| 21. |
- Springer, W, et al.
(författare)
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Heterozygous PINK1 p.G411S mutation increases risk for Parkinson's disease (PD)
- 2016
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Ingår i: Movement Disorders. - : Wiley. - 0885-3185. ; 31:Suppl. S2, s. 282-282
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Konferensbidrag (refereegranskat)abstract
- Objective: To investigate the possible disease-association and pathogenic mechanisms of heterozygous PINK1 mutations from a genetic, functional, and structural perspective. Background: It has been postulated that heterozygous mutations in recessive PD genes may increase disease risk. In particular, the PINK1 p.G411S mutation has been reported in families with dominant inheritance patterns, suggesting that it might confer a sizeable disease risk. Methods: We performed a pedigree analysis of seven patients with a heterozygous PINK1 p.G411S mutation with at least one additional affected family member. We screened five case-control series and performed a meta-analysis of previous studies that had examined the variant. For functional cell-based analyses, we used patients skin fibroblast from PINK1 p.G411S or p.Q456X heterozygotes and investigated endogenous protein levels and kinase activity by biochemistry and imaging. For structural analyses, we performed molecular modeling and generated monomeric and dimeric forms of wild type (WT) and mutant PINK1 protein. Using molecular dynamics simulations, we analyzed effects of the p.G411S mutation on WT PINK1 in a heterodimeric complex over time. Results: Our analyses revealed a genetic association of heterozygous PINK1 p.G411S mutation with an increased risk for PD and a possible dominant inheritance with incomplete co-segregation. In patients skin fibroblasts, we establish a dominant negative mode for heterozygous p.G411S mutations under endogenous conditions. While total PINK1 protein levels were similar to controls upon mitochondrial stress, cellular PINK1 kinase activity was significantly reduced in p.G411S heterozygotes compared to WT and importantly to p.Q456X heterozygotes, which resulted in 50% reduction of PINK1 protein levels. Structural analyses supported our hypothesis that the p.G411S mutation can poison PINK1 WT in a heterodimeric complex and thus effectively reduce cellular PINK1 kinase activity. This in turn impairs the protective functions of the PINK1/PARKIN-mediated mitochondrial quality control. Conclusions: Our study uncovers increased disease risk and molecular mechanisms of a particular heterozygous mutation in a recessive PD gene. Based on genetic and clinical evaluation as well as functional and structural characterization, we established PINK1 p.G411S as a rare genetic risk factor with a relatively large effect size conferred by a dominant negative function phenotype.
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| 22. |
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| 23. |
- Tews, Ingo, et al.
(författare)
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Nuclear Forces for Precision Nuclear Physics: A Collection of Perspectives
- 2022
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Ingår i: Few-Body Systems. - : Springer Science and Business Media LLC. - 1432-5411 .- 0177-7963. ; 63:4
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Tidskriftsartikel (refereegranskat)abstract
- This is a collection of perspective pieces contributed by the participants of the Institute for Nuclear Theory's Program on Nuclear Physics for Precision Nuclear Physics which was held virtually from April 19 to May 7, 2021. The collection represents the reflections of a vibrant and engaged community of researchers on the status of theoretical research in low-energy nuclear physics, the challenges ahead, and new ideas and strategies to make progress in nuclear structure and reaction physics, effective field theory, lattice QCD, quantum information, and quantum computing. The contributed pieces solely reflect the perspectives of the respective authors and do not represent the viewpoints of the Institute for Nuclear theory or the organizers of the program.
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| 24. |
- Wang, Y., et al.
(författare)
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Evaluation of liquid from the Papanicolaou test and other liquid biopsies for the detection of endometrial and ovarian cancers
- 2018
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 10:433, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- We report the detection of endometrial and ovarian cancers based on genetic analyses of DNA recovered from the fluids obtained during a routine Papanicolaou (Pap) test. The new test, called PapSEEK, incorporates assays for mutations in 18 genes as well as an assay for aneuploidy. In Pap brush samples from 382 endometrial cancer patients, 81% [95% confidence interval (CI), 77 to 85%] were positive, including 78% of patients with early-stage disease. The sensitivity in 245 ovarian cancer patients was 33% (95% CI, 27 to 39%), including 34% of patients with early-stage disease. In contrast, only 1.4% of 714 women without cancer had positive Pap brush samples (specificity, ~99%). Next, we showed that intrauterine sampling with a Tao brush increased the detection of malignancy over endocervical sampling with a Pap brush: 93% of 123 (95% CI, 87 to 97%) patients with endometrial cancer and 45% of 51 (95% CI, 31 to 60%) patients with ovarian cancer were positive, whereas none of the samples from 125 women without cancer were positive (specificity, 100%). Finally, in 83 ovarian cancer patients in whom plasma was available, circulating tumor DNA was found in 43% of patients (95% CI, 33 to 55%). When plasma and Pap brush samples were both tested, the sensitivity for ovarian cancer increased to 63% (95% CI, 51 to 73%). These results demonstrate the potential of mutation-based diagnostics to detect gynecologic cancers at a stage when they are more likely to be curable.
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| 25. |
- Wang, Y. X., et al.
