Electron Attachment to the Nucleobase Uracil in Diethylene Glycol: The Signature of a Doorway.

The cellular environment plays a significant role in low energy electron-mediated radiation damage to genetic materials. In this study, we have modeled the effect of the bulk medium on electron attachment to nucleobases in diethylene glycol (DEG) using uracil as a test case, in accordance with recent experimental work on the observation of dissociative quasi-free electron attachment to nucleoside via excited anion radical in solution (in DEG). Our EOM-CCSD-based quantum mechanical/molecular mechanical (QM/MM) simulations indicate that the electron scavenging by uracil in DEG is much slower than that observed in the aqueous medium due to its viscosity. This work also establishes that a doorway mechanism exists in uracil microsolvated and bulk solvated with DEG, with the dipole-bound state and solvent-bound state acting as doorway states, respectively.

Loss of Cells in the Retinal Ganglion Cell Layer as an Early Indication of Neurodegeneration in Multiple Sclerosis.

BACKGROUND: Multiple Sclerosis (MS) is a debilitating neurological disease affecting the central nervous system and significantly impacting patients' quality of life. MS is known as an autoimmune disease affecting the white matter. The disease involves inflammation, demyelination, and neurodegeneration, causing irreversible disabilities. Current treatments for MS target the inflammatory phase, with limited effects on long-term disability. While neuronal damage significantly contributes to MS pathology, mechanisms of neurodegeneration are not well studied. METHODS: This study evaluated neurodegenerative changes in the retina during disease progression, using data collected from an experimental MS model (Experimental Autoimmune Encephalomyelitis, EAE). Utilizing Hematoxylin and Eosin-stained retinal sections and assessment using Optical Coherence Tomography (OCT), the study investigated the neurodegenerative changes, such as loss of cells in the retinal ganglion cell layer (GCL) and retinal thinning in the retina of the EAE model and the control groups. RESULTS: Our results showed a significant reduction in the number of cells in the GCL of the EAE retina at two different time points studied, suggesting loss of neurons compared to the control group. Thickness measurements showed a reduction in the total retina and inner retinal layer thicknesses in the EAE retina compared to the controls. Our results indicate evidence of neurodegenerative changes in the retina of the experimental model of MS. No significant differences were observed between the percent losses of cells between the two time points studied. The pattern of cell loss suggests that neurodegeneration occurs at an earlier stage of disease progression. CONCLUSIONS: Overall, the retina is an excellent model to investigate neurodegeneration in MS, and possibly, loss of cells in the GCL could be used as an early indicator of neurodegeneration in MS and to identify novel therapeutic agents to treat the disease.

Initiation of H1-T6SS dueling between Pseudomonas aeruginosa.

The Type VI secretion system (T6SS) is a multicomponent apparatus, present in many Gram-negative bacteria, which can inhibit bacterial prey in various ecological niches. Pseudomonas aeruginosa assembles one of its three T6SS (H1-T6SS) to respond to attacks from adjacent competing bacteria. Surprisingly, repeated assemblies of the H1-T6SS, termed dueling, were described in a monoculture in the absence of an attacker strain; however, the underlying mechanism was unknown. Here, we explored the role of H2-T6SS of P. aeruginosa in triggering H1-T6SS assembly. We show that H2-T6SS inactivation in P. aeruginosa causes a significant reduction in H1-T6SS dueling and that H2-T6SS activity directly triggers retaliation by the H1-T6SS. Intraspecific competition experiments revealed that elimination of H2-T6SS in non-immune prey cells conferred protection from H1-T6SS. Moreover, we show that the H1-T6SS response is triggered independently of the characterized lipase effectors of the H2-T6SS, as well as those of Acinetobacter baylyi and Vibrio cholerae. Our results suggest that H1-T6SS response to H2-T6SS in P. aeruginosa can impact intraspecific competition, particularly when the H1-T6SS effector-immunity pairs differ between strains, and could determine the outcome of multistrain colonization.IMPORTANCEThe opportunistic pathogen Pseudomonas aeruginosa harbors three different Type VI secretion systems (H1, H2, and H3-T6SS), which can translocate toxins that can inhibit bacterial competitors or inflict damage to eukaryotic host cells. Unlike the unregulated T6SS assembly in other Gram-negative bacteria, the H1-T6SS in P. aeruginosa is precisely assembled as a response to various cell damaging attacks from neighboring bacterial cells. Surprisingly, it was observed that neighboring P. aeruginosa cells repeatedly assemble their H1-T6SS toward each other. Mechanisms triggering this "dueling" behavior between sister cells were unknown. In this report, we used a combination of microscopy, genetic and intraspecific competition experiments to show that H2-T6SS initiates H1-T6SS dueling. Our study highlights the interplay between different T6SS clusters in P. aeruginosa, which may influence the outcomes of multistrain competition in various ecological settings such as biofilm formation and colonization of cystic fibrosis lungs.

