Iron-carbohydrate complexes treating iron anaemia: Understanding the nano-structure and interactions with proteins through orthogonal characterisation.

Intravenous (IV) iron-carbohydrate complexes are widely used nanoparticles (NPs) to treat iron deficiency anaemia, often associated with medical conditions such as chronic kidney disease, heart failure and various inflammatory conditions. Even though a plethora of physicochemical characterisation data and clinical studies are available for these products, evidence-based correlation between physicochemical properties of iron-carbohydrate complexes and clinical outcome has not fully been elucidated yet. Studies on other metal oxide NPs suggest that early interactions between NPs and blood upon IV injection are key to understanding how differences in physicochemical characteristics of iron-carbohydrate complexes cause variance in clinical outcomes. We therefore investigated the core-ligand structure of two clinically relevant iron-carbohydrate complexes, iron sucrose (IS) and ferric carboxymaltose (FCM), and their interactions with two structurally different human plasma proteins, human serum albumin (HSA) and fibrinogen, using a combination of cryo-scanning transmission electron microscopy (cryo-STEM), x-ray diffraction (XRD), small-angle x-ray scattering (SAXS) and small-angle neutron scattering (SANS). Using this orthogonal approach, we defined the nano-structure, individual building blocks and surface morphology for IS and FCM. Importantly, we revealed significant differences in the surface morphology of the iron-carbohydrate complexes. FCM shows a localised carbohydrate shell around its core, in contrast to IS, which is characterised by a diffuse and dynamic layer of carbohydrate ligand surrounding its core. We hypothesised that such differences in carbohydrate morphology determine the interaction between iron-carbohydrate complexes and proteins and therefore investigated the NPs in the presence of HSA and fibrinogen. Intriguingly, IS showed significant interaction with HSA and fibrinogen, forming NP-protein clusters, while FCM only showed significant interaction with fibrinogen. We postulate that these differences could influence bio-response of the two formulations and their clinical outcome. In conclusion, our study provides orthogonal characterisation of two clinically relevant iron-carbohydrate complexes and first hints at their interaction behaviour with proteins in the human bloodstream, setting a prerequisite towards complete understanding of the correlation between physicochemical properties and clinical outcome.

Dynamic modulation of mouse thalamocortical visual activity by salient sounds.

Visual responses of the primary visual cortex (V1) are altered by sound. Sound-driven behavioral arousal suggests that, in addition to direct inputs from the primary auditory cortex (A1), multiple other sources may shape V1 responses to sound. Here, we show in anesthetized mice that sound (white noise, ≥70dB) drives a biphasic modulation of V1 visually driven gamma-band activity, comprising fast-transient inhibitory and slow, prolonged excitatory (A1-independent) arousal-driven components. An analogous yet quicker modulation of the visual response also occurred earlier in the visual pathway, at the level of the dorsolateral geniculate nucleus (dLGN), where sound transiently inhibited the early phasic visual response and subsequently induced a prolonged increase in tonic spiking activity and gamma rhythmicity. Our results demonstrate that sound-driven modulations of visual activity are not exclusive to V1 and suggest that thalamocortical inputs from the dLGN to V1 contribute to shaping V1 visual response to sound.

Modified 2-stage IPAA has similar postoperative complication rates and functional outcomes compared to 3-stage IPAA.

INTRODUCTION: Reconstructive ileal-pouch anal anastomosis (IPAA) for ulcerative colitis (UC) is often created in 3-stages: colectomy â€‹+ â€‹ileostomy, proctectomy â€‹+ â€‹pouch creation with diverting loop ileostomy, then subsequent ileostomy closure. Modified 2-stage IPAA is without pouch diversion, thus avoiding a third operation. This study compares perioperative complications, quality of life (QOL) and functional outcomes of 3- versus modified 2-stage IPAA. METHODS: Charts were reviewed for adult UC patients undergoing IPAA between 2010 and 2020. QOL and function were assessed with EQ-5D-3L Quality of Life and Pouch Functional Score questionnaires. RESULTS: 152 patients were identified. 43 modified 2-stage and 109 3-stage IPAA were similar for anastomotic leak (9.3% vs. 1.8%, p â€‹= â€‹0.06), SSI (34.9% vs. 29.7%, p â€‹= â€‹0.51) and ileus (32.6% vs. 33%, p â€‹= â€‹0.96). Modified 2-stage had less bowel obstruction than 3-stage IPAA (7.0% vs. 30.1%, p â€‹= â€‹0.006). 92 patients returned questionnaires with similar QOL and pouch function. CONCLUSIONS: Perioperative complications, QOL and function are similar for 3-stage IPAA and modified 2-stage IPAA. Modified 2-stage IPAA in select patients is safe and has less postoperative bowel obstruction than 3-stage IPAA.

