| 1. |
|
|
| 2. |
- Strakova, A., et al.
(författare)
-
Recurrent horizontal transfer identifies mitochondrial positive selection in a transmissible cancer
- 2020
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11
-
Tidskriftsartikel (refereegranskat)abstract
- Autonomous replication and segregation of mitochondrial DNA (mtDNA) creates the potential for evolutionary conflict driven by emergence of haplotypes under positive selection for 'selfish' traits, such as replicative advantage. However, few cases of this phenomenon arising within natural populations have been described. Here, we survey the frequency of mtDNA horizontal transfer within the canine transmissible venereal tumour (CTVT), a contagious cancer clone that occasionally acquires mtDNA from its hosts. Remarkably, one canine mtDNA haplotype, A1d1a, has repeatedly and recently colonised CTVT cells, recurrently replacing incumbent CTVT haplotypes. An A1d1a control region polymorphism predicted to influence transcription is fixed in the products of an A1d1a recombination event and occurs somatically on other CTVT mtDNA backgrounds. We present a model whereby 'selfish' positive selection acting on a regulatory variant drives repeated fixation of A1d1a within CTVT cells.
|
|
| 3. |
- Del Dotto, V., et al.
(författare)
-
SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder
- 2020
-
Ingår i: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738 .- 1558-8238. ; 130:1, s. 108-125
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 4. |
- Coccolini, F., et al.
(författare)
-
Aortic balloon occlusion (REBOA) in pelvic ring injuries: preliminary results of the ABO Trauma Registry
- 2020
-
Ingår i: Updates in Surgery. - : Springer Science and Business Media LLC. - 2038-131X .- 2038-3312. ; 2020:72, s. 527-536
-
Tidskriftsartikel (refereegranskat)abstract
- EndoVascular and Hybrid Trauma Management (EVTM) has been recently introduced in the treatment of severe pelvic ring injuries. This multimodal method of hemorrhage management counts on several strategies such as the REBOA (resuscitative endovascular balloon occlusion of the aorta). Few data exist on the use of REBOA in patients with a severely injured pelvic ring. The ABO (aortic balloon occlusion) Trauma Registry is designed to capture data for all trauma patients in hemorrhagic shock where management includes REBOA placement. Among all patients included in the ABO registry, 72 patients presented with severe pelvic injuries and were the population under exam. 66.7% were male. Mean and median ISS were respectively 43 and 41 (SD ± 13). Isolated pelvic injuries were observed in 12 patients (16.7%). Blunt trauma occurred in 68 patients (94.4%), penetrating in 2 (2.8%) and combined in 2 (2.8%). Type of injury: fall from height in 15 patients (23.1%), traffic accident in 49 patients (75.4%), and unspecified impact in 1 patient (1.5%). Femoral access was gained pre-hospital in 1 patient, in emergency room in 43, in operating room in 12 and in angio-suite in 16. REBOA was positioned in zone 1 in 59 patients (81,9%), in zone 2 in 1 (1,4%) and in zone 3 in 12 (16,7%). Aortic occlusion was partial/periodical in 35 patients (48,6%) and total occlusion in 37 patients (51,4%). REBOA associated morbidity rate: 11.1%. Overall mortality rate was 54.2% and early mortality rate (≤ 24h) was 44.4%. In the univariate analysis, factors related to early mortality (≤ 24h) are lower pH values (p = 0.03), higher base deficit (p = 0.021), longer INR (p = 0.012), minor increase in systolic blood pressure after the REBOA inflation (p = 0.03) and total aortic occlusion (p = 0.008). None of these values resulted significant in the multivariate analysis. In severe hemodynamically unstable pelvic trauma management, REBOA is a viable option when utilized in experienced centers as a bridge to other treatments; its use might be, however, accompanied with severe-to-lethal complications. © 2020, Italian Society of Surgery (SIC).
|
|
| 5. |
- Erdinc, Direnis, et al.
(författare)
-
Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability
- 2023
-
Ingår i: Embo Molecular Medicine. - 1757-4676. ; 15:5
-
Tidskriftsartikel (refereegranskat)abstract
- Topoisomerase 3 alpha (TOP3A) is an enzyme that removes torsional strain and interlinks between DNA molecules. TOP3A localises to both the nucleus and mitochondria, with the two isoforms playing specialised roles in DNA recombination and replication respectively. Pathogenic variants in TOP3A can cause a disorder similar to Bloom syndrome, which results from bi-allelic pathogenic variants in BLM, encoding a nuclear-binding partner of TOP3A. In this work, we describe 11 individuals from 9 families with an adult-onset mitochondrial disease resulting from bi-allelic TOP3A gene variants. The majority of patients have a consistent clinical phenotype characterised by bilateral ptosis, ophthalmoplegia, myopathy and axonal sensory-motor neuropathy. We present a comprehensive characterisation of the effect of TOP3A variants, from individuals with mitochondrial disease and Bloom-like syndrome, upon mtDNA maintenance and different aspects of enzyme function. Based on these results, we suggest a model whereby the overall severity of the TOP3A catalytic defect determines the clinical outcome, with milder variants causing adult-onset mitochondrial disease and more severe variants causing a Bloom-like syndrome with mitochondrial dysfunction in childhood.
|
|
| 6. |
- Kukat, C., et al.
