| 1. |
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| 2. |
- Bruton, Joseph D., et al.
(författare)
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Increased fatigue resistance linked to Ca(2+)-stimulated mitochondrial biogenesis in muscle fibres of cold-acclimated mice
- 2010
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Ingår i: Journal of Physiology. - : Wiley. - 0022-3751 .- 1469-7793. ; 588:21, s. 4275-4288
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Tidskriftsartikel (refereegranskat)abstract
- Mammals exposed to a cold environment initially generate heat by repetitive muscle activity (shivering). Shivering is successively replaced by the recruitment of uncoupling protein-1 (UCP1)-dependent heat production in brown adipose tissue. Interestingly, adaptations observed in skeletal muscles of cold-exposed animals are similar to those observed with endurance training. We hypothesized that increased myoplasmic free [Ca2+] ([Ca2+]i) is important for these adaptations. To test this hypothesis, experiments were performed on flexor digitorum brevis (FDB) muscles, which do not participate in the shivering response, of adult wild-type (WT) and UCP1-ablated (UCP1-KO) mice kept either at room temperature (24 ºC) or cold-acclimated (4 ºC) for 4-5 weeks. [Ca2+]i (measured with indo-1) and force were measured under control conditions and during fatigue induced by repeated tetanic stimulation in intact single fibres. The results show no differences between fibres from WT and UCP1-KO mice. However, muscle fibres from cold-acclimated mice showed significant increases in basal [Ca2+]i (~50%), tetanic [Ca2+]i (~40%), and sarcoplasmic reticulum (SR) Ca2+ leak (~four-fold) as compared to fibres from room-temperature mice. Muscles of cold-acclimated mice showed increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and increased citrate synthase activity (reflecting increased mitochondrial content). Fibres of cold-acclimated mice were more fatigue resistant with higher tetanic [Ca2+]i and less force loss during fatiguing stimulation. In conclusion, cold exposure induces changes in FDB muscles similar to those observed with endurance training and we propose that increased [Ca2+]i is a key factor underlying these adaptations.
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| 3. |
- Altay, Özlem, et al.
(författare)
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Combined Metabolic Activators Accelerates Recovery in Mild-to-Moderate COVID-19
- 2021
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Ingår i: Advanced Science. - : Wiley. - 2198-3844. ; 8:17
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Tidskriftsartikel (refereegranskat)abstract
- COVID-19 is associated with mitochondrial dysfunction and metabolic abnormalities, including the deficiencies in nicotinamide adenine dinucleotide (NAD+) and glutathione metabolism. Here it is investigated if administration of a mixture of combined metabolic activators (CMAs) consisting of glutathione and NAD+ precursors can restore metabolic function and thus aid the recovery of COVID-19 patients. CMAs include l-serine, N-acetyl-l-cysteine, nicotinamide riboside, and l-carnitine tartrate, salt form of l-carnitine. Placebo-controlled, open-label phase 2 study and double-blinded phase 3 clinical trials are conducted to investigate the time of symptom-free recovery on ambulatory patients using CMAs. The results of both studies show that the time to complete recovery is significantly shorter in the CMA group (6.6 vs 9.3 d) in phase 2 and (5.7 vs 9.2 d) in phase 3 trials compared to placebo group. A comprehensive analysis of the plasma metabolome and proteome reveals major metabolic changes. Plasma levels of proteins and metabolites associated with inflammation and antioxidant metabolism are significantly improved in patients treated with CMAs as compared to placebo. The results show that treating patients infected with COVID-19 with CMAs lead to a more rapid symptom-free recovery, suggesting a role for such a therapeutic regime in the treatment of infections leading to respiratory problems.
