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2.
  • Såmark-Roth, Anton, et al. (author)
  • Spectroscopy along flerovium decay chains: Discovery of 280Ds and an excited state in 282Cn
  • 2021
  • In: Physical Review Letters. - 1079-7114. ; 126:3
  • Journal article (peer-reviewed)abstract
    • A nuclear spectroscopy experiment was conducted to study α-decay chains stemming from isotopes of flerovium (element Z=114). An upgraded TASISpec decay station was placed behind the gas-filled separator TASCA at the GSI Helmholtzzentrum für Schwerionenforschung in Darmstadt, Germany. The fusion-evaporation reactions 48Ca+242Pu and 48Ca+244Pu provided a total of 32 flerovium-candidate decay chains, of which two and eleven were firmly assigned to 286Fl and 288Fl, respectively. A prompt coincidence between a 9.60(1)-MeV α-particle event and a 0.36(1)-MeV conversion electron marked the first observation of an excited state in an even-even isotope of the heaviest man-made elements, namely 282Cn. Spectroscopy of 288Fl decay chains fixed Qα=10.06(1) MeV. In one case, a Qα=9.46(1)-MeV decay from 284Cn into 280Ds was observed, with 280Ds fissioning after only 518 μs. The impact of these findings, aggregated with existing data on decay chains of 286,288Fl, on the size of an anticipated shell gap at proton number Z=114 is discussed in light of predictions from two beyond-mean-field calculations, which take into account triaxial deformation.
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3.
  • Tsiligiannis, Epameinondas, et al. (author)
  • A Four Carbon Organonitrate as a Significant Product of Secondary Isoprene Chemistry
  • 2022
  • In: Geophysical Research Letters. - : American Geophysical Union (AGU). - 0094-8276 .- 1944-8007. ; 49:11
  • Journal article (peer-reviewed)abstract
    • Oxidation of isoprene by nitrate radicals (NO3) or by hydroxyl radicals (OH) under high NOx conditions forms a substantial amount of organonitrates (ONs). ONs impact NOx concentrations and consequently ozone formation while also contributing to secondary organic aerosol. Here we show that the ONs with the chemical formula C4H7NO5 are a significant fraction of isoprene-derived ONs, based on chamber experiments and ambient measurements from different sites around the globe. From chamber experiments we found that C4H7NO5 isomers contribute 5%-17% of all measured ONs formed during nighttime and constitute more than 40% of the measured ONs after further daytime oxidation. In ambient measurements C4H7NO5 isomers usually dominate both nighttime and daytime, implying a long residence time compared to C-5 ONs which are removed more rapidly. We propose potential nighttime sources and secondary formation pathways, and test them using a box model with an updated isoprene oxidation scheme.
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4.
  • Darst, B. F., et al. (author)
  • Pathway-Specific Polygenic Risk Scores as Predictors of Amyloid-beta Deposition and Cognitive Function in a Sample at Increased Risk for Alzheimer's Disease
  • 2017
  • In: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 55:2, s. 473-484
  • Journal article (peer-reviewed)abstract
    • Polygenic risk scores (PRSs) have been used to combine the effects of variants with small effects identified by genome-wide association studies. We explore the potential for using pathway-specific PRSs as predictors of early changes in Alzheimer's disease (AD)-related biomarkers and cognitive function. Participants were from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of adults who were cognitively asymptomatic at enrollment and enriched for a parental history of AD. Using genes associated with AD in the International Genomics of Alzheimer's Project's meta-analysis, we identified clusters of genes that grouped into pathways involved in amyloid-beta (A beta) deposition and neurodegeneration: A beta clearance, cholesterol metabolism, and immune response. Weighted pathway-specific and overall PRSs were developed and compared to APOE alone. Mixed models were used to assess whether each PRS was associated with cognition in 1,200 individuals, cerebral A beta deposition measured using amyloid ligand (Pittsburgh compound B) positron emission imaging in 168 individuals, and cerebrospinal fluid A beta deposition, neurodegeneration, and tau pathology in 111 individuals, with replication performed in an independent sample. We found that PRSs including APOE appeared to be driven by the inclusion of APOE, suggesting that the pathway-specific PRSs used here were not more predictive than an overall PRS or APOE alone. However, pathway-specific PRSs could prove to be useful as more knowledge is gained on the genetic variants involved in specific biological pathways of AD.