(författare)
-
Cross-strand binding of TFAM to a single mtDNA molecule forms the mitochondrial nucleoid
- 2015
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 112:36, s. 11288-11293
-
Tidskriftsartikel (refereegranskat)abstract
- Mammalian mitochondrial DNA (mtDNA) is packaged by mitochondrial transcription factor A (TFAM) into mitochondrial nucleoids that are of key importance in controlling the transmission and expression of mtDNA. Nucleoid ultrastructure is poorly defined, and therefore we used a combination of biochemistry, super-resolution microscopy, and electron microscopy to show that mitochondrial nucleoids have an irregular ellipsoidal shape and typically contain a single copy of mtDNA. Rotary shadowing electron microscopy revealed that nucleoid formation in vitro is a multistep process initiated by TFAM aggregation and cross-strand binding. Superresolution microscopy of cultivated cells showed that increased mtDNA copy number increases nucleoid numbers without altering their sizes. Electron cryo-tomography visualized nucleoids at high resolution in isolated mammalian mitochondria and confirmed the sizes observed by superresolution microscopy of cell lines. We conclude that the fundamental organizational unit of the mitochondrial nucleoid is a single copy of mtDNA compacted by TFAM, and we suggest a packaging mechanism.
|
|
| 7. |
- Olahova, M., et al.
(författare)
-
POLRMT mutations impair mitochondrial transcription causing neurological disease
- 2021
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 8. |
|
|
| 9. |
- Terzioglu, M., et al.
(författare)
-
MTERF1 Binds mtDNA to Prevent Transcriptional Interference at the Light-Strand Promoter but Is Dispensable for rRNA Gene Transcription Regulation
- 2013
-
Ingår i: Cell Metabolism. - : Elsevier BV. - 1550-4131 .- 1932-7420. ; 17:4, s. 618-626
-
Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial transcription termination factor 1, MTERF1, has been reported to couple rRNA gene transcription initiation with termination and is therefore thought to be a key regulator of mammalian mitochondrial ribosome biogenesis. The prevailing model is based on a series of observations published over the last two decades, but no in vivo evidence exists to show that MTERF1 regulates transcription of the heavy-strand region of mtDNA containing the rRNA genes. Here, we demonstrate that knockout of Mterf1 in mice has no effect on mitochondrial rRNA levels or mitochondrial translation. Instead, loss of Mterf1 influences transcription initiation at the light-strand promoter, resulting in a decrease of de novo transcription manifested as reduced 7S RNA levels. Based on these observations, we suggest that MTERF1 does not regulate heavy-strand transcription, but rather acts to block transcription on the opposite strand of mtDNA to prevent transcription interference at the light-strand promoter.
|
|
| 10. |
- Amare, Azmeraw T, et al.
(författare)
-
Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.
- 2023
-
Ingår i: Molecular psychiatry. - 1476-5578. ; 28, s. 5251-5261
-
Tidskriftsartikel (refereegranskat)abstract
- Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental healthdisorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P=9.8×10-12, R2=1.9%) and continuous (P=6.4×10-9, R2=2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P=3.9×10-4, R2=0.9%), but not for the continuous outcome (P=0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
|
|
| 11. |
|
|
| 12. |
- Kuhl, I, et al.
(författare)
-
POLRMT does not transcribe nuclear genes
- 2014
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 514:7521, s. E7-E11
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
|
|
| 13. |
- Milenkovic, D., et al.
(författare)
-
TWINKLE is an essential mitochondrial helicase required for synthesis of nascent D-loop strands and complete mtDNA replication
- 2013
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 22:10, s. 1983-1993
-
Tidskriftsartikel (refereegranskat)abstract
- Replication of the mammalian mitochondrial DNA (mtDNA) is dependent on the minimal replisome, consisting of the heterotrimeric mtDNA polymerase (POLG), the hexameric DNA helicase TWINKLE and the tetrameric single-stranded DNA-binding protein (mtSSB). TWINKLE has been shown to unwind DNA during the replication process and many disease-causing mutations have been mapped to its gene. Patients carrying Twinkle mutations develop multiple deletions of mtDNA, deficient respiratory chain function and neuromuscular symptoms. Despite its importance in human disease, it has been unclear whether TWINKLE is the only replicative DNA helicase in mammalian mitochondria. Furthermore, a substantial portion of mtDNA replication events is prematurely terminated at the end of mitochondrial control region (D-loop) and it is unknown whether TWINKLE also has a role in this abortive replication. Here, we present a conditional mouse knockout for Twinkle and demonstrate that TWINKLE is essential for mouse embryonic development and thus is the only replicative DNA helicase in mammalian mitochondria. Conditional knockout of Twinkle results in severe and rapid mtDNA depletion in heart and skeletal muscle. No replication intermediates or deleted mtDNA molecules are observed after Twinkle knockout, suggesting that TWINKLE once loaded is very processive. We also demonstrate that TWINKLE is essential for nascent H-strand synthesis in the D-loop, thus showing that there is no separate DNA helicase responsible for replication of this region. Our data thus suggest that the relative levels of abortive D-loop synthesis versus complete mtDNA replication are regulated and may provide a mechanism to control progression to complete mtDNA replication.
|
|
| 14. |
- Misic, J., et al.
(författare)
-
Mammalian RNase H1 directs RNA primer formation for mtDNA replication initiation and is also necessary for mtDNA replication completion
- 2022
-
Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 50:15, s. 8749-8766
-
Tidskriftsartikel (refereegranskat)abstract
- The in vivo role for RNase H1 in mammalian mitochondria has been much debated. Loss of RNase H1 is embryonic lethal and to further study its role in mtDNA expression we characterized a conditional knockout of Rnaseh1 in mouse heart. We report that RNase H1 is essential for processing of RNA primers to allow site-specific initiation of mtDNA replication. Without RNase H1, the RNA:DNA hybrids at the replication origins are not processed and mtDNA replication is initiated at non-canonical sites and becomes impaired. Importantly, RNase H1 is also needed for replication completion and in its absence linear deleted mtDNA molecules extending between the two origins of mtDNA replication are formed accompanied by mtDNA depletion. The steady-state levels of mitochondrial transcripts follow the levels of mtDNA, and RNA processing is not altered in the absence of RNase H1. Finally, we report the first patient with a homozygous pathogenic mutation in the hybrid-binding domain of RNase H1 causing impaired mtDNA replication. In contrast to catalytically inactive variants of RNase H1, this mutant version has enhanced enzyme activity but shows impaired primer formation. This finding shows that the RNase H1 activity must be strictly controlled to allow proper regulation of mtDNA replication.
|
|
| 15. |
- Wilson, W. C., et al.