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| 4. |
- Aydin, Jan
(författare)
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Skeletal muscle calcium homeostasis during fatigue : modulation by kinases and mitochondria
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The use of skeletal muscles in daily activities and even during strenuous exercise resulting in fatigue requires precise regulation of force and the timing of contraction. To achieve such performance characteristics, vertebrate skeletal muscles have developed a unique control mechanism for regulating the free Ca2+ concentration in their myoplasm ([Ca2+]i). A basic knowledge of cellular and molecular mechanisms regulating these mechanisms is essential in understanding pathological alterations in Ca2+ handling. This thesis deals with how these mechanisms are modulated by (i) mitochondria, (ii) Ca2+/calmodulin dependent protein kinase II (CaMKII) and (iii) protein kinase A (PKA). (i) Mitochondrial free [Ca2+] ([Ca2+]mit) increased during fatiguing stimulation in most, but not all, slow‐twitch soleus fibres and fast‐twitch extensor digitorum longus (EDL) fibres and was back to pre‐fatiguing levels within 20 min in both fibre types. [Ca2+]mit did not affect tetanic [Ca2+]i and thus, mitochondria do not acutely modulate tetanic [Ca2+]i. [Ca2+]mit was also investigated in mice with skeletal muscle specific disruption of mitochondrial transcription factor A (Tfam KO). Fibres from fast‐twitch flexor digitorum brevis (FDB) muscle normally do not accumulate Ca2+ in their mitochondria during fatigue, but in Tfam KO FDB fibres there was a marked increase in [Ca2+]mit. Tetanic [Ca2+]i was significantly lower in Tfam KO compared to controls, due to downregulation of the sarcoplasmic reticulum (SR) Ca2+ buffering protein calsequestrin‐1. The increased [Ca2+]mit in Tfam KO could be a means by which ATP‐production is boosted. These data suggest that mitochondria do not acutely affect tetanic [Ca2+]i, but that they play a more long‐term role in regulation of Ca2+‐handling by modulating sarcoplasmic reticulum proteins responsible for Ca2+ buffering. (ii) The modulatory role of CaMKII on Ca2+ handling was investigated by inhibiting CaMKII in FDB fibres using either KN‐93 or an inhibitory peptide. CaMKII inhibition resulted in a significant decrease in tetanic [Ca2+]i when contractions occurred at intervals of 2 s or 300 ms, but not 5 s. Mathematical modelling shows that there is some activation of CaMKII using all protocols but suggests that there is an activity threshold that has to be surpassed to permit sustained SR Ca2+ release when contractions occur close together in time. (iii) During cold exposure there is an increase in systemic sympathetic activity so the modulatory role of PKA on Ca2+‐ handling was investigated in cold‐acclimatized mice. FDB muscles fibres from coldacclimatized mice display increased resting [Ca2+]i, which was shown to be due to an increased SR Ca2+ leak. This increased SR Ca2+ leak was shown to be associated with PKA‐mediated phosphorylation of the SR Ca2+ channel, the ryanodine receptor (RyR), on ser2844 and moderate dissociation of the RyR regulatory protein calstabin‐1. An increased leak results in increased SR Ca2+ cycling and could be a local means of generating heat in the distally and superficially located FDB muscles. Our results show that there are several factors involved in the shaping of skeletal muscle [Ca2+]i handling, some which do so acutely and some are of more importance in the long term.
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| 5. |
- Bernson, Elin, 1987, et al.
(författare)
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Cytomegalovirus Serostatus Affects Autoreactive NK Cells and Outcomes of IL2-Based Immunotherapy in Acute Myeloid Leukemia
- 2018
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Ingår i: Cancer Immunology Research. - : American Association for Cancer Research (AACR). - 2326-6066 .- 2326-6074. ; 6:9, s. 1110-1119
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Tidskriftsartikel (refereegranskat)abstract
- Human cytomegalovirus (CMV) infection is reported to promote NK cell differentiation and education. The CMV-induced generation of highly differentiated adaptive-like NK cells has been proposed to affect favorably on the maintenance of remission in patients with acute myeloid leukemia (AML) after allogeneic stem cell transplantation (allo-SCT). The impact of CMV infection and adaptive-like NK cells on relapse and survival of patients with AML not receiving allo-SCT remains unknown. We assayed CMV IgG serostatus to determine past CMV infection in 81 nontransplanted AML patients who were receiving relapse-prevention immunotherapy comprising histamine dihydrochloride and low-dose interleukin-2 (HDC/IL2; NCT01347996). CMV seropositivity correlated negatively with leukemia-free and overall survival of patients receiving HDC/IL2, but did not correlate with outcomes in a contemporary control cohort. Analysis of outcome after stratification of patients based on concordant or discordant killer immunoglobulin-like receptor (KIR) and HLA genotypes implied that the negative impact of CMV seropositivity was restricted to patients lacking a ligand to inhibitory KIRs (iKIR). Previous CMV infection was also associated with fewer NK cells expressing only nonself iKIRs (NS-iKIR). We propose that CMV-driven NK cell education depletes the population of NS-iKIR NK cells, which in turn reduces the clinical benefit of relapse-preventive immunotherapy in AML.
