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| 2. |
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| 3. |
- Ruilope, LM, et al.
(author)
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Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial
- 2019
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In: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
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Journal article (peer-reviewed)abstract
- <b><i>Background:</i></b> Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. <b><i>Patients and</i></b> <b><i>Methods:</i></b> The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m<sup>2</sup> and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. <b><i>Conclusions:</i></b> FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.
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| 4. |
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| 5. |
- Olahova, M., et al.
(author)
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POLRMT mutations impair mitochondrial transcription causing neurological disease
- 2021
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Journal article (peer-reviewed)abstract
- While >300 disease-causing variants have been identified in the mitochondrial DNA (mtDNA) polymerase gamma, no mitochondrial phenotypes have been associated with POLRMT, the RNA polymerase responsible for transcription of the mitochondrial genome. Here, we characterise the clinical and molecular nature of POLRMT variants in eight individuals from seven unrelated families. Patients present with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype. Massive parallel sequencing of all subjects identifies recessive and dominant variants in the POLRMT gene. Patient fibroblasts have a defect in mitochondrial mRNA synthesis, but no mtDNA deletions or copy number abnormalities. The in vitro characterisation of the recombinant POLRMT mutants reveals variable, but deleterious effects on mitochondrial transcription. Together, our in vivo and in vitro functional studies of POLRMT variants establish defective mitochondrial transcription as an important disease mechanism. POLRMT is key for transcription of the mitochondrial genome, yet has not been implicated in mitochondrial disease to date. Here, the authors identify mutations in POLRMT in individuals with mitochondrial disease-related phenotypes and characterise underlying defects in mitochondrial transcription.
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| 6. |
- Del Dotto, V., et al.
(author)
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SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder
- 2020
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In: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738 .- 1558-8238. ; 130:1, s. 108-125
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Journal article (peer-reviewed)abstract
- Inherited optic neuropathies include complex phenotypes, mostly driven by mitochondrial dysfunction. We report an optic atrophy spectrum disorder, including retinal macular dystrophy and kidney insufficiency leading to transplantation, associated with mitochondrial DNA (mtDNA) depletion without accumulation of multiple deletions. By whole-exome sequencing, we identified mutations affecting the mitochondrial single-strand binding protein (SSBP1) in 4 families with dominant and 1 with recessive inheritance. We show that SSBP1 mutations in patient-derived fibroblasts variably affect the amount of SSBP1 protein and alter multimer formation, but not the binding to ssDNA. SSBP1 mutations impaired mtDNA, nucleoids, and 7S-DNA amounts as well as mtDNA replication, affecting replisome machinery. The variable mtDNA depletion in cells was reflected in severity of mitochondrial dysfunction, including respiratory efficiency, OXPHOS subunits, and complex amount and assembly. mtDNA depletion and cytochrome c oxidase-negative cells were found ex vivo in biopsies of affected tissues, such as kidney and skeletal muscle. Reduced efficiency of mtDNA replication was also reproduced in vitro, confirming the pathogenic mechanism. Furthermore, ssbp1 suppression in zebrafish induced signs of nephropathy and reduced optic nerve size, the latter phenotype complemented by WT mRNA but not by SSBP1 mutant transcripts. This previously unrecognized disease of mtDNA maintenance implicates SSBP1 mutations as a cause of human pathology.
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| 7. |
- Abdellaoui, A, et al.
