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Alterations of the normal redox state can be found in all stages of schizophrenia, suggesting a key role for oxidative stress in the etiology and maintenance of the disease. Pharmacological blockade of N-methyl-D-aspartic acid (NMDA) receptors can disrupt natural antioxidant defense systems and induce schizophrenia-like behaviors in animals and healthy human subjects. Perinatal administration of the NMDA receptor (NMDAR) antagonist ketamine produces persistent behavioral deficits in adult mice which mimic a range of positive, negative, and cognitive symptoms that characterize schizophrenia. Here we tested whether antioxidant treatment with the glutathione (GSH) precursor N-acetyl-cysteine (NAC) can prevent the development of these behavioral deficits. On postnatal days (PND) 7, 9 and 11, we treated mice with subanesthetic doses (30 mg/kg) of ketamine or saline. Two groups (either ketamine or saline treated) also received NAC throughout development. In adult animals (PND 70-120) we then assessed behavioral alterations in a battery of cognitive and psychomotor tasks. Ketamine-treated animals showed deficits in a task of cognitive flexibility, abnormal patterns of spontaneous alternation, deficits in novel-object recognition, as well as social interaction. Developmental ketamine treatment also induced behavioral stereotypy in response to an acute amphetamine challenge, and it impaired sensorimotor gating, measured as reduced prepulse inhibition (PPI) of the startle response. All of these behavioral abnormalities were either prevented or strongly ameliorated by NAC co-treatment. These results suggest that oxidative stress is a major factor for the development of the ketamine-induced behavioral dysfunctions, and that restoring oxidative balance during the prodromal stage of schizophrenia might be able to ameliorate the development of several major symptoms of the disease.

Bioretention systems, a common green stormwater infrastructure (GSI) installation for developed landscapes uses engineered soil media to capture and remove pollutants from stormwater. GSI focuses on intercepting and storing large volumes of stormwater runoff before it reaches downstream water bodies, removing these pollutants from runoff offers a potential solution to urban water quality issues.This study explores the use of woodchips and aluminum-rich drinking water treatment residuals (DWTR) as soil media amendments in bioretention systems. The first chapter offers a review of literature involving bioretention systems, vegetation used in them, and the soil media components included in this study. The second chapter evaluates the performance of twelve bioretention mesocosms’ capacities to filter and remove pollutants from stormwater runoff to improve water quality. Three replicates each of four “soil media” treatments (sand-only, topsoil+sand, topsoil+sand+woodchips, and topsoil+sand+DWTR) were subjected to simulated stormwater events, and the effluent water from each mesocosm was analyzed for nutrients and heavy metals. Differences in effluent pollutant concentrations from the synthetic stormwater influent gives insight into the effectiveness of the soil media amendments. The third chapter evaluates plant health across the bioretention soil media treatments for four vegetation types: Butterfly Milkweed (Asclepias tuberosa), Joe-pye Weed (Eupatorium maculatum), Purple Coneflower (Echinacea purpurea), and Blue Star Flower (Amsonia tabernaemontana). Vegetation health was assessed using measurements of vegetation height, survival, and percent green cover of the mesocosms’ surfaces.

Desert riparian ecosystems are among the most threatened biodiversity hotspots in the United States, and efforts to conserve them have been increasing. In 2010–2011 and 2014–2016, we examined shifts in the distribution, habitat characteristics, diet, nest success, and productivity of the gray hawk (Buteo plagiatus), 25 years after a Riparian National Conservation Area was established along the San Pedro River in Arizona, USA, to determine how the removal of grazing and agriculture may have affected the ecosystem. The gray hawk population increased and expanded from mesquite (Prosopis spp.)-dominated areas that they historically occupied into areas that were dominated by grassland. In contrast with the 1990s, percent of mesquite cover in pairs’ territories did not correlate with their productivity. Gray hawk diets also included more mammals in our study period, particularly in territories with more grassland. We propose that conservation measures created habitat for gray hawks in areas that were previously unsuitable by allowing grasslands to regenerate and become habitat for their prey, and that management strategies in the San Pedro Riparian National Conservation Area could serve as a model for conservation of other desert riparian ecosystems.

