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| 2. |
- Coley, Nicola, et al.
(författare)
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Plasma p-tau181 as an outcome and predictor of multidomain intervention effects: a secondary analysis of a randomised, controlled, dementia prevention trial
- 2024
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Ingår i: The Lancet Healthy Longevity. - 2666-7568. ; 5:2
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Tidskriftsartikel (refereegranskat)abstract
- Background: It is unknown whether multidomain interventions, which might preserve late-life cognition, affect Alzheimer's disease pathology. Previous studies measured cerebrospinal fluid and imaging Alzheimer's disease biomarkers in small subsamples of multidomain trial participants. Newly developed assays enable the measurement of blood-based Alzheimer's disease biomarkers in larger samples. We aimed to assess whether plasma tau phosphorylated at threonine 181 (p-tau181) was able to detect or predict 3-year multidomain intervention effects. Methods: This is a secondary analysis of the randomised, controlled, Multidomain Alzheimer Prevention Trial (MAPT) testing a 3-year multidomain intervention, omega-3 fatty acid supplementation, or both versus placebo, in individuals aged 70 years and older in 13 memory centres in France and Monaco. Plasma p-tau181 was measured in stored blood samples in a subsample of 527 participants on an intention-to-treat basis. Changes in cognitive score were calculated as a composite measure using the average of Z scores for the following tests: Mini Mental State Examination orientation items, Free and Cued Selective Reminding Test (sum of free and total recall scores), category fluency, and Digit Symbol Substitution Test. Intervention effects on 3-year change in p-tau181 concentration were estimated by use of a linear mixed model with centre-specific random intercepts. Findings: Recruitment took place between May 30, 2008, and Feb 24, 2011. Median baseline plasma p-tau181 was 8·8 pg/mL (IQR 6·7–11·9) in the total sample, and significantly higher in older individuals, men, APOE ε4 carriers, and participants with renal dysfunction or a positive PET amyloid scan. During 3-year follow-up, individuals with raised baseline p-tau181 underwent greater cognitive decline (eg, mean difference in 3-year change on the composite cognitive score between control group participants with normal and abnormal baseline levels of p-tau was −0·34 [effect size −0·52; 95% CI −0·61 to 0·07] in the fully adjusted model using a 12·4 pg/mL cutoff for abnormal baseline p-tau181), but there were no intervention effects on change in p-tau181 either in this subgroup or the total population, and no effect on cognitive change in individuals with raised baseline p-tau181 (eg, in the fully adjusted model using the 12·4 pg/mL cutoff for p-tau181 abnormality, the mean difference [95% CI] in this subgroup in 3-year decline on the composite cognitive score between the control group and the multidomain + omega-3 group, the omega-3 group, and the multidomain intervention group, was, respectively: 0·13 [−0·21 to 0·47], 0·03 [−0·30 to 0·36], and 0·10 [−0·26 to 0·46]). Surprisingly, individuals with raised baseline p-tau181 showed a decrease in p-tau181 during follow-up (eg, unadjusted mean [95% CI] 3-year change was −3·01 pg/mL (−4·45 to −1·56) in control group subjects with abnormal baseline p-tau181 [using the 12·4 pg/mL abnormal p-tau cutoff]). Interpretation: Our results support the utility of p-tau181 as a prognostic biomarker, but it did not predict or detect intervention effects in this study. Further investigation of its usefulness as a prevention trial outcome measure is required.
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| 3. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 4. |
- Gandouin, Emmanuel, et al.
(författare)
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Past environment and climate changes at the last interglacial/glacial transition (Les Echets, France) inferred from subfossil chironomids (Insecta)
- 2007
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Ingår i: Comptes rendus Geoscience. - : Elsevier BV. - 1631-0713 .- 1778-7025. ; 339:5, s. 337-346
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Tidskriftsartikel (refereegranskat)abstract
- Subfossil chironomid assemblages spanning the last Interglacial/Glacial transition at Les Echets (France) highlight the environmental and climatic changes that took place at this crucial period. The Early Eemian warming is marked by increased percentages of warm water taxa and decreased percentages of coldwater taxa. In the Middle Eemian, a lowering in water level is indicated by a rise of littoral taxa. In the Late Eemian, chironomids indicate anoxic deep waters and rise of water level, probably induced by increased rainfall. Melisey I and II and the beginning of the glacial period are marked by the reappearance of coldwater taxa, lower percentages of warmwater taxa, and dominance of littoral taxa, probably correlated with lower water level and climate aridity. St Germain I and II are marked by higher percentages of warmwater taxa, lower percentages, or absence of both coldwater and littoral taxa.
