Copper-Catalyzed Monooxygenation of Phenols: Evidence for a Mononuclear Reaction Mechanism.

The CuI salts [Cu(CH3 CN)4 ]PF and [Cu(oDFB)2 ]PF with the very weakly coordinating anion Al(OC(CF3 )3 )4- (PF) as well as [Cu(NEt3 )2 ]PF comprising the unique, linear bis-triethylamine complex [Cu(NEt3 )2 ]+ were synthesized and examined as catalysts for the conversion of monophenols to o-quinones. The activities of these CuI salts towards monooxygenation of 2,4-di-tert-butylphenol (DTBP-H) were compared to those of [Cu(CH3 CN)4 ]X salts with "classic" anions (BF4- , OTf- , PF6- ), revealing an anion effect on the activity of the catalyst and a ligand effect on the reaction rate. The reaction is drastically accelerated by employing CuII -semiquinone complexes as catalysts, indicating that formation of a CuII complex precedes the actual catalytic cycle. This result and other experimental observations show that with these systems the oxygenation of monophenols does not follow a dinuclear, but a mononuclear pathway analogous to that of topaquinone cofactor biosynthesis in amine oxidase.

Somatic symptoms in treatment-naïve Hispanic and non-Hispanic patients with major depression.

BACKGROUND: Somatic complaints are a major driver of health care costs among patients with major depressive disorder (MDD). Some epidemiologic and clinical data suggest that Hispanic and non-Hispanic Black patients with MDD endorse higher levels of somatic symptoms than non-Hispanic White patients. METHODS: Somatic symptoms in 102 Hispanic, 61 non-Hispanic Black, and 156 non-Hispanic White patients with treatment-naïve MDD were evaluated using the somatic symptom subscale of the Hamilton anxiety rating scale (HAM-A). The other seven items of the HAM-A comprise the psychic anxiety subscale, which was also evaluated across ethnicities. RESULTS: Hispanic patients reported significantly greater levels of somatic symptoms than non-Hispanic patients, but levels of psychic anxiety symptoms did not differ by ethnicity. Levels of somatic symptoms did not significantly differ between Black and White non-Hispanic patients. Within the Hispanic sample, somatic symptom levels were higher only among those who were evaluated in Spanish; Hispanics who spoke English showed no significant differences versus non-Hispanics. CONCLUSIONS: In this medically healthy sample of patients with MDD, monolingual Spanish-speaking Hispanic patients endorsed high levels of somatic symptoms. Clinicians should be mindful that the depressive experience may manifest somatically and be judicious in determining when additional medical work-up is warranted for somatic complaints.

Presence and predictors of anxiety disorder onset following cancer diagnosis among anxious cancer survivors.

PURPOSE: Despite cancer survivors' frequent endorsement of anxiety symptoms, assessing the full range of anxiety disorders (AD), their timing of onset relative to cancer diagnosis, co-morbidity with mood disorder, and predictors of post-cancer onset, is rare or absent to date. This study provides a step toward addressing these gaps. METHODS: Cancer survivors at re-entry after primary treatment completion who screened positively for anxiety symptoms (N = 133) and sought care through an intervention trial completed standardized diagnostic interviews, dimensional assessment of disorder severity, and timing of disorder onset relative to cancer diagnosis. We evaluated sociodemographic and medical predictors of developing a first AD after cancer diagnosis. RESULTS: Most ADs began after cancer diagnosis (58%); for 68% of affected patients, this represented their first AD episode. The most common was generalized anxiety disorder (GAD; 41%), where "cancer-focused GAD" was distinguished from "typical GAD"; the next most common were specific phobia (14%) and social anxiety disorder (13%). A minority (31%) of ADs were comorbid with major depression. Relative to having no AD, experiencing more lingering treatment side effects predicted developing a first AD after cancer diagnosis. Relative to having an AD that began before cancer diagnosis, reporting a higher cancer stage predicted developing a first AD after diagnosis. CONCLUSIONS: Cancer survivors at re-entry seeking care for anxiety symptoms manifested a broad range of ADs which most commonly developed after cancer diagnosis and were prompted by the experience of cancer. Such disorders represent an unusually late-life, cancer-linked etiology that warrants further investigation and clinical attention.

