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- Fromentin, S., et al.
(författare)
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Microbiome and metabolome features of the cardiometabolic disease spectrum
- 2022
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 28:2, s. 303-314
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Tidskriftsartikel (refereegranskat)abstract
- By studying individuals along a spectrum of cardiometabolic disease and adjusting for effects of lifestyle and medication, this investigation identifies alterations of the metabolome and microbiome from dysmetabolic conditions, such as obesity and type 2 diabetes, to ischemic heart disease. Previous microbiome and metabolome analyses exploring non-communicable diseases have paid scant attention to major confounders of study outcomes, such as common, pre-morbid and co-morbid conditions, or polypharmacy. Here, in the context of ischemic heart disease (IHD), we used a study design that recapitulates disease initiation, escalation and response to treatment over time, mirroring a longitudinal study that would otherwise be difficult to perform given the protracted nature of IHD pathogenesis. We recruited 1,241 middle-aged Europeans, including healthy individuals, individuals with dysmetabolic morbidities (obesity and type 2 diabetes) but lacking overt IHD diagnosis and individuals with IHD at three distinct clinical stages-acute coronary syndrome, chronic IHD and IHD with heart failure-and characterized their phenome, gut metagenome and serum and urine metabolome. We found that about 75% of microbiome and metabolome features that distinguish individuals with IHD from healthy individuals after adjustment for effects of medication and lifestyle are present in individuals exhibiting dysmetabolism, suggesting that major alterations of the gut microbiome and metabolome might begin long before clinical onset of IHD. We further categorized microbiome and metabolome signatures related to prodromal dysmetabolism, specific to IHD in general or to each of its three subtypes or related to escalation or de-escalation of IHD. Discriminant analysis based on specific IHD microbiome and metabolome features could better differentiate individuals with IHD from healthy individuals or metabolically matched individuals as compared to the conventional risk markers, pointing to a pathophysiological relevance of these features.
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| 2. |
- Ekanem, Emmanuel, et al.
(författare)
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Safety of pulsed field ablation in more than 17,000 patients with atrial fibrillation in the MANIFEST-17K study
- 2024
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Ingår i: Nature Medicine. - : NATURE PORTFOLIO. - 1078-8956 .- 1546-170X.
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Tidskriftsartikel (refereegranskat)abstract
- Pulsed field ablation (PFA) is an emerging technology for the treatment of atrial fibrillation (AF), for which pre-clinical and early-stage clinical data are suggestive of some degree of preferentiality to myocardial tissue ablation without damage to adjacent structures. Here in the MANIFEST-17K study we assessed the safety of PFA by studying the post-approval use of this treatment modality. Of the 116 centers performing post-approval PFA with a pentaspline catheter, data were received from 106 centers (91.4% participation) regarding 17,642 patients undergoing PFA (mean age 64, 34.7% female, 57.8% paroxysmal AF and 35.2% persistent AF). No esophageal complications, pulmonary vein stenosis or persistent phrenic palsy was reported (transient palsy was reported in 0.06% of patients; 11 of 17,642). Major complications, reported for similar to 1% of patients (173 of 17,642), were pericardial tamponade (0.36%; 63 of 17,642) and vascular events (0.30%; 53 of 17,642). Stroke was rare (0.12%; 22 of 17,642) and death was even rarer (0.03%; 5 of 17,642). Unexpected complications of PFA were coronary arterial spasm in 0.14% of patients (25 of 17,642) and hemolysis-related acute renal failure necessitating hemodialysis in 0.03% of patients (5 of 17,642). Taken together, these data indicate that PFA demonstrates a favorable safety profile by avoiding much of the collateral damage seen with conventional thermal ablation. PFA has the potential to be transformative for the management of patients with AF.
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| 4. |
- Addinsall, AB, et al.
(författare)
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Impaired exercise performance is independent of inflammation and cellular stress following genetic reduction or deletion of selenoprotein S
- 2020
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Ingår i: American journal of physiology. Regulatory, integrative and comparative physiology. - : American Physiological Society. - 1522-1490 .- 0363-6119. ; 318:5, s. R981-R996
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Tidskriftsartikel (refereegranskat)abstract
- Selenoprotein S (Seps1) can be protective against oxidative, endoplasmic reticulum (ER), and inflammatory stress. Seps1 global knockout mice are less active, possess compromised fast muscle ex vivo strength, and, depending on context, heightened inflammation. Oxidative, ER, and inflammatory stress modulates contractile function; hence, our aim was to investigate the effects of Seps1 gene dose on exercise performance. Seps1−/− knockout, Seps1−/+ heterozygous, and wild-type mice were randomized to 3 days of incremental, high-intensity treadmill running or a sedentary control group. On day 4, the in situ contractile function of fast tibialis anterior (TA) muscles was determined. Seps1 reduction or deletion compromised exercise capacity, decreasing distance run. TA strength was also reduced. In sedentary Seps1−/− knockout mice, TA fatigability was greater than wild-type mice, and this was ameliorated with exercise. Whereas, in Seps1+/− heterozygous mice, exercise compromised TA endurance. These impairments in exercise capacity and TA contractile function were not associated with increased inflammation or a dysregulated redox state. Seps1 is highly expressed in muscle fibers and blood vessels. Interestingly, Nos1 and Vegfa mRNA transcripts were decreased in TA muscles from Seps1−/− knockout and Seps1−/+ heterozygous mice. Impaired exercise performance with Seps1 reduction or deletion cannot be attributed to heightened cellular stress, but it may potentially be mediated, in part, by the effects of Seps1 on the microvasculature.
