| 1. |
- Oddsson, Asmundur, et al.
(författare)
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Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.
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| 2. |
- Kunnus, Kristjan, et al.
(författare)
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Vibrational wavepacket dynamics in Fe carbene photosensitizer determined with femtosecond X-ray emission and scattering
- 2020
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The non-equilibrium dynamics of electrons and nuclei govern the function of photoactive materials. Disentangling these dynamics remains a critical goal for understanding photoactive materials. Here we investigate the photoinduced dynamics of the [Fe(bmip)2]2+ photosensitizer, where bmip = 2,6-bis(3-methyl-imidazole-1-ylidine)-pyridine, with simultaneous femtosecond-resolution Fe Kα and Kβ X-ray emission spectroscopy (XES) and X-ray solution scattering (XSS). This measurement shows temporal oscillations in the XES and XSS difference signals with the same 278 fs period oscillation. These oscillations originate from an Fe-ligand stretching vibrational wavepacket on a triplet metal-centered (3MC) excited state surface. This 3MC state is populated with a 110 fs time constant by 40% of the excited molecules while the rest relax to a 3MLCT excited state. The sensitivity of the Kα XES to molecular structure results from a 0.7% average Fe-ligand bond length shift between the 1 s and 2p core-ionized states surfaces.
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| 3. |
- Cardinale, Daniele A., 1982-, et al.
(författare)
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Short term intensified training temporarily impairs mitochondrial respiratory capacity in elite endurance athletes.
- 2021
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Ingår i: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 131:1, s. 388-400
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Tidskriftsartikel (refereegranskat)abstract
- AIM: The maintenance of healthy and functional mitochondria is the result of a complex mitochondrial turnover and herein quality-control program which includes both mitochondrial biogenesis and autophagy of mitochondria. The aim of this study was to examine the effect of an intensified training load on skeletal muscle mitochondrial quality control in relation to changes in mitochondrial oxidative capacity, maximal oxygen consumption and performance in highly trained endurance athletes.METHODS: 27 elite endurance athletes performed high intensity interval exercise followed by moderate intensity continuous exercise 3 days per week for 4 weeks in addition to their usual volume of training. Mitochondrial oxidative capacity, abundance of mitochondrial proteins, markers of autophagy and antioxidant capacity of skeletal muscle were assessed in skeletal muscle biopsies before and after the intensified training period.RESULTS: The intensified training period increased several autophagy markers suggesting an increased turnover of mitochondrial and cytosolic proteins. In permeabilized muscle fibers, mitochondrial respiration was ~20 % lower after training although some markers of mitochondrial density increased by 5-50%, indicative of a reduced mitochondrial quality by the intensified training intervention. The antioxidative proteins UCP3, ANT1, and SOD2 were increased after training, whereas we found an inactivation of aconitase. In agreement with the lower aconitase activity, the amount of mitochondrial LON protease that selectively degrades oxidized aconitase, was doubled.CONCLUSION: Together, this suggests that mitochondrial respiratory function is impaired during the initial recovery from a period of intensified endurance training while mitochondrial quality control is slightly activated in highly trained skeletal muscle.
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| 4. |
- Gejl, Kasper Degn, et al.