(författare)
-
A human mitochondrial poly(A) polymerase mutation reveals the complexities of post-transcriptional mitochondrial gene expression
- 2014
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:23, s. 6345-6355
-
Tidskriftsartikel (refereegranskat)abstract
- The p.N478D missense mutation in human mitochondrial poly(A) polymerase (mtPAP) has previously been implicated in a form of spastic ataxia with optic atrophy. In this study, we have investigated fibroblast cell lines established from family members. The homozygous mutation resulted in the loss of polyadenylation of all mitochondrial transcripts assessed; however, oligoadenylation was retained. Interestingly, this had differential effects on transcript stability that were dependent on the particular species of transcript. These changes were accompanied by a severe loss of oxidative phosphorylation complexes I and IV, and perturbation of de novo mitochondrial protein synthesis. Decreases in transcript polyadenylation and in respiratory chain complexes were effectively rescued by overexpression of wild-type mtPAP. Both mutated and wild-type mtPAP localized to the mitochondrial RNA-processing granules thereby eliminating mislocalization as a cause of defective polyadenylation. In vitro polyadenylation assays revealed severely compromised activity by the mutated protein, which generated only short oligo(A) extensions on RNA substrates, irrespective of RNA secondary structure. The addition of LRPPRC/SLIRP, a mitochondrial RNA-binding complex, enhanced activity of the wild-type mtPAP resulting in increased overall tail length. The LRPPRC/SLIRP effect although present was less marked with mutated mtPAP, independent of RNA secondary structure. We conclude that (i) the polymerase activity of mtPAP can be modulated by the presence of LRPPRC/SLIRP, (ii) N478D mtPAP mutation decreases polymerase activity and (iii) the alteration in poly(A) length is sufficient to cause dysregulation of post-transcriptional expression and the pathogenic lack of respiratory chain complexes.
|
|
| 16. |
- Abrams, AL, et al.
(författare)
-
Legislative landscape for traditional health practitioners in Southern African development community countries: a scoping review
- 2020
-
Ingår i: BMJ open. - : BMJ. - 2044-6055. ; 10:1, s. e029958-
-
Tidskriftsartikel (refereegranskat)abstract
- Globally, contemporary legislation surrounding traditional health practitioners (THPs) is limited. This is also true for the member states of the Southern African Development Community (SADC). The main aim of this study is to map and review THP-related legislation among SADC countries. In order to limit the scope of the review, the emphasis is on defining THPs in terms of legal documents.MethodsThis scoping review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews methods. Two independent reviewers reviewed applicable legal definitions of THPs by searching the Southern African Legal Information Institute (SAFLII) database in April 2018 for legislation and bills. To identify additional legislation applicable in countries not listed on SAFLII and/or further relevant SADC legislation, the search engines, Google and PubMed, were used in August 2018 and results were reviewed by two independent reviewers. Full texts of available policy and legal documents were screened to identify policies and legislation relating to the regulation of THPs. Legislation was deemed relevant if it was a draft of or promulgated legislation relating to THPs.ResultsFour of 14 Southern African countries have legislation relating to THPs. Three countries, namely South Africa, Namibia and Zimbabwe, have acknowledged the roles and importance of THPs in healthcare delivery by creating a council to register and formalise practices, although they have not operationalised nor registered and defined THPs. In contrast, Tanzania has established a definition couched in terms that acknowledge the context-specific and situational knowledge of THPs, while also outlining methods and the importance of local recognition. Tanzanian legislation; thus, provides a definition of THP that specifically operationalises THPs, whereas legislation in South Africa, Namibia and Zimbabwe allocates the power to a council to decide or recognise who a THP is; this council can prescribe procedures to be followed for the registration of a THP.ConclusionsThis review highlights the differences and similarities between the various policies and legislation pertaining to THPs in SADC countries. Legislation regarding THPs is available in four of the 14 SADC countries. While South Africa, Tanzania, Namibia and Zimbabwe have legislation that provides guidance as to THP recognition, registration and practices, THPs continue to be loosely defined in most of these countries. Not having an exact definition for THPs may hamper the promotion and inclusion of THPs in national health systems, but it may also be something that is unavoidable given the tensions between lived practices and rigid legalistic frameworks.
|
|
| 17. |
|
|
| 18. |
- Amare, Azmeraw, et al.
(författare)
-
Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder.
- 2023
-
Ingår i: Research square. - : Research Square Platform LLC.
-
Tidskriftsartikel (refereegranskat)abstract
- Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium's possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N=2,367) and replicated in the combined PsyCourse (N=89) and BipoLife (N=102) studies. The associations of Li+PGS and lithium treatment response - defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������.
|
|
| 19. |
|
|
| 20. |
|
|
| 21. |
|
|
| 22. |
- Berggård, T, et al.