The impact of diabetes mellitus on blood-tissue barrier regulation and vascular complications: Is the lung different from other organs?

Diabetes Mellitus presents a formidable challenge as one of the most prevalent and complex chronic diseases, exerting significant strain on both patients and the world economy. It is recognized as a common comorbidity among severely ill individuals, often leading to a myriad of micro- and macro-vascular complications. Despite extensive research dissecting the pathophysiology and molecular mechanisms underlying vascular complications of diabetes, relatively little attention has been paid to potential lung-related complications. This review aims to illuminate the impact of diabetes on prevalent respiratory diseases, including chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), tuberculosis (TB), pneumonia infections, and asthma, and compare the vascular complications with other vascular beds. Additionally, we explore the primary mechanistic pathways contributing to these complications, such as the expression modulation of blood-tissue-barrier proteins, resulting in increased paracellular and transcellular permeability, and compromised immune responses rendering diabetes patients more susceptible to infections. The activation of inflammatory pathways leading to cellular injury and hastening the onset of these respiratory complications is also discussed.

Comparative Proteomic Analysis of Type 2 Diabetic versus Non-Diabetic Vitreous Fluids.

BACKGROUND: Diabetic retinopathy (DR) is a leading cause of vision loss, with complex mechanisms. The study aimed to comprehensively explore vitreous humor of diabetic and non-diabetic individuals, paving the way for identifying the potential molecular mechanisms underlying DR. METHODS: Vitreous samples from type 2 diabetic and non-diabetic subjects, collected post-mortem, were analyzed using liquid chromatography-mass spectrometry. Pathway enrichment and gene ontology analyses were conducted to identify dysregulated pathways and characterize protein functions. RESULTS: Pathway analysis revealed dysregulation in multiple metabolic and signaling pathways associated with diabetes, including glycerolipid metabolism, histidine metabolism, and Wnt signaling. Gene ontology analysis identified proteins involved in inflammation, immune response dysregulation, and calcium signaling. Notably, proteins such as Inositol 1,4,5-trisphosphate receptor type 2 (ITPR2), Calcium homeostasis endoplasmic reticulum protein (CHERP), and Coronin-1A (CORO1A) were markedly upregulated in diabetic vitreous, implicating aberrant calcium signaling, inflammatory responses, and cytoskeletal reorganization in DR. CONCLUSIONS: Our study provides valuable insights into the intricate mechanisms underlying DR and highlights the significance of inflammation, immune dysregulation, and metabolic disturbances in disease progression. Identification of specific proteins as potential biomarkers underscores the multifactorial nature of DR. Future research in this area is vital for advancing therapeutic interventions and translating findings into clinical practice.

The Space Omics and Medical Atlas (SOMA) and international astronaut biobank.

Spaceflight induces molecular, cellular and physiological shifts in astronauts and poses myriad biomedical challenges to the human body, which are becoming increasingly relevant as more humans venture into space1-6. Yet current frameworks for aerospace medicine are nascent and lag far behind advancements in precision medicine on Earth, underscoring the need for rapid development of space medicine databases, tools and protocols. Here we present the Space Omics and Medical Atlas (SOMA), an integrated data and sample repository for clinical, cellular and multi-omic research profiles from a diverse range of missions, including the NASA Twins Study7, JAXA CFE study8,9, SpaceX Inspiration4 crew10-12, Axiom and Polaris. The SOMA resource represents a more than tenfold increase in publicly available human space omics data, with matched samples available from the Cornell Aerospace Medicine Biobank. The Atlas includes extensive molecular and physiological profiles encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics and microbiome datasets, which reveal some consistent features across missions, including cytokine shifts, telomere elongation and gene expression changes, as well as mission-specific molecular responses and links to orthologous, tissue-specific mouse datasets. Leveraging the datasets, tools and resources in SOMA can help to accelerate precision aerospace medicine, bringing needed health monitoring, risk mitigation and countermeasure data for upcoming lunar, Mars and exploration-class missions.

Collection of biospecimens from the inspiration4 mission establishes the standards for the space omics and medical atlas (SOMA).