(författare)
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Effects of Acute Exercise and Training on the Sarcoplasmic Reticulum Ca(2+)Release and Uptake Rates in Highly Trained Endurance Athletes
- 2020
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Ingår i: Frontiers in Physiology. - : Frontiers Media SA. - 1664-042X. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Little is presently known about the effects of acute high-intensity exercise or training on release and uptake of Ca(2+)by the sarcoplasmic reticulum (SR). The aims here were to characterize this regulation in highly trained athletes following (1) repeated bouts of high-intensity exercise and (2) a period of endurance training including high-intensity sessions. Eleven cross-country skiers (25 +/- 4 years, 65 +/- 4 mL O-2.kg(-1).min(-1)) performed four self-paced sprint time-trials (STT 1-4) lasting approximate to 4 min each (STT 1-4) and separated by 45 min of recovery; while 19 triathletes and road cyclists (25 +/- 4 years, 65 +/- 5 mL O-2.kg(-1).min(-1)) completed 4 weeks of endurance training in combination with three sessions of high-intensity interval cycling per week. Release (mu mol.g(-1)prot.min(-1)) and uptake [tau (s)] of Ca(2+)by SR vesicles isolated from m.triceps brachiiand m.vastus lateraliswere determined before and after STT 1 and 4 in the skiers and in m.vastus lateralisbefore and after the 4 weeks of training in the endurance athletes. The Ca(2+)release rate was reduced by 17-18% in both limbs already after STT 1 (arms: 2.52 +/- 0.74 to 2.08 +/- 0.60; legs: 2.41 +/- 0.45 to 1.98 +/- 0.51,P< 0.0001) and attenuated further following STT 4 (arms: 2.24 +/- 0.67 to 1.95 +/- 0.45; legs: 2.13 +/- 0.51 to 1.83 +/- 0.36,P< 0.0001). Also, there was a tendency toward an impairment in the SR Ca(2+)uptake from pre STT1 to post STT4 in both arms and legs (arms: from 22.0 +/- 3.7 s to 25.3 +/- 6.0 s; legs: from 22.5 +/- 4.7 s to 25.5 +/- 7.7 s,P= 0.05). Endurance training combined with high-intensity exercise increased the Ca(2+)release rate by 9% (1.76 +/- 0.38 to 1.91 +/- 0.44,P= 0.009), without altering the Ca(2+)uptake (29.6 +/- 7.0 to 29.1 +/- 8.7 s;P= 0.98). In conclusion, the Ca(2+)release and uptake rates by SR in exercising limbs of highly trained athletes declines gradually by repetitive bouts of high-intensity exercise. We also demonstrate, for the first time, that the SR Ca(2+)release rate can be enhanced by a specific program of training in highly trained athletes, which may have important implications for performance parameters.
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| 5. |
- Häfner, Sophia J., et al.
(författare)
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Ribosomal RNA 2′-O-methylation dynamics impact cell fate decisions
- 2023
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Ingår i: Developmental Cell. - 1534-5807. ; 58:17, s. 9-1609
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Tidskriftsartikel (refereegranskat)abstract
- Translational regulation impacts both pluripotency maintenance and cell differentiation. To what degree the ribosome exerts control over this process remains unanswered. Accumulating evidence has demonstrated heterogeneity in ribosome composition in various organisms. 2′-O-methylation (2′-O-me) of rRNA represents an important source of heterogeneity, where site-specific alteration of methylation levels can modulate translation. Here, we examine changes in rRNA 2′-O-me during mouse brain development and tri-lineage differentiation of human embryonic stem cells (hESCs). We find distinct alterations between brain regions, as well as clear dynamics during cortex development and germ layer differentiation. We identify a methylation site impacting neuronal differentiation. Modulation of its methylation levels affects ribosome association of the fragile X mental retardation protein (FMRP) and is accompanied by an altered translation of WNT pathway-related mRNAs. Together, these data identify ribosome heterogeneity through rRNA 2′-O-me during early development and differentiation and suggest a direct role for ribosomes in regulating translation during cell fate acquisition.
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| 6. |
- Kjaersgaard, Alexander, et al.
