| 1. |
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| 2. |
- Strakova, A., et al.
(författare)
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Recurrent horizontal transfer identifies mitochondrial positive selection in a transmissible cancer
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11
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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.
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| 3. |
- Coccolini, F., et al.
(författare)
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Aortic balloon occlusion (REBOA) in pelvic ring injuries: preliminary results of the ABO Trauma Registry
- 2020
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Ingår i: Updates in Surgery. - : Springer Science and Business Media LLC. - 2038-131X .- 2038-3312. ; 2020:72, s. 527-536
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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).
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| 4. |
- Farge, G., et al.
(författare)
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Protein sliding and DNA denaturation are essential for DNA organization by human mitochondrial transcription factor A
- 2012
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 3
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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.
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| 5. |
- Amare, Azmeraw, et al.
(författare)
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Association of Polygenic Score and the involvement of Cholinergic and Glutamatergic Pathways with Lithium Treatment Response in Patients with Bipolar Disorder.
- 2023
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Ingår i: Research square. - : Research Square Platform LLC.
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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<����������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������������.
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| 6. |
- Amare, Azmeraw T, et al.
(författare)
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Association of polygenic score and the involvement of cholinergic and glutamatergic pathways with lithium treatment response in patients with bipolar disorder.
- 2023
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Ingår i: Molecular psychiatry. - 1476-5578. ; 28, s. 5251-5261
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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.
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| 7. |
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| 8. |
- Dzhigaev, D., et al.
(författare)
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Bragg coherent x-ray diffractive imaging of a single indium phosphide nanowire
- 2016
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Ingår i: Journal of Optics. - : IOP Publishing. - 2040-8978 .- 2040-8986. ; 18:6
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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.
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| 9. |
- Erdinc, Direnis, et al.
(författare)
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Pathological variants in TOP3A cause distinct disorders of mitochondrial and nuclear genome stability
- 2023
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Ingår i: Embo Molecular Medicine. - 1757-4676. ; 15:5
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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.
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| 10. |
- Farge, G., et al.
(författare)
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In Vitro-Reconstituted Nucleoids Can Block Mitochondrial DNA Replication and Transcription
- 2014
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 8:1, s. 66-74
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Tidskriftsartikel (refereegranskat)abstract
- The mechanisms regulating the number of active copies of mtDNA are still unclear. A mammalian cell typically contains 1,000-10,000 copies of mtDNA, which are packaged into nucleoprotein complexes termed nucleoids. The main protein component of these structures is mitochondrial transcription factor A (TFAM). Here, we reconstitute nucleoid-like particles in vitro and demonstrate that small changes in TFAM levels dramatically impact the fraction of DNA molecules available for transcription and DNA replication. Compaction by TFAM is highly cooperative, and at physiological ratios of TFAM to DNA, there are large variations in compaction, from fully compacted nucleoids to naked DNA. In compacted nucleoids, TFAMforms stable protein filaments onDNAthat block melting and prevent progression of the replication and transcription machineries. Based on our observations, we suggest that small variations in the TFAM-to-mtDNA ratio may be used to regulate mitochondrial gene transcription and DNA replication.
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