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| 5. |
- Pearce, Elena A., et al.
(författare)
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Substantial light woodland and open vegetation characterized the temperate forest biome before Homo sapiens
- 2023
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Ingår i: Science Advances. - 2375-2548. ; 9:45
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Tidskriftsartikel (refereegranskat)abstract
- The extent of vegetation openness in past European landscapes is widely debated. In particular, the temperate forest biome has traditionally been defined as dense, closed-canopy forest; however, some argue that large herbivores maintained greater openness or even wood-pasture conditions. Here, we address this question for the Last Interglacial period (129,000–116,000 years ago), before Homo sapiens–linked megafauna declines and anthropogenic landscape transformation. We applied the vegetation reconstruction method REVEALS to 96 Last Interglacial pollen records. We found that light woodland and open vegetation represented, on average, more than 50% cover during this period. The degree of openness was highly variable and only partially linked to climatic factors, indicating the importance of natural disturbance regimes. Our results show that the temperate forest biome was historically heterogeneous rather than uniformly dense, which is consistent with the dependency of much of contemporary European biodiversity on open vegetation and light woodland.
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| 6. |
- Peterlongo, Paolo, et al.
(författare)
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FANCM c.5791C>T nonsense mutation (rs144567652) induces exon skipping, affects DNA repair activity and is a familial breast cancer risk factor.
- 2015
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 24:18, s. 5345-5355
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Tidskriftsartikel (refereegranskat)abstract
- Numerous genetic factors that influence breast cancer risk are known. However, approximately two-thirds of the overall familial risk remain unexplained. To determine whether some of the missing heritability is due to rare variants conferring high to moderate risk, we tested for an association between the c.5791C>T nonsense mutation (p.Arg1931*; rs144567652) in exon 22 of FANCM gene and breast cancer. An analysis of genotyping data from 8635 familial breast cancer cases and 6625 controls from different countries yielded an association between the c.5791C>T mutation and breast cancer risk [odds ratio (OR) = 3.93 (95% confidence interval (CI) = 1.28-12.11; P = 0.017)]. Moreover, we performed two meta-analyses of studies from countries with carriers in both cases and controls and of all available data. These analyses showed breast cancer associations with OR = 3.67 (95% CI = 1.04-12.87; P = 0.043) and OR = 3.33 (95% CI = 1.09-13.62; P = 0.032), respectively. Based on information theory-based prediction, we established that the mutation caused an out-of-frame deletion of exon 22, due to the creation of a binding site for the pre-mRNA processing protein hnRNP A1. Furthermore, genetic complementation analyses showed that the mutation influenced the DNA repair activity of the FANCM protein. In summary, we provide evidence for the first time showing that the common p.Arg1931* loss-of-function variant in FANCM is a risk factor for familial breast cancer.
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| 8. |
- Ponel, Philippe, et al.
(författare)
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Novel insights from coleopteran and pollen evidence into the Lateglacial/Holocene transition in Aubrac, French Massif Central
- 2016
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Ingår i: Palaeogeography, Palaeoclimatology, Palaeoecology. - : Elsevier BV. - 0031-0182. ; 463, s. 83-102
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study is to describe the environmental and climate changes that occurred in the mountains of Aubrac at the transition between the Lateglacial and the Holocene, from a comparative analysis of fossil Coleoptera and pollen, and a series of 23 14C dates. The changes affecting the ecological categories of Coleoptera lead to a division of the sequence into 5 beetle assemblage zones (BAZ): the lowermost BAZ A is characterized by extremely poor assemblages (periglacial environment); BAZ B (Oldest Dryas and Lateglacial Interstadial) is marked by regular occurrences of taxa associated with open environments, aquatic taxa associated with running and highly oxygenated water, and cold adapted taxa with relatively low numbers; BAZ C (Younger Dryas) corresponds to two important events: a particular abundance of cold adapted taxa and a marked decrease of running water taxa, beetles associated with herbaceous vegetation and open environments are also well represented; BAZ D (Early Holocene) corresponds to the total disappearance of cold adapted taxa; the transition BAZ C/BAZ D is marked also by a dramatic peak of running water taxa; the uppermost BAZ E (Early/Mid Holocene) is marked by a total absence of running water taxa which are replaced by standing water or taxa tolerant of a range of water conditions, a particular abundance of wetland taxa, and taxa associated with herbaceous vegetation and open environments. Beetle and pollen data suggest that the harsh climatic conditions prevailing in the Aubrac mountains did not allow warm dependent fauna and trees to establish during the Lateglacial Interstadial, at least in the Roustières region, and that wide open landscapes occupied the plateau at that time. The Older Dryas, a cold spell previously recorded at La Taphanel (Cantal), is not visible in the Roustières record, probably because of the higher altitude at Roustières, whereas the Younger Dryas is strongly expressed. During the Holocene, concordant beetles and pollen data enable to reconstruct the rapid recolonization of the plateau by mesophilous trees (Ulmus, Quercus), suggesting the possible presence of refugia to the southern slopes of the Aubrac plateau. Insect/pollen comparisons provide evidence for hydrological changes in the former lake of Roustières and suggest that lacustrine water level changes often used as indicator of precipitation regime changes should be taken with caution.
