A Second Space Age Spanning Omics, Platforms, and Medicine Across Orbits.

The recent acceleration of commercial, private, and multi-national spaceflight has created an unprecedented level of activity in low Earth orbit (LEO), concomitant with the highest-ever number of crewed missions entering space and preparations for exploration-class (>1 year) missions. Such rapid advancement into space from many new companies, countries, and space-related entities has enabled a"Second Space Age." This new era is also poised to leverage, for the first time, modern tools and methods of molecular biology and precision medicine, thus enabling precision aerospace medicine for the crews. The applications of these biomedical technologies and algorithms are diverse, encompassing multi-omic, single-cell, and spatial biology tools to investigate human and microbial responses to spaceflight. Additionally, they extend to the development of new imaging techniques, real-time cognitive assessments, physiological monitoring, and personalized risk profiles tailored for astronauts. Furthermore, these technologies enable advancements in pharmacogenomics (PGx), as well as the identification of novel spaceflight biomarkers and the development of corresponding countermeasures. In this review, we highlight some of the recent biomedical research from the National Aeronautics and Space Administration (NASA), Japan Aerospace Exploration Agency (JAXA), European Space Agency (ESA), and other space agencies, and also detail the commercial spaceflight sector's (e.g. SpaceX, Blue Origin, Axiom, Sierra Space) entrance into aerospace medicine and space biology, the first aerospace medicine biobank, and the myriad upcoming missions that will utilize these tools to ensure a permanent human presence beyond LEO, venturing out to other planets and moons.

Space radiation damage rescued by inhibition of key spaceflight associated miRNAs.

Our previous research revealed a key microRNA signature that is associated with spaceflight that can be used as a biomarker and to develop countermeasure treatments to mitigate the damage caused by space radiation. Here, we expand on this work to determine the biological factors rescued by the countermeasure treatment. We performed RNA-sequencing and transcriptomic analysis on 3D microvessel cell cultures exposed to simulated deep space radiation (0.5 Gy of Galactic Cosmic Radiation) with and without the antagonists to three microRNAs: miR-16-5p, miR-125b-5p, and let-7a-5p (i.e., antagomirs). Significant reduction of inflammation and DNA double strand breaks (DSBs) activity and rescue of mitochondria functions are observed after antagomir treatment. Using data from astronaut participants in the NASA Twin Study, Inspiration4, and JAXA missions, we reveal the genes and pathways implicated in the action of these antagomirs are altered in humans. Our findings indicate a countermeasure strategy that can potentially be utilized by astronauts in spaceflight missions to mitigate space radiation damage.

Transcriptomics analysis reveals molecular alterations underpinning spaceflight dermatology.

BACKGROUND: Spaceflight poses a unique set of challenges to humans and the hostile spaceflight environment can induce a wide range of increased health risks, including dermatological issues. The biology driving the frequency of skin issues in astronauts is currently not well understood. METHODS: To address this issue, we used a systems biology approach utilizing NASA's Open Science Data Repository (OSDR) on space flown murine transcriptomic datasets focused on the skin, biochemical profiles of 50 NASA astronauts and human transcriptomic datasets generated from blood and hair samples of JAXA astronauts, as well as blood samples obtained from the NASA Twins Study, and skin and blood samples from the first civilian commercial mission, Inspiration4. RESULTS: Key biological changes related to skin health, DNA damage & repair, and mitochondrial dysregulation are identified as potential drivers for skin health risks during spaceflight. Additionally, a machine learning model is utilized to determine gene pairings associated with spaceflight response in the skin. While we identified spaceflight-induced dysregulation, such as alterations in genes associated with skin barrier function and collagen formation, our results also highlight the remarkable ability for organisms to re-adapt back to Earth via post-flight re-tuning of gene expression. CONCLUSION: Our findings can guide future research on developing countermeasures for mitigating spaceflight-associated skin damage.

Spaceflight is a hostile environment which can lead to health problems in astronauts, including in the skin. It is not currently well understood why these skin problems occur. Here, we analyzed data from the skin of space flown mice and astronauts to try and identify possible explanations for these skin problems. It appears that changes in the activation of genes related to damage to DNA, skin barrier health, and mitochondria (the energy-producing parts of cells) may play a role in these skin problems. Further research will be needed to confirm exactly how these changes influence skin health, which could lead to solutions for preventing and managing such issues in astronauts.

Delayed effects of radiation exposure in a C57L/J mouse model of partial body irradiation with ~2.5% bone marrow shielding.

Introduction: Mouse models of radiation injury are critical to the development of medical countermeasures (MCMs) against radiation. Now that MCMs against hematopoietic acute radiation syndrome (H-ARS) have achieved regulatory approval, attention is shifting to develop MCMs against the adverse effects of gastrointestinal acute radiation syndrome (GI-ARS) and delayed effects of acute radiation exposure (DEARE). The C57L/J mouse model of partial body irradiation (PBI) with 2.5% bone marrow shielding (BM2.5) is being leveraged to examine both GI-ARS and DEARE effects. Within days of PBI, mice may develop H- and GI-ARS followed several months later by DEARE as a multi-organ injury, which typically involves the lung and kidney (L- and K-DEARE, respectively). The objective of this manuscript is to describe the dose response relationship and progression of radiation injury in the C57L/J mouse and to evaluate its suitability for use in DEARE MCM testing. Materials and methods: In two separate studies conducted over 2 years, male and female C57L/J mice were exposed to PBI BM2.5 with one hindlimb shielded from radiation, representing ~2.5% bone marrow shielding/sparing. Mice were X-ray irradiated at doses ranging from 9 to 13 Gy at 10 to 12 weeks of age for the purposes of assessing ARS survival at 30 days and DEARE survival at 182 days post-irradiation. Clinical indicators of ARS and DEARE were determined by clinical observations, body weights, hematology, clinical chemistry, magnetic resonance imaging (MRI) of lung, and histopathology of selected tissues. Results: C57L/J mice developed canonical ARS responses of hematopoietic atrophy and gastrointestinal injury resulting in dose dependent mortality at doses ≥11 Gy between 1- and 15-days post-irradiation. In animals that survived ARS, DEARE associated mortality occurred in dose dependent fashion at ≥9 Gy for both sexes between 60- and 159-days post-irradiation with histopathology examinations indicating lung injury as the primary cause of death in moribund animals. Conclusion: The PBI BM2.5 C57L/J mouse model reliably produced known H- and GI-ARS effects at doses greater than those resulting in DEARE effects. Because of this, the C57L/J mouse can be used to test MCMs against L-DEARE injury, while avoiding ARS associated mortality.

Projected health and economic outcomes of extending public funding of pharmacy services to include administration of Pneu23 and Td/Tdap immunizations by pharmacy practitioners in New Brunswick.

Background: Although legislation permits New Brunswick pharmacy professionals to administer a wide range of immunizations, public funding for these services is currently limited to immunizations against influenza and COVID-19 and was recently extended to include pneumococcal immunization (Pneu23) in individuals aged 65 years or older. We used administrative data to project health and economic outcomes associated with the current Pneu23 program and with extension of public funding to include: 1) younger adults aged 19 years or older in the Pneu23 program, and 2) tetanus boosters (Td/Tdap). Methods: Two model scenarios were compared: a Physician-Only model in which physicians remain the only practitioners to administer publicly funded Pneu23 and Td/Tdap, and a Blended model in which this service is also provided by pharmacy professionals. Immunization rates by practitioner type were projected based on physician billing data accessed via the New Brunswick Institute for Research, Data and Training in conjunction with trends observed with influenza immunization by pharmacists. These projections were used along with published data to estimate health and economic outcomes under each model. Results: Public funding of Pneu23 (65+), Pneu23 (19+) and Td/Tdap (19+) administration by pharmacy professionals is projected to yield increased immunization rates and physician time savings compared with the Physician-Only model. Public funding of Pneu23 and Td/Tdap administration by pharmacy professionals in those aged ≥19 years would result in cost savings, owing primarily to productivity losses avoided in the working age population. Discussion: Increased immunization rates, physician time savings and cost savings may be realized if public funding were extended to include administration of Pneu23 in younger adults and Td/Tdap, by pharmacy practitioners.

Removal of hydrophilic, hydrophobic, and charged xenobiotic organic compounds from greywater using green wall media.

Green walls offer a novel on-site approach for greywater treatment and reuse in densely build urban environments. However, they need to be engineered for effective removal of a wide range of emerging contaminants such as xenobiotic organic compounds (XOCs), which may be present in greywater due to extensive use of personal care products and household chemicals. This study used laboratory column design and batch experiments to investigate the performance of three lightweight green wall media (coco coir, zeolite, and perlite) and their mixture in three different combinations for the removal of twelve XOCs, covering wide range of hydrophilic, hydrophobic, and charged pollutants in greywater. The experiments were designed to assess the removal of targeted XOCs under different operational condition (i.e., hydraulic loading, infiltration rate, drying) and uncover the dominant mechanisms of their removal. Results showed excellent removal (>90%) of all XOCs in coco coir and media mix columns at the start of the experiment (i.e., fresh media and initial 2 pore volume (PV) of greywater dosing). The removal of highly hydrophobic and positively charged XOCs remained high (>90%) under all operational conditions, while hydrophilic and negatively charged XOCs exhibited significant reduction in removal after 25 PV and 50 PV, possibly due to their low adsorption affinity and electrostatic repulsion from negatively charged media. The effect of infiltration rate on the removal of XOCs was not significant; however, higher removal was achieved after 2-weeks of drying in coco coir and media mix columns. The dominant removal mechanism for most XOCs was found to be adsorption, however, a few hydrophilic XOCs (i.e., acetaminophen and atrazine) exhibited both adsorption and biodegradation removal processes. While findings showed promising prospects of unvegetated media for removing XOCs from greywater, long term studies on vegetated green wall systems are needed to understand any synergetic contribution of plants and media in removing these XOCs.

Characterization of GATA3 and Mammaglobin in breast tumors from African American Women.

GATA3 and Mammaglobin are often used in the clinic to identify metastases of mammary origin due to their robust and diffuse expression in mammary tissue. However, the expression of these markers has not been well characterized in tumors from African American women. The goal of this study was to characterize and evaluate the expression of GATA3 and mammaglobin in breast tumors from African American women and determine their association with clinicopathological outcomes including breast cancer subtypes. Tissue microarrays (TMAs) were constructed from well preserved, morphologically representative tumors in archived formalin-fixed, paraffin-embedded (FFPE) surgical blocks from 202 patients with primary invasive ductal carcinoma. Mammaglobin and GATA3 expression was assessed using immunohistochemistry (IHC). Univariate analysis was carried out to determine the association between expression of GATA3, mammaglobin and clinicopathological characteristics. Kaplan-Meier estimates of overall survival and disease-free survival were also plotted and a log-rank test performed to compare estimates among groups. GATA3 expression showed statistically significant association with lower grade (p<0.001), ER-positivity (p<0.001), PR-positivity (p<0.001), and the luminal subtype (p<0.001). Mammaglobin expression was also significantly associated with lower grade (p=0.031), ER-positivity (p=0.007), and PR-positivity (p=0.022). There was no association with recurrence-free or overall survival. Our results confirm that GATA3 and mammaglobin demonstrate expression predominantly in luminal breast cancers from African American women. Additional markers with improved specificity and sensitivity are warranted for triple negative breast tumors given the high prevalence in women of African descent.

Innovation in lignocellulosics dewatering and drying for energy sustainability and enhanced utilization of forestry, agriculture, and marine resources - A review.

Efficient utilization of forestry, agriculture, and marine resources in various manufacturing sectors requires optimizing fiber transformation, dewatering, and drying energy consumption. These processes play a crucial role in reducing the carbon footprint and boosting sustainability within the circular bioeconomy framework. Despite efforts made in the paper industry to enhance productivity while conserving resources and energy through lower grammage and higher machine speeds, reducing thermal energy consumption during papermaking remains a significant challenge. A key approach to address this challenge lies in increasing dewatering of the fiber web before entering the dryer section of the paper machine. Similarly, the production of high-value-added products derived from alternative lignocellulosic feedstocks, such as nanocellulose and microalgae, requires advanced dewatering techniques for techno-economic viability. This critical and systematic review aims to comprehensively explore the intricate interactions between water and lignocellulosic surfaces, as well as the leading technologies used to enhance dewatering and drying. Recent developments in technologies to reduce water content during papermaking, and advanced dewatering techniques for nanocellulosic and microalgal feedstocks are addressed. Existing research highlights several fundamental and technical challenges spanning from the nano- to macroscopic scales that must be addressed to make lignocellulosics a suitable feedstock option for industry. By identifying alternative strategies to improve water removal, this review intends to accelerate the widespread adoption of lignocellulosics as feasible manufacturing feedstocks. Moreover, this review aims to provide a fundamental understanding of the interactions, associations, and bonding mechanisms between water and cellulose fibers, nanocellulosic materials, and microalgal feedstocks. The findings of this review shed light on critical research directions necessary for advancing the efficient utilization of lignocellulosic resources and accelerating the transition towards sustainable manufacturing practices.

Characterization of GATA3 and Mammaglobin in breast tumors from African American women.

GATA3 and Mammaglobin are often used in the clinic to identify metastases of mammary origin due to their robust and diffuse expression in mammary tissue. However, the expression of these markers has not been well characterized in tumors from African American women. The goal of this study was to characterize and evaluate the expression of GATA3 and mammaglobin breast tumors from African American women and determine their association with clinicopathological outcomes including breast cancer subtypes. Tissue microarrays (TMAs) were constructed from well preserved, morphologically representative tumors in archived formalin-fixed, paraffin-embedded (FFPE) surgical blocks from 202 patients with primary invasive ductal carcinoma. Mammaglobin, and GATA3 expression was assessed using immunohistochemistry (IHC). Univariate analysis was carried out to determine the association between expression of GATA3, mammaglobin and clinicopathological characteristics. Kaplan-Meier estimates of overall survival and disease-free survival were also plotted and a log-rank test performed to compare estimates among groups. GATA3 expression showed statistically significant association with lower grade (p<0.001), ER-positivity (p<0.001), PR-positivity (p<0.001), and the luminal subtype (p<0.001). Mammaglobin expression was also significantly associated with lower grade (p=0.031), ER-positivity (p=0.007), and PR-positivity (p=0.022). There was no association with recurrence-free or overall survival. Our results confirm that GATA3 and mammaglobin demonstrate expression predominantly in luminal breast cancers from African American women. Markers with improved specificity and sensitivity are warranted given the high prevalence of triple negative breast cancer in the group.

More than a Feeling: Dermatological Changes Impacted by Spaceflight.

Spaceflight poses a unique set of challenges to humans and the hostile Spaceflight environment can induce a wide range of increased health risks, including dermatological issues. The biology driving the frequency of skin issues in astronauts is currently not well understood. To address this issue, we used a systems biology approach utilizing NASA's Open Science Data Repository (OSDR) on spaceflown murine transcriptomic datasets focused on the skin, biomedical profiles from fifty NASA astronauts, and confirmation via transcriptomic data from JAXA astronauts, the NASA Twins Study, and the first civilian commercial mission, Inspiration4. Key biological changes related to skin health, DNA damage & repair, and mitochondrial dysregulation were determined to be involved with skin health risks during Spaceflight. Additionally, a machine learning model was utilized to determine key genes driving Spaceflight response in the skin. These results can be used for determining potential countermeasures to mitigate Spaceflight damage to the skin.

Impact of the coronavirus disease 2019 (COVID-19) pandemic on the presentation of paediatric acute appendicitis: an observational study.