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| 6. |
- Bhowmick, Asmit, et al.
(författare)
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Structural evidence for intermediates during O2 formation in photosystem II
- 2023
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Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 617:7961, s. 629-636
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Tidskriftsartikel (refereegranskat)abstract
- In natural photosynthesis, the light-driven splitting of water into electrons, protons and molecular oxygen forms the first step of the solar-to-chemical energy conversion process. The reaction takes place in photosystem II, where the Mn4CaO5 cluster first stores four oxidizing equivalents, the S0 to S4 intermediate states in the Kok cycle, sequentially generated by photochemical charge separations in the reaction center and then catalyzes the O–O bond formation chemistry. Here, we report room temperature snapshots by serial femtosecond X-ray crystallography to provide structural insights into the final reaction step of Kok’s photosynthetic water oxidation cycle, the S3→[S4]→S0 transition where O2 is formed and Kok’s water oxidation clock is reset. Our data reveal a complex sequence of events, which occur over micro- to milliseconds, comprising changes at the Mn4CaO5 cluster, its ligands and water pathways as well as controlled proton release through the hydrogen-bonding network of the Cl1 channel. Importantly, the extra O atom Ox, which was introduced as a bridging ligand between Ca and Mn1 during the S2→S3 transition, disappears or relocates in parallel with Yz reduction starting at approximately 700 μs after the third flash. The onset of O2 evolution, as indicated by the shortening of the Mn1–Mn4 distance, occurs at around 1,200 μs, signifying the presence of a reduced intermediate, possibly a bound peroxide.
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| 7. |
- Hematimatin, Narges, et al.
(författare)
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Biochar application regulating soil inorganic nitrogen and organic carbon content in cropland in the Central Europe : a seven-year field study
- 2024
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Ingår i: Biochar. - : Springer. - 2524-7972 .- 2524-7867. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Biochar incorporation into soil has shown potential, in enhancing nitrogen fertilizer (N-fertilizer) efficacy and soil organic carbon content (SOC). This study addresses a critical gap in the literature by investigating the effects of biochar addition over a seven-year period (2014-2020) on inorganic N, SOC, and pH in Haplic Luvisol. The research involved a rain-fed field experiment, with a crop rotation comprising spring barley, maize, spring wheat, and pea. Biochar, applied at the rates of 0, 10, and 20 t ha-1 in 2014, was reapplied to specific plots in 2018. Biochar was also combined with N-fertilizer at three level (N0, N1, and N2). Results showed a significant interactive influence of biochar and N-fertilizer combination on NO3- and NH4+ contents. Intriguingly, the addition of 10 t biochar ha-1 consistently decreased soil inorganic N levels across most of the examined months. Increasing biochar application rates led to a significant rise in pH, establishing a clear, negative correlation between soil pH and inorganic N content. Biochar significantly increased SOC compared to the control, particularly after the reapplication in 2018. However, this effect showed a diminishing trend over time. The study suggests that incorporating biochar treatments may enhance N-fertilizer effectiveness. However, the long-term implications of biochar application with N-fertilizer on N mineralization are specific to individual soil and biochar combinations. Except the application of 20 t ha-1 biochar at N2 in 2019, biochar did not affect the crop yields. Studied soil properties, including those influenced by biochar had nuanced impact on different aspects of crop yield. Biochar obtained from mixed paper fiber sludge and the grain husks resulted in a significant increase of SOC over 7 years.Biochar aging resulted in a decrease in pH one year after its application in 2015 and 2019.The combination of N-fertilizer with biochar caused an improvement in soil inorganic N content in 2014 and reapplication in 2018.
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| 8. |
- Kiemeney, Lambertus A, et al.
(författare)
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A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer.
