treeline and the transplants at species limit. Overall, we found asymmetric adaptation: Compared with treeline saplings, those at species limit (147 m above treeline) were more tolerant of extremes in the growing season but less tolerant of extremes in winter and early mid‐spring, displaying local adaptation in a more complex manner than simply home advantage, and complicating predictions about impacts of future regional climate change.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2022

Strong parallel evidence of selection during switchgrass sward establishment in hybrid and lowland ecotypes

Switchgrass sward establishment results in up to 90% seedling mortality. The degree of selection during sward establishment has not been reported using modern genetic methods. Pooled leaf samples were sequenced from replicated swards of 46 half-sib families from two breeding groups (lowland and hybrid) before and through 3 years of stand establishment. Pooled allele frequencies were then assessed using fixation indices (Fst) and an independent data set was used to predict the polygenic impact of establishment selection on two traits (heading date and winter survivorship). Last, the DNA pools were assigned survival rankings to predict the sward survival genomically estimated breeding values within the training data set. Strong and parallel selection occured in both breeding groups. Five genomic regions exceeded the significant threshold of 99.9% in >10 families, indicating consistent selection across families and breeding groups. Polygenic trait predictions determined that establishment selection was partially associated with winter survivorship but resulted in variable heading date alterations. The genomewide variation is consistent with selection for a small number of related parental lines. This study observed strong selection for a small number of hybrid and coastal ecotype individuals which are promising germplasm sources for improved sward survival. This confirms prior reports of sward selection during grassland establishment and highlights the strength of pooled DNA sequencing for survival traits.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2021

Photosynthetic adaptation to polar life: Energy balance, photoprotection and genetic redundancy

The persistent low temperature that characterize polar habitats combined with the requirement for light for all photoautotrophs creates a conundrum. The absorption of too much light at low temperature can cause an energy imbalance that decreases photosynthetic performance that has a negative impact on growth and can affect long-term survival. The goal of this review is to survey the mechanism(s) by which polar photoautotrophs maintain cellular energy balance, that is, photostasis to overcome the potential for cellular energy imbalance in their low temperature environments. Photopsychrophiles are photosynthetic organisms that are obligately adapted to low temperature (0⁰- 15 °C) but usually die at higher temperatures (≥20 °C). In contrast, photopsychrotolerant species can usually tolerate and survive a broad range of temperatures (5⁰- 40 °C). First, we summarize the basic concepts of excess excitation energy, energy balance, photoprotection and photostasis and their importance to survival in polar habitats. Second, we compare the photoprotective mechanisms that underlie photostasis and survival in aquatic cyanobacteria and green algae as well as terrestrial Antarctic and Arctic plants. We show that polar photopsychrophilic and photopsychrotolerant organisms attain energy balance at low temperature either through a regulated reduction in the efficiency of light absorption or through enhanced capacity to consume photosynthetic electrons by the induction of O 2 as an alternative electron acceptor. Finally, we compare the published genomes of three photopsychrophilic and one photopsychrotolerant alga with five mesophilic green algae including the model green alga, Chlamydomonas reinhardtii. We relate our genomic analyses to photoprotective mechanisms that contribute to the potential attainment of photostasis. Finally, we discuss how the observed genomic redundancy in photopsychrophilic genomes may confer energy balance, photoprotection and resilience to their harsh polar environment. Primary production in aquatic, Antarctic and Arctic environments is dependent on diverse algal and cyanobacterial communities. Although mosses and lichens dominate the Antarctic terrestrial landscape, only two extant angiosperms exist in the Antarctic. Furthermore, the identification of a single ‘molecular key’ to unravel adaptation of photopsychrophily and photopsychrotolerance remains elusive. Since these photoautotrophs represent excellent biomarkers to assess the impact of global warming on polar ecosystems, increased study of these polar photoautotrophs remains essential.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Immunophenotypic characterization and therapeutics effects of human bone marrow- and umbilical cord-derived mesenchymal stromal cells in an experimental model of sepsis

Highlights: • Mesenchymal stromal cells (MSCs) may be a therapeutic option for sepsis. • Bone marrow (BM) vs. umbilical cord (UC) -MSCs induce different M1/M2 gene profiles. • In a CLP model of sepsis, only BM-MSCs improved survival and bacterial clearance. Sepsis is a complicated multi-system disorder characterized by a dysregulated host response to infection. Despite substantial progress in the understanding of mechanisms of sepsis, translation of these advances into clinically effective therapies remains challenging. Mesenchymal Stromal Cells (MSCs) possess immunomodulatory properties that have shown therapeutic promise in preclinical models of sepsis. The therapeutic effects of MSCs may vary depending on the source and type of these cells. In this comparative study, the gene expression pattern and surface markers of bone marrow-derived MSCs (BM-MSCs) and umbilical cord-derived MSCs (UC-MSCs) as well as their therapeutic effects in a clinically relevant mouse model of polymicrobial sepsis, cecal ligation and puncture (CLP), were investigated. The results showed remarkable differences in gene expression profile, surface markers and therapeutic potency in terms of enhancing survival and pro/anti-inflammatory responses between the two MSC types. BM-MSCs improved survival concomitant with an enhanced systemic bacterial clearance and improved inflammatory profile post CLP surgery. Despite some improvement in the inflammatory profile of the septic animals, treatment with UC-MSCs did not enhance survival or bacterial clearance. Overall, the beneficial therapeutic effects of BM-MSCs over UC-MSCs may likely be attributed to their pro-inflammatory function, and to some extent anti-inflammatory features, reflected in their gene expression pattern enhancing macrophage polarization to M1/M2 phenotypes resulting in a balanced pro- and anti-inflammatory response against polymicrobial sepsis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