(author)
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Phenome-wide investigation of health outcomes associated with genetic predisposition to loneliness
- 2019
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In: Human molecular genetics. - : Oxford University Press (OUP). - 1460-2083 .- 0964-6906. ; 28:22, s. 3853-3865
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Journal article (peer-reviewed)abstract
- Humans are social animals that experience intense suffering when they perceive a lack of social connection. Modern societies are experiencing an epidemic of loneliness. Although the experience of loneliness is universally human, some people report experiencing greater loneliness than others. Loneliness is more strongly associated with mortality than obesity, emphasizing the need to understand the nature of the relationship between loneliness and health. Although it is intuitive that circumstantial factors such as marital status and age influence loneliness, there is also compelling evidence of a genetic predisposition toward loneliness. To better understand the genetic architecture of loneliness and its relationship with associated outcomes, we extended the genome-wide association study meta-analysis of loneliness to 511 280 subjects, and detect 19 significant genetic variants from 16 loci, including four novel loci, as well as 58 significantly associated genes. We investigated the genetic overlap with a wide range of physical and mental health traits by computing genetic correlations and by building loneliness polygenic scores in an independent sample of 18 498 individuals with EHR data to conduct a PheWAS with. A genetic predisposition toward loneliness was associated with cardiovascular, psychiatric, and metabolic disorders and triglycerides and high-density lipoproteins. Mendelian randomization analyses showed evidence of a causal, increasing, the effect of both BMI and body fat on loneliness. Our results provide a framework for future studies of the genetic basis of loneliness and its relationship to mental and physical health.
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| 8. |
- Gesheva, Kostadinka, et al.
(author)
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Optical, structural and electrochromic properties of sputter deposited W-Mo oxide thin films
- 2016
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In: INERA CONFERENCE. - : Institute of Physics Publishing (IOPP).
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Conference paper (peer-reviewed)abstract
- Thin metal oxide films were investigated by a series of characterization techniques including impedance spectroscopy, spectroscopic ellipsometry, Raman spectroscopy, and Atomic Force Microscopy. Thin film deposition by reactive DC magnetron sputtering was performed at the Ångström Laboratory. W and Mo targets (5 cm diameter) and various oxygen gas flows were employed to prepare samples with different properties, whereas the gas pressure was kept constant at about 30 mTorr. The substrates were 5×5 cm2 plates of unheated glass pre-coated with ITO having a resistance of 40 ohm/sq. Film thicknesses were around 300nm as determined by surface profilometry. Newly acquired equipment was used to study optical spectra, optoelectronic properties, and film structure. Films of WO3 and of mixed W–Mo oxide with three compositions showed coloring and bleaching under the application of a small voltage. Cyclic voltammograms were recorded with a scan rate of 5 mV s–1. Ellipsometric data for the optical constants show dependence on the amount of MoOx in the chemical composition. Single MoOx film, and the mixed one with only 8% MoOx have the highest value of refractive index, and similar dispersion in the visible spectral range. Raman spectra displayed strong lines at wavenumbers between 780 cm–1 and 950 cm–1 related to stretching vibrations of WO3, and MoO3. AFM gave evidence for domains of different composition in mixed W-Mo oxide films.
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| 9. |
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| 10. |
- Szilagyi, Csaba, et al.
(author)
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Chaplain leadership during COVID-19 : an international expert panel
- 2022
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In: Journal of Pastoral Care & Counseling. - : Sage Publications. - 1542-3050 .- 2167-776X. ; 76:1, s. 56-65
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Journal article (peer-reviewed)abstract
- Chaplain leadership may have played a pivotal role in shaping chaplains’ roles in health care amidst the COVID-19 pandemic. We convened an international expert panel to identify expert perception on key chaplain leadership factors. Six leadership themes of professional confidence, engaging and trust-building with executives, decision-making, innovation and creativity, building integrative and trusting connections with colleagues, and promoting cultural competencies emerged as central to determining chaplains’ integration, perceived value, and contributions during the pandemic.
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| 11. |
- Boyadjiev, Stefan I., et al.
(author)
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Study of the electrochromic properties of MAPLE and PLD deposited WO3 thin films
- 2017
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Conference paper (peer-reviewed)abstract
- Tungsten trioxide (WO3) thin films were grown by matrix assisted pulsed laser evaporation (MAPLE) and pulsed laser deposition (PLD), and their properties were investigated for electrochromic applications. The structure, morphology and optical properties of these MAPLE and PLD grown from monoclinic WO3 nano-sized particles WO3 thin films were also studied. A KrF* excimer (λ=248 nm, ζFWHM=25 ns) laser source was used in all experiments. The films were studied by atomic force microscopy (AFM), grazing incidence X-ray diffraction (GIXRD) and Fourier transform infrared spectroscopy (FTIR). Cyclic voltammetry measurements were also performed in glove box with Ar atmosphere towards Li electrode, and the coloring and bleaching states were investigated. The morpho-structural investigations disclosed the synthesis of single-phase monoclinic WO3 films consisting of crystalline nano-grains embedded in an amorphous matrix. All thin films showed good electrochromic properties - strong coloration and fast and full bleaching. The effect was observed for many cycles, the strong coloration and full bleaching being preserved. These results are promising for future application of MAPLE and PLD deposited WO3 thin films in the development of electrochromic devices.