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| 8. |
- Andrikopoulos, Prokopis C., et al.
(författare)
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Femtosecond-to-nanosecond dynamics of flavin mononucleotide monitored by stimulated Raman spectroscopy and simulations
- 2020
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Ingår i: Physical Chemistry Chemical Physics. - : Royal Society of Chemistry (RSC). - 1463-9084 .- 1463-9076. ; 22:12, s. 6538-6552
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Tidskriftsartikel (refereegranskat)abstract
- Flavin mononucleotide (FMN) belongs to the large family of flavins, ubiquitous yellow-coloured biological chromophores that contain an isoalloxazine ring system. As a cofactor in flavoproteins, it is found in various enzymes and photosensory receptors, like those featuring the light-oxygen-voltage (LOV) domain. The photocycle of FMN is triggered by blue light and proceeds via a cascade of intermediate states. In this work, we have studied isolated FMN in an aqueous solution in order to elucidate the intrinsic electronic and vibrational changes of the chromophore upon excitation. The ultrafast transitions of excited FMN were monitored through the joint use of femtosecond stimulated Raman spectroscopy (FSRS) and transient absorption spectroscopy encompassing a time window between 0 ps and 6 ns with 50 fs time resolution. Global analysis of the obtained transient visible absorption and transient Raman spectra in combination with extensive quantum chemistry calculations identified unambiguously the singlet and triplet FMN populations and addressed solvent dynamics effects. The good agreement between the experimental and theoretical spectra facilitated the assignment of electronic transitions and vibrations. Our results represent the first steps towards more complex experiments aimed at tracking structural changes of FMN embedded in light-inducible proteins upon photoexcitation.
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| 9. |
- Bountouris, Ioannis, et al.
(författare)
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Serum leptin levels in patients undergoing carotid endarterectomy: a pilot study.
- 2009
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Ingår i: Angiology. - : SAGE Publications. - 1940-1574 .- 0003-3197. ; 60:6, s. 698-704
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Elevated serum leptin levels are associated with cardiovascular events. We investigated the role of serum leptin in patients undergoing carotid endarterectomy (CEA). METHODS: A total of 74 patients (55 men; 38 symptomatic and 36 asymptomatic; mean age 66.9 +/- 8.2 years) undergoing CEA for >70% carotid artery stenosis were enrolled. RESULTS: Serum leptin levels were lower in symptomatic compared with asymptomatic patients (7.1 +/- 1.3 vs 14.4 +/- 4.7 ng/dL; P < .001). Interleukin-6 (IL-6) levels were higher in symptomatic compared with asymptomatic patients (4.3 +/- 1.7 vs 3.3 +/- 1.1 pg/dL; P = .017). Symptomatic patients had more intense macrophage accumulation (0.7% +/- 0.1% vs 0.3% +/- 0.1%; P < .001). Serum leptin and serum IL-6 levels were independently associated with the presence of symptoms in multivariate analysis. CONCLUSION: Serum leptin levels were decreased in symptomatic carotid artery disease. This finding requires further investigation in larger studies.
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| 10. |
- Chaudhari, Aditya S., et al.
(författare)
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Genetically encoded non-canonical amino acids reveal asynchronous dark reversion of chromophore, backbone, and side-chains in EL222
- 2023
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Ingår i: Protein Science. - : John Wiley & Sons. - 0961-8368 .- 1469-896X. ; 32:4
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Tidskriftsartikel (refereegranskat)abstract
- Photoreceptors containing the light-oxygen-voltage (LOV) domain elicit biological responses upon excitation of their flavin mononucleotide (FMN) chromophore by blue light. The mechanism and kinetics of dark-state recovery are not well understood. Here we incorporated the non-canonical amino acid p-cyanophenylalanine (CNF) by genetic code expansion technology at 45 positions of the bacterial transcription factor EL222. Screening of light-induced changes in infrared (IR) absorption frequency, electric field and hydration of the nitrile groups identified residues CNF31 and CNF35 as reporters of monomer/oligomer and caged/decaged equilibria, respectively. Time-resolved multi-probe UV/visible and IR spectroscopy experiments of the lit-to-dark transition revealed four dynamical events. Predominantly, rearrangements around the A'α helix interface (CNF31 and CNF35) precede FMN-cysteinyl adduct scission, folding of α-helices (amide bands), and relaxation of residue CNF151. This study illustrates the importance of characterizing all parts of a protein and suggests a key role for the N-terminal A'α extension of the LOV domain in controlling EL222 photocycle length.
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