Experimental evidence for temporal uncoupling of brain Aβ deposition and neurodegenerative sequelae

Brain A beta deposition is a key early event in the pathogenesis of Alzheimer ' s disease (AD), but the long presymptomatic phase and poor correlation between A beta deposition and clinical symptoms remain puzzling. To elucidate the dependency of downstream pathologies on A beta, we analyzed the trajectories of cerebral A beta accumulation, A beta seeding activity, and neurofilament light chain (NfL) in the CSF (a biomarker of neurodegeneration) in A beta-precursor protein transgenic mice. We find that A beta deposition increases linearly until it reaches an apparent plateau at a late age, while A beta seeding activity increases more rapidly and reaches a plateau earlier, coinciding with the onset of a robust increase of CSF NfL. Short-term inhibition of A beta generation in amyloid-laden mice reduced A beta deposition and associated glial changes, but failed to reduce A beta seeding activity, and CSF NfL continued to increase although at a slower pace. When short-term or long-term inhibition of A beta generation was started at pre-amyloid stages, CSF NfL did not increase despite some A beta deposition, microglial activation, and robust brain A beta seeding activity. A dissociation of A beta load and CSF NfL trajectories was also found in familial AD, consistent with the view that A beta aggregation is not kinetically coupled to neurotoxicity. Rather, neurodegeneration starts when A beta seeding activity is saturated and before A beta deposition reaches critical (half-maximal) levels, a phenomenon reminiscent of the two pathogenic phases in prion disease. The poor correlation between brain A beta deposition and clinical symptoms in Alzheimer ' s disease remains puzzling. Here, the authors show a temporal dissociation of A beta deposition and neurodegeneration

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

AGN STORM 2: V. Anomalous Behavior of the CIV Light Curve in Mrk 817

An intensive reverberation mapping campaign on the Seyfert 1 galaxy Mrk817 using the Cosmic Origins Spectrograph (COS) on the Hubble Space Telescope (HST) revealed significant variations in the response of the broad UV emission lines to fluctuations in the continuum emission. The response of the prominent UV emission lines changes over a $\sim$60-day duration, resulting in distinctly different time lags in the various segments of the light curve over the 14 months observing campaign. One-dimensional echo-mapping models fit these variations if a slowly varying background is included for each emission line. These variations are more evident in the CIV light curve, which is the line least affected by intrinsic absorption in Mrk817 and least blended with neighboring emission lines. We identify five temporal windows with distinct emission line response, and measure their corresponding time delays, which range from 2 to 13 days. These temporal windows are plausibly linked to changes in the UV and X-ray obscuration occurring during these same intervals. The shortest time lags occur during periods with diminishing obscuration, whereas the longest lags occur during periods with rising obscuration. We propose that the obscuring outflow shields the ultraviolet broad lines from the ionizing continuum. The resulting change in the spectral energy distribution of the ionizing continuum, as seen by clouds at a range of distances from the nucleus, is responsible for the changes in the line response.Comment: 20 pages, 8 figures, submitted to Ap

AGN STORM 2. IV. Swift X-ray and ultraviolet/optical monitoring of Mrk 817

The AGN STORM 2 campaign is a large, multiwavelength reverberation mapping project designed to trace out the structure of Mrk 817 from the inner accretion disk to the broad emission line region and out to the dusty torus. As part of this campaign, Swift performed daily monitoring of Mrk 817 for approximately 15 months, obtaining observations in X-rays and six UV/optical filters. The X-ray monitoring shows that Mrk 817 was in a significantly fainter state than in previous observations, with only a brief flare where it reached prior flux levels. The X-ray spectrum is heavily obscured. The UV/optical light curves show significant variability throughout the campaign and are well correlated with one another, but uncorrelated with the X-rays. Combining the Swift UV/optical light curves with Hubble UV continuum light curves, we measure interband continuum lags, $\tau(\lambda)$, that increase with increasing wavelength roughly following $\tau(\lambda) \propto \lambda^{4/3}$, the dependence expected for a geometrically thin, optically thick, centrally illuminated disk. Modeling of the light curves reveals a period at the beginning of the campaign where the response of the continuum is suppressed compared to later in the light curve - the light curves are not simple shifted and scaled versions of each other. The interval of suppressed response corresponds to a period of high UV line and X-ray absorption, and reduced emission line variability amplitudes. We suggest that this indicates a significant contribution to the continuum from the broad line region gas that sees an absorbed ionizing continuum.Comment: 20 pages, 13 figures, 3 tables, accepted for publication in Ap

