| 201. |
- Bergström, Anders, et al.
(författare)
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A high-definition view of functional genetic variation from natural yeast genomes.
- 2014
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Ingår i: Molecular biology and evolution. - : Oxford University Press (OUP). - 1537-1719 .- 0737-4038. ; 31:4, s. 872-88
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Tidskriftsartikel (refereegranskat)abstract
- The question of how genetic variation in a population influences phenotypic variation and evolution is of major importance in modern biology. Yet much is still unknown about the relative functional importance of different forms of genome variation and how they are shaped by evolutionary processes. Here we address these questions by population level sequencing of 42 strains from the budding yeast Saccharomyces cerevisiae and its closest relative S. paradoxus. We find that genome content variation, in the form of presence or absence as well as copy number of genetic material, is higher within S. cerevisiae than within S. paradoxus, despite genetic distances as measured in single-nucleotide polymorphisms being vastly smaller within the former species. This genome content variation, as well as loss-of-function variation in the form of premature stop codons and frameshifting indels, is heavily enriched in the subtelomeres, strongly reinforcing the relevance of these regions to functional evolution. Genes affected by these likely functional forms of variation are enriched for functions mediating interaction with the external environment (sugar transport and metabolism, flocculation, metal transport, and metabolism). Our results and analyses provide a comprehensive view of genomic diversity in budding yeast and expose surprising and pronounced differences between the variation within S. cerevisiae and that within S. paradoxus. We also believe that the sequence data and de novo assemblies will constitute a useful resource for further evolutionary and population genomics studies.
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| 202. |
- Bruno, Raphael Romano, et al.
(författare)
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The Clinical Frailty Scale for mortality prediction of old acutely admitted intensive care patients: a meta-analysis of individual patient-level data
- 2023
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Ingår i: Annals of Intensive Care. - : SPRINGER. - 2110-5820. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Background This large-scale analysis pools individual data about the Clinical Frailty Scale (CFS) to predict outcome in the intensive care unit (ICU). Methods A systematic search identified all clinical trials that used the CFS in the ICU (PubMed searched until 24th June 2020). All patients who were electively admitted were excluded. The primary outcome was ICU mortality. Regression models were estimated on the complete data set, and for missing data, multiple imputations were utilised. Cox models were adjusted for age, sex, and illness acuity score (SOFA, SAPS II or APACHE II). Results 12 studies from 30 countries with anonymised individualised patient data were included (n = 23,989 patients). In the univariate analysis for all patients, being frail (CFS >= 5) was associated with an increased risk of ICU mortality, but not after adjustment. In older patients (>= 65 years) there was an independent association with ICU mortality both in the complete case analysis (HR 1.34 (95% CI 1.25-1.44), p < 0.0001) and in the multiple imputation analysis (HR 1.35 (95% CI 1.26-1.45), p < 0.0001, adjusted for SOFA). In older patients, being vulnerable (CFS 4) alone did not significantly differ from being frail. After adjustment, a CFS of 4-5, 6, and >= 7 was associated with a significantly worse outcome compared to CFS of 1-3. Conclusions Being frail is associated with a significantly increased risk for ICU mortality in older patients, while being vulnerable alone did not significantly differ. New Frailty categories might reflect its "continuum" better and predict ICU outcome more accurately.
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| 203. |
- Brussee, Janneke M., et al.
(författare)
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Characterization of Intestinal and Hepatic CYP3A-Mediated Metabolism of Midazolam in Children Using a Physiological Population Pharmacokinetic Modelling Approach
- 2018
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Ingår i: Pharmaceutical research. - : Springer. - 0724-8741 .- 1573-904X. ; 35:9
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Changes in drug absorption and first-pass metabolism have been reported throughout the pediatric age range. Our aim is to characterize both intestinal and hepatic CYP3A-mediated metabolism of midazolam in children in order to predict first-pass and systemic metabolism of CYP3A substrates. Methods Pharmacokinetic (PK) data of midazolam and 1-OH-midazolam from 264 post-operative children 1-18 years of age after oral administration were analyzed using a physiological population PK. modelling approach. In the model, consisting of physiological compartments representing the gastro-intestinal tract and liver,intrinsic intestinal and hepatic clearances were estimated to derive values for bioavailability and plasma clearance. Results The whole-organ intrinsic clearance in the gut wall and liver were found to increase with body weight, with a 105 (95% confidence interval (CI): 5-405) times lower intrinsic gut wall clearance than the intrinsic hepatic dearance (i.e. 5.08 L/h (relative standard error (RSE) 10%) versus 527 L/h (RSE 7%) for a 16 kg individual, respectively). When expressed per gram of organ, intrinsic clearance increases with increasing body weight in the gut wall, but decreases in the liver, indicating that CYP3A-mediated intrinsic clearance and local bioavailability in the gut wall and liver do not change with age in parallel. The resulting total bioavailability was found to be age-independent with a median of 20.8% in children (95%CI: 3.8-50.0%). Conclusion In conclusion, the intrinsic CYP3A-mediated gut wall clearance is substantially lower than the intrinsic hepatic CYP3A-mediated clearance in children from 1 to 18 years of age, and contributes less to the overall first-pass metabolism compared to adults.
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| 204. |
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| 205. |
- Burger, N., et al.
(författare)
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ND3 Cys39 in complex I is exposed mitochondrial
- 2022
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Ingår i: Cell Chemical Biology. - : Elsevier BV. - 2451-9448 .- 2451-9456. ; 29:4
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Tidskriftsartikel (refereegranskat)abstract
- Mammalian complex I can adopt catalytically active (A-) or deactive (D-) states. A defining feature of the reversible transition between these two defined states is thought to be exposure of the ND3 subunit Cys39 residue in the D-state and its occlusion in the A-state. As the catalytic A/D transition is important in health and disease, we set out to quantify it by measuring Cys39 exposure using isotopic labeling and mass spectrometry, in parallel with complex I NADH/CoQ oxidoreductase activity. To our surprise, we found significant Cys39 exposure during NADH/CoQ oxidoreductase activity. Furthermore, this activity was unaffected if Cys39 alkylation occurred during complex I-linked respiration. In contrast, alkylation of catalytically inactive complex I irreversibly blocked the reactivation of NADH/CoQ oxidoreductase activity by NADH. Thus, Cys39 of ND3 is exposed in complex I during mitochondrial respiration, with significant implications for our understanding of the A/D transition and the mechanism of complex I.
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| 206. |
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| 207. |
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| 208. |
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| 209. |
- Edgerton, Michael
(författare)
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Pitch profile of the Glottal Whistle
- 2013
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Ingår i: Malaysian Journal of Science. - 0126-7906. ; 32:1, s. 78-85
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents a previously unreported method of laryngeal vocal sound production that is capable of producing pitches even higher than the whistle register (M3). Colloquially known as the glottal whistle (here referred to as M4), this method has a wider range than M3 and features frequent instances of biphonation, which is of interest for those involved with contemporary and improvised music. Pitch profile analyses of M4 have found the majority of fundamental frequency (f0) activity to be between 1 and 3 kHz, while the most frequently seen range was between 1000 to 1,500 Hz. Remarkably, multiple singers were able to produce f0 higher than the highest tone on the piano.
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| 210. |
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