Environmental pollutant risk factors for worse COVID-19 related clinical outcomes in predominately hispanic and latino populations.

BACKGROUND: Per- and poly-fluorinated compounds (PFAS) and heavy metals constitute two classes of environmental exposures with known immunotoxicant effects. In this pilot study, we aimed to evaluate the impact of exposure to heavy metals and PFAS on COVID-19 severity. We hypothesized that elevated plasma-PFAS concentrations and urinary heavy metal concentrations would be associated with increased odds of ICU admission in COVID-19 hospitalized individuals. METHODS: Using the University of Southern California Clinical Translational Sciences Institute (SC-CTSI) biorepository of hospitalized COVID-19 patients, urinary concentrations of 15 heavy metals and urinary creatinine were measured in n = 101 patients and plasma concentrations of 13 PFAS were measured in n = 126 patients. COVID-19 severity was determined based on whether a patient was admitted to the ICU during hospitalization. Associations of metals and PFAS with ICU admission were assessed using logistic regression models, controlling for age, sex, ethnicity, smoking status, and for metals, urinary dilution. RESULTS: The average age of patients was 55 ± 14.2 years. Among SC-CTSI participants with urinary measurement of heavy metals and blood measures of PFAS, 54.5% (n = 61) and 54.8% (n = 80) were admitted to the ICU, respectively. For heavy metals, we observed higher levels of Cd, Cr, and Cu in ICU patients. The strongest associations were with Cadmium (Cd). After accounting for covariates, each 1 SD increase in Cd resulted in a 2.00 (95% CI: 1.10-3.60; p = 0.03) times higher odds of admission to the ICU. When including only Hispanic or Latino participants, the effect estimates between cadmium and ICU admission remained similar. Results for PFAS were less consistent, with perfluorodecanesulfonic acid (PFDS) exhibiting a positive but non-significant association with ICU admission (Odds ratio, 95% CI: 1.50, 0.97-2.20) and perfluorodecanoic acid (PFDA) exhibiting a negative association with ICU admission (0.53, 0.31-0.88). CONCLUSIONS: This study supports the hypothesis that environmental exposures may impact COVID-19 severity.

Lipopolysaccharide-binding protein and future Parkinson's disease risk: a European prospective cohort.

INTRODUCTION: Lipopolysaccharide (LPS) is the outer membrane component of Gram-negative bacteria. LPS-binding protein (LBP) is an acute-phase reactant that mediates immune responses triggered by LPS and has been used as a blood marker for LPS. LBP has recently been indicated to be associated with Parkinson's disease (PD) in small-scale retrospective case-control studies. We aimed to investigate the association between LBP blood levels with PD risk in a nested case-control study within a large European prospective cohort. METHODS: A total of 352 incident PD cases (55% males) were identified and one control per case was selected, matched by age at recruitment, sex and study center. LBP levels in plasma collected at recruitment, which was on average 7.8 years before diagnosis of the cases, were analyzed by enzyme linked immunosorbent assay. Odds ratios (ORs) were estimated for one unit increase of the natural log of LBP levels and PD incidence by conditional logistic regression. RESULTS: Plasma LBP levels were higher in prospective PD cases compared to controls (median (interquartile range) 26.9 (18.1-41.0) vs. 24.7 (16.6-38.4) µg/ml). The OR for PD incidence per one unit increase of log LBP was elevated (1.46, 95% CI 0.98-2.19). This association was more pronounced among women (OR 2.68, 95% CI 1.40-5.13) and overweight/obese subjects (OR 1.54, 95% CI 1.09-2.18). CONCLUSION: The findings suggest that higher plasma LBP levels may be associated with an increased risk of PD and may thus pinpoint to a potential role of endotoxemia in the pathogenesis of PD, particularly in women and overweight/obese individuals.

Lanthanide-based luminescent probes for biological magnesium: accessing polyphosphate-bound Mg2.

Biomolecule-bound Mg2+ species, particularly polyphosphate complexes, represent a large and dynamic fraction of the total cellular magnesium that is essential for cellular function but remains invisible to most indicators. Here we report a new family of Eu(III)-based indicators, the MagQEu family, functionalized with a 4-oxo-4H-quinolizine-3-carboxylic acid metal recognition group/sensitization antenna for turn-on, luminescence-based detection of biologically relevant Mg2+ species.

Untargeted metabolomics reveals that multiple reproductive toxicants are present at the endometrium.

