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  • 1
    In: Nature Genetics, Springer Science and Business Media LLC, Vol. 54, No. 12 ( 2022-12), p. 1786-1794
    Abstract: Alzheimer’s disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70% 1 . The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants 2 . Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals—16,036 AD cases and 16,522 controls. Next to variants in TREM2 , SORL1 and ABCA7 , we observed a significant association of rare, predicted damaging variants in ATP8B4 and ABCA1 with AD risk, and a suggestive signal in ADAM10 . Additionally, the rare-variant burden in RIN3, CLU, ZCWPW1 and ACE highlighted these genes as potential drivers of respective AD-genome-wide association study loci. Variants associated with the strongest effect on AD risk, in particular loss-of-function variants, are enriched in early-onset AD cases. Our results provide additional evidence for a major role for amyloid-β precursor protein processing, amyloid-β aggregation, lipid metabolism and microglial function in AD.
    Type of Medium: Online Resource
    ISSN: 1061-4036 , 1546-1718
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 2
    In: Journal of Geophysical Research, American Geophysical Union (AGU), Vol. 113, No. D16 ( 2008-06-10)
    Type of Medium: Online Resource
    ISSN: 0148-0227
    Language: English
    Publisher: American Geophysical Union (AGU)
    Publication Date: 2008
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  • 3
    In: Journal of Geophysical Research: Atmospheres, American Geophysical Union (AGU), Vol. 101, No. D6 ( 1996-04-30), p. 9583-9601
    Abstract: The Cryogenic Limb Array Etalon Spectrometer (CLAES) measured emission from the 792 cm −1 Q branch of CO 2 , from which temperature distributions in the stratosphere and low mesosphere were derived. Here we briefly review the measurement technique, concentrating on aspects that affect the temperature determination. Comparison of many pairs of retrievals at the same location (near 32°N or 32°S) measured on sequential orbits (time separation of 96 min) shows a precision ranging from approximately 0.8 K at 68 mbar to about 3.5 K at 0.2 mbar, which agrees with simulations incorporating random noise and short‐period spacecraft motions. Comparisons of globally analyzed CLAES data with National Meteorological Center (NMC) and U.K. Meteorological Office (UKMO) analyses show general agreement, with CLAES tending to be cooler by about 2 K, except in the tropics and high‐latitude winter conditions. This is supported by comparisons with individual radiosondes and several lidars that indicate that the agreement is within 2 K throughout the profile (except for a narrow layer around 3 mbar). An error analysis also indicates that systematic errors should be roughly 2 K, independent of altitude. The systematic differences at low latitudes appear to be due to tropical waves, which have vertical wavelengths too short to be seen by the TIROS Operational Vertical Sounder (TOVS) instruments. There are no correlative rocketsondes or lidars to help resolve the reasons for the high‐latitude differences. Comparisons with other Upper Atmosphere Research Satellite (UARS) data should shed additional light on this question.
    Type of Medium: Online Resource
    ISSN: 0148-0227
    Language: English
    Publisher: American Geophysical Union (AGU)
    Publication Date: 1996
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  • 4
    In: Pure and Applied Geophysics PAGEOPH, Springer Science and Business Media LLC, Vol. 118, No. 1 ( 1980-3), p. 591-615
    Type of Medium: Online Resource
    ISSN: 0033-4553 , 1420-9136
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 1980
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  • 5
    In: Genome Medicine, Springer Science and Business Media LLC, Vol. 14, No. 1 ( 2022-12)
    Abstract: Alzheimer disease (AD) is a common complex disorder with a high genetic component. Loss-of-function (LoF) SORL1 variants are one of the strongest AD genetic risk factors. Estimating their age-related penetrance is essential before putative use for genetic counseling or preventive trials. However, relative rarity and co-occurrence with the main AD risk factor, APOE -ε4, make such estimations difficult. Methods We proposed to estimate the age-related penetrance of SORL1 -LoF variants through a survival framework by estimating the conditional instantaneous risk combining (i) a baseline for non-carriers of SORL1- LoF variants, stratified by APOE-ε4 , derived from the Rotterdam study ( N = 12,255), and (ii) an age-dependent proportional hazard effect for SORL1- LoF variants estimated from 27 extended pedigrees (including 307 relatives ≥ 40 years old, 45 of them having genotyping information) recruited from the French reference center for young Alzheimer patients. We embedded this model into an expectation-maximization algorithm to accommodate for missing genotypes. To correct for ascertainment bias, proband phenotypes were omitted. Then, we assessed if our penetrance curves were concordant with age distributions of APOE -ε4-stratified SORL1- LoF variant carriers detected among sequencing data of 13,007 cases and 10,182 controls from European and American case-control study consortia. Results SORL1- LoF variants penetrance curves reached 100% (95% confidence interval [99–100%]) by age 70 among APOE -ε4ε4 carriers only, compared with 56% [40–72%] and 37% [26–51%] in ε4 heterozygous carriers and ε4 non-carriers, respectively. These estimates were fully consistent with observed age distributions of SORL1- LoF variant carriers in case-control study data. Conclusions We conclude that SORL1- LoF variants should be interpreted in light of APOE genotypes for future clinical applications.
