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DOE OSTI2020

RCSB Protein Data Bank 1D tools and services

Abstract Motivation Interoperability between polymer sequences and structural data is essential for providing a complete picture of protein and gene features and helping to understand biomolecular function. Results Herein, we present two resources designed to improve interoperability between the RCSB Protein Data Bank, the NCBI and the UniProtKB data resources and visualize integrated data therefrom. The underlying tools provide a flexible means of mapping between the different coordinate spaces and an interactive tool allows convenient visualization of the 1-dimensional data over the web. Availabilityand implementation https://1d-coordinates.rcsb.org and https://rcsb.github.io/rcsb-saguaro. Supplementary information Supplementary data are available at Bioinformatics online.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2025

Polyphenol rewiring of the microbiome reduces methane emissions

Methane mitigation is regarded as a critical strategy to combat the scale of global warming. Currently, ~40% of methane emissions originate from microbial sources, which is causing strategies to suppress methanogens—either through direct toxic effects or by diverting their substrates and energy—to gain traction. Problematically, current microbial methane mitigation knowledge lacks detailed microbiome-centered insights, limiting translation across conditions and ecosystems. Here we utilize genome-resolved metatranscriptomes and metabolomes to assess the impact of a proposed methane inhibitor, catechin, on greenhouse gas emissions for high-methane-emitting peatlands. In microcosms, catechin drastically reduced methane emissions by 72%–84% compared to controls. Longitudinal sampling allowed for reconstruction of a catechin degradation pathway involving Actinomycetota and Clostridium, which break down catechin into smaller phenolic compounds within the first 21 days, followed by degradation of phenolic compounds by Pseudomonas_E from Days 21 to 35. These genomes co-expressed hydrogen-uptake genes, suggesting hydrogenases may act as a hydrogen sink during catechin degradation and consequently reduce hydrogen availability to methanogens. In support of this idea, there was decreased gene expression by hydrogenotrophic and hydrogen-dependent methylotrophic methanogens under catechin treatment. There was also reduced gene expression from genomes inferred to be functioning syntrophically with hydrogen-utilizing methanogens. We propose that catechin metabolic redirection effectively starves hydrogen-utilizing methanogens, offering a potent avenue for curbing methane emissions across diverse environments including ruminants, landfills, and constructed or managed wetlands.

54 ENVIRONMENTAL SCIENCES↗

DOE OSTI2021

Spatiotemporal cytokinin response imaging and ISOPENTENYLTRANSFERASE 3 function in Medicago nodule development

Most legumes can establish a symbiotic association with soil rhizobia that trigger the development of root nodules. These nodules host the rhizobia and allow them to fix nitrogen efficiently. The perception of bacterial lipo-chitooligosaccharides (LCOs) in the epidermis initiates a signaling cascade that allows rhizobial intracellular infection in the root and de-differentiation and activation of cell division that gives rise to the nodule. Thus, nodule organogenesis and rhizobial infection need to be coupled in space and time for successful nodulation. The plant hormone cytokinin (CK) contributes to the coordination of this process, acting as an essential positive regulator of nodule organogenesis. However, the temporal regulation of tissue-specific CK signaling and biosynthesis in response to LCOs or Sinorhizobium meliloti inoculation in Medicago truncatula remains poorly understood. In this study, using a fluorescence-based CK sensor (pTCSn::nls:tGFP), we performed a high-resolution tissue-specific temporal characterization of the sequential activation of CK response during root infection and nodule development in M. truncatula after inoculation with S. meliloti. Loss-of-function mutants of the CK-biosynthetic gene ISOPENTENYLTRANSFERASE 3 (IPT3) showed impairment of nodulation, suggesting that IPT3 is required for nodule development in M. truncatula. Simultaneous live imaging of pIPT3::nls:tdTOMATO and the CK sensor showed that IPT3 induction in the pericycle at the base of nodule primordium contributes to CK biosynthesis, which in turn promotes expression of positive regulators of nodule organogenesis in M. truncatula.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2026