CDHR3 Asthma-Risk Genotype Affects Susceptibility of Airway Epithelium to Rhinovirus C Infections.

CDHR3 (cadherin-related family member 3) is a transmembrane protein that is highly expressed in airway epithelia and the only known receptor for rhinovirus C (RV-C). A CDHR3 SNP (rs6967330) with G to A base change has been linked to severe exacerbations of asthma and increased susceptibility to RV-C infections in young children. The goals of this study were to determine the subcellular localization of CDHR3 and to test the hypothesis that CDHR3 asthma-risk genotype affects epithelial cell function and susceptibility to RV-C infections of the airway epithelia. We used immunofluorescence imaging, Western blot analysis, and transmission electron microscopy to show CDHR3 subcellular localization in apical cells, including expression in the cilia of airway epithelia. Polymorphisms in CDHR3 rs6967330 locus (G→A) that were previously associated with childhood asthma were related to differences in CDHR3 expression and epithelial cell function. The rs6967330 A allele was associated with higher overall protein expression and RV-C binding and replication compared with the rs6967330 G allele. Furthermore, the rs6967330 A allele was associated with earlier ciliogenesis and higher FOXJ1 expression. Finally, CDHR3 genotype had no significant effects on membrane integrity or ciliary beat function. These findings provide information on the subcellular localization and possible functions of CDHR3 in the airways and link CDHR3 asthma-risk genotype to increased RV-C binding and replication.

The Longitudinal Effect of Emotion Regulation Strategies on Anxiety Levels in Children and Adolescents.

There is growing evidence linking emotion dysregulation to anxiety. However, few studies have examined this relationship longitudinally or developmentally. Additionally, no studies have specifically examined the predictive relevance of the emotion regulation skills taught in mindfulness- and acceptance-based therapies. We explore whether specific emotion regulation processes differentially predict specific anxiety symptoms over time among children and adolescents. METHODS: Initial emotion non-awareness, nonacceptance, and difficulties with goal-directed behavior were assessed in a community sample (n = 312, age range = 8-16, mean age = 11.68, 59% female, 69% Caucasian). Social anxiety, separation anxiety, and physical anxiety symptoms were assessed every 3 months for 3 years. Hierarchical linear modeling was used to examine the concurrent and longitudinal effects of emotion dysregulation assessed at baseline or 18 months on anxiety. RESULTS: After controlling for depression, age, and gender, all three processes concurrently predicted physical and social anxiety, and all but nonacceptance predicted separation anxiety. Only difficulties with goal-directed behavior, however, predicted longitudinal change in separation anxiety over time with covariates. Additionally, emotion non-awareness and difficulties with goal-directed behavior predicted subsequent changes in social anxiety. CONCLUSIONS: Emotion dysregulation may serve as a potential risk factor for the development of anxiety symptoms among youth. It may be beneficial to target reductions in maladaptive strategies in prevention or intervention work.

Rhinovirus C targets ciliated airway epithelial cells.