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5.
  • Langefeld, Carl D., et al. (author)
  • Transancestral mapping and genetic load in systemic lupus erythematosus
  • 2017
  • In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 8
  • Journal article (peer-reviewed)abstract
    • Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 10(-8)), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.
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6.
  • van Meel, Evelien R., et al. (author)
  • Early-life respiratory tract infections and the risk of school-age lower lung function and asthma: a meta-analysis of 150 000 European children
  • 2022
  • In: European Respiratory Journal. - : EUROPEAN RESPIRATORY SOC JOURNALS LTD. - 0903-1936 .- 1399-3003. ; 60:4
  • Journal article (peer-reviewed)abstract
    • Background Early-life respiratory tract infections might affect chronic obstructive respiratory diseases, but conclusive studies from general populations are lacking. Our objective was to examine if children with early-life respiratory tract infections had increased risks of lower lung function and asthma at school age. Methods We used individual participant data of 150 090 children primarily from the EU Child Cohort Network to examine the associations of upper and lower respiratory tract infections from age 6 months to 5 years with forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC, forced expiratory flow at 75% of FVC (FEF75%) and asthma at a median (range) age of 7 (4-15) years. Results Children with early-life lower, not upper, respiratory tract infections had a lower school-age FEV1, FEV1/FVC and FEF75% (z-score range: -0.09 (95% CI -0.14- -0.04) to -0.30 (95% CI -0.36- -0.24)). Children with early-life lower respiratory tract infections had a higher increased risk of school-age asthma than those with upper respiratory tract infections (OR range: 2.10 (95% CI 1.98-2.22) to 6.30 (95% CI 5.64-7.04) and 1.25 (95% CI 1.18-1.32) to 1.55 (95% CI 1.47-1.65), respectively). Adjustment for preceding respiratory tract infections slightly decreased the strength of the effects. Observed associations were similar for those with and without early-life wheezing as a proxy for early-life asthma. Conclusions Our findings suggest that early-life respiratory tract infections affect development of chronic obstructive respiratory diseases in later life, with the strongest effects for lower respiratory tract infections.
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7.
  • Benzinou, Michael, et al. (author)
  • Common nonsynonymous variants in PCSK1 confer risk of obesity.
  • 2008
  • In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 40:8, s. 943-5
  • Journal article (peer-reviewed)abstract
    • Mutations in PCSK1 cause monogenic obesity. To assess the contribution of PCSK1 to polygenic obesity risk, we genotyped tag SNPs in a total of 13,659 individuals of European ancestry from eight independent case-control or family-based cohorts. The nonsynonymous variants rs6232, encoding N221D, and rs6234-rs6235, encoding the Q665E-S690T pair, were consistently associated with obesity in adults and children (P = 7.27 x 10(-8) and P = 2.31 x 10(-12), respectively). Functional analysis showed a significant impairment of the N221D-mutant PC1/3 protein catalytic activity.
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8.