- 2010
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:5, s. 415-9
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Tidskriftsartikel (refereegranskat)abstract
- Previously, we reported germline DNA variants associated with risk of urinary bladder cancer (UBC) in Dutch and Icelandic subjects. Here we expanded the Icelandic sample set and tested the top 20 markers from the combined analysis in several European case-control sample sets, with a total of 4,739 cases and 45,549 controls. The T allele of rs798766 on 4p16.3 was found to associate with UBC (odds ratio = 1.24, P = 9.9 x 10(-12)). rs798766 is located in an intron of TACC3, 70 kb from FGFR3, which often harbors activating somatic mutations in low-grade, noninvasive UBC. Notably, rs798766[T] shows stronger association with low-grade and low-stage UBC than with more aggressive forms of the disease and is associated with higher risk of recurrence in low-grade stage Ta tumors. The frequency of rs798766[T] is higher in Ta tumors that carry an activating mutation in FGFR3 than in Ta tumors with wild-type FGFR3. Our results show a link between germline variants, somatic mutations of FGFR3 and risk of UBC.
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| 9. |
- Moshontz, Hannah, et al.
(författare)
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The Psychological Science Accelerator: Advancing Psychology Through a Distributed Collaborative Network
- 2018
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Ingår i: Advances in Methods and Practices in Psychological Science. - : SAGE Publications. - 2515-2459 .- 2515-2467. ; 1:4, s. 501-515
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Tidskriftsartikel (refereegranskat)abstract
- Concerns about the veracity of psychological research have been growing. Many findings in psychological science are based on studies with insufficient statistical power and nonrepresentative samples, or may otherwise be limited to specific, ungeneralizable settings or populations. Crowdsourced research, a type of large-scale collaboration in which one or more research projects are conducted across multiple lab sites, offers a pragmatic solution to these and other current methodological challenges. The Psychological Science Accelerator (PSA) is a distributed network of laboratories designed to enable and support crowdsourced research projects. These projects can focus on novel research questions or replicate prior research in large, diverse samples. The PSA’s mission is to accelerate the accumulation of reliable and generalizable evidence in psychological science. Here, we describe the background, structure, principles, procedures, benefits, and challenges of the PSA. In contrast to other crowdsourced research networks, the PSA is ongoing (as opposed to time limited), efficient (in that structures and principles are reused for different projects), decentralized, diverse (in both subjects and researchers), and inclusive (of proposals, contributions, and other relevant input from anyone inside or outside the network). The PSA and other approaches to crowdsourced psychological science will advance understanding of mental processes and behaviors by enabling rigorous research and systematic examination of its generalizability.
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| 10. |
- Ragnarsson, Charlotte, et al.
(författare)
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Constitutional and acquired genetic variants in ARID5B in pediatric B-cell precursor acute lymphoblastic leukemia
- 2024
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Ingår i: Genes Chromosomes and Cancer. - 1045-2257. ; 63:5
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Tidskriftsartikel (refereegranskat)abstract
- Constitutional polymorphisms in ARID5B are associated with an increased risk of developing high hyperdiploid (HeH; 51–67 chromosomes) pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL). Here, we investigated constitutional and somatic ARID5B variants in 1335 BCP ALL cases from five different cohorts, with a particular focus on HeH cases. In 353 HeH ALL that were heterozygous for risk alleles and trisomic for chromosome 10, where ARID5B is located, a significantly higher proportion of risk allele duplication was seen for the SNPs rs7090445 (p = 0.009), rs7089424 (p = 0.005), rs7073837 (p = 0.03), and rs10740055 (p = 0.04). Somatic ARID5B deletions were seen in 16/1335 cases (1.2%), being more common in HeH than in other genetic subtypes (2.2% vs. 0.4%; p = 0.002). The expression of ARID5B in HeH cases with genomic deletions was reduced, consistent with a functional role in leukemogenesis. Whole-genome sequencing and RNA-sequencing in HeH revealed additional somatic events involving ARID5B, resulting in a total frequency of 3.6% of HeH cases displaying a somatic ARID5B aberration. Overall, our results show that both constitutional and somatic events in ARID5B are involved in the leukemogenesis of pediatric BCP ALL, particularly in the HeH subtype.
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