Autoimmune thyroid disease and rheumatoid arthritis: where the twain meet.

Autoimmune thyroid disease (AITD) is the most prevalent autoimmune disease. It shares multiple genetic, clinical, and serologic characteristics with rheumatoid arthritis (RA). Although frequently described as a classic form of single-organ autoimmunity, the AITD disease burden in a subset of patients extends well beyond the thyroid gland. This review explores the complex interaction between the two diseases and the clinical consequences when they overlap. Beyond the well-known effects of AITD on thyroid function in RA, there is mounting evidence of the association of both conditions impacting the presentation and outcomes of diabetes, metabolic syndrome, and cardiovascular disease. An increasing number of studies suggest that there are negative effects of AITD on RA disease activity both in the presence and in the absence of thyroid dysfunction. Recent evidence suggests that AITD may not only worsen the cumulative damage of RA through higher disease activity but may also worsen secondary osteoarthritis changes. Less well-known is the significant association between AITD and chronic widespread pain syndromes including fibromyalgia. Importantly, the presence of fibromyalgia, which is increased in RA patients, appears to be further increased when it overlaps with AITD. Lastly, we probe the possible influence of AITD interacting with RA on fertility and clinical depression. Key Points • Autoimmune thyroid disease is the most common autoimmune disease and is frequently associated with rheumatoid arthritis. • Autoimmune thyroid disease can present with osteoarthritis, inflammatory arthritis, and chronic widespread pain syndromes. • The co-occurrence of autoimmune thyroid disease and rheumatoid arthritis may worsen disease activity and exacerbate other disease manifestations including cardiovascular disease, fertility, and depression. • The overlap of rheumatoid arthritis with autoimmune thyroid disease needs further research and should be sought in general clinical practice.

Facilitative and competitive interactions between mycorrhizal and nonmycorrhizal plants in an extremely phosphorus-impoverished environment: role of ectomycorrhizal fungi and native oomycete pathogens in shaping species coexistence.

Nonmycorrhizal cluster root-forming species enhance the phosphorus (P) acquisition of mycorrhizal neighbours in P-impoverished megadiverse systems. However, whether mycorrhizal plants facilitate the defence of nonmycorrhizal plants against soil-borne pathogens, in return and via their symbiosis, remains unknown. We characterised growth and defence-related compounds in Banksia menziesii (nonmycorrhizal) and Eucalyptus todtiana (ectomycorrhizal, ECM) seedlings grown either in monoculture or mixture in a multifactorial glasshouse experiment involving ECM fungi and native oomycete pathogens. Roots of B. menziesii had higher levels of phytohormones (salicylic and jasmonic acids, jasmonoyl-isoleucine and 12-oxo-phytodienoic acid) than E. todtiana which further activated a salicylic acid-mediated defence response in roots of B. menziesii, but only in the presence of ECM fungi. We also found that B. menziesii induced a shift in the defence strategy of E. todtiana, from defence-related secondary metabolites (phenolic and flavonoid) towards induced phytohormone response pathways. We conclude that ECM fungi play a vital role in the interactions between mycorrhizal and nonmycorrhizal plants in a severely P-impoverished environment, by introducing a competitive component within the facilitation interaction between the two plant species with contrasting nutrient-acquisition strategies. This study sheds light on the interplay between beneficial and detrimental soil microbes that shape plant-plant interaction in severely nutrient-impoverished ecosystems.

pH-dependent structural transitions in cationic ionizable lipid mesophases are critical for lipid nanoparticle function.