    Type of Medium: Online Resource
    ISSN: 1756-994X
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 6
    In: Journal of Geophysical Research: Atmospheres, American Geophysical Union (AGU), Vol. 101, No. D6 ( 1996-04-30), p. 9757-9773
    Abstract: Validation studies of multiwavelength Cryogenic Limb Array Etalon Spectrometer (CLAES) observations of stratospheric aerosol are discussed. An error analysis of the CLAES aerosol extinction data is presented. Aerosol extinction precision values are estimated at latitudes and times at which consecutive Upper Atmosphere Research Satellite (UARS) orbits overlap. Comparisons of CLAES aerosol data with theoretical Mie calculations, based upon in situ particle size measurements at Laramie, Wyoming, are presented. CLAES aerosol data are also compared to scaled aerosol extinction measured by the Stratospheric Aerosol and Gas Experiment (SAGE II) and Atmospheric Trace Molecule Spectroscopy (ATMOS) experiments. Observed and calculated extinction spectra, from CLAES, Improved Stratospheric and Mesospheric Sounder (ISAMS), and Halogen Occultation Experiment (HALOE) data, are compared. CLAES extinction data have precisions between 10 and 25%, instrumental biases near 30%, and accuracies between 33 and 43%.
    Type of Medium: Online Resource
    ISSN: 0148-0227
    Language: English
    Publisher: American Geophysical Union (AGU)
    Publication Date: 1996
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  • 7
    Online Resource
    Online Resource
    American Geophysical Union (AGU) ; 1967
    In:  Transactions, American Geophysical Union Vol. 48, No. 1 ( 1967), p. 273-
    In: Transactions, American Geophysical Union, American Geophysical Union (AGU), Vol. 48, No. 1 ( 1967), p. 273-
    Type of Medium: Online Resource
    ISSN: 0002-8606
    Language: English
    Publisher: American Geophysical Union (AGU)
    Publication Date: 1967
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  • 8
    In: Journal of Geophysical Research: Atmospheres, American Geophysical Union (AGU), Vol. 89, No. D4 ( 1984-06-30), p. 5115-5124
    Abstract: The LIMS experiment on NIMBUS 7 used the technique of thermal infrared limb scanning to sound the composition and structure of the upper atmosphere. One of the LIMS channels was spectrally centered at 6.9 μm to measure the vertical profile and global distribution of stratospheric water vapor. This paper describes the characteristics of and data from the water vapor channel and the steps taken to validate results. The mean difference between LIMS measurements and data from 13 balloon under‐flights is about 0.6 ppmv with LIMS mixing ratios biased high with respect to in situ data. This difference is of about the same order as the estimated LIMS accuracy and is less than the sum of the errors for LIMS and the balloon techniques. The precision measured in orbit is 0.2–0.3 ppmv, and the accuracy, based on computer simulations, is estimated to be 20–30% over the range from 50 mbar to about the stratopause. The vertical distribution in the tropics shows the presence of a hygropause where the mixing ratio decreases to a minimum above the tropopause and then increases with altitude. In extratropical regions, the profile is nearly constant with height and has a value of about 5 ppmv. An unexplained diurnal variation exists in the data which is largest at the 1‐mbar level (1–2 ppmv) and virtually nonexistant at 10 mbar. Day values are higher than night. Until this phenomenon is better understood, caution must be used in drawing conclusions about the H 2 O altitude behavior in the upper stratosphere. An anti‐correlation exists in the fine structure of the vertical water and temperature profiles. This is brought about primarily by small temperature errors and should not be taken as real. For this and other reasons, more confidence is placed in zonal mean distributions averaged over several days rather than in single profiles. A zonal mean pressure‐latitude cross section is described for January.