  • Carlsson, Christian J., et al. (author)
  • An evaluation of the interference of hydroxycobalamin with chemistry and co-oximetry tests on nine commonly used instruments
  • 2011
  • In: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 71:5, s. 378-386
  • Journal article (peer-reviewed)abstract
    • The administration of hydroxocobalamin (OHCob), alone or with sodium thiosulfate, is a standard therapy for cyanide poisoning. OHCob is a red chromophore, and its interference with co-oximetric and colorimetric laboratory measurements has been evaluated in a few conflicting reports. The interference of OHCob was investigated in samples spiked with 10 different concentrations of OHCob (0-1500 mg/L). The concentration of 73 different analytes was measured using nine different analysers (ABL 800 Flex, Advia 1800, Advia Centaur Xp, Architect ci8200, Immulite 2500, Konelab 30i, Modular Analytics SWA, Synchron LX 20 and Vitros 5.1). All instruments yielded some results that were affected by OHCob at concentrations equivalent to a single therapeutic dose. Of the 73 different analytes, 64% showed interference on at least one instrument. Of all 187 tests performed, 47% were biased with more than 10%. Interference was generally limited to photometric assays, whereas immunological and ion-selective electrode measurements were unaffected. OHCob present in the blood after treatment for cyanide poisoning interfered with many laboratory assays in an unpredictable way, making some results invalid. Some affected tests are important in the treatment of cyanide poisoning. The interference is not solely due to wavelength, but also to chemical interaction. Without delaying the administration of OHCob, blood should, preferably, be drawn in advance, or, at least, the laboratory should be informed about the OHCob treatment. If the laboratory receives OHCob-containing samples, methods and instruments should be selected to minimize bias, and the manufacturer of the OHCob should recommend relevant precautions to customers in the package insert.
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9.
  • Carlsson, Thomas, et al. (author)
  • Reversal of dyskinesias in an animal model of Parkinson's disease by continuous L-DOPA delivery using rAAV vectors.
  • 2005
  • In: Brain. - : Oxford University Press (OUP). - 1460-2156. ; 128:3, s. 559-569
  • Journal article (peer-reviewed)abstract
    • Dyskinesias are a major complication of long-term l-3,4-dihydroxyphenylalanine (L-DOPA) treatment in Parkinson's disease, and are believed to result from the intermittent and pulsatile supply of L-DOPA. Daily injections of L-DOPA can prime similar abnormal involuntary movements of the limb, orolingual and axial muscles in rats rendered parkinsonian by destruction of the nigrostriatal dopamine (DA) neurons. In this study we used 33 rats with severe nigrostriatal dopamine depletion and showed that in vivo gene transfer of the DA-synthetic enzymes tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) using recombinant adeno-associated virus vectors can provide a constant source of DOPA production locally in the striatum, at a level that is effective in reducing L-DOPA-induced dyskinesias by >85%, and reverse lesion-induced motor impairments. Furthermore, the abnormal expression of DeltaFosB, prodynorphin and preproenkephalin mRNA within the striatal projection neurons normally seen in dyskinetic animals was completely reversed by TH-GCH1 gene transfer. These findings form a strong basis for replacing, or supplementing, conventional systemic L-DOPA therapy by continuous intrastriatal DOPA using in vivo gene transfer in the treatment of patients with advanced Parkinson's disease.
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10.
  • Ennis, G. E., et al. (author)
  • Insulin resistance is related to cognitive decline but not change in CSF biomarkers of Alzheimer's disease in non-demented adults
  • 2021
  • In: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 13:1
  • Journal article (peer-reviewed)abstract
    • Introduction We investigated whether insulin resistance (IR) was associated with longitudinal age-related change in cognition and biomarkers of Alzheimer's disease (AD) pathology and neurodegeneration in middle-aged and older adults who were non-demented at baseline. Methods IR was measured with homeostatic model assessment of insulin resistance (HOMA2-IR). Core AD-related cerebrospinal fluid (CSF) biomarkers and cognition were assessed, respectively, on n = 212 (1 to 5 visits) and n = 1299 (1 to 6 visits). Linear mixed models tested whether HOMA2-IR moderated age-related change in CSF biomarkers and cognition. Linear regressions tested whether HOMA2-IR x apolipoprotein E epsilon 4 allele (APOE epsilon 4) carrier status predicted amyloid beta [A beta] chronicity (estimated duration of amyloid positron emission tomography [PET] positivity) (n = 253). Results Higher HOMA2-IR was associated with greater cognitive decline but not with changes in CSF biomarkers. HOMA2-IR x APOE4 was not related to A beta chronicity but was significantly associated with CSF phosphorylated tau (P-tau)(181)/A beta(42) level. Discussion In non-demented adults IR may not be directly associated with age-related change in AD biomarkers. Additional research is needed to determine mechanisms linking IR to cognitive decline.