Herein we describe the synthesis, charcterization, and role several iron complexes in the coupling of pyrrole and phenylboronic acid to form 2-phenylpyrrole. The oxidation state and spin state of the iron complexes were characterized using X-ray crystallography, UV-vis absorbance spectroscopy, cyclic voltammetry, and in some cases electron paramagnetic reasonance spectroscopy. Furthermore, the results indicate that the iron(III) complexes are essential for catalytic and regioselective production of the 2-phenylpyrrole product. The complexes were compared to evaluate the effect of five properties on catalyst reaction yields: the coordination requirements of the catalyst, half-potential, topological constraint/rigidity, N-atom modification(s), increasing oxidative stability of the complex, and geometric parameters. The need for two labile cis-coordination sites was confirmed based on a 42% decrease in catalytic reaction yield observed when complexes containing penta-dentate ligands were used in place of complexes with tetra-dentate ligands. A strong correlation between iron(III/II) redox potential and catalytic reaction yields was also observed, with [Fe 2+L6(Cl)2] providing the highest yield (81%, -405 mV). A Lorentzian fitting of redox potential versus yields predicts that these catalysts can undergo more fine tuning to further increase yields. Interestingly, the remaining properties explored did not show a direct, strong relationship to catalytic reaction yields. Furthermore, the role of the sacrificial oxidant, the lack of radical participation, and the formation of µ-oxodiiron species was established leading to a more detailed mechanistic cycle. Finally, a library of five pyclen-based ligands have been developed for use as iron and europium chelators. A preliminary investigation into iron PCTA complexes indicate that the iron center can bind to all seven of the ligand donors, however, the iron complex does not afford a CEST signal. Establishing that heptadentate ligands containing carboxylic acid pendent arms are not ideal for the developments of iron PARACEST agents.

In our model, preepidemic human norovirus variants harbor genetic diversification that translates into novel antigenic features without compromising viral fitness. Through surveillance, we identified two viruses fitting this profile, forming long branches on a phylogenetic tree. Understanding the complex interactions between virus and host that drive new strain evolution is key to predicting the emergence potential of variants and informing vaccine development. Under our hypothesis, future dominant human norovirus GII.4 variants with critical antigenic properties that allow them to spread are currently circulating undetected, having diverged years earlier. Through large-scale sequencing of GII.4 surveillance samples, we identified two variants with extensive divergence within domains that mediate neutralizing antibody binding. Subsequent serological characterization of these strains using temporally resolved adult and child sera suggests that neither candidate could spread globally in adults with multiple GII.4 exposures, yet young children with minimal GII.4 exposure appear susceptible. Antigenic cartography of surveillance and outbreak sera indicates that continued population exposure to GII.4 Sydney 2012 and antigenically related variants over a 6-year period resulted in a broadening of immunity to heterogeneous GII.4 variants, including those identified here. We show that the strongest antibody responses in adults exposed to GII.4 Sydney 2012 are directed to previously circulating GII.4 viruses. Our data suggest that the broadening of antibody responses compromises establishment of strong GII.4 Sydney 2012 immunity, thereby allowing the continued persistence of GII.4 Sydney 2012 and modulating the cycle of norovirus GII.4 variant replacement. Our results indicate a cycle of norovirus GII.4 variant replacement dependent upon population immunity. Young children are susceptible to divergent variants; therefore, emergence of these strains worldwide is driven proximally by changes in adult serological immunity and distally by viral evolution that confers fitness in the context of immunity. IMPORTANCE In our model, preepidemic human norovirus variants harbor genetic diversification that translates into novel antigenic features without compromising viral fitness. Through surveillance, we identified two viruses fitting this profile, forming long branches on a phylogenetic tree. Neither evades current adult immunity, yet young children are likely susceptible. By comparing serological responses, we demonstrate that population immunity varies by age/exposure, impacting predicted susceptibility to variants. Repeat exposure to antigenically similar variants broadens antibody responses, providing immunological coverage of diverse variants but compromising response to the infecting variant, allowing continued circulation. These data indicate norovirus GII.4 variant replacement is driven distally by virus evolution and proximally by immunity in adults.