(författare)
-
Prothrombin, albumin and immunoglobulin A form covalent complexes with alpha1-microglobulin in human plasma
- 1997
-
Ingår i: European Journal of Biochemistry. - : Wiley. - 0014-2956 .- 1432-1033. ; 245:3, s. 83-676
-
Tidskriftsartikel (refereegranskat)abstract
- Molecules containing the 33-kDa plasma protein alpha1-microglobulin were isolated from human plasma by anti-(alpha1-microglobulin) affinity chromatography. Five major bands could be seen after electrophoretic separation of the alpha1-microglobulin-containing proteins under native conditions. Immunoblotting demonstrated alpha1-microglobulin in all five bands. Two of these have been described previously: free alpha1-microglobulin and alpha1-microglobulin complexed with IgA (IgA x alpha1-microglobulin). The other three bands were identified as prothrombin alpha1-microglobulin, albumin x alpha1-microglobulin and dimeric alpha1-microglobulin. Prothrombin x alpha1-microglobulin were 1:2 and 1:1 complexes which carried approximately 1% of total alpha1-microglobulin, had molecular masses of about 145 kDa and 110 kDa upon SDS/PAGE and dissociated completely to free alpha1-microglobulin and prothrombin (72 kDa) when reducing agents were added, suggesting that the complexes were stabilized by disulfide bonds. The alpha1-microglobulin molecules did not inhibit cleavage of prothrombin by factor Xa and were bound to the peptides which were released upon activation of prothrombin. Albumin x alpha1-microglobulin, corresponding to 7% of total plasma alpha1-microglobulin, was a mixture between 1:1 and 1:2 complexes, with masses upon SDS/PAGE of approximately 100 kDa and 135 kDa, respectively. Both these complexes dissociated only partially to free alpha1-microglobulin and albumin when reducing agents were added. The albumin x alpha1-microglobulin complexes carried a yellow-brown chromophore similar to free alpha1-microglobulin. The complex-binding to alpha1-microglobulin did not block the fatty-acid-binding ability of albumin. The plasma concentrations of albumin x alpha1-microglobulin and prothrombin x alpha1-microglobulin were estimated to 5.2 mg/l and 1.1 mg/l, respectively.
|
|
| 23. |
- Bergquist, Jonas, et al.
(författare)
-
Capillary electrophoresis with laser-induced fluorescence detection : a sensitive method for monitoring extracellular concentrations of amino acids in the periaqueductal grey matter.
- 1996
-
Ingår i: Journal of Neuroscience Methods. - : Elsevier BV. - 0165-0270 .- 1872-678X. ; 65:1, s. 33-42
-
Tidskriftsartikel (refereegranskat)abstract
- The use of capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) for the analysis of microdialysate samples from the periaqueductal grey matter (PAG) of freely moving rats is described. By employing 3-(4-carboxybenzoyl)-2-quinoline-carboxaldehyde (CBQCA) as a derivatization agent, we simultaneously monitored the concentrations of 8 amino acids (arginine, glutamine, valine, gamma-amino-n-butyric acid (GABA), alanine, glycine, glutamate, and aspartate), with nanomolar and subnanomolar detection limits. Two of the amino acids (GABA and glutamate) were analysed in parallel by conventional high-performance liquid chromatography (HPLC) in order to directly compare the two analytical methods. Other CE methods for analysis of microdialysate have been previously described, and this improved method offers greater sensitivity, ease of use, and the possibility to monitor several amino acids simultaneously. By using this technique together with an optimised form of microdialysis technique, the tiny sample consumption and the improved detection limits permit the detection of fast and transient transmitter changes.
|
|
| 24. |
|
|
| 25. |
- Burr, S. P., et al.
(författare)
-
Cell lineage-specific mitochondrial resilience during mammalian organogenesis
- 2023
-
Ingår i: Cell. - : Elsevier BV. - 0092-8674. ; 186:6
-
Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial activity differs markedly between organs, but it is not known how and when this arises. Here we show that cell lineage-specific expression profiles involving essential mitochondrial genes emerge at an early stage in mouse development, including tissue-specific isoforms present before organ formation. However, the nuclear transcriptional signatures were not independent of organelle function. Genetically disrupting intra-mitochondrial protein synthesis with two different mtDNA mutations induced cell lineage-specific compensatory responses, including molecular pathways not previously implicated in organellar maintenance. We saw downregulation of genes whose expression is known to exacerbate the effects of exogenous mito-chondrial toxins, indicating a transcriptional adaptation to mitochondrial dysfunction during embryonic devel-opment. The compensatory pathways were both tissue and mutation specific and under the control of tran-scription factors which promote organelle resilience. These are likely to contribute to the tissue specificity which characterizes human mitochondrial diseases and are potential targets for organ-directed treatments.
|
|
| 26. |
- Dzhigaev, D., et al.
(författare)
-
Bragg coherent x-ray diffractive imaging of a single indium phosphide nanowire
- 2016
-
Ingår i: Journal of Optics. - : IOP Publishing. - 2040-8978 .- 2040-8986. ; 18:6
-
Tidskriftsartikel (refereegranskat)abstract
- Three-dimensional (3D) Bragg coherent x-ray diffractive imaging (CXDI) with a nanofocused beam was applied to quantitatively map the internal strain field of a single indium phosphide nanowire. The quantitative values of the strain were obtained by pre-characterization of the beam profile with transmission ptychography on a test sample. Our measurements revealed the 3D strain distribution in a region of 150 nm below the catalyst Au particle. We observed a slight gradient of the strain in the range of 0.6% along the [111] growth direction of the nanowire. We also determined the spatial resolution in our measurements to be about 10 nm in the direction perpendicular to the facets of the nanowire. The CXDI measurements were compared with the finite element method simulations and show a good agreement with our experimental results. The proposed approach can become an effective tool for in operando studies of the nanowires.
|
|
| 27. |
- Falkenberg, Anna, et al.
(författare)
-
Social support at work and leisure time and its association with self-rated health and sickness absence
- 2012
-
Ingår i: Work. - 1051-9815 .- 1875-9270. ; 43:4, s. 469-474
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of this longitudinal study is to investigate how different aspects of social support at work and in leisure time are associated with self rated health and sickness absence. Participants: The 541 participants in the study were representative for a working population in the public sector in Sweden with a majority being woman. Methods: Most of the variables were created from data from a questionnaire in March - April 2005. There were four independent variables and two dependent variables. The dependent were based on data from November 2006. A logistic regression model was used for the analysis of associations. A separate model was adapted for each of the explanatory variables for each outcome, which gave five models per independent variable. Results: The study has given a greater awareness of the importance of employees receiving social support, regardless of type of support or from whom the support is coming. Conclusion: Social support has a strong association with SRH in a longitudinal perspective and no association between social support and sickness absence.
|
|
| 28. |
|
|
| 29. |
- Falkenberg, C, et al.