Lipid nanoparticles (LNPs) are advanced core-shell particles for messenger RNA (mRNA) based therapies that are made of polyethylene glycol (PEG) lipid, distearoylphosphatidylcholine (DSPC), cationic ionizable lipid (CIL), cholesterol (chol), and mRNA. Yet the mechanism of pH-dependent response that is believed to cause endosomal release of LNPs is not well understood. Here, we show that eGFP (enhanced green fluorescent protein) protein expression in the mouse liver mediated by the ionizable lipids DLin-MC3-DMA (MC3), DLin-KC2-DMA (KC2), and DLinDMA (DD) ranks MC3 ≥ KC2 > DD despite similar delivery of mRNA per cell in all cell fractions isolated. We hypothesize that the three CIL-LNPs react differently to pH changes and hence study the structure of CIL/chol bulk phases in water. Using synchrotron X-ray scattering a sequence of ordered CIL/chol mesophases with lowering pH values are observed. These phases show isotropic inverse micellar, cubic Fd3m inverse micellar, inverse hexagonal [Formula: see text] and bicontinuous cubic Pn3m symmetry. If polyadenylic acid, as mRNA surrogate, is added to CIL/chol, excess lipid coexists with a condensed nucleic acid lipid [Formula: see text] phase. The next-neighbor distance in the excess phase shows a discontinuity at the Fd3m inverse micellar to inverse hexagonal [Formula: see text] transition occurring at pH 6 with distinctly larger spacing and hydration for DD vs. MC3 and KC2. In mRNA LNPs, DD showed larger internal spacing, as well as retarded onset and reduced level of DD-LNP-mediated eGFP expression in vitro compared to MC3 and KC2. Our data suggest that the pH-driven Fd3m-[Formula: see text] transition in bulk phases is a hallmark of CIL-specific differences in mRNA LNP efficacy.

Form factor determination of biological molecules with X-ray free electron laser small-angle scattering (XFEL-SAS).

Free-electron lasers (FEL) are revolutionizing X-ray-based structural biology methods. While protein crystallography is already routinely performed at FELs, Small Angle X-ray Scattering (SAXS) studies of biological macromolecules are not as prevalent. SAXS allows the study of the shape and overall structure of proteins and nucleic acids in solution, in a quasi-native environment. In solution, chemical and biophysical parameters that have an influence on the structure and dynamics of molecules can be varied and their effect on conformational changes can be monitored in time-resolved XFEL and SAXS experiments. We report here the collection of scattering form factors of proteins in solution using FEL X-rays. The form factors correspond to the scattering signal of the protein ensemble alone; the scattering contributions from the solvent and the instrument are separately measured and accurately subtracted. The experiment was done using a liquid jet for sample delivery. These results pave the way for time-resolved studies and measurements from dilute samples, capitalizing on the intense and short FEL X-ray pulses.

Leaf phosphorus allocation to chemical fractions and its seasonal variation in south-western Australia is a species-dependent trait.

South-western Australia is a global biodiversity hotspot and has some of the oldest and most phosphorus (P)-impoverished soils in the world. Proteaceae is one of the dominant P-efficient plant families there, but it is unknown how leaf P concentrations and foliar P allocation of Proteaceae and coexisting dominant plant families vary between seasons and habitats. To investigate this, we selected 18 species from Proteaceae, Myrtaceae and Fabaceae, six from each family, in two habitats from Alison Baird Reserve (32°1'19''S 15°58'52''E) in Western Australia. Total leaf P and nitrogen (N) concentrations, leaf mass per area, photosynthetic rate, pre-dawn leaf water potential and foliar P fractions were determined for each species both at the end of summer (March 2019 and early April 2020) and at the end of winter (September 2019). Soil P availability was also determined for each site. This is the very first study that focused on seasonal changes of foliar P fractions from different P-impoverished environments in three plant families. However, contrary to our expectation, we found little evidence for convergence of foliar P allocation within family, season or habitat. Each species exhibited a specific species-dependent pattern of foliar P allocation, and many species showed differences between seasons. Native plants in south-western Australia converged on a high photosynthetic P-use efficiency, but each species showed its own unique way associated with that outcome.

Reduction of Paraoxonase Expression Followed by Inactivation across Independent Semiaquatic Mammals Suggests Stepwise Path to Pseudogenization.

Convergent adaptation to the same environment by multiple lineages frequently involves rapid evolutionary change at the same genes, implicating these genes as important for environmental adaptation. Such adaptive molecular changes may yield either change or loss of protein function; loss of function can eliminate newly deleterious proteins or reduce energy necessary for protein production. We previously found a striking case of recurrent pseudogenization of the Paraoxonase 1 (Pon1) gene among aquatic mammal lineages-Pon1 became a pseudogene with genetic lesions, such as stop codons and frameshifts, at least four times independently in aquatic and semiaquatic mammals. Here, we assess the landscape and pace of pseudogenization by studying Pon1 sequences, expression levels, and enzymatic activity across four aquatic and semiaquatic mammal lineages: pinnipeds, cetaceans, otters, and beavers. We observe in beavers and pinnipeds an unexpected reduction in expression of Pon3, a paralog with similar expression patterns but different substrate preferences. Ultimately, in all lineages with aquatic/semiaquatic members, we find that preceding any coding-level pseudogenization events in Pon1, there is a drastic decrease in expression, followed by relaxed selection, thus allowing accumulation of disrupting mutations. The recurrent loss of Pon1 function in aquatic/semiaquatic lineages is consistent with a benefit to Pon1 functional loss in aquatic environments. Accordingly, we examine diving and dietary traits across pinniped species as potential driving forces of Pon1 functional loss. We find that loss is best associated with diving activity and likely results from changes in selective pressures associated with hypoxia and hypoxia-induced inflammation.