Ecological and genomic variation in ectomycorrhizal fungal exploration types

Ectomycorrhizal fungi (EMF) produce mycelia with variable extension and complexity, which can be classified according to soil ‘exploration types’ (ETs). ETs have received attention as one of the few mycorrhizal trait frameworks, but without an empirical classification of ET functional diversity and environmental preferences, understanding and interpreting EMF biogeographic patterns has been difficult. We conducted a synthesis combining: comparative EMF genomics to describe functional divergence in decomposition and nutrient cycling genes across ETs; and EMF trait distribution modeling across continental Europe, pairing soil and root EMF surveys to establish biogeographic ET niche profiles. We demonstrate a signature of ETs encoded in EMF genomes, which is independent from phylogeny and linked to biomass production strategies. EMF ET relative abundances were separated by soil, root, and dominant tree leaf type habitats and exhibited unique correlations with forest biotic (e.g. plant productivity and plant pathogen densities) and abiotic (e.g. nitrogen deposition and soil pH) conditions. These findings support a theory that EMF niche partitioning can be partially explained by extraradical mycelial traits, with underlying variation in ET biogeography likely arising from distinct decomposition and nutrient cycling potentials. We also identify important limitations to this trait framework and provide a guided outlook for future research.

biogeography↗

DOE OSTI2021

Root angle in maize influences nitrogen capture and is regulated by calcineurin B-like protein (CBL)-interacting serine/threonine-protein kinase 15 ( ZmCIPK15 )

Crops with reduced nutrient and water requirements are urgently needed in global agriculture. Root growth angle plays an important role in nutrient and water acquisition. A maize diversity panel of 481 genotypes was screened for variation in root angle employing a high-throughput field phenotyping platform. Genome-wide association mapping identified several single nucleotide polymorphisms (SNPs) associated with root angle, including one located in the root expressed CBL-interacting serine/threonine-protein kinase 15 (ZmCIPK15) gene (LOC100285495). Reverse genetic studies validated the functional importance of ZmCIPK15, causing a approximately 10° change in root angle in specific nodal positions. A steeper root growth angle improved nitrogen capture in silico and in the field. OpenSimRoot simulations predicted at 40 days of growth that this change in angle would improve nitrogen uptake by 11% and plant biomass by 4% in low nitrogen conditions. In field studies under suboptimal N availability, the cipk15 mutant with steeper growth angles had 18% greater shoot biomass and 29% greater shoot nitrogen accumulation compared to the wild type after 70 days of growth. We propose that a steeper root growth angle modulated by ZmCIPK15 will facilitate efforts to develop new crop varieties with optimal root architecture for improved performance under edaphic stress.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Tomato deploys defence and growth simultaneously to resist bacterial wilt disease

Abstract Plant disease limits crop production, and host genetic resistance is a major means of control. Plant pathogenic Ralstonia causes bacterial wilt disease and is best controlled with resistant varieties. Tomato wilt resistance is multigenic, yet the mechanisms of resistance remain largely unknown. We combined metaRNAseq analysis and functional experiments to identify core Ralstonia ‐responsive genes and the corresponding biological mechanisms in wilt‐resistant and wilt‐susceptible tomatoes. While trade‐offs between growth and defence are common in plants, wilt‐resistant plants activated both defence responses and growth processes. Measurements of innate immunity and growth, including reactive oxygen species production and root system growth, respectively, validated that resistant plants executed defence‐related processes at the same time they increased root growth. In contrast, in wilt‐susceptible plants roots senesced and root surface area declined following Ralstonia inoculation. Wilt‐resistant plants repressed genes predicted to negatively regulate water stress tolerance, while susceptible plants repressed genes predicted to promote water stress tolerance. Our results suggest that wilt‐resistant plants can simultaneously promote growth and defence by investing in resources that act in both processes. Infected susceptible plants activate defences, but fail to grow and so succumb to Ralstonia , likely because they cannot tolerate the water stress induced by vascular wilt.

Meline, Valerian↗

DOE OSTI2020

An algal enzyme required for biosynthesis of the most abundant marine carotenoids

Fucoxanthin and its derivatives are the main light-harvesting pigments in the photosynthetic apparatus of many chromalveolate algae and represent the most abundant carotenoids in the world’s oceans, thus being major facilitators of marine primary production. A central step in fucoxanthin biosynthesis that has been elusive so far is the conversion of violaxanthin to neoxanthin. Here, we show that in chromalveolates, this reaction is catalyzed by violaxanthin de-epoxidase–like (VDL) proteins and that VDL is also involved in the formation of other light-harvesting carotenoids such as peridinin or vaucheriaxanthin. VDL is closely related to the photoprotective enzyme violaxanthin de-epoxidase that operates in plants and most algae, revealing that in major phyla of marine algae, an ancient gene duplication triggered the evolution of carotenoid functions beyond photoprotection toward light harvesting.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2022