(författare)
-
Alpha1-microglobulin and bikunin in rats with collagen II-induced arthritis : plasma levels and liver mRNA content
- 1997
-
Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 46:2, s. 8-122
-
Tidskriftsartikel (refereegranskat)abstract
- The plasma proteins alpha1-microglobulin (alpha1-m) and bikunin are synthesized in the liver as a common precursor which is cleaved just before secretion. Half of plasma alpha1-m is covalently linked to fibronectin and alpha1-inhibitor-3, and more than 95% of bikunin is part of pre-alpha-inhibitor, inter-alpha-inhibitor and related large molecules. Both alpha1-m and bikunin have been shown to be involved in inflammation, but the regulation of their synthesis is not clear. The authors have measured the plasma and urinary concentrations of alpha1-m and bikunin as well as their hepatic mRNA levels in rats during the development of collagen-induced arthritis. Also, the plasma concentrations of acknowledged acute-phase proteins were measured. The results suggested a biphasic inflammatory reaction: an early response after 1 week, represented by an elevated fibronectin level; and a late response after 3 weeks, represented by elevated alpha1-acid glycoprotein and decreased albumin and alpha1-inhibitor-3 levels. The alpha1-m-bikunin mRNA content in liver was slightly reduced after 1 week and elevated after 3 weeks, but the total concentrations of free and bound alpha1-m and bikunin in plasma were unchanged. The free bikunin fraction as well as the fibronectin/alpha1-m complex in plasma, however, were elevated after 1 week. Urinary bikunin levels were also elevated after 1 week, whereas urinary alpha1-m levels remained unchanged. The results thus suggest that free bikunin in plasma is increased and excreted in the urine at an early stage during the development of collagen-induced arthritis. Later, when the synthesis rate of alpha1-m-bikunin is elevated, both proteins are most likely directed to other locations in the body.
|
|
| 30. |
- Falkenberg, C, et al.
(författare)
-
Isolation and characterization of fibronectin-alpha 1-microglobulin complex in rat plasma
- 1994
-
Ingår i: The Biochemical journal. - : Portland Press Ltd.. - 0264-6021 .- 1470-8728. ; 301:3, s. 51-745
-
Tidskriftsartikel (refereegranskat)abstract
- Molecules containing the 28 kDa immunoregulatory protein alpha 1-microglobulin (alpha 1-m), also known as protein HC, were isolated from rat plasma or serum by immunoaffinity chromatography. Three molecular species were distinguished on the basis of nondenaturing PAGE. Two of these have been described previously: uncomplexed alpha 1-m, and the complex of alpha 1-m with alpha 1-inhibitor-3. The third species was analysed by denaturing PAGE, immunoblotting, proteinase digestion and N-terminal-sequence analyses, and shown to consist of a complex between alpha 1-m and fibronectin. This complex, with a mass of about 560 kDa, was resistant to dissociation in the presence of denaturants, but not in the presence of reducing agents in combination with denaturants, and we conclude that the two components are linked by disulphide bonds. About 60% of the total detectable plasma alpha 1-m exists as high-molecular-mass complexes distributed approximately evenly between fibronectin and alpha 1-inhibitor-3. Immunochemical analyses were used to determine the proportion of the total plasma pools of fibronectin and alpha 1-inhibitor-3 that circulate in complex with alpha 1-m. About 3-7% of the total plasma fibronectin from three different rat strains contained alpha 1-m, whereas 0.3-0.8% of the total plasma alpha 1-inhibitor-3 contained alpha 1-m. Complexes were found at similar levels in plasma and serum, indicating that coagulation is not responsible for complex formation. Moreover, immunochemical analyses of human plasma revealed small amounts of alpha 1-m in complex with fibronectin and alpha 2-macroglobulin (an alpha 1-inhibitor-3 homologue). The existence of a complex between alpha 1-m and fibronectin in rats and humans suggests a mechanism for the incorporation of the immunoregulatory molecule alpha 1-m into the extracellular matrix.
|
|
| 31. |
- Falkenberg, C, et al.
(författare)
-
Isolation of rat serum alpha 1-microglobulin. Identification of a complex with alpha 1-inhibitor-3, a rat alpha 2-macroglobulin homologue
- 1990
-
Ingår i: Journal of Biological Chemistry. - 0021-9258. ; 265:27, s. 16150-16157
-
Tidskriftsartikel (refereegranskat)abstract
- Alpha 1-Microglobulin (alpha 1-m), or protein HC, a low molecular weight plasma protein with immunoregulatory properties, was isolated from rat serum by affinity chromatography using Sepharose-coupled monoclonal anti-alpha 1-m antibodies. High molecular weight forms of alpha 1-m were then separated from the low molecular weight alpha 1-m by gel chromatography of the eluted proteins. The apparent Mr (28,000), the charge heterogeneity, the N-linked carbohydrate, and yellow-brown chromophore suggest that the low molecular weight alpha 1-m is the serum counterpart to urinary alpha 1-m, which was purified previously. A high molecular weight complex of alpha 1-m was also isolated by the gel chromatography. It was homogeneous as judged by nondenaturing polyacrylamide gel electrophoresis. The molecule was bound by antibodies against human alpha 2-macroglobulin, and experiments with antisera against the three alpha-macroglobulin variants in rat serum, alpha 1-macroglobulin, alpha 2-macroglobulin, and alpha 1-inhibitor-3 (alpha 1I3) suggested that alpha 1I3 was the complex-partner of alpha 1-m. An antiserum raised against high molecular weight alpha 1-m was then used to isolate the complex-partner of alpha 1-m from rat serum with affinity chromatography, and this molecule was positively identified as alpha 1I3 by its physicochemical properties. Gel chromatography of the alpha 1I3.alpha 1-m complex suggested a molecule with an Mr of 266,000. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis, however, it migrated as three major molecular species with apparent molecular weights of 224,000, 205,000, and 194,000 and several minor species of both higher and lower molecular weights, suggesting a complex subunit structure. alpha 1-m and alpha 1I3 could be detected in all three major species by Western blotting, and NH2-terminal amino acid sequencing suggested a molar ratio of 1:1 of alpha 1-m and alpha 1I3 in all three species. alpha 1I3.alpha 1-m was colorless, did not show light absorbance beyond 300 nm which is typical of low molecular weight alpha 1-m and was electrophoretically homogeneous, suggesting that it lacks the chromophore. Finally, the serum concentrations of the alpha 1I3.alpha 1-m complex and free alpha 1-m were determined as 0.16 and 0.010 g/liter, respectively. Thus, alpha 1I3.alpha 1-m constitutes 1-3% of the total alpha 1I3 in rat serum (w/w) and approximately 60% of the total alpha 1-m.