Inherited and germ-line de novo copy number variants (CNVs) are increasingly found to be correlated with human developmental and cancerous phenotypes. Several models for template switching during replication have been proposed to explain the generation of these gross chromosomal rearrangements. We proposed a model of template switching (ODIRA—origin dependent inverted repeat amplification) in which simultaneous ligation of the leading and lagging strands at diverging replication forks could generate segmental inverted triplications through an extrachromosomal inverted circular intermediate. Here, we created a genetic assay using split- ura3 cassettes to trap the proposed inverted intermediate. However, instead of recovering circular inverted intermediates, we found inverted linear chromosomal fragments ending in native telomeres—suggesting that a template switch had occurred at the centromere-proximal fork of a replication bubble. As telomeric inverted hairpin fragments can also be created through double strand breaks we tested whether replication errors or repair of double stranded DNA breaks were the most likely initiating event. The results from CRISPR/Cas9 cleavage experiments and growth in the replication inhibitor hydroxyurea indicate that it is a replication error, not a double stranded break that creates the inverted junctions. Since inverted amplicons of the SUL1 gene occur during long-term growth in sulfate-limited chemostats, we sequenced evolved populations to look for evidence of linear intermediates formed by an error in replication. All of the data are compatible with a two-step version of the ODIRA model in which sequential template switching at short inverted repeats between the leading and lagging strands at a replication fork, followed by integration via homologous recombination, generates inverted interstitial triplications.

Prostate cancer is characterized by an immunosuppressive tumour environment. This work combines Raman spectroscopy with group-and-bases-restricted non-negative matrix factorization (GBR-NMF) and machine learning to assemble models of immune cell densities within the needle-core biopsies of patients undergoing high-dose-rate brachytherapy (HDR-BT). Raman spectral acquisition, as well as immunohistochemistry staining of CD68[Formula: see text], CD3[Formula: see text], and [Formula: see text] cells, was completed for biopsies collected before and 2 weeks following the first fraction of HDR-BT. Regression techniques, constructed using GBR-NMF scores, that produced the most accurate predictions of immune cell density by metrics of root mean-squared error (RMSE) and R[Formula: see text] were the gradient-boosted trees model of [Formula: see text] density (RMSE: 163 counts[Formula: see text], [Formula: see text]: 0.65) and the elastic net model of [Formula: see text]/ [Formula: see text] (RMSE: 0.25, [Formula: see text]: 0.82). The accuracy of these models, herein defined as the fraction of patient predictions within [Formula: see text] standard deviation of their measured values was 11/16 and 12/16, for CD68[Formula: see text] CD3[Formula: see text] and CD68[Formula: see text]/ CD8[Formula: see text] models, respectively. To further delineate which metabolites were most important in the CD68[Formula: see text]/ CD8[Formula: see text] model, this ratio was further predicted in stromal and epithelial tissues within the biopsies, and resulting models utilized the GBR-NMF scores of glutathione, collagen, palmitic acid, and the pre- or post-HDR-BT label to produce an optimal performance level according to RMSE and R[Formula: see text]. In summary, this study illustrates a novel methodology in which supervised machine learning techniques are used to model immune cells, which are prognostic indicators of disease progression.

Peatland ecosystems cover only 3% of the world’s land area; however, they store one-third of the global soil carbon (C). Microbial communities are the main drivers of C decomposition in peatlands, yet we have limited knowledge of their structure and function. While the microbial communities in the Northern Hemisphere peatlands are well documented, we have limited understanding of microbial community composition and function in the Southern Hemisphere peatlands, especially in Australia. We investigated the vertical stratification of prokaryote and fungal communities from Wellington Plains peatland in the Australian Alps. Within the peatland complex, bog peat was sampled from the intact peatland and dried peat from the degraded peatland along a vertical soil depth gradient (i.e., acrotelm, mesotelm, and catotelm). We analyzed the prokaryote and fungal community structure, predicted functional profiles of prokaryotes using PICRUSt, and assigned soil fungal guilds using FUNGuild. We found that the structure and function of prokaryotes were vertically stratified in the intact bog. Soil carbon, manganese, nitrogen, lead, and sodium content best explained the prokaryote composition. Prokaryote richness was significantly higher in the intact bog acrotelm compared to degraded bog acrotelm. Fungal composition remained similar across the soil depth gradient; however, there was a considerable increase in saprotroph abundance and decrease in endophyte abundance along the vertical soil depth gradient. The abundance of saprotrophs and plant pathogens was two-fold higher in the degraded bog acrotelm. Soil manganese and nitrogen content, electrical conductivity, and water table level (cm) best explained the fungal composition. Our results demonstrate that both fungal and prokaryote communities are shaped by soil abiotic factors and that peatland degradation reduces microbial richness and alters microbial functions. Thus, current and future changes to the environmental conditions in these peatlands may lead to altered microbial community structures and associated functions which may have implications for broader ecosystem function changes in peatlands.