Health consequences of exposure to aircraft contaminated air and fume events: a narrative review and medical protocol for the investigation of exposed aircrew and passengers.

Thermally degraded engine oil and hydraulic fluid fumes contaminating aircraft cabin air conditioning systems have been well documented since the 1950s. Whilst organophosphates have been the main subject of interest, oil and hydraulic fumes in the air supply also contain ultrafine particles, numerous volatile organic hydrocarbons and thermally degraded products. We review the literature on the effects of fume events on aircrew health. Inhalation of these potentially toxic fumes is increasingly recognised to cause acute and long-term neurological, respiratory, cardiological and other symptoms. Cumulative exposure to regular small doses of toxic fumes is potentially damaging to health and may be exacerbated by a single higher-level exposure. Assessment is complex because of the limitations of considering the toxicity of individual substances in complex heated mixtures.There is a need for a systematic and consistent approach to diagnosis and treatment of persons who have been exposed to toxic fumes in aircraft cabins. The medical protocol presented in this paper has been written by internationally recognised experts and presents a consensus approach to the recognition, investigation and management of persons suffering from the toxic effects of inhaling thermally degraded engine oil and other fluids contaminating the air conditioning systems in aircraft, and includes actions and investigations for in-flight, immediately post-flight and late subsequent follow up.

3-O sulfation of syndecan-1 mediated by the sulfotransferase HS3ST3a1 enhances myeloma aggressiveness.

Multiple myeloma is a hematological neoplasm derived from plasma cells invariably developing in the bone marrow (BM). The persisting clinical challenge in MM resides in its high ability to resist drugs as shown by the frequent relapses observed in patients regardless of the treatment applied. In a mouse model of MM, we identified a subpopulation of cells harboring increased resistance to current MM drugs. These cells bound a proliferation inducing ligand (APRIL), a key MM promoting/survival factor. APRIL binding involved the heparan sulfate (HS) chain present on syndecan-1 (SDC-1), and correlated with reactivity to the anti-HS antibody 10e4. 10e4+cells had a high proliferation activity, and were able to form colonies in 3-D cultures. 10e4+ cells were the only cells able to develop in BM after intravenous injection. They also resisted drugs in vivo, since their number increased after treatment in BM. Notably, 10e4+ cells differentiated into 10e4- cells upon in vitro and in vivo expansion. Expression of one sulfotransferase, HS3ST3a1, allowed modification of syndecan-1 to confer reactivity to 10e4 and binding to APRIL. HS3ST3a1 deletion inhibited tumorigenesis in BM. Notably, the two populations coexisted at a variable frequency in the BM of MM patients at diagnosis. In total, our results indicate that 3-O-sulfation on SDC-1 carried out by HS3ST3a1 defines aggressive MM cells, and that targeting of this enzyme could possibly be used to better control drug resistance.

Association of the anti-thyroid peroxidase antibody with chronic hand pain in older adults in the Third National Health and Nutrition Examination Survey: a cross-sectional study.

Background: Autoimmune thyroid disease (AITD) is the commonest autoimmune disease. Although viewed as a classic form of single-organ autoimmunity, AITD is increasingly associated with non-thyroid sequelae including musculoskeletal manifestations and chronic pain syndromes. However, large population-based studies are needed. Objectives: To examine the relationships between chronic hand pain and the AITD autoantibodies, anti-thyroid peroxidase antibody (TPOAb), and anti-thyroglobulin antibody (TgAb), in the Third National Health and Nutrition Examination Survey (NHANES III). Design: This is a cross-sectional study. Methods: We examined data from NHANES III on 4820 persons aged 60 years or older with respect to hand pain and its association with TPOAb and TgAb. Log-binomial regressions were fit to examine the associations between the anti-thyroid autoantibodies and hand pain. Results: Positive TPOAb was associated with a higher prevalence of hand pain than negative TPOAb [prevalence ratio (PR) = 1.158, p = 0.048] in the unadjusted model. This association was no longer significant after controlling for age, body mass index, gender, and diabetes (p = 0.313). When positive TPOAb was considered as a categorical variable with four levels, the highest quartile was associated with hand pain in the unadjusted (PR = 1.489, p = 0.005) and adjusted models (PR = 1.325, p = 0.042). There was no significant association between TgAb and hand pain when covariates were controlled for. Conclusion: TPOAb may be associated with the presence of chronic hand pain in persons aged over 60 years, especially at higher serum levels.

Controlled modulation of the dynamics of the Deinococcus grandis Dps N-terminal tails by divalent metals.

DNA-binding proteins from starved cells (Dps) are small multifunctional nanocages expressed by prokaryotes in acute oxidative stress conditions or during the starvation-induced stationary phase, as a bacterial defense mechanism. Dps proteins protect bacterial DNA from damage by either direct binding or by removing precursors of reactive oxygen species from solution. The DNA-binding properties of most Dps proteins studied so far are related to their unordered, flexible, N- and C-terminal extensions. In a previous work, we revealed that the N-terminal tails of Deinoccocus grandis Dps shift from an extended to a compact conformation depending on the ionic strength of the buffer and detected a novel high-spin ferrous iron center in the proximal ends of those tails. In this work, we further explore the conformational dynamics of the protein by probing the effect of divalent metals binding to the tail by comparing the metal-binding properties of the wild-type protein with a binding site-impaired D34A variant using size exclusion chromatography, dynamic light scattering, synchrotron radiation circular dichroism, and small-angle X-ray scattering. The N-terminal ferrous species was also characterized by Mössbauer spectroscopy. The results herein presented reveal that the conformation of the N-terminal tails is altered upon metal binding in a gradual, reversible, and specific manner. These observations may point towards the existence of a regulatory process for the DNA-binding properties of Dps proteins through metal binding to their N- and/or C-terminal extensions.

Subtle Malformation of the Cochlear Apex and Genetic Abnormalities: Beyond the "Thorny" Cochlea.

With the routine use of high-resolution heavily T2-weighted sequences to evaluate patients with hearing deficits, new, subtle phenotypes of cochlear malformations are being discovered and an increasing number of genotype-phenotype correlations are being found through a reverse phenotype approach, which can help guide geneticists. In this brief report, we present subtle malformations of the apical turn of the cochlea related to 3 genetic mutations, emphasizing the importance of a careful assessment of the cochlear apex.

Phosphorus fractions in leaves.

Leaf phosphorus (P) comprises four major fractions: inorganic phosphate (Pi ), nucleic acids, phospholipids, P-containing metabolites and a residual fraction. In this review paper, we investigated whether allocation of P fractions varies among groups of terrestrial vascular plants, and is indicative of a species' strategy to use P efficiently. We found that as leaf total P concentration increases, the Pi fraction increases the most, without a plateau, while other fractions plateau. Variability of the concentrations of leaf P fractions is greatest among families > species(family) > regions > plant life forms. The percentage of total P allocated to nucleic acid-P (20-35%) and lipid-P (14-34%) varies less among families/species. High photosynthetic P-use efficiency is associated with low concentrations of all P fractions, and preferential allocation of P to metabolite-P and mesophyll cells. Sequential resorption of P from senescing leaves starts with Pi , followed by metabolite-P, and then other organic P fractions. Allocation of P to leaf P fractions varies with season. Leaf phytate concentrations vary considerably among species, associated with variation in photosynthesis and defence. Plasticity of P allocation to its fractions is important for acclimation to low soil P availability, and species-specific P allocation is needed for co-occurrence with other species.

Differences in foliar phosphorus fractions, rather than in cell-specific phosphorus allocation, underlie contrasting photosynthetic phosphorus use efficiency among chickpea genotypes.

Although significant intraspecific variation in photosynthetic phosphorus (P) use efficiency (PPUE) has been shown in numerous species, we still know little about the biochemical basis for differences in PPUE among genotypes within a species. Here, we grew two high PPUE and two low PPUE chickpea (Cicer arietinum) genotypes with low P supply in a glasshouse to compare their photosynthesis-related traits, total foliar P concentration ([P]) and chemical P fractions (i.e. inorganic P (Pi), metabolite P, lipid P, nucleic acid P, and residual P). Foliar cell-specific nutrient concentrations including P were characterized using elemental X-ray microanalysis. Genotypes with high PPUE showed lower total foliar [P] without slower photosynthetic rates. No consistent differences in cellular [P] between the epidermis and mesophyll cells occurred across the four genotypes. In contrast, high PPUE was associated with lower allocation to Pi and metabolite P, with PPUE being negatively correlated with the percentage of these two fractions. Furthermore, a lower allocation to Pi and metabolite P was correlated with a greater allocation to nucleic acid P, but not to lipid P. Collectively, our results suggest that a different allocation to foliar P fractions, rather than preferential P allocation to specific leaf tissues, underlies the contrasting PPUE among chickpea genotypes.