|
|
| 32. |
- Falkenberg, C, et al.
(författare)
-
Localization of the binding site for streptococcal protein G on human serum albumin. Identification of a 5.5-kilodalton protein G binding albumin fragment
- 1992
-
Ingår i: Biochemistry. - : American Chemical Society (ACS). - 0006-2960 .- 1520-4995. ; 31:5, s. 7-1451
-
Tidskriftsartikel (refereegranskat)abstract
- Protein G is a streptococcal cell wall protein with separate and repetitively arranged binding domains for immunoglobulin G (IgG) and human serum albumin (HSA). In this work, the binding of protein G to HSA was studied. The results suggest that a single binding site is present on HSA: the apparent size of the HSA-protein G complex (230 kDa) corresponded to two or three HSA molecules bound to one protein G molecule, and Ouchterlony immunodiffusion did not yield any precipitate between protein G and HSA. HSA was cleaved by pepsin and CNBr into several fragments which were identified by SDS-PAGE and N-terminal amino acid sequencing, and the binding of protein G to the fragments was studied in Western blot experiments. The results indicated that the binding area was located in disulfide loops 6-8, involving both the second (loop 6) and the third (loops 7 and 8) domain of HSA. One of the protein G binding pepsin fragments, with an apparent molecular mass of 5.5 kDa, located in loops 7 and 8, was isolated and found to completely inhibit the binding between protein G and the intact HSA, again suggesting a single protein G binding site on serum albumin. Reducing the disulfide bonds of HSA, and subsequent alkylation of the half-cystine residues, significantly decreased the affinity for protein G. Protein G bound to albumin from baboon, cat, guinea pig, hamster, hen, horse, man, mouse, and rat, but not to albumin from cow, dog, goat, pig, rabbit, sheep, snake, or turkey.
|
|
| 33. |
- Falkenberg, C, et al.
(författare)
-
Purification of streptococcal protein G expressed by Escherichia coli by high performance liquid affinity chromatography using immobilized immunoglobulin G and albumin
- 1987
-
Ingår i: Biomedical Chromatography. - : Wiley. - 0269-3879 .- 1099-0801. ; 2:5, s. 5-221
-
Tidskriftsartikel (refereegranskat)abstract
- A one-step HPLC method was developed for the purification of protein G, a cell wall molecule from group C and G streptococci with immunoglobulin G- and albumin-binding properties. Lysed Escherichia coli bacteria infected with lambda-phages containing the protein G gene from group G streptococci were used as a starting material for the preparations. The lysate was applied to a column with immobilized human immunoglobulin G or human serum albumin. Protein G was selectively bound and eluted at pH 2.0. A 750-fold purification was achieved. Sodium dodecylsulfate + polyacrylamide gel electrophoresis showed that the highly purified protein G consisted of three sets of doublets with the apparent molecular weight of 64 and 67, 56 and 58, and 45 and 47 kilodaltons, respectively. A specific method for quantitation of small amounts of protein G was developed and used for specific tracing of the protein after the affinity chromatography. Goat polyclonal antibodies were bound to an antigen coated to the plastic walls of microtiter plates, causing the Fc-region of the immunoglobulins to be directed outwards. Unknown samples of protein G were then allowed to compete with radio-iodinated protein G (solid phase radioassay) or protein G coupled to alkaline phosphatase (enzyme linked sorbent assay) for the Fc-regions.
|
|
| 34. |
- Falkenberg, L. J., et al.
(författare)
-
Low sensitivity of reproductive life-stages in the Pacific oyster (Crassostrea gigas) to abamectin
- 2017
-
Ingår i: Chemosphere. - : Elsevier BV. - 0045-6535. ; 182, s. 665-671
-
Tidskriftsartikel (refereegranskat)abstract
- Hard surfaces submerged in the marine environment often become colonised by macro-organisms unless the surfaces have some form of biofouling protection. While protective paints that contain tributyltin or copper work well to prevent biofouling, release of these materials into the environment has been shown to have wider negative impacts. Consequently, new low-release antifouling paints are being developed with alternative active ingredients, such as avermectins, yet little is known about their potential effects on non-target organisms in marine environments. Here we investigated the toxicity of a key avermectin, specifically abamectin, on several aspects of reproduction (sperm motility, fertilisation success, early larval development) in the Pacific oyster, Crassostrea gigas. Oyster reproduction was generally insensitive to the low concentrations of abamectin, although greater concentrations of abamectin did negatively affect all three endpoints – LOECs were 1000μgl−1, 500μgl−1, and 100μgl−1 abamectin for sperm motility, fertilisation success, and larval development, respectively. A similar pattern was found in the EC50s of the three endpoints (mean±SE) 934±59μgl−1, 1076.26±725.61μgl−1, and 140±78μgl−1 abamectin (sperm motility, fertilisation success, and larval development, respectively). Together, these results clearly indicate that of the three endpoints considered, larval development was more sensitive to abamectin (lower LOEC, EC50) than fertilisation success and sperm motility. Although more data are needed from a wider range of marine species and environments to fully assess potential toxicity effects on non-target organisms, our results highlight the potential utility of abamectin in low-release antifouling paints. © 2017 Elsevier Ltd
|
|
| 35. |
- Falkenberg, L. J., et al.