The SpaceX Inspiration4 mission provided a unique opportunity to study the impact of spaceflight on the human body. Biospecimen samples were collected from four crew members longitudinally before (Launch: L-92, L-44, L-3 days), during (Flight Day: FD1, FD2, FD3), and after (Return: R + 1, R + 45, R + 82, R + 194 days) spaceflight, spanning a total of 289 days across 2021-2022. The collection process included venous whole blood, capillary dried blood spot cards, saliva, urine, stool, body swabs, capsule swabs, SpaceX Dragon capsule HEPA filter, and skin biopsies. Venous whole blood was further processed to obtain aliquots of serum, plasma, extracellular vesicles and particles, and peripheral blood mononuclear cells. In total, 2,911 sample aliquots were shipped to our central lab at Weill Cornell Medicine for downstream assays and biobanking. This paper provides an overview of the extensive biospecimen collection and highlights their processing procedures and long-term biobanking techniques, facilitating future molecular tests and evaluations.As such, this study details a robust framework for obtaining and preserving high-quality human, microbial, and environmental samples for aerospace medicine in the Space Omics and Medical Atlas (SOMA) initiative, which can aid future human spaceflight and space biology experiments.

Single-cell multi-ome and immune profiles of the Inspiration4 crew reveal conserved, cell-type, and sex-specific responses to spaceflight.

Spaceflight induces an immune response in astronauts. To better characterize this effect, we generated single-cell, multi-ome, cell-free RNA (cfRNA), biochemical, and hematology data for the SpaceX Inspiration4 (I4) mission crew. We found that 18 cytokines/chemokines related to inflammation, aging, and muscle homeostasis changed after spaceflight. In I4 single-cell multi-omics data, we identified a "spaceflight signature" of gene expression characterized by enrichment in oxidative phosphorylation, UV response, immune function, and TCF21 pathways. We confirmed the presence of this signature in independent datasets, including the NASA Twins Study, the I4 skin spatial transcriptomics, and 817 NASA GeneLab mouse transcriptomes. Finally, we observed that (1) T cells showed an up-regulation of FOXP3, (2) MHC class I genes exhibited long-term suppression, and (3) infection-related immune pathways were associated with microbiome shifts. In summary, this study reveals conserved and distinct immune disruptions occurring and details a roadmap for potential countermeasures to preserve astronaut health.

Secretome profiling reveals acute changes in oxidative stress, brain homeostasis, and coagulation following short-duration spaceflight.

As spaceflight becomes more common with commercial crews, blood-based measures of crew health can guide both astronaut biomedicine and countermeasures. By profiling plasma proteins, metabolites, and extracellular vesicles/particles (EVPs) from the SpaceX Inspiration4 crew, we generated "spaceflight secretome profiles," which showed significant differences in coagulation, oxidative stress, and brain-enriched proteins. While >93% of differentially abundant proteins (DAPs) in vesicles and metabolites recovered within six months, the majority (73%) of plasma DAPs were still perturbed post-flight. Moreover, these proteomic alterations correlated better with peripheral blood mononuclear cells than whole blood, suggesting that immune cells contribute more DAPs than erythrocytes. Finally, to discern possible mechanisms leading to brain-enriched protein detection and blood-brain barrier (BBB) disruption, we examined protein changes in dissected brains of spaceflight mice, which showed increases in PECAM-1, a marker of BBB integrity. These data highlight how even short-duration spaceflight can disrupt human and murine physiology and identify spaceflight biomarkers that can guide countermeasure development.

Spatial multi-omics of human skin reveals KRAS and inflammatory responses to spaceflight.

Spaceflight can change metabolic, immunological, and biological homeostasis and cause skin rashes and irritation, yet the molecular basis remains unclear. To investigate the impact of short-duration spaceflight on the skin, we conducted skin biopsies on the Inspiration4 crew members before (L-44) and after (R + 1) flight. Leveraging multi-omics assays including GeoMx™ Digital Spatial Profiler, single-cell RNA/ATAC-seq, and metagenomics/metatranscriptomics, we assessed spatial gene expressions and associated microbial and immune changes across 95 skin regions in four compartments: outer epidermis, inner epidermis, outer dermis, and vasculature. Post-flight samples showed significant up-regulation of genes related to inflammation and KRAS signaling across all skin regions. These spaceflight-associated changes mapped to specific cellular responses, including altered interferon responses, DNA damage, epithelial barrier disruptions, T-cell migration, and hindered regeneration were located primarily in outer tissue compartments. We also linked epithelial disruption to microbial shifts in skin swab and immune cell activity to PBMC single-cell data from the same crew and timepoints. Our findings present the inaugural collection and examination of astronaut skin, offering insights for future space missions and response countermeasures.