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11.
  • Erickson, C. M., et al. (author)
  • KLOTHO heterozygosity attenuates APOE4-related amyloid burden in preclinical AD
  • 2019
  • In: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 92:16
  • Journal article (peer-reviewed)abstract
    • Objective To examine whether the KLOTHO gene variant KL-VS attenuates APOE4-associated beta-amyloid (A beta) accumulation in a late-middle-aged cohort enriched with Alzheimer disease (AD) risk factors. Three hundred nine late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were genotyped to determine KL-VS and APOE4 status and underwent CSF sampling (n = 238) and/or 11C-Pittsburgh compound B (PiB)-PET imaging (n = 183). Covariate-adjusted regression analyses were used to investigate whether APOE4 exerted expected effects on A beta burden. Follow-up regression analyses stratified by KL-VS genotype (i.e., noncarrier vs heterozygous; there were no homozygous individuals) evaluated whether the influence of APOE4 on A beta was different among KL-VS heterozygotes compared to noncarriers. APOE4 carriers exhibited greater A beta burden than APOE4-negative participants. This effect was stronger in CSF (t = -5.12, p < 0.001) compared with PiB-PET (t = 3.93, p < 0.001). In the stratified analyses, this APOE4 effect on A beta load was recapitulated among KL-VS noncarriers (CSF: t = -5.09, p < 0.001; PiB-PET: t = 3.77, p < 0.001). In contrast, among KL-VS heterozygotes, APOE4-positive individuals did not exhibit higher A beta burden than APOE4-negative individuals (CSF: t = -1.03, p = 0.308; PiB-PET: t = 0.92, p = 0.363). These differential APOE4 effects remained after KL-VS heterozygotes and noncarriers were matched on age and sex. In a cohort of at-risk late-middle-aged adults, KL-VS heterozygosity was associated with an abatement of APOE4-associated A beta aggregation, suggesting KL-VS heterozygosity confers protections against APOE4-linked pathways to disease onset in AD.
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12.
  • Henningsson, Anna J., et al. (author)
  • Complement activation in Lyme neuroborreliosis : increased levels of C1q and C3a in cerebrospinal fluid indicate complement activation in the CNS
  • 2007
  • In: Journal of Neuroimmunology. - : Elsevier BV. - 0165-5728 .- 1872-8421. ; 183:1-2, s. 200-207
  • Journal article (peer-reviewed)abstract
    • A strong initial inflammatory response is important in neuroborreliosis. Since complement is a main player in early inflammation, we monitored the concentration and activation of complement in plasma and cerebrospinal fluid from 298 patients, of whom 23 were diagnosed with neuroborreliosis. Using sandwich ELISAs, we found significantly elevated levels of C1q, C4, C3, and C3a in cerebrospinal fluid, but not in plasma, in patients with neuroborreliosis. This finding indicates that complement plays a role in the human immune response in neuroborreliosis, that the immunologic process is compartmentalized to the CNS, and that complement activation may occur via the classical pathway.
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13.
  • Ishikawa, Ryohko, et al. (author)
  • Mapping solar magnetic fields from the photosphere to the base of the corona
  • 2021
  • In: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 7:8
  • Journal article (peer-reviewed)abstract
    • Routine ultraviolet imaging of the Sun’s upper atmosphere shows the spectacular manifestation of solar activity; yet, we remain blind to its main driver, the magnetic field. Here, we report unprecedented spectropolarimetric observations of an active region plage and its surrounding enhanced network, showing circular polarization in ultraviolet (Mg ii h & k and Mn i) and visible (Fe i) lines. We infer the longitudinal magnetic field from the photosphere to the very upper chromosphere. At the top of the plage chromosphere, the field strengths reach more than 300 G, strongly correlated with the Mg ii k line core intensity and the electron pressure. This unique mapping shows how the magnetic field couples the different atmospheric layers and reveals the magnetic origin of the heating in the plage chromosphere.