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| 12. |
- Gisselsson, A, et al.
(author)
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Role of histidines in the binding of violaxanthin de-epoxidase to the thylakoid membrane as studied by site-directed mutagenesis
- 2004
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In: Physiologia Plantarum. - : Wiley. - 0031-9317 .- 1399-3054. ; 122:3, s. 337-343
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Journal article (peer-reviewed)abstract
- Regulation of violaxanthin de-epoxidase (VDE) involves a conformational change at low lumenal pH, followed by binding of the enzyme to the thylakoid membrane. The role of histidine residues in this process was studied by release of unbound enzyme from thylakoids upon sonication, on a pH scale from 4.7 to 7.1. The co-operativity for binding of spinach VDE (four histidines) to the membrane was found to be 3.8, with respect to protons, and had an inflexion point at pH 6.6, whereas VDE from wheat (three histidines) showed a co-operativity of 2.9 and had an inflexion point at pH 6.2. Mutant forms of VDE were constructed and probed for their binding to the outside of thylakoid membranes. With one or two histidines substituted for alanine or arginine, a lower co-operativity (1.6-2.3) was found, compared with the wild type. Based on these findings, and that the pKa value for histidine is within the range where the VDE binding takes place, we propose that protonation of the histidine residues at low pH induces the conformational change of VDE, and hence indirectly regulates binding of the enzyme to the thylakoid membrane.
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| 13. |
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| 14. |
- Heinonen, M., et al.
(author)
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Investigation of the Equivalence of National Dew-Point Temperature Realizations in the -50 C to + 20 C Range
- 2012
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In: International journal of thermophysics. - : Springer Science and Business Media LLC. - 0195-928X .- 1572-9567. ; 33:8-9, s. 1422-1437
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Journal article (peer-reviewed)abstract
- In the field of humidity quantities, the first CIPM key comparison, CCT-K6 is at its end. The corresponding European regional key comparison, EUROMET.T-K6, was completed in early 2008, about 4 years after the starting initial measurements in the project. In total, 24 NMIs from different countries took part in the comparison. This number includes 22 EURAMET countries, and Russia and South Africa. The comparison covered the dew-point temperature range from -50 C to +20 C. It was carried out in three parallel loops, each with two chilled mirror hygrometers as transfer standards in each loop. The comparison scheme was designed to ensure high quality results with evenly spread workload for the participants. It is shown that the standard uncertainty due to the long-term instability was smaller than 0.008 C in all loops. The standard uncertainties due to links between the loops were found to be smaller than 0.025 C at -50 C and 0.010 C elsewhere. Conclusions on the equivalence of the dew-point temperature standards are drawn on the basis of calculated bilateral degrees of equivalence and deviations from the EURAMET comparison reference values (ERV). Taking into account 16 different primary dew-point realizations and 8 secondary realizations, the results demonstrate the equivalence of a large number of laboratories at an uncertainty level that is better than achieved in other multilateral comparisons so far in the humidity field.
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| 15. |
- Huse, Nils, et al.
(author)
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Probing the hydrogen-bond network of water via time-resolved soft X-ray spectroscopy
- 2009
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In: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry (RSC). - 1463-9076 .- 1463-9084. ; 11:20, s. 3951-3957
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Journal article (peer-reviewed)abstract
- We report time-resolved studies of hydrogen bonding in liquid H2O, in response to direct excitation of the O-H stretch mode at 3 mm, probed via soft X-ray absorption spectroscopy at the oxygen K-edge. This approach employs a newly developed nanofluidic cell for transient soft X-ray spectroscopy in the liquid phase. Distinct changes in the near-edge spectral region (XANES) are observed, and are indicative of a transient temperature rise of 10 K following transient laser excitation and rapid thermalization of vibrational energy. The rapid heating occurs at constant volume and the associated increase in internal pressure, estimated to be 8 MPa, is manifested by distinct spectral changes that differ from those induced by temperature alone. We conclude that the near-edge spectral shape of the oxygen K-edge is a sensitive probe of internal pressure, opening new possibilities for testing the validity of water models and providing new insight into the nature of hydrogen bonding in water.