BACKGROUND: The Rhinovirus C (RV-C), first identified in 2006, produce high symptom burdens in children and asthmatics, however, their primary target host cell in the airways remains unknown. Our primary hypotheses were that RV-C target ciliated airway epithelial cells (AECs), and that cell specificity is determined by restricted and high expression of the only known RV-C cell-entry factor, cadherin related family member 3 (CDHR3). METHODS: RV-C15 (C15) infection in differentiated human bronchial epithelial cell (HBEC) cultures was assessed using immunofluorescent and time-lapse epifluorescent imaging. Morphology of C15-infected differentiated AECs was assessed by immunohistochemistry. RESULTS: C15 produced a scattered pattern of infection, and infected cells were shed from the epithelium. The percentage of cells infected with C15 varied from 1.4 to 14.7% depending on cell culture conditions. Infected cells had increased staining for markers of ciliated cells (acetylated-alpha-tubulin [aat], p < 0.001) but not markers of goblet cells (wheat germ agglutinin or Muc5AC, p = ns). CDHR3 expression was increased on ciliated epithelial cells, but not other epithelial cells (p < 0.01). C15 infection caused a 27.4% reduction of ciliated cells expressing CDHR3 (p < 0.01). During differentiation of AECs, CDHR3 expression progressively increased and correlated with both RV-C binding and replication. CONCLUSIONS: The RV-C only replicate in ciliated AECs in vitro, leading to infected cell shedding. CDHR3 expression positively correlates with RV-C binding and replication, and is largely confined to ciliated AECs. Our data imply that factors regulating differentiation and CDHR3 production may be important determinants of RV-C illness severity.

Nutrient Cycling in Grassed Roadside Ditches and Lawns in a Suburban Watershed.

Roadside ditches are ubiquitous in developed landscapes. They are designed to route water from roads for safety, with little consideration of water quality or biogeochemical implications in ditch design and minimal data on environmental impacts. We hypothesize that periodic saturation and nutrient influxes may make roadside ditches hotspots for nitrogen (N) removal via denitrification as well as biological production of the greenhouse gases (GHGs) nitrous oxide (NO), methane (CH), and carbon dioxide (CO). Research sites included 12 grassed ditches and adjacent lawns with varying fertilization in a suburban watershed in central New York, where lawns represented a reference with similar soils as ditches but differing hydrology. We measured potential denitrification using the denitrification enzyme assay in fall 2014 and GHG fluxes using in situ static chambers between summer 2014 and 2015, including sample events after storms. Potential denitrification in ditches was significantly higher than in lawns, and rates were comparable to those in stream riparian areas, features traditionally viewed as denitrification hotspots. Ditches had higher rates of CH emissions, particularly sites that were wettest. Lawns were hotspots for NO and CO respiratory emissions, which were driven by nutrient availability and fertilizer application. Extrapolating up to the watershed, ditches have the potential to remove substantial N loads via denitrification if managed optimally. Ditch GHG emissions extrapolated across the watershed were minimal given their much smaller area compared with lawns, which were the greater contributor of GHGs. These findings suggest that roadside ditches may offer new management opportunities for mitigating nonpoint source N pollution in residential watersheds.

Trade-offs between soil-based functions in wetlands restored with soil amendments of differing lability.

Soil amendments have been proposed as a means to speed the development of plant and soil processes that contribute to water quality, habitat, and biodiversity functions in restored wetlands. However, because natural wetlands often act as significant methane sources, it remains unknown if amendments will also stimulate emissions of this greenhouse gas from restored wetlands. In this study, we investigated the potential trade-offs of incorporating soil amendments into wetland restoration methodology. We used controlled field-scale manipulations in four recently restored depressional freshwater wetlands in western New York, USA to investigate the impact that soils amended with organic materials have on water-quality functions and methane production in the first three years of development. Results showed that amendments, topsoil in particular, were effective for stimulating the development of a suite of biological (microbial biomass increased by 106% and respiration by 26%) and physicochemical (cation exchange capacity increased by 10%) soil properties indicative of water-quality functions. Furthermore, increases in microbial biomass and activity lasted for a significantly longer period of time (years instead of days) than studies examining less recalcitrant amendments. However, amended plots also had 20% times higher potential net methane production than control plots three years after restoration. Wetlands restoration projects are implemented to achieve a variety of goals, commonly including habitat provision, biodiversity, and water-quality functions, but also carbon sequestration, flood abatement, cultural heritage and livelihood preservation, recreation, education, and others. Projects should strive to achieve their specific goals while also evaluating the potential tradeoffs between wetland functions.

In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses.