AGN STORM 2. I. First results: A Change in the Weather of Mrk 817

We present the first results from the ongoing, intensive, multiwavelength monitoring program of the luminous Seyfert 1 galaxy Mrk 817. While this active galactic nucleus was, in part, selected for its historically unobscured nature, we discovered that the X-ray spectrum is highly absorbed, and there are new blueshifted, broad, and narrow UV absorption lines, which suggest that a dust-free, ionized obscurer located at the inner broad-line region partially covers the central source. Despite the obscuration, we measure UV and optical continuum reverberation lags consistent with a centrally illuminated Shakura–Sunyaev thin accretion disk, and measure reverberation lags associated with the optical broad-line region, as expected. However, in the first 55 days of the campaign, when the obscuration was becoming most extreme, we observe a de-coupling of the UV continuum and the UV broad emission-line variability. The correlation recovered in the next 42 days of the campaign, as Mrk 817 entered a less obscured state. The short C IV and Lyα lags suggest that the accretion disk extends beyond the UV broad-line region. Unified

ARIA digital anamorphosis : Digital transformation of health and care in airway diseases from research to practice

Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.Peer reviewe

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

AGN STORM 2. IV. Swift X-Ray and Ultraviolet/Optical Monitoring of Mrk 817

The AGN STORM 2 campaign is a large, multiwavelength reverberation mapping project designed to trace out the structure of Mrk 817 from the inner accretion disk to the broad emission line region and out to the dusty torus. As part of this campaign, Swift performed daily monitoring of Mrk 817 for approximately 15 months, obtaining observations in X-rays and six UV/optical filters. The X-ray monitoring shows that Mrk 817 was in a significantly fainter state than in previous observations, with only a brief flare where it reached prior flux levels. The X-ray spectrum is heavily obscured. The UV/optical light curves show significant variability throughout the campaign and are well correlated with one another, but uncorrelated with the X-rays. Combining the Swift UV/optical light curves with Hubble Space Telescope UV continuum light curves, we measure interband continuum lags, τ(λ), that increase with increasing wavelength roughly following τ(λ) ∝ λ 4/3, the dependence expected for a geometrically thin, optically thick, centrally illuminated disk. Modeling of the light curves reveals a period at the beginning of the campaign where the response of the continuum is suppressed compared to later in the light curve—the light curves are not simple shifted and scaled versions of each other. The interval of suppressed response corresponds to a period of high UV line and X-ray absorption, and reduced emission line variability amplitudes. We suggest that this indicates a significant contribution to the continuum from the broad-line region gas that sees an absorbed ionizing continuum

AGN STORM 2. VI. Mapping Temperature Fluctuations in the Accretion Disk of Mrk 817

We fit the UV/optical lightcurves of the Seyfert 1 galaxy Mrk 817 to produce maps of the accretion disk temperature fluctuations δ T resolved in time and radius. The δ T maps are dominated by coherent radial structures that move slowly (v ≪ c) inward and outward, which conflicts with the idea that disk variability is driven only by reverberation. Instead, these slow-moving temperature fluctuations are likely due to variability intrinsic to the disk. We test how modifying the input lightcurves by smoothing and subtracting them changes the resulting δ T maps and find that most of the temperature fluctuations exist over relatively long timescales (hundreds of days). We show how detrending active galactic nucleus (AGN) lightcurves can be used to separate the flux variations driven by the slow-moving temperature fluctuations from those driven by reverberation. We also simulate contamination of the continuum emission from the disk by continuum emission from the broad-line region (BLR), which is expected to have spectral features localized in wavelength, such as the Balmer break contaminating the U band. We find that a disk with a smooth temperature profile cannot produce a signal localized in wavelength and that any BLR contamination should appear as residuals in our model lightcurves. Given the observed residuals, we estimate that only ∼20% of the variable flux in the U and u lightcurves can be due to BLR contamination. Finally, we discus how these maps not only describe the data but can make predictions about other aspects of AGN variability

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes