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.

Arginase: A Multifaceted Enzyme Important in Health and Disease.

The arginase enzyme developed in early life forms and was maintained during evolution. As the last step in the urea cycle, arginase cleaves l-arginine to form urea and l-ornithine. The urea cycle provides protection against excess ammonia, while l-ornithine is needed for cell proliferation, collagen formation, and other physiological functions. In mammals, increases in arginase activity have been linked to dysfunction and pathologies of the cardiovascular system, kidney, and central nervous system and also to dysfunction of the immune system and cancer. Two important aspects of the excessive activity of arginase may be involved in diseases. First, overly active arginase can reduce the supply of l-arginine needed for the production of nitric oxide (NO) by NO synthase. Second, too much l-ornithine can lead to structural problems in the vasculature, neuronal toxicity, and abnormal growth of tumor cells. Seminal studies have demonstrated that increased formation of reactive oxygen species and key inflammatory mediators promote this pathological elevation of arginase activity. Here, we review the involvement of arginase in diseases affecting the cardiovascular, renal, and central nervous system and cancer and discuss the value of therapies targeting the elevated activity of arginase.

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.

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.

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.

Electron Attachment to DNA: The Protective Role of Amino Acids.

We have studied the effect of amino acids on the electron attachment properties of a DNA nucleobase, with cytosine as a model system. The equation of motion coupled cluster theory with an extended basis set has been used to simulate the electron-attached state of the DNA model system. Arginine, alanine, lysine, and glycine are the four amino acids considered to investigate their role in electron attachment to a DNA nucleobase. The electron attachment to cytosine in all the four cytosine-amino acid gas-phase dimer complexes follows a doorway mechanism, where the electron gets transferred from the initial dipole-bound doorway state to the final nucleobase-bound state through the mixing of electronic and nuclear degrees of freedom. When cytosine is bulk-solvated with glycine, the glycine-bound state acts as the doorway state, where the initial electron density is localized on the bulk amino acid and away from the nucleobase, thus leading to the physical shielding of the nucleobase from the incoming electron. At the same time, the presence of amino acids can increase the stability of the nucleobase-bound anionic state, which can suppress the sugar-phosphate bond rupture caused by dissociative electron attachment to DNA.

Electron Attachment to Wobble Base Pairs.

We have analyzed the low-energy electron attachment to wobble base pairs using the equation of motion coupled cluster method and extended basis sets. A doorway mechanism exists for the attachment of the additional electron to the base pairs, where the initially formed dipole-bound anion captures the incoming electron. The doorway dipole-bound anionic state subsequently leads to the formation of a valence-bound state, and the transfer of extra electron occurs by mixing of electronic and nuclear degrees of freedom. The formation of the valence-bound anion is associated with proton transfer in hypoxanthine-cytosine and hypoxanthine-adenine base pairs, which happens through a concerted electron-proton transfer process. The calculated rate constant for the dipole-bound to valence-bound transition in wobble base pairs is slower than that observed in the Watson-Crick guanine-cytosine base pair.

Prediction of successful hearing aid treatment in first-time and experienced hearing aid users: Using the International Outcome Inventory for Hearing Aids.

OBJECTIVE: Primarily to understand whether clinically relevant factors affect the International Outcome Inventory (IOI-HA) scores and to examine if IOI-HA scores improve when renewing the hearing aids (HA) for experienced users. Secondly, to estimate the overall HA effectiveness using the IOI-HA. DESIGN: A prospective observational study. STUDY SAMPLE: In total, 1961 patients with hearing loss were included. All patients underwent a hearing examination, were fitted with HAs, and answered the IOI-HA. Factor analysis of IOI-HA separated the items into a Factor 1 (use of HA, perceived benefits, satisfaction, and quality of life) and Factor 2 (residual activity limitation, residual participation restriction and impact on others) score. RESULTS: Degree of hearing loss, word recognition score, motivation, HA usage time, tinnitus, asymmetry, and sex were significantly associated with total IOI-HA, Factor 1, or Factor 2 scores. The seven IOI-HA items increased on average by 0.4 (p < 0.001) when renewing HAs. The total median IOI-HA score at follow-up was 29 (7) for experienced (n = 460) and first-time users (n = 1189), respectively. CONCLUSIONS: Degree of hearing loss, word recognition score, motivation, tinnitus, asymmetry, and sex may be used to identify patients who require special attention to become successful HA users.

Pharmacological Inhibition of Spermine Oxidase Suppresses Excitotoxicity Induced Neuroinflammation in Mouse Retina.

Polyamine oxidation plays a major role in neurodegenerative diseases. Previous studies from our laboratory demonstrated that spermine oxidase (SMOX, a member of the polyamine oxidase family) inhibition using MDL 72527 reduced neurodegeneration in models of retinal excitotoxicity and diabetic retinopathy. However, the mechanisms behind the neuroprotection offered by SMOX inhibition are not completely studied. Utilizing the experimental model of retinal excitotoxicity, the present study determined the impact of SMOX blockade in retinal neuroinflammation. Our results demonstrated upregulation in the number of cells positive for Iba-1 (ionized calcium-binding adaptor molecule 1), CD (Cluster Differentiation) 68, and CD16/32 in excitotoxicity-induced retinas, while MDL 72527 treatment reduced these changes, along with increases in the number of cells positive for Arginase1 and CD206. When retinal excitotoxicity upregulated several pro-inflammatory genes, MDL 72527 treatment reduced many of them and increased anti-inflammatory genes. Furthermore, SMOX inhibition upregulated antioxidant signaling (indicated by elevated Nrf2 and HO-1 levels) and reduced protein-conjugated acrolein in excitotoxic retinas. In vitro studies using C8-B4 cells showed changes in cellular morphology and increased reactive oxygen species formation in response to acrolein (a product of SMOX activity) treatment. Overall, our findings indicate that the inhibition SMOX pathway reduced neuroinflammation and upregulated antioxidant signaling in the retina.

Morbidity, mortality, and emerging drug resistance in Device-associated infections (DAIs) in intensive care patients at a 1000-bedded tertiary care teaching hospital.

Background: Device-associated infections (DAIs) such as ventilator associated pneumonia (VAP), central line-associated blood stream infection (CLABSI), and catheter-related urinary tract infection (CAUTI) are principal contributors to health hazard and a major preventable threat to patient safety. Robust surveillance of DAI delineates infections, pathogens, resistograms, and facilitates antimicrobial therapy, infection-control, antimicrobial stewardship, and improvement in quality of care. Methods: This prospective outcome surveillance study was conducted amongst 2067 ICU patients in a 1000-bedded teaching hospital. Clinical, laboratory, and environmental surveillance, as well as screening of health care professionals (HCPs) were conducted using the modified US Centers for Disease Control and Prevention-National Healthcare Safety Network definitions and methods. Morbidity, mortality, and health-care indices were analyzed and two-tier infection prevention and control was promulgated. Results: Mean occupancy was 95.34% for 2061 patients of 7381 patients/bed/ICU days. One hundred seventeen episodes of DAI occurred in 1258 patients of 12,882 device-days with mean device utilization ratio of 1.79. Mean rate of DAI was 7.40 per 1000 device days. Multiresistant Pseudomonas aeruginosa was most commonly followed by Acinetobacter. Mean all-cause mortality in ICU was 24.85%, whereas all-cause mortality after DAI was 9.79%. Methicillin-resistant Staphylococcus aureus prevalence was 38.46% amongst health-care professionals. Conclusion: Mean rates of VAP, CLABSI, and CAUTI were 20.69, 2.53, and 2.23 per 1000 device days comparable with Indian and global ICUs. Resolute conviction and sustained momentum in infection prevention and control is an essential step toward patient safety.

Akt-independent effects of triciribine on ACE2 expression in human lung epithelial cells: Potential benefits in restricting SARS-CoV2 infection.

The severe acute respiratory syndrome coronavirus 2 that causes coronavirus disease 2019 (COVID-19) binds to the angiotensin-converting enzyme 2 (ACE2) to gain cellular entry. Akt inhibitor triciribine (TCBN) has demonstrated promising results in promoting recovery from advanced-stage acute lung injury in preclinical studies. In the current study, we tested the direct effect of TCBN on ACE2 expression in human bronchial (H441) and lung alveolar (A549) epithelial cells. Treatment with TCBN resulted in the downregulation of both messenger RNA and protein levels of ACE2 in A549 cells. Since HMGB1 plays a vital role in the inflammatory response in COVID-19, and because hyperglycemia has been linked to increased COVID-19 infections, we determined if HMGB1 and hyperglycemia have any effect on ACE2 expression in lung epithelial cells and whether TCBN has any effect on reversing HMGB1- and hyperglycemia-induced ACE2 expression. We observed increased ACE2 expression with both HMGB1 and hyperglycemia treatment in A549 as well as H441 cells, which were blunted by TCBN treatment. Our findings from this study, combined with our previous reports on the potential benefits of TCBN in the treatment of acute lung injury, generate reasonable optimism on the potential utility of TCBN in the therapeutic management of patients with COVID-19.

Spatially-resolved nanometer-scale measurement of cartilage extracellular matrix mobility.

OBJECTIVE: Tissues have complex structures, comprised of solid and fluid phases. Improved understanding of interactions between joint fluid and extracellular matrix (ECM) is required in models of cartilage mechanics. X-ray photon correlation spectroscopy (XPCS) directly measures nanometer-scale dynamics and can provide insight into biofluid-biosolid interactions in cartilage. This study applies XPCS to evaluate dynamic interactions between intact cartilage and biofluids. DESIGN: Cartilage biopsies were collected from bovine femoral condyles. During XPCS measurements, cartilage samples were exposed to different fluids: deionized water, PBS, synovial fluid, or sonicated synovial fluid. ECM-biofluid interactions were also assessed at different length scales and different depths from the cartilage surface. RESULTS: Using XPCS, cartilage ECM mobility was detected at length scales from 50 to 207 nm. As length scale decreased, time scale for autocorrelation decay decreased, suggesting smaller ECM components are more mobile. ECM dynamics were slowed by dehydrating the sample, demonstrating XPCS assesses matrix mobility in hydrated environments. At all length scales, the matrix was more mobile in deionized water and slowest in synovial fluid. Using the 207 nm length scale assessment, ECM dynamics in synovial fluid were fastest at the cartilage surface and progressively slowed as depth into the sample increased, demonstrating XPCS can assess spatial distribution of ECM dynamics. Finally, ECM mobility increased for degraded synovial fluid. CONCLUSIONS: This study demonstrates the potential of XPCS to provide unique insights into nanometer-scale cartilage ECM mobility in a spatially resolved manner and illustrates the importance of biosolid-biofluid interactions in dictating ECM dynamics.

Quercetin-rGO based mercury-free electrode for the determination of toxic Cd (II) and Pb (II) ions using DPASV technique.

Metal ion pollution poses serious threat to environment. Analysis of Cd (II) and Pb (II) ions using chemically modified mercury free electrode is a feasible routine analytical tool. Developing an electrode surface modified with conductive 2D carbon and metal complexing ligand created a synergetic effect towards sensitive and selective electrochemical determination of metal ions. The present study focused on green chemistry approach towards synthesis of reduced graphene oxide using a natural flavonoid (Quercetin) that acts as a reducing, functionalizing agent and also as metal complexing agent. This quercetin reduced graphene oxide (Q-rGO) was surface modified over paraffin wax impregnated graphite electrode. The resulting Q-rGO electrode was used as a mercury-free electrode for simultaneous analysis of Pb (II) and Cd (II) ions. Physico-chemical parameters of the synthesized Q-rGO and modified electrodes were characterized using X-ray diffraction, UV-Vis, FT-IR, and Raman spectrometer. The morphology of the material and surface topography of the modified electrode was observed using HR-TEM and FESEM, respectively. Cyclic voltammetry (CV) and AC impedance (EIS) were adopted for electrochemical characterization and Differential pulse anodic stripping voltammetry (DPASV) was chosen for simultaneous sensing of metal ions using Q-rGO electrode. Analytical parameters such as effect of electrolyte, effect of pH, preconcentration time and deposition potential were optimized. The experimental results suggested that the Q-rGO electrode is capable of sensing Pb (II) and Cd (II) ions individually and simultaneously. Inference from the calibration plot showed that the Q-rGO electrode was capable of sensing the concentration range of Cd (II) ion form 0.19 to 2.5 µgL-1 with LOD-0.05 µgL-1 and Pb (II) ions from 0.19 to 3.1 µgL-1 with LOD 0.06 µgL-1.

Effects of high temperature stress during anthesis and grain filling periods on photosynthesis, lipids and grain yield in wheat.

BACKGROUND: Short episodes of high temperature (HT) stress during reproductive stages of development cause significant yield losses in wheat (Triticum aestivum L.). Two independent experiments were conducted to quantify the effects of HT during anthesis and grain filling periods on photosynthesis, leaf lipidome, and yield traits in wheat. In experiment I, wheat genotype Seri82 was exposed to optimum temperature (OT; 22/14 °C; day/night) or HT (32/22 °C) for 14 d during anthesis stage. In experiment II, the plants were exposed to OT or HT for 14 d during the grain filling stage. During the HT stress, chlorophyll index, thylakoid membrane damage, stomatal conductance, photosynthetic rate and leaf lipid composition were measured. At maturity, grain yield and its components were quantified. RESULTS: HT stress during anthesis or grain filling stage decreased photosynthetic rate (17 and 25%, respectively) and grain yield plant- 1 (29 and 44%, respectively), and increased thylakoid membrane damage (61 and 68%, respectively) compared to their respective control (OT). HT stress during anthesis or grain filling stage increased the molar percentage of less unsaturated lipid species [36:5- monogalactosyldiacylglycerol (MGDG) and digalactosyldiacylglycerol (DGDG)]. However, at grain filling stage, HT stress decreased the molar percentage of more unsaturated lipid species (36:6- MGDG and DGDG). There was a significant positive relationship between photosynthetic rate and grain yield plant- 1, and a negative relationship between thylakoid membrane damage and photosynthetic rate. CONCLUSIONS: The study suggests that maintaining thylakoid membrane stability, and seed-set per cent and individual grain weight under HT stress can improve the photosynthetic rate and grain yield, respectively.

Efficient and Selective Electrochemically Driven Enzyme-Catalyzed Reduction of Carbon Dioxide to Formate using Formate Dehydrogenase and an Artificial Cofactor.

Increasing levels of carbon dioxide in the atmosphere and the growing need for energy necessitate a shift toward reliance on renewable energy sources and the utilization of carbon dioxide. Thus, producing carbonaceous fuel by the electrochemical reduction of carbon dioxide has been very appealing. We have focused on addressing the principal challenges of poor selectivity and poor energy efficiency in the electrochemical reduction of carbon dioxide. We have demonstrated here a viable pathway for the efficient and continuous electrochemical reduction of CO2 to formate using the metal-independent enzyme type of formate dehydrogenase (FDH) derived from C andida boidinii yeast. This type of FDH is attractive because it is commercially produced. In natural metabolic processes, this type of metal-independent FDH oxidizes formate to carbon dioxide using NAD+ as a cofactor. We show that FDH can catalyze the reverse process to generate formate when the natural cofactor NADH is replaced with an artificial cofactor, the methyl viologen radical cation. The methyl viologen radical cation is generated in situ, electrochemically. Our approach relies on the special properties of methyl viologen as a "unidirectional" redox cofactor for the conversion of CO2 to formate. Methyl viologen (in the oxidized form) does not catalyze formate oxidation, while the methyl viologen radical cation is an effective cofactor for the reduction of carbon dioxide. Thus, although the thermodynamic driving force is favorable for the oxidized form of methyl viologen to oxidize formate to carbon dioxide, the kinetic factors are not favorable. Only the reverse reaction of carbon dioxide reduction to formate is kinetically viable with the cofactor, methyl viologen radical cation. Binding free energy calculated from atomistic molecular dynamics (MD) simulations consolidate our understanding of these special binding properties of the methyl viologen radical cation and its ability to facilitate the two-electron reduction of carbon dioxide to formate in metal-independent FDH. By carrying out the reactions in a novel three-compartment cell, we have demonstrated the continuous production of formate at high energy efficiency and yield. This cell configuration uses judiciously selected ion-exchange membranes to separate the reaction compartments to preserve the yields of the methyl viologen radical cation and formate. By the electroregeneration of the methyl viologen radical cation at -0.44 V versus the normal hydrogen electrode, we could produce formate at 20 mV negative to the reversible electrode potential for carbon dioxide reduction to formate. Our results are in sharp contrast to the large overpotentials of -800 to -1000 mV required on metal catalysts, vindicating the selectivity and kinetic facility provided by FDH. Formate yields as high as 97% ± 1% could be realized by avoiding the adventitious reoxidation of the methyl viologen radical cation by molecular oxygen. We anticipate that the insights from the electrochemical studies and the MD simulations to be useful in redesigning the metal-independent FDH and alternate artificial cofactors to achieve even higher rates of conversion.

Nanoscale Critical Phenomena in a Complex Fluid Studied by X-Ray Photon Correlation Spectroscopy.

The advent of high-speed x-ray photon correlation spectroscopy now allows the study of critical phenomena in fluids to much smaller length scales and over a wider range of temperatures than is possible with dynamic light scattering. We present an x-ray photon correlation spectroscopy study of critical fluctuation dynamics in a complex fluid typical of those used in liquid-liquid extraction (LLE) of ions, dodecane-DMDBTDMA with extracted aqueous Ce(NO_{3})_{3}. We observe good agreement with both static and dynamic scaling without the need for significant noncritical background corrections. Critical exponents agree with 3D Ising values, and the fluctuation dynamics are described by simple exponential relaxation. The form of the dynamic master curve deviates somewhat from the Kawasaki result, with a more abrupt transition between the critical and noncritical asymptotic behavior. The concepts of critical phenomena thus provide a quantitative framework for understanding the structure and dynamics of LLE systems and a path forward to new LLE processes.