MCL1 inhibition enhances the efficacy of docetaxel against airway-derived squamous cell carcinoma cells

Highlights: • Authentic squamous cell carcinoma (SqCC) cell lines of the lung are sparse. • HARA lung SqCC cells depend highly on MCL1 for survival in vitro and in vivo. • MCL1-silenced HARA cells decline in number upon docetaxel (DTX) exposure. • High MCL1 mRNA expression is linked with shorter survival in lung SqCC patients. • MCL1 depletion + DTX is highly effective against Detroit 562 pharyngeal SqCC cells. MCL1 is an anti-apoptotic BCL2 family member that is often overexpressed in various malignant tumors. However, few reports have described the role of MCL1 in squamous cell carcinoma (SqCC) derived from airways including the lung. In this study, we examined whether MCL1 could be a novel druggable target for airway-derived SqCC, for which effective molecular targeted drugs are unavailable. We searched the Kaplan–Meier Plotter database and found that high MCL1 mRNA expression was significantly associated with shorter survival in patients with lower airway (lung) or upper airway (head and neck) derived SqCC. We also explored the Expression Atlas database and learned that authentic lung SqCC cell lines expressing both TP63 and KRT5 mRNA were extremely sparse among the publicly available “lung SqCC cell lines”, with an exception being HARA cells. HARA cells were highly dependent on MCL1 for survival, and MCL1-depleted cells were not able to grow, and even declined in number, upon docetaxel (DTX) exposure in vitro and in vivo. Similar in vitro experimental findings, including those in a 3D culture model, were also obtained using Detroit 562 pharyngeal SqCC cells. These findings suggested that combined treatment with MCL1 silencing plus DTX appears highly effective against airway-derived SqCC.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

An IRE1-proteasome system signalling cohort controls cell fate determination in unresolved proteotoxic stress of the plant endoplasmic reticulum

Excessive accumulation of misfolded proteins in the endoplasmic reticulum (ER) causes ER stress, which is an underlying cause of major crop losses and devastating human conditions. Here, ER proteostasis surveillance is mediated by the conserved master regulator of the unfolded protein response (UPR), Inositol Requiring Enzyme 1 (IRE1), which determines cell fate by controlling pro-life and pro-death outcomes through as yet largely unknown mechanisms. Here we report that Arabidopsis IRE1 determines cell fate in ER stress by balancing the ubiquitin–proteasome system (UPS) and UPR through the plant-unique E3 ligase, PHOSPHATASE TYPE 2CA (PP2CA)-INTERACTING RING FINGER PROTEIN 1 (PIR1). Indeed, PIR1 loss leads to suppression of pro-death UPS and the lethal phenotype of an IRE1 loss-of-function mutant in unresolved ER stress in addition to activating pro-survival UPR. Specifically, in ER stress, PIR1 loss stabilizes ABI5, a basic leucine zipper (bZIP) transcription factor, that directly activates expression of the critical UPR regulator gene, bZIP60, triggering transcriptional cascades enhancing pro-survival UPR. Collectively, our results identify new cell fate effectors in plant ER stress by showing that IRE1’s coordination of cell death and survival hinges on PIR1, a key pro-death component of the UPS, which controls ABI5, a pro-survival transcriptional activator of bZIP60.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Blast from the past: constraining progenitor models of SN 1972E

ABSTRACT We present a novel technique to study Type Ia supernovae (SNe Ia) by constraining surviving companions of historical extragalactic SN by combining archival photographic plates and Hubble Space Telescope(HST) imaging. We demonstrate this technique for Supernova 1972E, the nearest known SN Ia in 125 yr. Some models of SNe Ia describe a white dwarf with a non-degenerate companion that donates enough mass to trigger thermonuclear detonation. Hydrodynamic simulations and stellar evolution models show that these donor stars will survive the explosion, and show increased luminosity for at least a 1000 yr. Thus, late-time observations of the exact location of a supernova can constrain the presence of a surviving donor star and progenitor models. We find the explosion site of SN 1972E by analysing 17 digitized photographic plates taken with the European Southern Observatory 1-m Schmidt and 1 plate taken with the Cerro Tololo Inter-American Observatory 1.5-m telescope. Using the Gaia eDR3 catalogue to determine Supernova 1972E’s location yields: α = 13h39m52${_{.}^{\rm s}}$708 ± 0${_{.}^{\rm s}}$004 and δ = −31°40’9${_{.}^{\prime\prime}}$00 ± 0${_{.}^{\prime\prime}}$04 (ICRS). In 2005, HST/ACS imaged the host galaxy of SN 1972E with the F435W, F555W, and F814W filters covering the explosion site. The nearest detected source is offset by 3.0 times our positional precision, and is inconsistent with the colours expected of a surviving donor star. Thus, the limiting magnitude of the HST observation (F555W > 28 mag) rules out all He star companion models and the most luminous main-sequence companion model currently in the literature. The remaining main-sequence companion models could be tested with a 10 orbit HST exposure in the F606W filter.

Do, Aaron↗