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| 16. |
- Jiang, M., et al.
(author)
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The mitochondrial single-stranded DNA binding protein is essential for initiation of mtDNA replication
- 2021
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In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:27
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Journal article (peer-reviewed)abstract
- We report a role for the mitochondrial single-stranded DNA binding protein (mtSSB) in regulating mitochondrial DNA (mtDNA) replication initiation in mammalian mitochondria. Transcription from the light-strand promoter (LSP) is required both for gene expression and for generating the RNA primers needed for initiation of mtDNA synthesis. In the absence of mtSSB, transcription from LSP is strongly up-regulated, but no replication primers are formed. Using deep sequencing in a mouse knockout model and biochemical reconstitution experiments with pure proteins, we find that mtSSB is necessary to restrict transcription initiation to optimize RNA primer formation at both origins of mtDNA replication. Last, we show that human pathological versions of mtSSB causing severe mitochondrial disease cannot efficiently support primer formation and initiation of mtDNA replication. © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science.
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| 17. |
- Munyuki, Gadzikano, et al.
(author)
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beta-Sheet Structures and Dimer Models of the Two Major Tyrocidines, Antimicrobial Peptides from Bacillus aneurinolyticus
- 2013
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In: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 52:44, s. 7798-7806
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Journal article (peer-reviewed)abstract
- The structures of two major tyrocidines, antibiotic peptides from Bacillus aneurinolyticus, in an aqueous environment were studied using nuclear magnetic resonance spectroscopy, restrained molecular dynamics (MD), circular dichroism, and mass spectrometry. TrcA and TrcC formed beta-structures in an aqueous environment. Hydrophobic and hydrophilic residues were not totally separated into nonpolar and polar faces of the peptides, indicating that tyrocidines have low amphipathicity. In all the beta-structures, residues Trp(4)/Phe(4) and Orn(9) were on the same face. The ability of the peptides to form dimers in aqueous environment was studied by replica exchange MD simulations. Both peptides readily dimerize, and predominant complex structures were characterized through cluster analysis. The peptides formed dimers by either associating sideways or stacking on top of each other. Dimers formed through sideways association were mainly stabilized by hydrogen bonding, while the other dimers were stabilized by hydrophobic interactions. The ability of tyrocidine peptides to form different types of dimers with different orientations suggests that they can form larger aggregates, as well.
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| 19. |
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| 20. |
- Vats, Nilesh, et al.
(author)
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Catalyzing Bond-Dissociation in Graphene via Alkali-Iodide Molecules
- 2021
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In: Small. - : John Wiley & Sons. - 1613-6810 .- 1613-6829. ; 17:42
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Journal article (peer-reviewed)abstract
- Atomic design of a 2D-material such as graphene can be substantially influenced by etching, deliberately induced in a transmission electron microscope. It is achieved primarily by overcoming the threshold energy for defect formation by controlling the kinetic energy and current density of the fast electrons. Recent studies have demonstrated that the presence of certain species of atoms can catalyze atomic bond dissociation processes under the electron beam by reducing their threshold energy. Most of the reported catalytic atom species are single atoms, which have strong interaction with single-layer graphene (SLG). Yet, no such behavior has been reported for molecular species. This work shows by experimentally comparing the interaction of alkali and halide species separately and conjointly with SLG, that in the presence of electron irradiation, etching of SLG is drastically enhanced by the simultaneous presence of alkali and iodine atoms. Density functional theory and first principles molecular dynamics calculations reveal that due to charge-transfer phenomena the C-C bonds weaken close to the alkali-iodide species, which increases the carbon displacement cross-section. This study ascribes pronounced etching activity observed in SLG to the catalytic behavior of the alkali-iodide species in the presence of electron irradiation.
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| 21. |
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