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14.
  • Jonaitis, Erin M, et al. (author)
  • Measuring longitudinal cognition: Individual tests versus composites.
  • 2019
  • In: Alzheimer's & dementia (Amsterdam, Netherlands). - : Wiley. - 2352-8729. ; 11, s. 74-84
  • Journal article (peer-reviewed)abstract
    • Longitudinal cohort studies of cognitive aging must confront several sources of within-person variability in scores. In this article, we compare several neuropsychological measures in terms of longitudinal error variance and relationships with biomarker-assessed brain amyloidosis (Aβ).Analyses used data from the Wisconsin Registry for Alzheimer's Prevention. We quantified within-person longitudinal variability and age-related trajectories for several global and domain-specific composites and their constituent scores. For a subset with cerebrospinal fluid or amyloid positron emission tomography measures, we examined how Aβ modified cognitive trajectories.Global and theoretically derived composites exhibited lower intraindividual variability and stronger age × Aβ interactions than did empirically derived composites or raw scores from single tests. For example, the theoretical executive function outperformed other executive function scores on both metrics.These results reinforce the need for careful selection of cognitive outcomes in study design, and support the emerging consensus favoring composites over single-test measures.
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16.
  • Parikh, Hemang, et al. (author)
  • TXNIP regulates peripheral glucose metabolism in humans
  • 2007
  • In: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1676. ; 4:5, s. 868-879
  • Journal article (peer-reviewed)abstract
    • Background Type 2 diabetes mellitus ( T2DM) is characterized by defects in insulin secretion and action. Impaired glucose uptake in skeletal muscle is believed to be one of the earliest features in the natural history of T2DM, although underlying mechanisms remain obscure. Methods and Findings We combined human insulin/glucose clamp physiological studies with genome-wide expression profiling to identify thioredoxin interacting protein ( TXNIP) as a gene whose expression is powerfully suppressed by insulin yet stimulated by glucose. In healthy individuals, its expression was inversely correlated to total body measures of glucose uptake. Forced expression of TXNIP in cultured adipocytes significantly reduced glucose uptake, while silencing with RNA interference in adipocytes and in skeletal muscle enhanced glucose uptake, confirming that the gene product is also a regulator of glucose uptake. TXNIP expression is consistently elevated in the muscle of prediabetics and diabetics, although in a panel of 4,450 Scandinavian individuals, we found no evidence for association between common genetic variation in the TXNIP gene and T2DM. Conclusions TXNIP regulates both insulin-dependent and insulin- independent pathways of glucose uptake in human skeletal muscle. Combined with recent studies that have implicated TXNIP in pancreatic beta-cell glucose toxicity, our data suggest that TXNIP might play a key role in defective glucose homeostasis preceding overt T2DM.
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18.