AIM: To determine whether there were differences in the clinical presentation of patients imaged to evaluate for acute appendicitis in 2020 compared to 2019 with the hope that this information might better identify patients who should undergo imaging work-up and those who should not. MATERIALS AND METHODS: This retrospective observational study included patients <18 years who were evaluated for appendicitis between 1 March and 31 May 2019 and 2020. A total of 465 patients were stratified by final diagnosis (appendicitis versus not appendicitis) and compared based on presenting symptoms, physical examination findings, vital signs, and laboratory test results. RESULTS: Symptoms and physical examination findings that were significant in the positive cohort in both years included right lower quadrant pain, pain with movement, migration of pain, right lower quadrant tenderness, and peritoneal findings. Reporting upper respiratory symptoms was an independent predictor of negative results among all patients and in 2019. Both negative cohorts were more likely to have negative physical examinations. Anorexia and nausea/vomiting were more likely among positive cases in 2019 whereas diarrhoea was more likely among positive cases in 2020. CONCLUSIONS: The COVID-19 pandemic did not significantly change the presenting features of acute appendicitis. The results of the present study emphasise the importance of the physical examination. The ambiguity of symptoms that mimic gastroenteritis justifies imaging in these patients.

Hereditary variants of unknown significance in African American women with breast cancer.

Expanded implementation of genetic sequencing has precipitously increased the discovery of germline and somatic variants. The direct benefit of identifying variants in actionable genes may lead to risk reduction strategies such as increased surveillance, prophylactic surgery, as well as lifestyle modifications to reduce morbidity and mortality. However, patients with African ancestry are more likely to receive inconclusive genetic testing results due to an increased number of variants of unknown significance decreasing the utility and impact on disease management and prevention. This study examines whole exome sequencing results from germline DNA samples in African American women with a family history of cancer including 37 cases that were diagnosed with breast cancer and 51 family members. Self-identified ancestry was validated and compared to the 1000 genomes population. The analysis of sequencing results was limited to 85 genes from three clinically available common genetic screening platforms. This target region had a total of 993 variants of which 6 (<1%) were pathogenic or likely pathogenic, 736 (74.1%) were benign, and 170 (17.1%) were classified as a variant of unknown significance. There was an average of 3.4±1.8 variants with an unknown significance per individual and 85 of 88 individuals (96.6%) harbored at least one of these in the targeted genes. Pathogenic or likely pathogenic variants were only found in 6 individuals for the BRCA1 (p.R1726fs, rs80357867), BRCA2 (p.K589fs, rs397507606 & p.L2805fs, rs397507402), RAD50 (p.E995fs, rs587780154), ATM (p.V2424G, rs28904921), or MUTYH (p.G396D, rs36053993) genes. Strategies to functionally validate the remaining variants of unknown significance, especially in understudied and hereditary cancer populations, are greatly needed to increase the clinical utility and utilization of clinical genetic screening platforms to reduce cancer incidence and mortality.

NRF2 Mediates Cellular Resistance to Transformation, Radiation, and Inflammation in Mice.

Nuclear factor erythroid 2-related factor 2 (NRF2) is recognized as a master transcription factor that regulates expression of numerous detoxifying and antioxidant cytoprotective genes. In fact, models of NRF2 deficiency indicate roles not only in redox regulation, but also in metabolism, inflammatory/autoimmune disease, cancer, and radioresistancy. Since ionizing radiation (IR) generates reactive oxygen species (ROS), it is not surprising it activates NRF2 pathways. However, unexpectedly, activation is often delayed for many days after the initial ROS burst. Here, we demonstrate that, as assayed by γ-H2AX staining, rapid DNA double strand break (DSB) formation by IR in primary mouse Nrf2-/- MEFs was not affected by loss of NRF2, and neither was DSB repair to any great extent. In spite of this, basal and IR-induced transformation was greatly enhanced, suggesting that NRF2 protects against late IR-induced genomic instability, at least in murine MEFs. Another possible IR- and NRF2-related event that could be altered is inflammation and NRF2 deficiency increased IR-induced NF-κB pro-inflammatory responses mostly late after exposure. The proclivity of NRF2 to restrain inflammation is also reflected in the reprogramming of tumor antigen-specific lymphocyte responses in mice where Nrf2 k.o. switches Th2 responses to Th1 polarity. Delayed NRF2 responses to IR may be critical for the immune transition from prooxidant inflammation to antioxidant healing as well as in driving cellular radioresistance and survival. Targeting NRF2 to reprogram immunity could be of considerable therapeutic benefit in radiation and immunotherapy.

The interplay between lncRNAs, RNA-binding proteins and viral genome during SARS-CoV-2 infection reveals strong connections with regulatory events involved in RNA metabolism and immune response.