Background HIV pre-exposure prophylaxis (PrEP) remains underutilized in communities over-burdened by HIV. Same-day PrEP, prescribing and starting PrEP at the initial visit, may be an implementation strategy to address this gap. Federally qualified health centers (FQHC) and community-based organizations (CBO) provide healthcare to un- and under-insured populations and have the potential to increase PrEP services via same-day PrEP. This exploratory mixed methods study explored same-day PrEP program implementation strategies and determinants. Methods Key stakeholders, recruited from FQHC and CBO in Georgia, Texas, and Illinois, participated in virtual interviews (qualitative strand) grounded in the Consolidated Framework for Implementation Science. Thematic analysis in NVivo identified implementation strategies. Purposively sampled FQHC and CBO stakeholder focus groups (FG) rank-ordered same-day PrEP implementation strategies (quantitative strand) based on perceived effectiveness and feasibility to create meta-inferences. N  = 5 individuals participated in both interviews and FG. We then calculated the mean rank order score for each implementation strategy (range = 1–12), within each state and across all three states. We calculated these mean scores separately for both perceived strategy effectiveness/impact and perceived feasibility within their respective settings. Results Twenty-four stakeholders completed interviews. 46% ( N  = 11) were clinic directors/managers, 63% ( N  = 15) were affiliated with a CBO, 71% ( N  = 17) worked in settings where same-day oral PrEP was offered. Theme 1) Medicaid expansion is a useful resource for same-day PrEP implementation; however, same-day PrEP is feasible in non-Medicaid expansion states by leveraging additional financial resources. Theme 2) Leadership buy-in and PrEP champions spearhead programs. Theme 3) Intercommunity relationships and formal evaluation are needed . The three most highly ranked strategies in terms of perceived effectiveness were: 1. Leadership buy-in (mean ranking = 2.51); 2. PrEP champion (mean ranking = 3.62); and 3. PrEP navigators (mean ranking = 4.68). Leadership buy-in first (mean ranking = 2.91), followed by the use of a PrEP champion second (mean ranking = 3.91) and consumer outreach (mean ranking = 4.81) were ranked highest in terms of perceived feasibility. Conclusions Diversification of funding, support from leaders, and customization of implementation strategies are consistent factors necessary for same-day PrEP programs.

Human norovirus is a leading cause of acute gastroenteritis, driven by antigenic variants within the GII.4 genotype. Antibody responses to GII.4 vaccination in adults are shaped by immune memory. How children without extensive immune memory will respond to GII.4 vaccination has not been reported. Here, we characterized the GII.4 neutralizing antibody (nAb) landscape following natural infection using a surrogate assay and antigenic site chimera virus-like particles. We demonstrate that the nAb landscape changes with age and virus exposure. Among sites A, C, and G, nAbs from first infections are focused on sites A and C. As immunity develops with age/exposure, site A is supplemented with antibodies that bridge site A to sites C and G. Cross-site nAbs continue to develop into adulthood, accompanied by an increase in nAb to site G. Continued exposure to GII.4 2012 Sydney correlated with a shift to co-dominance of sites A and G. Furthermore, site G nAbs correlated with the broadening of nAb titer across antigenically divergent variants. These data describe fundamental steps in the development of immunity to GII.4 over a lifetime, and illustrate how the antigenicity of one pandemic variant could influence the pandemic potential of another variant through the redirection of immunodominant epitopes.