Deletion of E184L, a Putative DIVA Target from the Pandemic Strain of African Swine Fever Virus, Produces a Reduction in Virulence and Protection against Virulent Challenge

African swine fever (ASF) is currently causing a major pandemic affecting the swine industry and protein availability from Central Europe to East and South Asia. No commercial vaccines are available, making disease control dependent on the elimination of affected animals. Here, we show that the deletion of the African swine fever virus (ASFV) E184L gene from the highly virulent ASFV Georgia 2010 (ASFV-G) isolate produces a reduction in virus virulence during the infection in swine. Of domestic pigs intramuscularly inoculated with a recombinant virus lacking the E184L gene (ASFV-GDE184L), 40% experienced a significantly (5 days) delayed presentation of clinical disease and, overall, had a 60% rate of survival compared to animals inoculated with the virulent parental ASFV-G. Importantly, all animals surviving ASFV-G-DE184L infection developed a strong antibody response and were protected when challenged with ASFV-G. As expected, a pool of sera from ASFV-G-DE184L-inoculated animals lacked any detectable antibody response to peptides partially representing the E184L protein, while sera from animals inoculated with an efficacious vaccine candidate, ASFV-GDMGF, strongly recognize the same set of peptides. These results support the potential use of the E184L deletion for the development of vaccines able to differentiate infected from vaccinated animals (DIVA). Therefore, it is shown here that the E184L gene is a novel ASFV determinant of virulence that can potentially be used to increase safety in preexisting vaccine candidates, as well as to provide them with DIVA capabilities. To our knowledge, E184L is the first ASFV gene product experimentally shown to be a functional DIVA antigenic marker.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2020

Combinatorial Biosynthesis of Sulfated Benzenediol Lactones with a Phenolic Sulfotransferase from Fusarium graminearum PH-1

Total biosynthesis or whole-cell biocatalytic production of sulfated small molecules relies on the discovery and implementation of appropriate sulfotransferase enzymes. Although fungi are prominent biocatalysts and have been used to sulfate drug-like phenolics, no gene encoding a sulfotransferase enzyme has been functionally characterized from these organisms. Here, we identify a phenolic sulfotransferase, FgSULT1, by genome mining from the plant-pathogenic fungus Fusarium graminearum PH-1. We expressed FgSULT1 in a Saccharomyces cerevisiae chassis to modify a broad range of benzenediol lactones and their nonmacrocyclic congeners, together with an anthraquinone, with the resulting unnatural natural product (uNP) sulfates displaying increased solubility. FgSULT1 shares low similarity with known animal and plant sulfotransferases. Instead, it forms a sulfotransferase family with putative bacterial and fungal enzymes for phase II detoxification of xenobiotics and allelochemicals. Among fungi, putative FgSULT1 homologues are encoded in the genomes of Fusarium spp. and a few other genera in nonsyntenic regions, some of which may be related to catabolic sulfur recycling. Computational structure modeling combined with site-directed mutagenesis revealed that FgSULT1 retains the key catalytic residues and the typical fold of characterized animal and plant sulfotransferases. Our work opens the way for the discovery of hitherto unknown fungal sulfotransferases and provides a synthetic biological and enzymatic platform that can be adapted to produce bioactive sulfates, together with sulfate ester standards and probes for masked mycotoxins, precarcinogenic toxins, and xenobiotics.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2019

Orally Bioavailable Androgen Receptor Degrader, Potential Next-Generation Therapeutic for Enzalutamide-Resistant Prostate Cancer

Androgen receptor (AR)-targeting prostate cancer drugs, which are predominantly competitive ligand-binding domain (LBD)-binding antagonists, are inactivated by common resistance mechanisms. It is important to develop next-generation mechanistically distinct drugs to treat castration- and drug-resistant prostate cancers. Second-generation AR pan antagonist UT-34 was selected from a library of compounds and tested in competitive AR binding and transactivation assays. In this study, UT-34 was tested using biophysical methods for binding to the AR activation function-1 (AF-1) domain. Western blot, gene expression, and proliferation assays were performed in various AR-positive enzalutamide-sensitive and -resistant prostate cancer cell lines. Pharmacokinetic and xenograft studies were performed in immunocompromised rats and mice. UT-34 inhibits the wild-type and LBD-mutant ARs comparably and inhibits the in vitro proliferation and in vivo growth of enzalutamide-sensitive and -resistant prostate cancer xenografts. In preclinical models, UT-34 induced the regression of enzalutamide-resistant tumors at doses when the AR is degraded; but, at lower doses, when the AR is just antagonized, it inhibits, without shrinking, the tumors. This indicates that degradation might be a prerequisite for tumor regression. Mechanistically, UT-34 promotes a conformation that is distinct from the LBD-binding competitive antagonist enzalutamide and degrades the AR through the ubiquitin proteasome mechanism. UT-34 has a broad safety margin and exhibits no cross-reactivity with G-protein–coupled receptor kinase and nuclear receptor family members. Collectively, UT-34 exhibits the properties necessary for a next-generation prostate cancer drug.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2024