BACKGROUND: Recent epidemiologic research shows many environmental chemicals exhibit endocrine disrupting effects on the female reproductive system. Few studies have examined exposure at reproductive organs. Our aim was to perform a preliminary untargeted metabolomic characterization of menstrual blood, a novel biofluid, to identify environmental toxins present in the endometrium and evaluate the suitability of this sample type for exposome research. METHODS: Whole blood menstrual samples were collected from four women using a menstrual cup. Samples were analyzed for small molecules that include both environmental chemicals and endogenous metabolites using untargeted liquid chromatography with high-resolution mass spectrometry (LC-HRMS). Principal component analysis (PCA) and ANOVA was used to identify differences within and between individuals' menstrual blood metabolomic profiles, and the influence of the sample processing method. To assess the presence of environmental exposures, LC-HRMS chemical profiles were matched to the ToxCast chemical database, which includes 4557 commonly used commercial chemicals. Select compounds were confirmed by comparison to reference standards. RESULTS: PCA of metabolome profiles showed analysis of menstrual blood samples were highly reproducible, with high variability in detected metabolites between participants and low variability between analytical replicates of an individual's sample. Endogenous metabolites detected in menstrual blood samples achieved good coverage of the human blood metabolome. We found 1748 annotations for environmental chemicals, including suspected reproductive toxicants such as phenols, parabens, phthalates, and organochlorines. Storage temperature for the first 24 h did not significantly influence global metabolomic profiles. CONCLUSION: Our results show chemical exposures linked to reproductive toxicity and endocrine disruption are present in menstrual blood, a sampling medium for the endometrium.

Fluorescence Quenching Effects of Tetrazines and Their Diels-Alder Products: Mechanistic Insight Toward Fluorogenic Efficiency.

Inverse electron demand Diels-Alder reactions between s-tetrazines and strained dienophiles have numerous applications in fluorescent labeling of biomolecules. Herein, we investigate the effect of the dienophile on the fluorescence enhancement obtained upon reaction with a tetrazine-quenched fluorophore and study the possible mechanisms of fluorescence quenching by both the tetrazine and its reaction products. The dihydropyridazine obtained from reaction with a strained cyclooctene shows a residual fluorescence quenching effect, greater than that exerted by the pyridazine arising from reaction with the analogous alkyne. Linear and ultrabroadband two-dimensional electronic spectroscopy experiments reveal that resonance energy transfer is the mechanism responsible for the fluorescence quenching effect of tetrazines, whereas a mechanism involving more intimate electronic coupling, likely photoinduced electron transfer, is responsible for the quenching effect of the dihydropyridazine. These studies uncover parameters that can be tuned to maximize fluorogenic efficiency in bioconjugation reactions and reveal that strained alkynes are better reaction partners for achieving maximum contrast ratio.

Resolving the Fluorescence Quenching Mechanism of an Oxazine Dye Using Ultrabroadband Two-Dimensional Electronic Spectroscopy.

The design and optimization of fluorescent labels and fluorogenic probes rely heavily on their ability to distinguish among multiple competing fluorescence quenching mechanisms. Cresyl violet, a member of the 1,4-oxazine family of dyes, has generally been regarded as an exemplary fluorescent probe; however, recent ultrafast experiments revealed an excited-state decay kinetic of 1.2 ps, suggesting the presence of a transient photochemical state. Here, we present ultrabroadband two-dimensional electronic spectroscopy (2D ES) measurements of cresyl violet in the presence of the fluorescence quenching agent 3,6-di(2-hydroxyethyl)-1,2,4,5-tetrazine. The broad spectral bandwidth allows for the evaluation of multiple fluorescence quenching mechanisms such as exciton formation, photoinduced electron transfer, resonance energy transfer, and excited-state proton transfer. The 2D electronic spectra in the presence and absence of the quencher suggest that excited-state proton transfer drives the system's excited-state dynamics and leads to a cresyl violet tautomer involved in fluorescence quenching. The invocation of the tautomeric form of cresyl violet neatly resolves longstanding inconsistencies in the photophysics of oxazine dyes more generally. Although still under development, the application of ultrabroadband 2D ES to a molecular system represents a compelling demonstration of the technique's future role in the study of photochemical reaction mechanisms.

Formation of ternary complexes with MgATP: effects on the detection of Mg2+ in biological samples by bidentate fluorescent sensors.

Fluorescent indicators based on ß-keto-acid bidentate coordination motifs display superior metal selectivity profiles compared to current o-aminophenol-N,N,O-triacetic acid (APTRA) based chelators for the study of biological magnesium. These low denticity chelators, however, may allow for the formation of ternary complexes with Mg(2+) and common ligands present in the cellular milieu. In this work, absorption, fluorescence, and NMR spectroscopy were employed to study the interaction of turn-on and ratiometric fluorescent indicators based on 4-oxo-4H-quinolizine-3-carboxylic acid with Mg(2+) and ATP, the most abundant chelator of biological magnesium, thus revealing the formation of ternary complexes under conditions relevant to fluorescence imaging. The formation of ternary species elicits comparable or greater optical changes than those attributed to the formation of binary complexes alone. Dissociation of the fluorescent indicators from both ternary and binary species have apparent equilibrium constants in the low millimolar range at pH 7 and 25 °C. These results suggest that these bidentate sensors are incapable of distinguishing between free Mg(2+) and MgATP based on ratio or intensity-based steady-state fluorescence measurements, thus posing challenges in the interpretation of results from fluorescence imaging of magnesium in nucleotide-rich biological samples.