Regulation of blood-retinal barrier cell-junctions in diabetic retinopathy.

Loss of the blood-retinal barrier (BRB) integrity and subsequent damage to the neurovascular unit in the retina are the underlying reasons for diabetic retinopathy (DR). Damage to BRB eventually leads to severe visual impairment in the absence of prompt intervention. Diabetic macular edema and proliferative DR are the advanced stages of the disease where BRB integrity is altered. Primary mechanisms contributing to BRB dysfunction include loss of cell-cell barrier junctions, vascular endothelial growth factor, advanced glycation end products-induced damage, and oxidative stress. Although much is known about the involvement of adherens and tight-junction proteins in the regulation of vascular permeability in various diseases, there is a significant gap in our knowledge on the junctional proteins expressed in the BRB and how BRB function is modulated in the diabetic retina. In this review article, we present our current understanding of the molecular composition of BRB, the changes in the BRB junctional protein turnover in DR, and how BRB functional modulation affects vascular permeability and macular edema in the diabetic retina.

Inflammation-induced lymphatic architecture and bone turnover changes are ameliorated by irisin treatment in chronic inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic disease with gastrointestinal dysfunction as well as comorbidities such as inflammation-induced bone loss and impaired immune response. Current treatments for IBD all have negative, potentially severe side effects. We aimed to test whether exogenous treatment with irisin, a novel immunomodulatory adipomyokine, could ameliorate IBD-induced lymphatic and bone alterations. Irisin treatment improved both gut and bone outcomes by mitigating inflammation and restoring structure. In the gut, IBD caused colonic lymphatic hyperproliferation into the mucosal and submucosal compartments. This proliferation in the rodent model is akin to what is observed in IBD patient case studies. In bone, IBD increased osteoclast surface and decreased bone formation. Both gut and osteocytes in bone exhibited elevated levels of TNF-α and receptor activator of NF-κB ligand (RANKL) protein expression. Exogenous irisin treatment restored normal colonic lymphatic architecture and increased bone formation rate concurrent with decreased osteoclast surfaces. After irisin treatment, gut and osteocyte TNF-α and RANKL protein expression levels were no different from vehicle controls. Our data indicate that the systemic immunologic changes that occur in IBD are initiated by damage in the gut and likely linked through the lymphatic system. Additionally, irisin is a potential novel intervention mitigating both local inflammatory changes in the gut and distant changes in bone.-Narayanan, S. A., Metzger, C. E., Bloomfield, S. A., Zawieja, D. C. Inflammation-induced lymphatic architecture and bone turnover changes are ameliorated by irisin treatment in chronic inflammatory bowel disease.

Spermine oxidase: A promising therapeutic target for neurodegeneration in diabetic retinopathy.

Diabetic Retinopathy (DR), is a significant public health issue and the leading cause of blindness in working-aged adults worldwide. The vision loss associated with DR affects patients' quality of life and has negative social and psychological effects. In the past, diabetic retinopathy was considered as a vascular disease; however, it is now recognized to be a neuro-vascular disease of the retina. Current therapies for DR, such as laser photocoagulation and anti-VEGF therapy, treat advanced stages of the disease, particularly the vasculopathy and have adverse side effects. Unavailability of effective treatments to prevent the incidence or progression of DR is a major clinical problem. There is a great need for therapeutic interventions capable of preventing retinal damage in DR patients. A growing body of evidence shows that neurodegeneration is an early event in DR pathogenesis. Therefore, studies of the underlying mechanisms that lead to neurodegeneration are essential for identifying new therapeutic targets in the early stages of DR. Deregulation of the polyamine metabolism is implicated in various neurodegenerative diseases, cancer, renal failure, and diabetes. Spermine Oxidase (SMOX) is a highly inducible enzyme, and its dysregulation can alter polyamine homeostasis. The oxidative products of polyamine metabolism are capable of inducing cell damage and death. The current review provides insight into the SMOX-regulated molecular mechanisms of cellular damage and dysfunction, and its potential as a therapeutic target for diabetic retinopathy. Structural and functional changes in the diabetic retina and the mechanisms leading to neuronal damage (excitotoxicity, loss of neurotrophic factors, oxidative stress, mitochondrial dysfunction etc.) are also summarized in this review. Furthermore, existing therapies and new approaches to neuroprotection are discussed.