Antarctic lake viromes reveal potential virus associated influences on nutrient cycling in ice-covered lakes

The McMurdo Dry Valleys (MDVs) of Antarctica are a mosaic of extreme habitats which are dominated by microbial life. The MDVs include glacial melt holes, streams, lakes, and soils, which are interconnected through the transfer of energy and flux of inorganic and organic material via wind and hydrology. For the first time, we provide new data on the viral community structure and function in the MDVs through metagenomics of the planktonic and benthic mat communities of Lakes Bonney and Fryxell. Viral taxonomic diversity was compared across lakes and ecological function was investigated by characterizing auxiliary metabolic genes (AMGs) and predicting viral hosts. Our data suggest that viral communities differed between the lakes and among sites: these differences were connected to microbial host communities. AMGs were associated with the potential augmentation of multiple biogeochemical processes in host, most notably with phosphorus acquisition, organic nitrogen acquisition, sulfur oxidation, and photosynthesis. Viral genome abundances containing AMGs differed between the lakes and microbial mats, indicating site specialization. Using procrustes analysis, we also identified significant coupling between viral and bacterial communities (p = 0.001). Finally, host predictions indicate viral host preference among the assembled viromes. Collectively, our data show that: (i) viruses are uniquely distributed through the McMurdo Dry Valley lakes, (ii) their AMGs can contribute to overcoming host nutrient limitation and, (iii) viral and bacterial MDV communities are tightly coupled.

Microbiology↗

DOE OSTI2023

Downregulation of barley ferulate 5-hydroxylase dramatically alters straw lignin structure without impact on mechanical properties

Barley is a major cereal crop for temperate climates, and a diploid genetic model for polyploid wheat. Cereal straw biomass is an attractive source of feedstock for green technologies but lignin, a key determinant of feedstock recalcitrance, complicates bio-conversion processes. However, manipulating lignin content to improve the conversion process could negatively affect agronomic traits. An alternative approach is to manipulate lignin composition which influences the physical and chemical properties of straw. This study validates the function of a barley ferulate 5-hydroxylase gene and demonstrates that its downregulation using the RNA-interference approach substantially impacts lignin composition. We identified five barley genes having putative ferulate 5-hydroxylase activity. Downregulation of HvF5H1 substantially reduced the lignin syringyl/guaiacyl (S/G) ratio in straw while the lignin content, straw mechanical properties, plant growth habit, and grain characteristics all remained unaffected. Metabolic profiling revealed significant changes in the abundance of 173 features in the HvF5H1-RNAi lines. The drastic changes in the lignin polymer of transgenic lines highlight the plasticity of barley lignification processes and the associated potential for manipulating and improving lignocellulosic biomass as a feedstock for green technologies. On the other hand, our results highlight some differences between the lignin biosynthetic pathway in barley, a temperate climate grass, and the warm climate grass, rice, and underscore potential diversity in the lignin biosynthetic pathways in grasses.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2024

Factors affecting the production of sugarcane yield and sucrose accumulation: suggested potential biological solutions

Environmental stresses are the main constraints on agricultural productivity and food security worldwide. This issue is worsened by abrupt and severe changes in global climate. The formation of sugarcane yield and the accumulation of sucrose are significantly influenced by biotic and abiotic stresses. Understanding the biochemical, physiological, and environmental phenomena associated with these stresses is essential to increase crop production. This review explores the effect of environmental factors on sucrose content and sugarcane yield and highlights the negative effects of insufficient water supply, temperature fluctuations, insect pests, and diseases. This article also explains the mechanism of reactive oxygen species (ROS), the role of different metabolites under environmental stresses, and highlights the function of environmental stress-related resistance genes in sugarcane. This review further discusses sugarcane crop improvement approaches, with a focus on endophytic mechanism and consortium endophyte application in sugarcane plants. Endophytes are vital in plant defense; they produce bioactive molecules that act as biocontrol agents to enhance plant immune systems and modify environmental responses through interaction with plants. This review provides an overview of internal mechanisms to enhance sugarcane plant growth and environmental resistance and offers new ideas for improving sugarcane plant fitness and crop productivity.