  • Sandholm, Kerstin, et al. (author)
  • Early Immune Responses to Borrelia garinii and Borrelia afzeliiin Lyme Borreliosis : Local Complement Activation in Erythema Migrans and in vitro Studies ofComplement Activation, Phagocytosis and Cytokine Profile
  • Other publication (other academic/artistic)abstract
    • An optimal eradication of spirochetes in Lyme borreliosis depends on the early immune response, including the potent actions of the complement system. We here assessed possible differences between two Borrelia burgdorferi genospecies in their ability to activate complement, and the consequences of complement activation in terms of phagocytosis and induction of cytokines.Early local complement activation was assessed immunohistochemically in skin biopsies from patients with erythema migrans (EM) caused by B. afzelii or B. garinii. Complement activation, phagocytosis and early cytokine and chemokine release were studied in vitro by incubating clinical isolates of B. afzelii (K78 from a human skin biopsy) and B. garinii (LU59 from human cerebrospinal fluid) in human whole blood.B. afzelii and B. garinii were detected in skin biopsies from EM and deposition of C3-fragments and IgG was found adjacent to the spirochetes. In vitro, B. garinii LU59 induced higher complement activation (measured as the generation of C3a and C5b-9), while B. afzelii K78 recruited more factor H. Phagocytosis by granulocytes and monocytes was demonstrated to be largely dependent on complement activation since phagocytosis was substantially reduced by addition of the C3 inhibitor compstatin or a C5a receptor antagonist. The early cytokine and chemokine release in human blood in response to live spirochetes revealed a rapid and pronounced pro-inflammatory response, mainly associated with the Th1- and Th17-types.We conclude that complement is activated locally in the skin in EM, and that B. garinii LU59 activates complement more than B. afzelii K78. Complement activation is pivotal for efficient phagocytosis of Borrelia spirochetes, especially in early infection before specific antibodies are produced. Both B. garinii LU59 and B. afzelii K78 induce proinflammatory cytokines rapidly, but no clear differences were seen between the two genospecies in this respect.
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19.
  • Song, Donguk, et al. (author)
  • Polarization Accuracy Verification of the Chromospheric LAyer SpectroPolarimeter
  • 2022
  • In: Solar Physics. - : Springer Science and Business Media LLC. - 0038-0938 .- 1573-093X. ; 297:10
  • Journal article (peer-reviewed)abstract
    • We have developed an advanced UV spectropolarimeter called Chromospheric LAyer SpectroPolarimeter (CLASP2), aimed at achieving very high accuracy measurements (<0.1% at 3σ) of the linear (Q/I and U/I) and circular (V/I) polarizations of the Mg II h and k lines (280 nm). CLASP2 was launched on board a NASA sounding rocket on April 11, 2019. It successfully detected the full Stokes vector in an active-region plage and in the quiet Sun near the limb across the Mg II h and k lines for the first time. To verify the polarization characteristics of CLASP2, the response matrix is estimated by combining the results obtained from the preflight calibration on the ground, with the results of the inflight calibration acquired at the solar-disk center. We find that the response matrix of CLASP2 in the Mg II h and k lines is notably close to an ideal response matrix, i.e., the scale factor and the crosstalk terms are close to 1 and 0, respectively. Moreover, the uncertainty of each Stokes parameter estimated by the repeatability of the measurements is verified to be within the required tolerance. Based on our investigation, we conclude that CLASP2 achieves 0.1% polarization accuracy at a 3σ3σ level.
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20.
  • Williams, Michael J., et al. (author)
  • Recurrent Sleep Fragmentation Induces Insulin and Neuroprotective Mechanisms in Middle-Aged Flies
  • 2016
  • In: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 8
  • Journal article (peer-reviewed)abstract
    • Lack of quality sleep increases central nervous system oxidative stress and impairs removal of neurotoxic soluble metabolites from brain parenchyma. During aging poor sleep quality, caused by sleep fragmentation, increases central nervous system cellular stress. Currently, it is not known how organisms offset age-related cytotoxic metabolite increases in order to safeguard neuronal survival. Furthermore, it is not understood how age and sleep fragmentation interact to affect oxidative stress protection pathways. We demonstrate sleep fragmentation increases systems that protect against oxidative damage and neuroprotective endoplasmic reticulum molecular chaperones, as well as neuronal insulin and dopaminergic expression in middle-aged Drosophila males. Interestingly, even after sleep recovery the expression of these genes was still upregulated in middle-aged flies. Finally, sleep fragmentation generates higher levels of reactive oxygen species (ROS) in middle-aged flies and after sleep recovery these levels remain significantly higher than in young flies. The fact that neuroprotective pathways remain upregulated in middle-aged flies beyond sleep fragmentation suggests it might represent a strong stressor for the brain during later life.
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