    Type of Medium: Online Resource
    ISSN: 0148-0227
    Language: English
    Publisher: American Geophysical Union (AGU)
    Publication Date: 1984
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  • 9
    Online Resource
    Online Resource
    American Geophysical Union (AGU) ; 1984
    In:  Journal of Geophysical Research: Atmospheres Vol. 89, No. D4 ( 1984-06-30), p. 5141-5146
    In: Journal of Geophysical Research: Atmospheres, American Geophysical Union (AGU), Vol. 89, No. D4 ( 1984-06-30), p. 5141-5146
    Abstract: The Limb Infrared Monitor of the Stratosphere (LIMS) instrument on the NIMBUS 7 spacecraft sensed limb emission profiles for 7 months starting in October 1979. Vertical temperature profiles are inferred from measurements in two CO 2 channels, and constituent profiles are obtained from the O 3 , HNO 3 , NO 2 , and water vapor channels. The line parameters used to calculate transmittances in the retrieval algorithm are presented. Their adequacy for LIMS and for other applications are assessed, and recommendations for future investigations are outlined.
    Type of Medium: Online Resource
    ISSN: 0148-0227
    Language: English
    Publisher: American Geophysical Union (AGU)
    Publication Date: 1984
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  • 10
    In: Journal of Geophysical Research: Atmospheres, American Geophysical Union (AGU), Vol. 89, No. D4 ( 1984-06-30), p. 5179-5190
    Abstract: The LIMS is a six channel limb scanning IR radiometer flying on the NIMBUS 7 spacecraft. It measured radiances from October 24, 1978, to May 28, 1979, from which vertical profiles of temperature, ozone, water vapor, nitrogen dioxide, and nitric acid were determined. Nitric acid (HNO 3 ) plays an important role in stratospheric chemistry, both as reservoir and as sink for the nitrogen compounds and because of its relationship to the hydroxyl radical. This paper describes the validation of the HNO 3 results, beginning with an outline of the measurements and data reduction leading to the retrievals. The error sources due to instrumental effects and data reduction are described, and their effects on the results are calculated. The predicted random errors are shown to be somewhat larger than the observed values of ∼0.10 ppbv. The LIMS results are within 20% of a set of 15 correlative balloon‐borne measurements, obtained with several techniques over a range of season, latitude, and pressure between 100 and 20 mbar, the region of largest HNO 3 mixing ratio. This is about the accuracy of the correlative measurements. The percent differences are larger at altitudes above 10 mbar. LIMS results agree with earlier measurements at all but the highest levels. Total overburdens above 200 mbar calculated from LIMS agree with those measured spectroscopically from aircraft. LIMS and other HNO 3 measurements show similar agreement with model predictions. The consistency suggests that the major LIMS error sources are reasonably well understood. The HNO 3 /NO 2 ratio also leads to reasonable OH concentrations. The global distribution of HNO 3 in November shows strong latitudinal variation at the altitude of the maximum, with a large build up over the northern hemisphere pole at ∼40 mbar, but lower values over the southern pole. This reverses by early northern spring. Some characteristics and limits on the data are noted, but the LIMS HNO 3 determinations are usually of comparable accuracy to other determinations. These results provide a valuable addition to our knowledge of the distributions of trace gases in the stratosphere. By themselves, but especially in conjunction with the LIMS measurements of temperature, ozone, water vapor, and nitrogen dioxide, they form the basis for a wide range of atmospheric studies.
    Type of Medium: Online Resource
    ISSN: 0148-0227
    Language: English
    Publisher: American Geophysical Union (AGU)
    Publication Date: 1984
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