Mehdi, Faisal↗

DOE OSTI2022

Phage K gp102 Drives Temperature-Sensitive Antibacterial Activity on USA300 MRSA

There is widespread interest in using obligately lytic bacteriophages (“phages”) to treat human bacterial infections. Among Staphylococcus aureus infections, the USA300 lineage is a frequent cause of invasive disease. We observed that phage K, a model S. aureus myophage, exhibits temperature-sensitive growth on USA300 strains, with the wild-type phage providing poorer growth suppression in broth and forming smaller and fainter plaques at 37 °C vs. 30 °C. We isolated 65 mutants of phage K that had improved plaquing characteristics at 37 °C when compared to the parental phage. In all 65 mutants, this phenotype was attributable to loss-of-function (LoF) mutations in gp102, which encodes a protein of unknown function that has homologs only among the Herelleviridae (SPO1-like myophages infecting gram-positive bacteria). Additional experiments with representative mutants consistently showed that the temperature-sensitive plaque phenotype was specific to USA300 MRSA strains and that Gp102 disruption was correlated with improved suppression of bacterial growth in broth and improved antibacterial activity in a mouse model of upper respiratory tract infection. The same genotype and in vitro phenotypes could be replicated in close relatives of phage K. Gp102 disruption did not have a detectable effect on adsorption but did delay cell culture lysis relative to wild-type under permissive infection conditions, suggesting that gp102 conservation might be maintained by selective pressure for more rapid replication. Expression of gp102 on a plasmid was toxic to both an MSSA and a USA300 MRSA strain. Molecular modeling predicts a protein with two helix-turn-helix domains that displays some similarity to DNA-binding proteins such as transcription factors. While its function remains unclear, gp102 is a conserved gene that is important to the infection process of Kayvirus phages, and it appears that the manner in which USA300 strains defend against them at 37 °C can be overcome by gp102 LoF mutations.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2020

Analysis of zebrafish periderm enhancers facilitates identification of a regulatory variant near human KRT8/18

Genome-wide association studies for non-syndromic orofacial clefting (OFC) have identified single nucleotide polymorphisms (SNPs) at loci where the presumed risk-relevant gene is expressed in oral periderm. The functional subsets of such SNPs are difficult to predict because the sequence underpinnings of periderm enhancers are unknown. We applied ATAC-seq to models of human palate periderm, including zebrafish periderm, mouse embryonic palate epithelia, and a human oral epithelium cell line, and to complementary mesenchymal cell types. We identified sets of enhancers specific to the epithelial cells and trained gapped-kmer support-vector-machine classifiers on these sets. We used the classifiers to predict the effects of 14 OFC-associated SNPs at 12q13 near KRT18. All the classifiers picked the same SNP as having the strongest effect, but the significance was highest with the classifier trained on zebrafish periderm. Reporter and deletion analyses support this SNP as lying within a periderm enhancer regulating KRT18/KRT8 expression.

59 BASIC BIOLOGICAL SCIENCES↗

NASA NTRS2004

Biodosimetry as a New Paradigm for Determination of Radiation Risks and Risk-Mitigation in Astronauts Exposed to Space Radiation

Predicting risk of cancer in astronauts exposed to space radiation is challenging partly because uncertainties of absorption of dose and the processing of dose-related damage at the cellular level degrade the confidence of predicting the expression of cancer. Cellular biodosimeters that simultaneously report: 1) the quantity of absorbed dose after exposure to ionizing radiation, 2) the quality of radiation delivering that dose, and 3) the macromolecular profiles related to malignant transformation in cells absorbing that dose would therefore be useful. An approach to such a multiparametric biodosimeter will be reported, This is the demonstration of two dose-responsive field-effects of enhanced protein-expression. In one case, expression of keratin 18 (K18) in cultures of human mammary epithelial cells (HMEC) irradiated with cesium-137 gamma-rays is enhanced following exposure of log phase cells to relatively low doses of 30 to 90 cGy. K18 has been reported by a marker for tumor staging and for apoptosis. In the second case, expression of connexin 43 (Cx43) is increased in irradiated stationary phase cultures of HMEC, indicating enhanced formation of gap junctions. Gap junctions have been reported to be involved in bystander effects following irradiation. It is a biodosimeter for assessing radiogenic damage. It is suggested further that such biomolecular dosimetry may introduce a new paradigm for assessing cancer risk and risk-mitigation in individuals, a requirement for managing radiation health in astronauts during extended missions in space. This new paradigm is built upon the statistical power provided by the use of functional genomics and proteomics represented in combined gene- and protein-expression assays.

