Serotonin Reduction in Post-acute Sequelae of Viral Infection

Post-acute sequelae of COVID-19 (PASC, Long COVID ) pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes

Gas-phase studies on the reactivity of charged, aromatic σ-radicals and differentiation of stereoisomers in a Fourier transform ion cyclotron resonance mass spectrometer

Radical-induced DNA degradation plays an important role in the action of many anti-tumor drugs. Radicals can abstract a hydrogen atom from a sugar moiety in DNA, leading to DNA cleavage. However, little is known about the factors (e.g., enthalpic, polar) that control the reactivity of these radical intermediates. This research explores the structure/reactivity relationships by aromatic a-radicals that control the efficiency of hydrogen atom abstraction from neutral atom donors. Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR) was employed to characterize the reactivity of aromatic σ-radicals. These radicals contain an electron withdrawing protonated or charged nitrogen atom that allows for mass spectrometric manipulation of the radicals. In addition, by variation of the position of the heteroatom, the rates of hydrogen atom abstraction were shown to be due to polar effects and not to changes in reaction exothermicities. Furthermore, the reactivity of aromatic σ,σ-radicals was shown to be controlled by both the magnitude of their singlet-triplet gap and polar effects. Development of methods to differentiate stereoisomeric compounds is an important area of research because simple and rapid methods are needed for the analysis of stereoisomeric pharmaceutical compounds. This thesis demonstrates that phosphenium ions can be used to rapidly differentiate certain diastereomeric hydroxysteroids in an FT-ICR. Reaction of the phosphenium ions with certain steroids gives rise to the formation of unique reaction products for only one of the isomers of a diastereomeric pair

Additional file 1: Figure S1. of A novel clinical approach to evaluating changes in fat oxidation in healthy, overnight-fasted subjects

Pre- and Post-Intralipid Respiratory Quotient Values. A. Average RQ values measured during the Pre-Intralipid/Baseline phase of the test visit and post-Intralipid RQ values. #Denotes significant difference in LG group Pre-Intralipid/Baseline measure with respect to the LS group. &Denotes significant difference in LG group Pre-Intralipid/Baseline measure with respect to the OS group. *Denotes significant difference within group, Post-Intralipid measure with respect to the average Pre-Intralipid/Baseline measure. B. RQ measured under fasting conditions, with (CHO Diet) or without (Ad Lib Diet) high carbohydrate dietary intake, ±Glucose, and following Intralipid infusion. *Denotes significant difference within group, Post-Intralipid measure with respect to the average Pre-Intralipid measure. $Denotes significant difference in Post-Intralipid measure with respect to the Ad Lib Diet measure. #Denotes significant difference in Pre-Intralipid measure with respect to the Ad Lib Diet measure. C. Comparison of fasting RQ values (“Between Day”) and RQ values obtained during the saline or glucose infusion phase of the test visit (“Within Day”) to post-Intralipid RQ values. *Denotes significant difference within group, Post-Intralipid measure with respect to the Pre-Intralipid/Baseline measure. Note: For all symbols: *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001. (DOCX 667 kb

Targeted Metabolomic Profiling of Plasma and Survival in Heart Failure Patients

OBJECTIVES: This study sought to derive and validate plasma metabolite associations with survival in heart failure (HF) patients. BACKGROUND: Profiling of plasma metabolites to predict the course of HF appears promising, but validation and incremental value of these profiles are less established. METHODS: Patients (n = 1,032) who met Framingham HF criteria with a history of reduced ejection fraction were randomly divided into derivation and validation cohorts (n = 516 each). Amino acids, organic acids, and acylcarnitines were quantified using mass spectrometry in fasting plasma samples. We derived a prognostic metabolite profile (PMP) in the derivation cohort using Lasso-penalized Cox regression. Validity was assessed by 10-fold cross validation in the derivation cohort and by standard testing in the validation cohort. The PMP was analyzed as both a continuous variable (PMPscore) and dichotomized at the median (PMPcat), in univariate and multivariate models adjusted for clinical risk score and N-terminal pro-B-type natriuretic peptide. RESULTS: Overall, 48% of patients were African American, 35% were women, and the average age was 69 years. After a median follow-up of 34 months, there were 256 deaths (127 and 129 in derivation and validation cohorts, respectively). Optimized modeling defined the 13 metabolite PMPs, which was cross validated as both the PMPscore (hazard ratio [HR]: 3.27; p \u3c 2 × 10 CONCLUSIONS: Plasma metabolite profiles varied across HF subgroups and were associated with survival incremental to conventional predictors. Additional investigation is warranted to define mechanisms and clinical applications

Targeted Metabolomic Profiling of Plasma and Survival in Heart Failure Patients

OBJECTIVES: This study sought to derive and validate plasma metabolite associations with survival in heart failure (HF) patients. BACKGROUND: Profiling of plasma metabolites to predict the course of HF appears promising, but validation and incremental value of these profiles are less established. METHODS: Patients (n = 1,032) who met Framingham HF criteria with a history of reduced ejection fraction were randomly divided into derivation and validation cohorts (n = 516 each). Amino acids, organic acids, and acylcarnitines were quantified using mass spectrometry in fasting plasma samples. We derived a prognostic metabolite profile (PMP) in the derivation cohort using Lasso-penalized Cox regression. Validity was assessed by 10-fold cross validation in the derivation cohort and by standard testing in the validation cohort. The PMP was analyzed as both a continuous variable (PMPscore) and dichotomized at the median (PMPcat), in univariate and multivariate models adjusted for clinical risk score and N-terminal pro-B-type natriuretic peptide. RESULTS: Overall, 48% of patients were African American, 35% were women, and the average age was 69 years. After a median follow-up of 34 months, there were 256 deaths (127 and 129 in derivation and validation cohorts, respectively). Optimized modeling defined the 13 metabolite PMPs, which was cross validated as both the PMPscore (hazard ratio [HR]: 3.27; p \u3c 2 × 10-16) and PMPcat (HR: 3.04; p = 2.93 × 10-8). The validation cohort showed similar results (PMPscore HR: 3.9; p \u3c 2 × 10-16 and PMPcat HR: 3.99; p = 3.47 × 10-9). In adjusted models, PMP remained associated with mortality in the cross-validated derivation cohort (PMPscore HR: 1.63; p = 0.0029; PMPcat HR: 1.47; p = 0.081) and the validation cohort (PMPscore HR: 1.54; p = 0.037; PMPcat HR: 1.69; p = 0.043). CONCLUSIONS: Plasma metabolite profiles varied across HF subgroups and were associated with survival incremental to conventional predictors. Additional investigation is warranted to define mechanisms and clinical applications

Correction: Isocitrate dehydrogenase 2 protects mice from high-fat diet-induced metabolic stress by limiting oxidative damage to the mitochondria from brown adipose tissue

An amendment to this paper has been published and can be accessed via a link at the top of the paper