(författare)
-
Sperm Accumulated Against Surface: A novel alternative bioassay for environmental monitoring
- 2016
-
Ingår i: Marine Environmental Research. - : Elsevier BV. - 0141-1136. ; 114, s. 51-57
-
Tidskriftsartikel (refereegranskat)abstract
- Forecasting the impacts of changes in water quality on broadcast spawning aquatic organisms is a key aspect of environmental monitoring. Rapid assays of reproductive potential are central to this monitoring, and there is a need to develop a variety of methods to identify responses. Here, we report a proof of-concept study that assesses whether quantification of "Sperm Accumulated Against Surface" (SAAS) of tissue culture well-plates could be a rapid and simple proxy measure of fertilisation success. Our results confirm that motile sperm (but not immotile sperm) actively accumulate at surfaces and that the pattern of accumulation reflects fertilisation success in the model oyster species Crassostrea gigas. Furthermore, we confirm these patterns of SAAS for another marine species, the polychaete Galeolaria caespitosa, as well as for a freshwater species, the fish Gasterosteus aculeatus. For all species considered, SAAS reflected changes in sperm performance caused by experimentally manipulated differences in water quality (here, salinity). These findings indicate that SAAS could be applied easily to a range of species when examining the effects of water quality. Measurement of SAAS could, therefore, form the basis of a rapid and reliable assay for bioassessments of broadcast spawning aquatic organisms. (C) 2015 Elsevier Ltd. All rights reserved.
|
|
| 36. |
- Falkenberg, L. J., et al.
(författare)
-
Sperm motility of oysters from distinct populations differs in response to ocean acidification and freshening
- 2019
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9
-
Tidskriftsartikel (refereegranskat)abstract
- Species' responses to climate change will reflect variability in the effects of physiological selection that future conditions impose. Here, we considered the effects of ocean acidification (increases in pCO(2); 606, 925, 1250 mu atm) and freshening (reductions in salinity; 33, 23, 13 PSU) on sperm motility in oysters (Crassostrea gigas) from two populations (one recently invaded, one established for 60+ years). Freshening reduced sperm motility in the established population, but this was offset by a positive effect of acidification. Freshening also reduced sperm motility in the recently invaded population, but acidification had no effect. Response direction, strength, and variance differed among individuals within each population. For the established population, freshening increased variance in sperm motility, and exposure to both acidification and freshening modified the performance rank of males (i.e. rank motility of sperm). In contrast, for the recently invaded population, freshening caused a smaller change in variance, and male performance rank was broadly consistent across treatments. That inter-population differences in response may be related to environmental history (recently invaded, or established), indicates this could influence scope for selection and adaptation. These results highlight the need to consider variation within and among population responses to forecast effects of multiple environmental change drivers.
|
|
| 37. |
- Farge, G., et al.
(författare)
-
Protein sliding and DNA denaturation are essential for DNA organization by human mitochondrial transcription factor A
- 2012
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 3
-
Tidskriftsartikel (refereegranskat)abstract
- Mitochondria organize their genome in protein-DNA complexes called nucleoids. The mitochondrial transcription factor A (TFAM), a protein that regulates mitochondrial transcription, is abundant in these nucleoids. TFAM is believed to be essential for mitochondrial DNA compaction, yet the exact mechanism has not been resolved. Here we use a combination of single-molecule manipulation and fluorescence microscopy to show the nonspecific DNA-binding dynamics and compaction by TFAM. We observe that single TFAM proteins diffuse extensively over DNA (sliding) and, by collisions, form patches on DNA in a cooperative manner. Moreover, we demonstrate that TFAM induces compaction by changing the flexibility of the DNA, which can be explained by local denaturation of the DNA (melting). Both sliding of TFAM and DNA melting are also necessary characteristics for effective, specific transcription regulation by TFAM. This apparent connection between transcription and DNA organization clarifies how TFAM can accomplish two complementary roles in the mitochondrial nucleoid at the same time.
|
|
| 38. |
|
|
| 39. |
|
|
| 40. |
- Glazyrin, K., et al.
(författare)
-
Sub-micrometer focusing setup for high-pressure crystallography at the Extreme Conditions beamline at PETRA III
- 2022
-
Ingår i: Journal of Synchrotron Radiation. - Chichester, United Kingdom : Wiley-Blackwell. - 0909-0495 .- 1600-5775. ; 29, s. 654-663
-
Tidskriftsartikel (refereegranskat)abstract
- Scientific tasks aimed at decoding and characterizing complex systems and processes at high pressures set new challenges for modern X-ray diffraction instrumentation in terms of X-ray flux, focal spot size and sample positioning. Presented here are new developments at the Extreme Conditions beamline (P02.2, PETRA III, DESY, Germany) that enable considerable improvements in data collection at very high pressures and small scattering volumes. In particular, the focusing of the X-ray beam to the sub-micrometer level is described, and control of the aberrations of the focusing compound refractive lenses is made possible with the implementation of a correcting phase plate. This device provides a significant enhancement of the signal-to-noise ratio by conditioning the beam shape profile at the focal spot. A new sample alignment system with a small sphere of confusion enables single-crystal data collection from grains of micrometer to sub-micrometer dimensions subjected to pressures as high as 200 GPa. The combination of the technical development of the optical path and the sample alignment system contributes to research and gives benefits on various levels, including rapid and accurate diffraction mapping of samples with sub-micrometer resolution at multimegabar pressures.
|
|
| 41. |
|
|
| 42. |
|
|
| 43. |
|
|
| 44. |
- Hok, J, et al.
