There is increasing evidence for a role of inflammation in Parkinson's disease. Recent research in murine models suggests that parkin and PINK1 deficiency leads to impaired mitophagy, which causes ...the release of mitochondrial DNA (mtDNA), thereby triggering inflammation. Specifically, the CGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway mitigates activation of the innate immune system, quantifiable as increased interleukin-6 (IL6) levels. However, the role of IL6 and circulating cell-free mtDNA in unaffected and affected individuals harbouring mutations in PRKN/PINK1 and idiopathic Parkinson's disease patients remain elusive. We investigated IL6, C-reactive protein, and circulating cell-free mtDNA in serum of 245 participants in two cohorts from tertiary movement disorder centres. We performed a hypothesis-driven rank-based statistical approach adjusting for multiple testing. We detected (i) elevated IL6 levels in patients with biallelic PRKN/PINK1 mutations compared to healthy control subjects in a German cohort, supporting the concept of a role for inflammation in PRKN/PINK1-linked Parkinson's disease. In addition, the comparison of patients with biallelic and heterozygous mutations in PRKN/PINK1 suggests a gene dosage effect. The differences in IL6 levels were validated in a second independent Italian cohort; (ii) a correlation between IL6 levels and disease duration in carriers of PRKN/PINK1 mutations, while no such association was observed for idiopathic Parkinson's disease patients. These results highlight the potential of IL6 as progression marker in Parkinson's disease due to PRKN/PINK1 mutations; (iii) increased circulating cell-free mtDNA serum levels in both patients with biallelic or with heterozygous PRKN/PINK1 mutations compared to idiopathic Parkinson's disease, which is in line with previous findings in murine models. By contrast, circulating cell-free mtDNA concentrations in unaffected heterozygous carriers of PRKN/PINK1 mutations were comparable to control levels; and (iv) that circulating cell-free mtDNA levels have good predictive potential to discriminate between idiopathic Parkinson's disease and Parkinson's disease linked to heterozygous PRKN/PINK1 mutations, providing functional evidence for a role of heterozygous mutations in PRKN or PINK1 as Parkinson's disease risk factor. Taken together, our study further implicates inflammation due to impaired mitophagy and subsequent mtDNA release in the pathogenesis of PRKN/PINK1-linked Parkinson's disease. In individuals carrying mutations in PRKN/PINK1, IL6 and circulating cell-free mtDNA levels may serve as markers of Parkinson's disease state and progression, respectively. Finally, our study suggests that targeting the immune system with anti-inflammatory medication holds the potential to influence the disease course of Parkinson's disease, at least in this subset of patients.
In the mid-1990s, the subpolar gyre of the North Atlantic underwent a remarkable rapid warming, with sea surface temperatures increasing by around 1°C in just 2 yr. This rapid warming followed a ...prolonged positive phase of the North Atlantic Oscillation (NAO) but also coincided with an unusually negative NAO index in the winter of 1995/96. By comparing ocean analyses and carefully designed model experiments, it is shown that this rapid warming can be understood as a delayed response to the prolonged positive phase of the NAO and not simply an instantaneous response to the negative NAO index of 1995/96. Furthermore, it is inferred that the warming was partly caused by a surge and subsequent decline in the meridional overturning circulation and northward heat transport of the Atlantic Ocean. These results provide persuasive evidence of significant oceanic memory on multiannual time scales and are therefore encouraging for the prospects of developing skillful predictions.
As a contribution towards improving the climate mean state of the atmosphere and the ocean in Earth system models (ESMs), we compare several coupled simulations conducted with the Max Planck ...Institute for Meteorology Earth System Model (MPI-ESM1.2) following the HighResMIP protocol. Our simulations allow to analyse the separate effects of increasing the horizontal resolution of the ocean (0.4 to 0.1∘) and atmosphere (T127 to T255) submodels, and the effects of substituting the Pacanowski and Philander (PP) vertical ocean mixing scheme with the K-profile parameterization (KPP). The results show clearly distinguishable effects from all three factors. The high resolution in the ocean removes biases in the ocean interior and in the atmosphere. This leads to the important conclusion that a high-resolution ocean has a major impact on the mean state of the ocean and the atmosphere. The T255 atmosphere reduces the surface wind stress and improves ocean mixed layer depths in both hemispheres. The reduced wind forcing, in turn, slows the Antarctic Circumpolar Current (ACC), reducing it to observed values. In the North Atlantic, however, the reduced surface wind causes a weakening of the subpolar gyre and thus a slowing down of the Atlantic meridional overturning circulation (AMOC), when the PP scheme is used. The KPP scheme, on the other hand, causes stronger open-ocean convection which spins up the subpolar gyres, ultimately leading to a stronger and stable AMOC, even when coupled to the T255 atmosphere, thus retaining all the positive effects of a higher-resolved atmosphere.
The Arctic plays a fundamental role in the climate system and has shown significant climate change in recent decades,including the Arctic warming and decline of Arctic sea-ice extent and thickness. ...In contrast to the Arctic warming and reduction of Arctic sea ice, Europe, East Asia and North America have experienced anomalously cold conditions, with record snowfall during recent years. In this paper, we review current understanding of the sea-ice impacts on the Eurasian climate.Paleo, observational and modelling studies are covered to summarize several major themes, including： the variability of Arctic sea ice and its controls; the likely causes and apparent impacts of the Arctic sea-ice decline during the satellite era,as well as past and projected future impacts and trends; the links and feedback mechanisms between the Arctic sea ice and the Arctic Oscillation/North Atlantic Oscillation, the recent Eurasian cooling, winter atmospheric circulation, summer precipitation in East Asia, spring snowfall over Eurasia, East Asian winter monsoon, and midlatitude extreme weather; and the remote climate response（e.g., atmospheric circulation, air temperature） to changes in Arctic sea ice. We conclude with a brief summary and suggestions for future research.
Abstract
X-linked dystonia-parkinsonism is a neurodegenerative disorder caused by a founder retrotransposon insertion, in which a polymorphic hexanucleotide repeat accounts for ~50% of age at onset ...variability. Employing a genome-wide association study to identify additional factors modifying age at onset, we establish that three independent loci are significantly associated with age at onset (
p
< 5 × 10
−8
). The lead single nucleotide polymorphisms collectively account for 25.6% of the remaining variance not explained by the hexanucleotide repeat and 13.0% of the overall variance in age at onset in X-linked dystonia-parkinsonism with the protective alleles delaying disease onset by seven years. These regions harbor or lie adjacent to
MSH3
and
PMS2
, the genes that were recently implicated in modifying age at onset in Huntington’s disease, likely through a common pathway influencing repeat instability. Our work indicates the existence of three modifiers of age at onset in X-linked dystonia-parkinsonism that likely affect the DNA mismatch repair pathway.
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