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| 9. |
- Schrijver, Lieske H, et al.
(författare)
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Oral contraceptive use and ovarian cancer risk for BRCA1/2 mutation carriers : an international cohort study
- 2021
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Ingår i: American Journal of Obstetrics and Gynecology. - : Elsevier BV. - 1097-6868 .- 0002-9378. ; 225:1, s. 1-51
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Ovarian cancer risk in BRCA1 and BRCA2 mutation carriers has been shown to decrease with longer duration of oral contraceptive preparations (OCPs) use. While the effects of OCPs in the general population are well established (∼50% reduction), the estimated risk reduction in mutation carriers is much less precise due to potential bias and small sample sizes. In addition, only a few studies have examined the associations between duration of use, time since last use, starting age, and calendar year of start with risk of ovarian cancer.OBJECTIVE(S): To investigate in more detail the associations between various characteristics of OCP use and risk of ovarian cancer, to provide health care providers and carriers with better risk estimates.STUDY DESIGN: In this international retrospective study, ovarian cancer risk associations were assessed using OCP data on 3,989 BRCA1 and 2,445 BRCA2 mutation carriers. Age-dependent weighted Cox regression analyses were stratified by study and birth cohort and included breast cancer diagnosis as covariate. To minimize survival bias, analyses were left-truncated at 5 years before baseline questionnaire. Separate analysis were conducted for each of the aspects of OCP use and in a multivariate analysis including all these aspects. In addition, the analysis of duration of OCP use was stratified by recency of use.RESULTS: OCPs were less often used by mutation carriers who were diagnosed with ovarian cancer (Ever use: BRCA1 58.6%, BRCA2 53.5%) than by unaffected carriers (Ever use: BRCA1 88.9%, BRCA2 80.7%. The median duration of use was 7 years for both BRCA1 and BRCA2 carriers who developed ovarian cancer, and 9 and 8 years for ovarian cancer unaffected BRCA1 and BRCA2 carriers, respectively. For BRCA1 mutation carriers univariate analyses showed that both a longer duration of OCP use and more recent use of OCPs were inversely associated with risk of ovarian cancer. However, in multivariate analyses including duration of use, age at first use and time since last use, duration of use proved to be the prominent protective factor (compared with <5 years, 5-9 years HR=0.67;95%CI 0.40-1.12, 10+ years HR=0.37;95%CI 0.19-0.73; ptrend=0.008). The inverse association between duration of use and ovarian cancer risk persisted for more than 15 years (Duration of ≥10 years; BRCA1: <15 years since last use: HR=0.24 95%CI 0.14-0.43, 15+ years since last use: HR 0.56 95%CI 0.18-0.59). Univariate results for BRCA2 mutation carriers were similar, but due to limit sample size inconclusive.CONCLUSION: For BRCA1 mutation carriers, a longer duration of OCP use is associated with a greater reduction of ovarian cancer risk and the protection is long term.
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| 10. |
- Veres, Daniel, et al.