High-Precision Spectroscopy of

The excited states of unstable ^{20}O were investigated via γ-ray spectroscopy following the ^{19}O(d,p)^{20}O reaction at 8 AMeV. By exploiting the Doppler shift attenuation method, the lifetimes of the 2_{2}^{+} and 3_{1}^{+} states were firmly established. From the γ-ray branching and E2/M1 mixing ratios for transitions deexciting the 2_{2}^{+} and 3_{1}^{+} states, the B(E2) and B(M1) were determined. Various chiral effective field theory Hamiltonians, describing the nuclear properties beyond ground states, along with a standard USDB interaction, were compared with the experimentally obtained data. Such a comparison for a large set of γ-ray transition probabilities with the valence space in medium similarity renormalization group ab initio calculations was performed for the first time in a nucleus far from stability. It was shown that the ab initio approaches using chiral effective field theory forces are challenged by detailed high-precision spectroscopic properties of nuclei. The reduced transition probabilities were found to be a very constraining test of the performance of the ab initio models.

Reducing Merkel cell activity in the whisker follicle disrupts cortical encoding of whisker movement amplitude and velocity.

Merkel cells (MCs) and associated primary sensory afferents of the whisker follicle-sinus complex, accurately code whisker self-movement, angle, and whisk phase during whisking. However, little is known about their roles played in cortical encoding of whisker movement. To this end, the spiking activity of primary somatosensory barrel cortex (wS1) neurons was measured in response to varying the whisker deflection amplitude and velocity in transgenic mice with previously established reduced mechanoelectrical coupling at MC-associated afferents. Under reduced MC activity, wS1 neurons exhibited increased sensitivity to whisker deflection. This appeared to arise from a lack of variation in response magnitude to varying the whisker deflection amplitude and velocity. This latter effect was further indicated by weaker variation in the temporal profile of the evoked spiking activity when either whisker deflection amplitude or velocity was varied. Nevertheless, under reduced MC activity, wS1 neurons retained the ability to differentiate stimulus features based on the timing of their first post-stimulus spike. Collectively, results from this study suggest that MCs contribute to cortical encoding of both whisker amplitude and velocity, predominantly by tuning wS1 response magnitude, and by patterning the evoked spiking activity, rather than by tuning wS1 response latency.

Examining the role of paraoxonase 2 in the dopaminergic system of the mouse brain.

BACKGROUND: Paraoxonase 2 (PON2) is an intracellular antioxidant enzyme located at the inner mitochondrial membrane. Previous studies have found PON2 to be an important antioxidant in a variety of cellular systems, such as the cardiovascular and renal system. Recent work has also suggested that PON2 plays an important role in the central nervous system (CNS), as decreased PON2 expression in the CNS leads to higher oxidative stress and subsequent cell toxicity. However, the precise role of PON2 in the CNS is still largely unknown, and what role it may play in specific regions of the brain remains unexamined. Dopamine metabolism generates considerable oxidative stress and antioxidant function is critical to the survival of dopaminergic neurons, providing a potential mechanism for PON2 in the dopaminergic system. METHODS: In this study, we investigated the role of PON2 in the dopaminergic system of the mouse brain by comparing transcript and protein expression of dopaminergic-related genes in wildtype (WT) and PON2 deficient (PON2-def) mouse striatum, and exposing WT cultured primary neurons to dopamine receptor agonists. RESULTS: We found alterations in multiple key dopaminergic genes at the transcript level, however many of these changes were not observed at the protein level. In cultured neurons, PON2 mRNA and protein were increased upon exposure to quinpirole, a dopamine receptor 2/3 (DRD2/3) agonist, but not fenoldopam, a dopamine receptor 1/5 (DRD1/5) agonist, suggesting a receptor-specific role in dopamine signaling. CONCLUSIONS: Our findings suggest PON2 deficiency significantly impacts the dopaminergic system at the transcript level and may play a role in mitigating oxidative stress in this system further downstream through dopamine receptor signaling.