(författare)
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Photolytic Studies of Norbornadiene Derivatives under High-Intensity Light Conditions
- 2022
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Ingår i: Journal of Physical Chemistry A. - : American Chemical Society (ACS). - 1089-5639 .- 1520-5215. ; 126:39, s. 6849-6857
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Tidskriftsartikel (refereegranskat)abstract
- The photoconversion of a norbornadiene (NBD) derivative was studied under high-intensity mono- and polychromatic light conditions at high concentrations. The photoisomerization quantum yield (φNBD→QC), proceeding from NBD to its quadricyclane (QC) isomer, was determined using a tunable OPO laser and a solar simulator light source. The solar simulator was designed to mimic the AM1.5G solar spectrum between 300 and 900 nm. Using the OPO laser, φNBD→QC was measured at discrete values between 310 and 350 nm in steps of 10 nm, and a variation between 0.81 and 0.96 was observed. Weighting these values of φNBD→QC with the spectral profile of the solar simulator, an averaged value of 0.87 ± 0.03 was obtained. Determination of φNBD→QC was also performed directly in the solar simulator providing a value of 0.97 ± 0.14, in good agreement with the weighted values from the OPO. Photoisomerization quantum yields were found to decrease slightly at higher concentrations. At high concentrations, we found that correcting for the presence of QC was important due to similar absorption coefficients of the NBD and QC isomers at the absorption tail. Cyclability of the forward and backward NBD/QC conversion was studied over several cycles. The NBD/QC couple exhibited excellent thermal stability, but a slight photodegradation per cycle was observed, increasing with the concentration of the sample. This result indicates that the molecules undergo some intermolecular reactions.
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| 7. |
- Korsholm, Kasper, et al.
(författare)
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Left Atrial Appendage Occlusion versus Novel Oral Anticoagulation for Stroke Prevention in Atrial Fibrillation: Rationale and Design of the Multicenter Randomized Occlusion-AF Trial.
- 2021
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Ingår i: American heart journal. - : Elsevier BV. - 1097-6744 .- 0002-8703. ; 243, s. 28-38
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Tidskriftsartikel (refereegranskat)abstract
- The prevalence of atrial fibrillation (AF) is increasing globally, which is a major clinical and public health concern due to the five-fold increased risk of stroke. Oral anticoagulation with novel oral anticoagulants (NOACs) is the current primary option for stroke prevention in patients with AF, although it increases the risk of major bleeding. Patients with prior ischemic cerebrovascular events are at particularly high risk of both recurrent ischemic events and major bleeding. Left atrial appendage occlusion (LAAO) provides an alternative option for stroke prevention in high-risk patients, however, with currently limited evidence. Thus, randomized trials comparing LAAO to NOACs are needed.The Occlusion-AF trial is designed to assess whether LAAO is non-inferior to NOAC therapy for reduction of the combined endpoint of stroke, systemic embolism, major bleeding (Bleeding Academic Research Consortium ≥ 3) and all-cause mortality in patients with AF and a recent ischemic stroke or transient ischemic attack (TIA).Investigator-initiated multicenter, multinational, randomized open-label non-inferiority trial with blinded outcome evaluation (PROBE design). Patients with documented AF, and an ischemic stroke or TIA within 6 months will be eligible for enrollment. Major exclusion criteria are modified Rankin Scale > 3 at enrollment, glomerular filtration rate < 15 ml/min, and life-expectancy less than 2 years. A total of 750 patients will be randomized 1:1 to receive either a NOAC or LAAO using the Amplatzer Amulet (Abbott, MN, USA) or Watchman FLX (Boston Scientific, MN, USA) with subsequent life-long aspirin 75 mg daily. Follow-up will be based on in-office and telephone follow-up in combination with long-term follow-up (10 years) through national hospital discharge registries in the individual Nordic countries. The primary outcome will be a composite endpoint of stroke, systemic embolism, major bleeding (BARC ≥ 3) and all-cause mortality at 2-year follow-up.The Occlusion-AF trial is designed to compare LAAO to NOAC therapy for secondary stroke prevention in AF patients with a high risk of recurrent thromboembolic events, i.e. with previous ischemic stroke or TIA, and otherwise eligible for anticoagulation. The results are expected to contribute significantly to the understanding of the effects of LAAO compared to the standard contemporary pharmacological treatment in these patients.