(författare)
-
What is an exceptional cancer trajectory?: Multiple stakeholder perspectives on cancer trajectories in relation to complementary and alternative medicine use
- 2009
-
Ingår i: Integrative cancer therapies. - : SAGE Publications. - 1534-7354 .- 1552-695X. ; 8:2, s. 153-163
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Although links between exceptional cancer trajectories (ECTs) and complementary and alternative medicines (CAMs) have been suggested, most research on ECT uses predefined criteria for ECTs without necessarily including CAM use. Little knowledge can be found about subjective perspectives of ECTs in relation to CAM. Objectives: This Swedish study explores how patients, significant others, and CAM and biomedical health care (BHC) providers reason about ECT, including the role of CAM. Methods: Using a case study approach, open interviews were conducted with multiple stakeholders about cancer trajectories reported as exceptional. Results: In-depth analysis of 5 cases indicated that although all stakeholders agreed that the reported cases were positive, in no case was the same trajectory considered exceptional by all stakeholders. Different stakeholders shared neither conceptualizations of what constituted an ECT nor attributions for positive trajectories. Patients, significant others, and CAM providers emphasized unexpectedly long survival and well-being in ECTs, whereas BHC providers only referred to survival. CAM and BHC providers normalized reported trajectories, although the forms for this differed between provider groups. Concluding discussion: Stakeholders' accounts are discussed relative to different health care domains, legitimization processes, and legal constraints, which have led to the lack of a public sphere for CAM use in cancer.
|
|
| 45. |
- Jemt, Elisabeth, et al.
(författare)
-
Regulation of DNA replication at the end of the mitochondrial D-loop involves the helicase TWINKLE and a conserved sequence element
- 2015
-
Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 43:19, s. 9262-9275
-
Tidskriftsartikel (refereegranskat)abstract
- The majority of mitochondrial DNA replication events are terminated prematurely. The nascent DNA remains stably associated with the template, forming a triple-stranded displacement loop (D-loop) structure. However, the function of the D-loop region of the mitochondrial genome remains poorly understood. Using a comparative genomics approach we here identify two closely related 15 nt sequence motifs of the D-loop, strongly conserved among vertebrates. One motif is at the D-loop 5'-end and is part of the conserved sequence block 1 (CSB1). The other motif, here denoted coreTAS, is at the D-loop 3'-end. Both these sequences may prevent transcription across the D-loop region, since light and heavy strand transcription is terminated at CSB1 and coreTAS, respectively. Interestingly, the replication of the nascent D-loop strand, occurring in a direction opposite to that of heavy strand transcription, is also terminated at coreTAS, suggesting that coreTAS is involved in termination of both transcription and replication. Finally, we demonstrate that the loading of the helicase TWINKLE at coreTAS is reversible, implying that this site is a crucial component of a switch between D-loop formation and full-length mitochondrial DNA replication.
|
|
| 46. |
- Jong, Mats, 1968-, et al.
(författare)
-
Integrative Nursing in Sweden
- 2014
-
Ingår i: Integrative Nursing. - : Oxford University Press. - 9780199860739 ; , s. 515-525
-
Bokkapitel (refereegranskat)
|
|
| 47. |
- Jong, Mats, 1968-, et al.
(författare)
-
Integrative Nursing in Sweden
- 2019. - 2
-
Ingår i: Integrative Nursing. - New York : Oxford University Press. - 9780190851040 ; , s. 652-662
-
Bokkapitel (refereegranskat)abstract
- This chapter describes the existing “core” of caring/nursing in the Nordic tradition and how that can be merged with the concepts of integrative nursing to form a vision and strategy for the future. Terms such as integrative nursing are unfamiliar among nurses in Sweden, but the concepts of holistic care and healing have been taught for a long time and are well integrated in education and legislation. This chapter discusses possible barriers, such as the level of decision-making in Swedish healthcare as well as the role and attitude towards legislation in the light of the dominant biomedical paradigm. Further discussion explores how integrative nursing may serve as a bridge between the caring, nursing, and biomedical perspectives in its effort to identify and construct evidence from the basis and understanding of complex interventions and complex systems science. Practical steps for progression are identified and suggested.
|
|
| 48. |
|
|
| 49. |
- Kukat, C, et al.
(författare)
-
Super-resolution microscopy reveals that mammalian mitochondrial nucleoids have a uniform size and frequently contain a single copy of mtDNA
- 2011
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 108:33, s. 13534-13539
-
Tidskriftsartikel (refereegranskat)abstract
- Mammalian mtDNA is packaged in DNA-protein complexes denoted mitochondrial nucleoids. The organization of the nucleoid is a very fundamental question in mitochondrial biology and will determine tissue segregation and transmission of mtDNA. We have used a combination of stimulated emission depletion microscopy, enabling a resolution well below the diffraction barrier, and molecular biology to study nucleoids in a panel of mammalian tissue culture cells. We report that the nucleoids labeled with antibodies against DNA, mitochondrial transcription factor A (TFAM), or incorporated BrdU, have a defined, uniform mean size of ∼100 nm in mammals. Interestingly, the nucleoid frequently contains only a single copy of mtDNA (average ∼1.4 mtDNA molecules per nucleoid). Furthermore, we show by molecular modeling and volume calculations that TFAM is a main constituent of the nucleoid, besides mtDNA. These fundamental insights into the organization of mtDNA have broad implications for understanding mitochondrial dysfunction in disease and aging.
|
|
| 50. |
|
|