Influenza A viruses cause recurrent outbreaks at local or global scale with potentially severe consequences for human health and the global economy. Recently, a new strain of influenza A virus was detected that causes disease in and transmits among humans, probably owing to little or no pre-existing immunity to the new strain. On 11 June 2009 the World Health Organization declared that the infections caused by the new strain had reached pandemic proportion. Characterized as an influenza A virus of the H1N1 subtype, the genomic segments of the new strain were most closely related to swine viruses. Most human infections with swine-origin H1N1 influenza viruses (S-OIVs) seem to be mild; however, a substantial number of hospitalized individuals do not have underlying health issues, attesting to the pathogenic potential of S-OIVs. To achieve a better assessment of the risk posed by the new virus, we characterized one of the first US S-OIV isolates, A/California/04/09 (H1N1; hereafter referred to as CA04), as well as several other S-OIV isolates, in vitro and in vivo. In mice and ferrets, CA04 and other S-OIV isolates tested replicate more efficiently than a currently circulating human H1N1 virus. In addition, CA04 replicates efficiently in non-human primates, causes more severe pathological lesions in the lungs of infected mice, ferrets and non-human primates than a currently circulating human H1N1 virus, and transmits among ferrets. In specific-pathogen-free miniature pigs, CA04 replicates without clinical symptoms. The assessment of human sera from different age groups suggests that infection with human H1N1 viruses antigenically closely related to viruses circulating in 1918 confers neutralizing antibody activity to CA04. Finally, we show that CA04 is sensitive to approved and experimental antiviral drugs, suggesting that these compounds could function as a first line of defence against the recently declared S-OIV pandemic.

Effects of rhinovirus species on viral replication and cytokine production.

BACKGROUND: Epidemiologic studies provide evidence of differential virulence of rhinovirus species (RV). We recently reported that RV-A and RV-C induced more severe illnesses than RV-B, which suggests that the biology of RV-B might be different from RV-A or RV-C. OBJECTIVE: To test the hypothesis that RV-B has lower replication and induces lesser cytokine responses than RV-A or RV-C. METHODS: We cloned full-length cDNA of RV-A16, A36, B52, B72, C2, C15, and C41 from clinical samples and grew clinical isolates of RV-A7 and RV-B6 in cultured cells. Sinus epithelial cells were differentiated at the air-liquid interface. We tested for differences in viral replication in epithelial cells after infection with purified viruses (10(8) RNA copies) and measured virus load by quantitative RT-PCR. We measured lactate dehydrogenase (LDH) concentration as a marker of cellular cytotoxicity, and cytokine and/or chemokine secretion by multiplex ELISA. RESULTS: At 24 hours after infection, the virus load of RV-B (RV-B52, RV-B72, or RV-B6) in adherent cells was lower than that of RV-A or RV-C. The growth kinetics of infection indicated that RV-B types replicate more slowly. Furthermore, RV-B released less LDH than RV-A or RV-C, and induced lower levels of cytokines and chemokines such as CXCL10, even after correction for viral replication. RV-B replicates to lower levels also in primary bronchial epithelial cells. CONCLUSIONS: Our results indicate that RV-B types have lower and slower replication, and lower cellular cytotoxicity and cytokine and/or chemokine production compared with RV-A or RV-C. These characteristics may contribute to reduced severity of illnesses that has been observed with RV-B infections.

Enhancing Hispanic participation in mental health clinical research: development of a Spanish-speaking depression research site.

BACKGROUND: Hispanics, particularly those with limited English proficiency, are underrepresented in psychiatric clinical research studies. We developed a bilingual and bicultural research clinic dedicated to the recruitment and treatment of Spanish-speaking subjects in the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study, a large clinical trial of treatment-naïve subjects with major depressive disorder (MDD). METHODS: Demographic and clinical data derived from screening evaluations of the first 1,174 subjects presenting for participation were compared between the Spanish-speaking site (N = 275) and the primary English-speaking site (N = 899). Reasons for ineligibility (N = 888) for the PReDICT study were tallied for each site. RESULTS: Compared to English speakers, Spanish speakers had a lower level of education and were more likely to be female, uninsured, and have uncontrolled medical conditions. Clinically, Spanish speakers demonstrated greater depression severity, with higher mean symptom severity scores, and a greater number of previous suicide attempts. Among the subjects who were not randomized into the PReDICT study, Spanish-speaking subjects were more likely to have an uncontrolled medical condition or refuse participation, whereas English-speaking subjects were more likely to have bipolar disorder or a non-MDD depressive disorder. CONCLUSION: Recruitment of Hispanic subjects with MDD is feasible and may enhance efforts at signal detection, given the higher severity of depression among Spanish-speaking participants presenting for clinical trials. Specific approaches for the recruitment and retention of Spanish-speaking participants are required.