Richmond, Robert↗

NASA NTRS2002

Selective norepinephrine reuptake inhibition as a human model of orthostatic intolerance

BACKGROUND: Observations in patients with functional mutations of the norepinephrine transporter (NET) gene suggest that impaired norepinephrine uptake may contribute to idiopathic orthostatic intolerance. METHODS AND RESULTS: We studied the effect of the selective NET blocker reboxetine and placebo in a randomized, double-blind, crossover fashion on cardiovascular responses to cold pressor testing, handgrip testing, and a graded head-up tilt test (HUT) in 18 healthy subjects. In a subset, we determined isoproterenol and phenylephrine sensitivities. Subjects ingested 8 mg reboxetine or placebo 12 hours and 1 hour before testing. In the supine position, heart rate was 65+/-2 bpm with placebo and 71+/-3 bpm with reboxetine. At 75 degrees HUT, heart rate was 84+/-3 and 119+/-4 bpm with placebo and with reboxetine (P<0.0001). Mean arterial pressure was 85+/-2 with placebo and 91+/-2 mm Hg with reboxetine while supine (P<0.01) and 88+/-2 mm Hg and 90+/-3 mm Hg at 75 degrees HUT. Blood pressure responses to cold pressor and handgrip testing were attenuated with reboxetine. Reboxetine increased the sensitivity to the chronotropic effect of isoproterenol and the pressor effect of phenylephrine. Vasovagal reactions occurred in 9 subjects on placebo and in 1 subject on reboxetine. CONCLUSIONS: Selective NET blockade creates a phenotype that resembles idiopathic orthostatic intolerance. This observation supports the hypothesis that disordered norepinephrine uptake mechanisms can contribute to human cardiovascular disease. Our study also suggests that NET inhibition might be useful in preventing vasovagal reactions.

Non-NASA Center↗

NASA NTRS2011

Molecular Mechanisms of Circadian Regulation During Spaceflight

Disruption of the regular environmental circadian cues in addition to stringent and demanding operational schedules are two main factors that undoubtedly impact sleep patterns and vigilant performance in the astronaut crews during spaceflight. Most research is focused on the behavioral aspects of the risk of circadian desynchronization, characterized by fatigue and health and performance decrement. A common countermeasure for circadian re-entrainment utilizes blue-green light to entrain the circadian clock and mitigate this risk. However, an effective countermeasure targeting the photoreceptor system requires that the basic circadian molecular machinery remains intact during spaceflight. The molecular clock consists of sets of proteins that perform different functions within the clock machinery: circadian oscillators (genes whose expression levels cycle during the day, keep the pass of cellular time and regulate downstream effector genes), the effector or output genes (those which impact the physiology of the tissue or organism), and the input genes (responsible for sensing the environmental cues that allow circadian entrainment). The main environmental cue is light. As opposed to the known photoreceptors (rods and cones), the non-visual light stimulus is received by a subset of the population of retinal ganglion cells called intrinsically photosensitive retinal ganglion cells (ipRGC) that express melanopsin (opsin 4 -Opn4-) as the photoreceptor. We hypothesize that spaceflight may affect ipRGC and melanopsin expression, which may be a contributing cause of circadian disruption during spaceflight. To answer this question, eyes from albino Balb/cJ mice aboard STS-133 were collected for histological analysis and gene expression profiling of the retina at 1 and 7 days after landing. Both vivarium and AEM (animal enclosure module) mice were used as ground controls. Opn4 expression was analyzed by real time RT/qPCR and retinal sections were stained for Opn4 immunofluorescence. Opn4 was decreased (abrogated in one case) in retinas that concurrently showed higher evidence of oxidative stress. We propose that oxidative stress can lead to a decrease in melanopsin expression, likely via ipRGC loss or impairment, and thus, it can be a contributing factor to circadian disruption during spaceflight. Countermeasures contemplating the use of light should therefore be complemented with melanopsin expression maintenance and/or reduction in oxidative stress.

Zanello, Susana↗