Liquid phase selective oxidation of veratryl alcohol to veratraldehyde using pure and Mg-doped copper chromite catalysts.

Mg-doped copper chromite (CuCr2O4) nanocomposites were synthesised through conventional technique. The pure and doped CuCr2-xMgx O4 (x = 0.00-0.1, 0.2 and 0.3%) nanocomposites were characterized in terms of their morphology, crystal structure, surface area and catalytic performance. The chemical composition of CuCr2-xMgx O4 was confirmed via FT-IR. The formation of pure and doped catalysts was validated by XRD results. TEM/SEM confirmed the formation of CuCr2-xMgxO4 nanoparticles. Mg-doped samples possess a high specific surface area compared to pure CuCr2O4. Thus, the effects of temperature, solvent, time, oxidant and the amount of catalyst on the oxidation of veratryl alcohol were reported. Furthermore, detailed mechanisms of the catalytic oxidation of veratryl alcohol as well as the reusability and stability of the nanomaterial were investigated. The resulting composites were shown to be effective heterogeneous catalysts for the oxidation of veratryl alcohol.

Spermine oxidase inhibitor, MDL 72527, reduced neovascularization, vascular permeability, and acrolein-conjugated proteins in a mouse model of ischemic retinopathy.

Disruptions in polyamine metabolism have been identified as contributing factors to various central nervous system disorders. Our laboratory has previously highlighted the crucial role of polyamine oxidation in retinal disease models, specifically noting elevated levels of spermine oxidase (SMOX) in inner retinal neurons. Our prior research demonstrated that inhibiting SMOX with MDL 72527 protected against vascular injury and microglial activation induced by hyperoxia in the retina. However, the effects of SMOX inhibition on retinal neovascularization and vascular permeability, along with the underlying molecular mechanisms of vascular protection, remain incompletely understood. In this study, we utilized the oxygen-induced retinopathy (OIR) model to explore the impact of SMOX inhibition on retinal neovascularization, vascular permeability, and the molecular mechanisms underlying MDL 72527-mediated vasoprotection in the OIR retina. Our findings indicate that inhibiting SMOX with MDL 72527 mitigated vaso-obliteration and neovascularization in the OIR retina. Additionally, it reduced OIR-induced vascular permeability and Claudin-5 expression, suppressed acrolein-conjugated protein levels, and downregulated P38/ERK1/2/STAT3 signaling. Furthermore, our results revealed that treatment with BSA-Acrolein conjugates significantly decreased the viability of human retinal endothelial cells (HRECs) and activated P38 signaling. These observations contribute valuable insights into the potential therapeutic benefits of SMOX inhibition by MDL 72527 in ischemic retinopathy.

Genome and clonal hematopoiesis stability contrasts with immune, cfDNA, mitochondrial, and telomere length changes during short duration spaceflight.

Background: The Inspiration4 (I4) mission, the first all-civilian orbital flight mission, investigated the physiological effects of short-duration spaceflight through a multi-omic approach. Despite advances, there remains much to learn about human adaptation to spaceflight's unique challenges, including microgravity, immune system perturbations, and radiation exposure. Methods: To provide a detailed genetics analysis of the mission, we collected dried blood spots pre-, during, and post-flight for DNA extraction. Telomere length was measured by quantitative PCR, while whole genome and cfDNA sequencing provided insight into genomic stability and immune adaptations. A robust bioinformatic pipeline was used for data analysis, including variant calling to assess mutational burden. Result: Telomere elongation occurred during spaceflight and shortened after return to Earth. Cell-free DNA analysis revealed increased immune cell signatures post-flight. No significant clonal hematopoiesis of indeterminate potential (CHIP) or whole-genome instability was observed. The long-term gene expression changes across immune cells suggested cellular adaptations to the space environment persisting months post-flight. Conclusion: Our findings provide valuable insights into the physiological consequences of short-duration spaceflight, with telomere dynamics and immune cell gene expression adapting to spaceflight and persisting after return to Earth. CHIP sequencing data will serve as a reference point for studying the early development of CHIP in astronauts, an understudied phenomenon as previous studies have focused on career astronauts. This study will serve as a reference point for future commercial and non-commercial spaceflight, low Earth orbit (LEO) missions, and deep-space exploration.

Catalogue of the moniligastrid earthworms (Clitellata, Moniligastrida, Moniligastridae) of the world.