Stimulating nitrate removal processes of restored wetlands.

The environmental and health effects caused by nitrate contamination of aquatic systems are a serious problem throughout the world. A strategy proposed to address nitrate pollution is the restoration of wetlands. However, although natural wetlands often remove nitrate via high rates of denitrification, wetlands restored for water quality functions often fall below expectations. This may be in part because key drivers for denitrification, in particular soil carbon, are slow to develop in restored wetlands. We added organic soil amendments that range along a gradient of carbon lability to four newly restored wetlands in western New York to investigate the effect of carbon additions on denitrification and other processes of the nitrogen cycle. Soil carbon increased by 12.67-63.30% with the use of soil amendments (p ≤ 0.0001). Soil nitrate, the carbon to nitrogen ratio, and microbial biomass nitrogen were the most significant predictors of denitrification potential. Denitrification potential, potential net nitrogen nitrification and mineralization, and soil nitrate and ammonium, were highest in topsoil-amended plots, with increases in denitrification potential of 161.27% over control plots. While amendment with topsoil more than doubled several key nitrogen cycling processes, more research is required to determine what type and level of amendment application are most effective for stimulating removal of exogenous nitrate and meeting functional goals within an acceptable time frame.

Groundwater inputs could be a significant but often overlooked source of phosphorus in lake ecosystems.

Freshwater lakes are severely threatened, due largely to excess inputs of nutrients and other contaminants. Phosphorus (P) is receiving renewed attention due to recent increases in toxic cyanobacteria blooms in lakes worldwide. We investigated groundwater seepage for its role in P loading dynamics at Oneida Lake, New York, USA-one of the most well-studied lakes globally. P loading was measured at representative sites along the 88 km shoreline over three summers by directly measuring groundwater flow using seepage meters and porewater samplers. Groundwater seepage was a continuous and significant source of dissolved P over the summer months, comparable to tributary sources to the lake during that time. This constant input has enriched the concentrations of P in the nearshore surface waters, significantly above levels in the pelagic zone. Pore Total Phosphorus (TP) concentrations and loads reached extremely high values (up to 100 mg/L), with inorganic P representing only ~ 10% of TP per site. Groundwater seepage flows and P loadings were highly variable across space and time, partially explained by adjacent land uses and precipitation. Our research concludes that groundwater seepage is a significant, but overlooked, source of dissolved P and a crucial factor driving summer primary production at Oneida Lake, and likely other temperate lakes.

Online trend estimation and detection of trend deviations in sub-sewershed time series of SARS-CoV-2 RNA measured in wastewater.

Wastewater surveillance has proven a cost-effective key public health tool to understand a wide range of community health diseases and has been a strong source of information on community levels and spread for health departments throughout the SARS- CoV-2 pandemic. Studies spanning the globe demonstrate the strong association between virus levels observed in wastewater and quality clinical case information of the population served by the sewershed. Few of these studies incorporate the temporal dependence present in sampling over time, which can lead to estimation issues which in turn impact conclusions. We contribute to the literature for this important public health science by putting forward time series methods coupled with statistical process control that (1) capture the evolving trend of a disease in the population; (2) separate the uncertainty in the population disease trend from the uncertainty due to sampling and measurement; and (3) support comparison of sub-sewershed population disease dynamics with those of the population represented by the larger downstream treatment plant. Our statistical methods incorporate the fact that measurements are over time, ensuring correct statistical conclusions. We provide a retrospective example of how sub-sewersheds virus levels compare to the upstream wastewater treatment plant virus levels. An on-line algorithm supports real-time statistical assessment of deviations of virus level in a population represented by a sub-sewershed to the virus level in the corresponding larger downstream wastewater treatment plant. This information supports public health decisions by spotlighting segments of the population where outbreaks may be occurring.