Rationale: Viral infections are complex processes based on an intricate network of molecular interactions. The infectious agent hijacks components of the cellular machinery for its profit, circumventing the natural defense mechanisms triggered by the infected cell. The successful completion of the replicative viral cycle within a cell depends on the function of viral components versus the cellular defenses. Non-coding RNAs (ncRNAs) are important cellular modulators, either promoting or preventing the progression of viral infections. Among these ncRNAs, the long non-coding RNA (lncRNA) family is especially relevant due to their intrinsic functional properties and ubiquitous biological roles. Specific lncRNAs have been recently characterized as modulators of the cellular response during infection of human host cells by single stranded RNA viruses. However, the role of host lncRNAs in the infection by human RNA coronaviruses such as SARS-CoV-2 remains uncharacterized. Methods: In the present work, we have performed a transcriptomic study of a cohort of patients with different SARS-CoV-2 viral load and analyzed the involvement of lncRNAs in supporting regulatory networks based on their interaction with RNA-binding proteins (RBPs). Results: Our results revealed the existence of a SARS-CoV-2 infection-dependent pattern of transcriptional up-regulation in which specific lncRNAs are an integral component. To determine the role of these lncRNAs, we performed a functional correlation analysis complemented with the study of the validated interactions between lncRNAs and RBPs. This combination of in silico functional association studies and experimental evidence allowed us to identify a lncRNA signature composed of six elements - NRIR, BISPR, MIR155HG, FMR1-IT1, USP30-AS1, and U62317.2 - associated with the regulation of SARS-CoV-2 infection. Conclusions: We propose a competition mechanism between the viral RNA genome and the regulatory lncRNAs in the sequestering of specific RBPs that modulates the interferon response and the regulation of RNA surveillance by nonsense-mediated decay (NMD).

MnTE-2-PyP protects fibroblast mitochondria from hyperglycemia and radiation exposure.

Radiation is a common anticancer therapy for prostate cancer, which transforms tumor-associated normal fibroblasts to myofibroblasts, resulting in fibrosis. Oxidative stress caused by radiation-mediated mitochondrial damage is one of the major contributors to fibrosis. As diabetics are oxidatively stressed, radiation-mediated reactive oxygen species cause severe treatment failure, treatment-related side effects, and significantly reduced survival for diabetic prostate cancer patients as compared to non-diabetic prostate cancer patients. Hyperglycemia and enhanced mitochondrial damage significantly contribute to oxidative damage and disease progression after radiation therapy among diabetic prostate cancer patients. Therefore, reduction of mitochondrial damage in normal prostate fibroblasts after radiation should improve the overall clinical state of diabetic prostate cancer patients. We previously reported that MnTE-2-PyP, a manganese porphyrin, reduces oxidative damage in irradiated hyperglycemic prostate fibroblasts by scavenging superoxide and activating NRF2. In the current study, we have investigated the potential role of MnTE-2-PyP to protect mitochondrial health in irradiated hyperglycemic prostate fibroblasts. This study revealed that hyperglycemia and radiation increased mitochondrial ROS via blocking the mitochondrial electron transport chain, altered mitochondrial dynamics, and reduced mitochondrial biogenesis. Increased mitochondrial damage preceeded an increase in myofibroblast differentiation. MnTE-2-PyP reduced myofibroblast differentiation, improved mitochondrial health by releasing the block on the mitochondrial electron transport chain, enhanced ATP production efficiency, and restored mitochondrial dynamics and metabolism in the irradiated-hyperglycemic prostate fibroblasts. Therefore, we are proposing that one of the mechanisms that MnTE-2-PyP protects prostate fibroblasts from irradiation and hyperglycemia-mediated damage is by protecting the mitochondrial health in diabetic prostate cancer patients.

Optimizing Bleaching Operating Conditions Based on Mathematical Programming to Reduce AOX Emissions.