This study presents a comprehensive catalogue of the moniligastrid earthworms (Moniligastrida, Moniligastridae) of the world. A total of 176 valid species/subspecies belonging to 5 genera are known to exist in this primitive family. Drawida is the speciose genus with 147 species/subspecies. Of the various moniligastrids, three species of Drawida are considered as peregrine outside its normal Asian range. Among the valid species, occurrence of 30.68% are known only from the type locality. It is noteworthy that the types of 125 (71.02%) species are currently known to exist in various repositories around the world. The existence of the remaining species can only be inferred from the literature since their types are either non-existent, missing, dried out, or lost. Present catalogue includes valid scientific names, synonyms, type locality, type respository details along with registration number, geographic distribution pattern within its native range, and references.

EXtraction or PREServation? EXPRESS survey of patients' preference for toothache in public health facilities of Eastern India.

OBJECTIVE: To investigate patients' preference for extraction or preservation for toothache and hypothetical anterior tooth pain along with the specific reason for their choice. BASIC RESEARCH DESIGN: Cross-sectional analytical semi-structured interview study. PARTICIPANTS: A sample of 703 adult dental outpatients visiting secondary and tertiary government health centres with toothache due to dental caries in Eastern India. MAIN OUTCOME MEASURES: Patients preferring restorative or extraction services for toothache, specific reason, and socio-demographic background factors for anterior and posterior teeth. RESULTS: Half (50.1%) choose preservation for present toothache and 79.9% for hypothetical front tooth pain. Immediate relief from toothache for extraction and the motive to preserve natural teeth for preservation were the main reasons expressed. In logistic regression, participants preferring extraction were more likely to be aged 25-34 years (OR = 1.94), 55+ years (OR=33.32), have primary and below education level (OR=1.99), have had a previous extraction (OR=1.99) and be unaware of preservation options (OR=2.34). For assumed anterior tooth pain, those between 25-34 years (OR=0.39) were more likely to choose preservation. Participants with primary and below education levels (OR=1.99) and unaware of preservation options (OR=1.95) chose extraction of the front tooth irrespective of their choice of treatment for the present toothache. CONCLUSION: Notable differences between the choices to preserve or extract a posterior tooth were not found. There was greater preference towards preserving anterior teeth. Future research should identify additional barriers to the preference and utilization of restorative services.

A comprehensive SARS-CoV-2 and COVID-19 review, Part 2: host extracellular to systemic effects of SARS-CoV-2 infection.

COVID-19, the disease caused by SARS-CoV-2, has caused significant morbidity and mortality worldwide. The betacoronavirus continues to evolve with global health implications as we race to learn more to curb its transmission, evolution, and sequelae. The focus of this review, the second of a three-part series, is on the biological effects of the SARS-CoV-2 virus on post-acute disease in the context of tissue and organ adaptations and damage. We highlight the current knowledge and describe how virological, animal, and clinical studies have shed light on the mechanisms driving the varied clinical diagnoses and observations of COVID-19 patients. Moreover, we describe how investigations into SARS-CoV-2 effects have informed the understanding of viral pathogenesis and provide innovative pathways for future research on the mechanisms of viral diseases.

Correlation between the particle size, structural and photoluminescence spectra of nano NiCr2O4 and La doped NiCr2O4 materials.

Nano NiCr2O4 undoped and La doped NiCr2O4 nanorods array were successfully prepared by solution based conventional method[sbcm]. The synthesized samples were characterized by the diffuse reflectance spectroscopy (DRS) and photoluminescence (PL) spectroscopy for finding optical properties. Further, the samples structure confirmed by Fourier transforms infrared (FTIR), and X-ray diffraction (XRD)techniques. High-resolution transmission electron microscopy (HRTEM) analysis revealed the attachment of NiCr2O4 nanorods on surface of nanoparticles. From the results, it was found that the reaction time, band gap energy, and particle size strongly influenced by changing the concentration of La in NiCr2O4. This work is notable for its examination of the impact of the precursor on the optical and structural characteristics of samples of La-doped and undoped NiCr2O4. This was the first time the investigation had been done. The average particle size of the La-doped and undoped NiCr2O4 samples is between 16 and 24 nm.

Pharmacological Modulation of ß-Catenin Preserves Endothelial Barrier Integrity and Mitigates Retinal Vascular Permeability and Inflammation.