Budesonide and formoterol effects on rhinovirus replication and epithelial cell cytokine responses.

BACKGROUND: Combination therapy with budesonide and formoterol reduces exacerbations of asthma, which are closely associated with human rhinovirus (RV) infections in both children and adults. These data suggest that budesonide and formoterol inhibit virus-induced inflammatory responses of airway epithelial cells. METHODS: To test this hypothesis, bronchial epithelial (BE) cells were obtained from airway brushings of 8 subjects with moderate-to-severe allergic asthma and 9 with neither asthma nor respiratory allergies. Cultured BE cells were incubated for 24 hours with budesonide (1.77 µM), formoterol (0.1 µM), both, or neither, and then inoculated with RV-16 (5×10(6) plaque forming units [PFU]/mL). After 24 hours, viral replication (RV RNA), cytokine secretion (CXCL8, CXCL10, TNFa, IFN-ß, IL-28) and mRNA expression (CXCL8, CXCL10, TNF, IFNB1, IL-28) were analyzed. RESULTS: RV infection induced CXCL10 protein secretion and IFNB1 and IL28 mRNA expression. Drug treatments significantly inhibited secretion of CXCL10 in mock-infected, but not RV-infected, BE cells, and inhibited secretion of TNFa under both conditions. Neither budesonide nor formoterol, alone or in combination, significantly affected viral replication, nor did they inhibit RV-induced upregulation of IFNB1 and IL28 mRNA. Overall, RV replication was positively related to CXCL10 secretion and induction of IFNB1 and IL28 mRNA, but the positive relationship between RV RNA and CXCL10 secretion was stronger in normal subjects than in subjects with asthma. CONCLUSIONS: Budesonide and formoterol can inhibit BE cell inflammatory responses in vitro without interfering with viral replication or production of interferons. These effects could potentially contribute to beneficial effects of budesonide/formoterol combination therapy in preventing RV-induced asthma exacerbations.

Roadside ditches as conduits of fecal indicator organisms and sediment: implications for water quality management.

Roadside ditches are ubiquitous, yet their role in water pollution conveyance has largely been ignored, especially for bacteria and sediment. The goal of this study was to determine if roadside ditches are conduits for fecal indicator organisms and sediment, and if land use, specifically manure amendment, affects the concentrations and loadings. Seven roadside ditches in central New York, adjacent to either manure amended fields or predominately forested land, were monitored for one year for Escherichia coli (E. coli), total suspended solids (TSS) and flow. E. coli concentrations in water samples following storms averaged 4616 MPN of E. coli/100 mL. Concentrations reached as high as >241,960 MPN of E. coli/100 mL and frequently exceeded New York State and US EPA recommendations. Concentrations peaked in both summers following manure spreading, with declining levels thereafter. However, viable organisms were detected throughout the year. The concentrations were also high in the forested sites, with possible sources including wildlife, pets, septic wastes and livestock. E. coli concentrations and loadings were related to TSS concentrations and loadings, whether manure had been spread in the last 30 days and for concentrations only, antecedent rainfall. Viable E. coli were also present in ditch sediment between storm events and were available for resuspension and transport. Total suspended solids concentrations averaged 0.51 g/L and reached as high as 52.2 g/L. Loads were similarly high, at an average of 631.6 kg/day. Both concentrations and loads tended to be associated with discharge and rainfall parameters. The cumulative pollutant contribution from the ditch network was estimated to be large enough to produce detectable and sometimes high concentrations in a receiving stream in a small, rural watershed. Roadside drainage networks need to be actively managed for water quality improvements, because they capture and rapidly shunt stormwater and associated contaminants to streams.