(författare)
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Climate-driven changes in lake conditions during late MIS 3 and MIS 2: a high-resolution geochemical record from Les Echets, France
- 2009
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Ingår i: Boreas. - : Wiley. - 1502-3885 .- 0300-9483. ; 38:2, s. 230-243
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Tidskriftsartikel (refereegranskat)abstract
- Veres, D., Lallier-Verges, E., Wohlfarth, B., Lacourse, T., KEravis, D., Bjorck, S., Preusser, F., Andrieu-Ponel, V. & Ampel, L.: Climate-driven changes in lake conditions during late MIS 3 and MIS 2: a high-resolution geochemical record from Les Echets, France. Boreas, 10.1111/j.1502-3885.2008.00066.x. ISSN 0300-9483. A new set of geochemical data obtained from a long sediment sequence from the Les Echets basin provides a new record of palaeoenvironmental change for western Europe. The sequence covers the late part of Marine Isotope Stage (MIS) 3 and MIS 2 (c. 46.1-15.0 cal. kyr BP) and extends over 30 m of sediment, allowing for high sampling resolution. Distinct cyclic fluctuations in aquatic productivity proxies suggest a tempo of environmental change at Les Echets that resembles the one established for Dansgaard-Oeschger cycles and Heinrich events. Increases in organic carbon are paralleled by high hydrogenous contents and enriched delta C-13(org) and C-org/N-tot ratios, implying a mixture of aquatic and land-derived constituents. The stable isotope values are directly linked to primary aquatic productivity and the input of terrestrial organic matter, enriched during warm, productive, periods, and drastically depleted during cold periods, particularly Heinrich events. Phases of relatively high productivity correlate with Dansgaard-Oeschger interstadials 8-2, while Heinrich events 3 and 2 are also clearly delineated by distinct lithological horizons with very low organic contents, high dry densities and enhanced organic matter oxidation. A large hiatus occurring about the time of Heinrich event 4 suggests that the cold and dry climate reconstructed for this event in the North Atlantic region also greatly affected Les Echets and its catchment.
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| 11. |
- Veres, Daniel, et al.
(författare)
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The lithostratigraphy of the Les Echets basin, France: tentative correlation between cores
- 2007
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Ingår i: Boreas. - 1502-3885. ; 36, s. 326-340
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Tidskriftsartikel (refereegranskat)abstract
- Two new long sediment cores (EC1 and EC3), recovered from different locations within the infilled basin at Les Echets, France, provide a new high-resolution record of terrestrial and lacustrine responses to climatic changes during Marine Isotope Stages (MIS) 3 and 2. The lithologies of the cores are described in detail and correlated with each other by stratigraphic marker horizons, fluctuations in organic matter and AMS radiocarbon ages. The tentative correlation of the new cores to those described and analysed by de Beaulieu et al. (1980) and de Beaulieu & Reille (1984a) provides a preliminary chronostratigraphic framework. Sedimentation during MIS3 started with accumulation of sands and silts and was followed by alternating gyttja and clayey gyttja silts. Exceptionally high sedimentation rates during MIS2 led to the infilling of the basin. Alternating organic-rich and minerogenicrich sediments appear to coincide with changes in pollen assemblages (de Beaulieu & Reille 1984a) and suggest that millennial-scale climatic changes controlled lake productivity and catchment stability during most of MIS3.
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| 13. |
- Wohlfarth, Barbara, et al.
(författare)
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Rapid ecosystem response to abrupt climate changes during the last glacial period in western Europe, 40-16 ka
- 2008
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Ingår i: Geology. - 0091-7613 .- 1943-2682. ; 36:5, s. 407-410
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Tidskriftsartikel (refereegranskat)abstract
- We present a high-resolution and independently dated multiproxy lake sediment record from the paleolake at Les Echets in southeastern France that displays synchronous changes in independent limnic and terrestrial ecosystem proxies, in concert with millennial-scale climate oscillations during the last glacial period. Distinct lake-level fluctuations, low lake organic productivity, and open, treeless vegetation indicate cold and dry conditions in response to Heinrich events. Alternating phases of higher and low lake organic productivity, stratified surface waters and long-lasting lake ice cover, decreased or increased catchment erosion, and tree-dominated or herb-dominated vegetation resemble Dansgaard-Oeschger interstadial-stadial variability. Transitions between different ecological states occurred in as little as 40-230 yr and seem to have been controlled by the position of the Polar Front. Ecosystem response after 30 ka suggests that local climate conditions became more important. Our results demonstrate that all parts of the terrestrial system responded to the abrupt and dramatic climatic changes associated with Dansgaard-Oeschger and Heinrich events, and that regional factors modulated ecosystem response.
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