Compromised blood-retinal barrier (BRB) integrity is a significant factor in ocular diseases like uveitis and retinopathies, leading to pathological vascular permeability and retinal edema. Adherens and tight junction (AJ and TJ) dysregulation due to retinal inflammation plays a pivotal role in BRB disruption. We investigated the potential of ICG001, which inhibits ß-catenin-mediated transcription, in stabilizing cell junctions and preventing BRB leakage. In vitro studies using human retinal endothelial cells (HRECs) showed that ICG001 treatment improved ß-Catenin distribution within AJs post lipopolysaccharide (LPS) treatment and enhanced monolayer barrier resistance. The in vivo experiments involved a mouse model of LPS-induced ocular inflammation. LPS treatment resulted in increased albumin leakage from retinal vessels, elevated vascular endothelial growth factor (VEGF) and Plasmalemmal Vesicle-Associated Protein (PLVAP) expression, as well as microglia and macroglia activation. ICG001 treatment (i.p.) effectively mitigated albumin leakage, reduced VEGF and PLVAP expression, and reduced the number of activated microglia/macrophages. Furthermore, ICG001 treatment suppressed the surge in inflammatory cytokine synthesis induced by LPS. These findings highlight the potential of interventions targeting ß-Catenin to enhance cell junction stability and improve compromised barrier integrity in various ocular inflammatory diseases, offering hope for better management and treatment options.

A multi-arm, parallel, preclinical study investigating the potential benefits of acetazolamide, candesartan, and triciribine in combination with fluconazole for the treatment of cryptococcal meningoencephalitis.

Cryptococcus neoformans, an opportunistic fungal pathogen, primarily infects immunodeficient patients frequently causing cryptococcal meningoencephalitis (CM). Increased intracranial pressure (ICP) is a serious complication responsible for increased morbidity and mortality in CM patients. Non-invasive pharmacological agents that mitigate ICP could be beneficial in treating CM patients. The objective of the study was to investigate the efficacy of acetazolamide (AZA), candesartan (CAN), and triciribine (TCBN), in combination with the antifungal fluconazole, on C. neoformans-induced endothelial, brain, and lung injury in an experimental mouse model of CM. Our study shows that C. neoformans increases the expression of brain endothelial cell (BEC) junction proteins Claudin-5 (Cldn5) and VE-Cadherin to induce pathological cell-barrier remodeling and gap formation associated with increased Akt and p38 MAPK activation. All three agents inhibited C. neoformans-induced endothelial gap formation, only CAN and TCBN significantly reduced C. neoformans-induced Cldn5 expression, and only TCBN was effective in inhibiting Akt and p38MAPK. Interestingly, although C. neoformans did not cause brain or lung edema in mice, it induced lung and brain injuries, which were significantly reversed by AZA, CAN, or TCBN. Our study provides novel insights into the direct effects of C. neoformans on BECs in vitro, and the potential benefits of using AZA, CAN, or TCBN in the management of CM patients.

Neurovascular dysfunction associated with erectile dysfunction persists after long-term recovery from simulations of weightlessness and deep space irradiation.

There has been growing interest within the space industry for long-duration manned expeditions to the Moon and Mars. During deep space missions, astronauts are exposed to high levels of galactic cosmic radiation (GCR) and microgravity which are associated with increased risk of oxidative stress and endothelial dysfunction. Oxidative stress and endothelial dysfunction are causative factors in the pathogenesis of erectile dysfunction, although the effects of spaceflight on erectile function have been unexplored. Therefore, the purpose of this study was to investigate the effects of simulated spaceflight and long-term recovery on tissues critical for erectile function, the distal internal pudendal artery (dIPA), and the corpus cavernosum (CC). Eighty-six adult male Fisher-344 rats were randomized into six groups and exposed to 4-weeks of hindlimb unloading (HLU) or weight-bearing control, and sham (0Gy), 0.75 Gy, or 1.5 Gy of simulated GCR at the ground-based GCR simulator at the NASA Space Radiation Laboratory. Following a 12-13-month recovery, ex vivo physiological analysis of the dIPA and CC tissue segments revealed differential impacts of HLU and GCR on endothelium-dependent and -independent relaxation that was tissue type specific. GCR impaired non-adrenergic non-cholinergic (NANC) nerve-mediated relaxation in the dIPA and CC, while follow-up experiments of the CC showed restoration of NANC-mediated relaxation of GCR tissues following acute incubation with the antioxidants mito-TEMPO and TEMPOL, as well as inhibitors of xanthine oxidase and arginase. These findings indicate that simulated spaceflight exerts a long-term impairment of neurovascular erectile function, which exposes a new health risk to consider with deep space exploration.