This study describes the optimization of a eucalyptus elemental chlorine-free (ECF) bleach plant to reduce adsorbable organic halogen (AOX). The correlations between operating conditions of each stage and pulp quality indices as well as the AOX content in wastewater are analyzed, taking an ECF bleaching technology (D0EpPD1) as an example. The calculation models of pulp quality indices and AOX content in wastewater are established. Then, an optimization model aiming at minimizing AOX emission is structured. The model shows a good simulation effect because the errors between the calculated and experimental values are within 6.3%. By analyzing the impact of various operating conditions on AOX emissions, it was found that chlorine dioxide reduced in the D0 stage has the greatest impact on AOX. The optimization results show that AOX can be reduced from 90.84 to 79.58 kg/h, a decrease of 12.5%. The verification experiment results based on the optimized operating conditions showed that the experimental results are in good agreement with the calculated results of the optimization model, and the effect of reducing AOX based on the optimization model is obvious.

MOP and NOP receptor interaction: Studies with a dual expression system and bivalent peptide ligands.

Opioids targeting mu;µ (MOP) receptors produce analgesia in the peri-operative period and palliative care. They also produce side effects including respiratory depression, tolerance/dependence and addiction. The N/OFQ opioid receptor (NOP) also produces analgesia but is devoid of the major MOP side effects. Evidence exists for MOP-NOP interaction and mixed MOP-NOP ligands produce analgesia with reduced side effects. We have generated a HEKMOP/NOP human expression system and used bivalent MOP-NOP and fluorescent ligands to (i) probe for receptor interaction and (ii) consequences of that interaction. We used HEKMOP/NOP cells and two bivalent ligands; Dermorphin-N/OFQ (MOP agonist-NOP agonist; DeNO) and Dermorphin-UFP101 (MOP agonist-NOP antagonist; De101). We have determined receptor binding profiles, GTPγ[35S] binding, cAMP formation and ERK1/2 activation. We have also probed MOP and NOP receptor interactions in HEK cells and hippocampal neurones using the novel MOP fluorescent ligand, DermorphinATTO488 and the NOP fluorescent ligand N/OFQATTO594. In HEKMOP/NOP MOP ligands displaced NOP binding and NOP ligands displaced MOP binding. Using fluorescent probes in HEKMOP/NOP cells we demonstrated MOP-NOP probe overlap and a FRET signal indicating co-localisation. MOP-NOP were also co-localised in hippocampal tissue. In GTPγ[35S] and cAMP assays NOP stimulation shifted the response to MOP rightwards. At ERK1/2 the response to bivalent ligands generally peaked later. We provide evidence for MOP-NOP interaction in recombinant and native tissue. NOP activation reduces responsiveness of MOP activation; this was shown with conventional and bivalent ligands.

Genomic Changes Driven by Radiation-Induced DNA Damage and Microgravity in Human Cells.

The space environment consists of a complex mixture of different types of ionizing radiation and altered gravity that represents a threat to humans during space missions. In particular, individual radiation sensitivity is strictly related to the risk of space radiation carcinogenesis. Therefore, in view of future missions to the Moon and Mars, there is an urgent need to estimate as accurately as possible the individual risk from space exposure to improve the safety of space exploration. In this review, we survey the combined effects from the two main physical components of the space environment, ionizing radiation and microgravity, to alter the genetics and epigenetics of human cells, considering both real and simulated space conditions. Data collected from studies on human cells are discussed for their potential use to estimate individual radiation carcinogenesis risk from space exposure.

Role of miR-2392 in driving SARS-CoV-2 infection.

MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provide an exciting avenue toward antiviral therapeutics. From patient transcriptomic data, we determined that a circulating miRNA, miR-2392, is directly involved with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) machinery during host infection. Specifically, we show that miR-2392 is key in driving downstream suppression of mitochondrial gene expression, increasing inflammation, glycolysis, and hypoxia, as well as promoting many symptoms associated with coronavirus disease 2019 (COVID-19) infection. We demonstrate that miR-2392 is present in the blood and urine of patients positive for COVID-19 but is not present in patients negative for COVID-19. These findings indicate the potential for developing a minimally invasive COVID-19 detection method. Lastly, using in vitro human and in vivo hamster models, we design a miRNA-based antiviral therapeutic that targets miR-2392, significantly reduces SARS-CoV-2 viability in hamsters, and may potentially inhibit a COVID-19 disease state in humans.