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| 8. |
- Manso, Mads, 1991, et al.
(författare)
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Donor-Acceptor Substituted Benzo-, Naphtho- and Phenanthro-Fused Norbornadienes
- 2020
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Ingår i: Molecules. - : MDPI AG. - 1420-3049 .- 1420-3049. ; 25:2
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Tidskriftsartikel (refereegranskat)abstract
- The photochromic norbornadiene/quadricyclane (NBD/QC) couple has found interest as a molecular solar thermal energy (MOST) system for storage of solar energy. To increase the energy difference between the two isomers, we present here the synthesis of a selection of benzo-fused NBD derivatives that contain an aromatic unit, benzene, naphthalene or phenanthrene, fused to one of the NBD double bonds, while the carbon atoms of the other double bond are functionalized with donor and acceptor groups. The synthesis protocols involve functionalization of benzo-fused NBDs with bromo/chloro substituents followed by a subjection of these intermediates to a cyanation reaction (introducing a cyano acceptor group) followed by a Sonogashira coupling (introducing an arylethynyl donor group, -CCC6H4NMe2 or -CCC6H4OMe). While the derivatives have good absorption properties in the visible region (redshifted relative to parent system) in the context of MOST applications, they lack the ability to undergo NBD-to-QC photoisomerization, even in the presence of a photosensitizer. It seems that loss of aromaticity of the fused aromatics is too significant to allow photoisomerization to occur. The concept of destroying aromaticity of a neighboring moiety as a way to enhance the energy density of the NBD/QC couple thus needs further structural modifications, in the quest for optimum MOST systems.
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| 9. |
- Manso, Mads, 1991, et al.
(författare)
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Establishing linear-free-energy relationships for the quadricyclane-to-norbornadiene reaction
- 2020
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Ingår i: Organic and Biomolecular Chemistry. - : Royal Society of Chemistry (RSC). - 1477-0539 .- 1477-0520. ; 18:11, s. 2113-2119
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Tidskriftsartikel (refereegranskat)abstract
- The kinetics of the thermal quadricyclane-to-norbornadiene (QC-to-NBD) isomerization reaction was studied for a large selection of derivatives where the one NBD double bond contains a cyano and aryl substituent of either electron-withdrawing or -donating character. While the kinetics data did not satisfy a linear-free-energy-relationship for all the derivatives based on Hammett sigma values, we found individual linear relationships for derivatives containing either electron-withdrawing or electron-donating para substituents on the aryl group; with the most electron-witdrawing substituent in the one series and with the most electron-donating substituent in the other providing the fastest reaction (corresponding to opposite slopes of the Hammett plots). All data were well described, however, by a linear relationship when using Creary radical values; the correlation could be slightly improved by using a combination of sigma and values (used in ratio of 0.104 : 1). The results imply a combination of polar and free radical effects for the isomerization reaction of this specific class of derivatives, with the latter playing the most significant role. The NBD derivatives were prepared by Diels-Alder cycloaddition reactions between cyclopentadiene and 3-arylpropiolonitriles, and in the case of bromophenyl derivatives further cyanation and Sonogashira coupling reactions were performed.
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| 10. |
- Panman, Matthijs R, 1983, et al.
(författare)
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Observing the Structural Evolution in the Photodissociation of Diiodomethane with Femtosecond Solution X-Ray Scattering
- 2020
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 125:22
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Tidskriftsartikel (refereegranskat)abstract
- Resolving the structural dynamics of the initial steps of chemical reactions is challenging. We report the femtosecond time-resolved wide-angle x-ray scattering of the photodissociation of diiodomethane in cyclohexane. The data reveal with structural detail how the molecule dissociates into radicals, how the radicals collide with the solvent, and how they form the photoisomer. We extract how translational and rotational kinetic energy is dispersed into the solvent. We also find that 85% of the primary radical pairs are confined to their original solvent cage and discuss how this influences the downstream recombination reactions.
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