(författare)
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Diagnostic potential of tumor DNA from ovarian cyst fluid
- 2016
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Ingår i: Elife. - 2050-084X. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- We determined whether the mutations found in ovarian cancers could be identified in the patients' ovarian cyst fluids. Tumor-specific mutations were detectable in the cyst fluids of 19 of 23 (83%) borderline tumors, 10 of 13 (77%) type I cancers, and 18 of 18 (100%) type II cancers. In contrast, no mutations were found in the cyst fluids of 18 patients with benign tumors or nonneoplastic cysts. Though large, prospective studies are needed to demonstrate the safety and clinical utility of this approach, our results suggest that the genetic evaluation of cyst fluids might be able to inform the management of the large number of women with these lesions.
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| 26. |
- Watzlawik, Jens O., et al.
(författare)
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Basal activity of PINK1 and PRKN in cell models and rodent brain
- 2023
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Ingår i: Autophagy. - 1554-8627.
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Tidskriftsartikel (refereegranskat)abstract
- The ubiquitin kinase-ligase pair PINK1-PRKN recognizes and transiently labels damaged mitochondria with ubiquitin phosphorylated at Ser65 (p-S65-Ub) to mediate their selective degradation (mitophagy). Complete loss of PINK1 or PRKN function unequivocally leads to early-onset Parkinson disease, but it is debated whether impairments in mitophagy contribute to disease later in life. While the pathway has been extensively studied in cell culture upon acute and massive mitochondrial stress, basal levels of activation under endogenous conditions and especially in vivo in the brain remain undetermined. Using rodent samples, patient-derived cells, and isogenic neurons, we here identified age-dependent, brain region-, and cell type-specific effects and determined expression levels and extent of basal and maximal activation of PINK1 and PRKN. Our work highlights the importance of defining critical risk and therapeutically relevant levels of PINK1-PRKN signaling which will further improve diagnosis and prognosis and will lead to better stratification of patients for future clinical trials.
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| 27. |
- Westerman, Michael, et al.
(författare)
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Phylogenetic relationships of dasyuromorphian marsupials revisited
- 2016
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Ingår i: Zoological Journal of the Linnean Society. - : Oxford University Press (OUP). - 0024-4082 .- 1096-3642. ; 176:3, s. 686-701
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Tidskriftsartikel (refereegranskat)abstract
- We reassessed the phylogenetic relationships of dasyuromorphians using a large molecular database comprising previously published and new sequences for both nuclear (nDNA) and mitochondrial (mtDNA) genes from the numbat (Myrmecobius fasciatus), most living species of Dasyuridae, and the recently extinct marsupial wolf, Thylacinus cynocephalus. Our molecular tree suggests that Thylacinidae is sister to Myrmecobiidae+Dasyuridae. We show robust support for the dasyurid intrafamilial classification proposed by Krajewski & Westerman as well as for placement of most dasyurid genera, which suggests substantial homoplasy amongst craniodental characters presently used to generate morphology-based taxonomies. Molecular dating with relaxed molecular clocks suggests that dasyuromorphian cladogenesis began in the Eocene, and that all three dasyuromorphian families originated prior to the end of this epoch. Radiation within Thylacinidae and Dasyuridae had occurred by the middle to late Oligocene, consistent with recognition of primitive thylacinids (e.g. Badjcinus turnbulli) in the later Oligocene and of putative dasyurids (e.g. Barinya wangala) by the early Miocene. We propose that all four extant dasyurid tribes were in existence by the early Miocene and that most modern dasyurid genera/species were established before the later Miocene. This is in marked contrast to the popularly accepted advocation of their origins in the latest Miocene-early Pliocene.
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| 28. |
- Westerman, M., et al.
(författare)
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Phylogenetic relationships of living and recently extinct bandicoots based on nuclear and mitochondrial DNA sequences
- 2012
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Ingår i: Molecular Phylogenetics and Evolution. - : Elsevier BV. - 1055-7903 .- 1095-9513. ; 62:1, s. 97-108
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Tidskriftsartikel (refereegranskat)abstract
- Bandicoots (Peramelemorphia) are a major order of australidelphian marsupials, which despite a fossil record spanning at least the past 25 million years and a pandemic Australasian range, remain poorly understood in terms of their evolutionary relationships. Many living peramelemorphians are critically endangered, making this group an important focus for biological and conservation research. To establish a phylogenetic framework for the group, we compiled a concatenated alignment of nuclear and mitochondrial DNA sequences, comprising representatives of most living and recently extinct species. Our analysis confirmed the currently recognised deep split between Macrons (Thylacomyidae), Chaeropus (Chaeropodidae) and all other living bandicoots (Peramelidae). The mainly New Guinean rainforest peramelids were returned as the sister clade of Australian dry-country species. The wholly New Guinean Peroryctinae was sister to Echymiperinae. The poorly known and perhaps recently extinct Seram Bandicoot (Rhynchomeles) is sister to Echymipera. Estimates of divergence times from relaxed-clock Bayesian methods suggest that living bandicoots originated in the late Oligocene or early Miocene, much earlier than currently thought based on fossils. Subsequent radiations within Peramelemorphia probably took place on the Australian mainland during the Miocene, with diversification of rainforest taxa on the newly emergent New Guinean landmasses through the middle-late Miocene and complete establishment of modern lineages by the early Pliocene.
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