| 1. |
- Vogel, Jacob W., et al.
(författare)
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Four distinct trajectories of tau deposition identified in Alzheimer’s disease
- 2021
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27:5, s. 871-881
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These ‘subtypes’ were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of ‘typical AD’ and a revisiting of tau pathological staging. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
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| 2. |
- Zhou, XP, et al.
(författare)
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Non-coding variability at the APOE locus contributes to the Alzheimer's risk
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3310-
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Tidskriftsartikel (refereegranskat)abstract
- Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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| 8. |
- Sitar, R J, et al.
(författare)
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Multi-instrument analysis of the ionospheric signatures of a hot flow anomaly occurring on July 24, 1996
- 1998
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Ingår i: JOURNAL OF GEOPHYSICAL RESEARCH-SPACE PHYSICS. ; 103, s. 23357-23372
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Tidskriftsartikel (refereegranskat)abstract
- We present the analysis of a coordinated set of observations from the POLAR ultraviolet imager (UVI), ground magnetometers, incoherent scatter radar, solar wind monitors, and the DMSP satellite, focused on a traveling convection vortex (TCV) event on July 24, 1996. Starting at approximately 1036 UT, ground magnetometers in Greenland and eastern Canada observe pulsations consistent with the passing overhead of a series of TCV field-aligned current pairs. Azimuthal scans by the Sondrestrom incoherent scatter radar located near Kangerlussuaq (formerly Sondrestrom), Greenland, at this time show strong modulation in the strength and direction of ionospheric plasma flow. The magnetometer pulsations grow in magnitude over the next hour, peaking in intensity at 1137 UT. Images from the UVI instrument show a localized intensification of auroral emissions over central and western Greenland at 1139 UT. Subsequent images show the intensification grow in strength and propagate westward (tailward) until approximately 1158 UT, at which time the intensification fades, These observations are consistent with the westward passage of four pairs of TCVs over central Greenland. The intensification of auroral emissions at 1139 UT is associated with the leading vortex of the fourth TCV pair, thought to be the result of an upward field-aligned current. The modulated flow observed by the radar is the result of the strong electric fields associated with the field-aligned current systems responsible for the impulsive TCV as they pass through the field of view of the radar. Measurements taken in the solar wind by the Wind spacecraft suggest that a pressure change triggers the onset of TCV activity. A subsequent sudden change in the orientation of the interplanetary magnetic field produces a hot flow anomaly which forms at the bow shock. We believe that the interaction of the hot flow anomaly with the magnetopause intensified the fourth TCV pair and. produced the associated auroral brightening. DMSP particle data indicate that the TCVs occur on field lines which map to the boundary plasma sheet-low latitude boundary layer interface. The ground observations associated with the hot flow anomaly are the first of their kind and provide a mechanism to tie an interplanetary magnetic field orientation change into the existing theory that TCVs result from a deformation of the magnetopause.
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| 9. |
- Cumnock, J. A., et al.
(författare)
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Interplanetary magnetic field control of theta aurora development
- 2002
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Ingår i: Journal of Geophysical Research. - : American Geophysical Union (AGU). - 0148-0227 .- 2156-2202. ; 107:A7
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Tidskriftsartikel (refereegranskat)abstract
- [1] We ascertain the influence of the B-y component of the interplanetary magnetic field (IMF) on theta aurora evolution. During most cases where a transpolar arc is observed to move across the polar region, and form a theta aurora, there are brief (minutes) southward excursions of IMF B-z, however northward IMF is required prior to theta aurora formation. Observations show that theta aurora can form during strictly northward IMF with its motion consistent with a change in sign of IMF B-y. It is important to note that since transpolar arcs can persist for 20-30 min after the IMF turns southward, errors will occur in assigning instantaneous IMF conditions to snapshots'' of particular auroral patterns. We consider the entire evolution of the theta aurora and the changing IMF conditions. The influence of IMF B-y is best illustrated by examples which occur during steady northward IMF as compared to times when the IMF is northward on average. We show examples, provided by the Polar UV imager, when the IMF is steady northward. For one case, DMSP F13 and F14 provide in situ measurements of precipitating particles, ionospheric plasma flows and ion density. This unique data set enables us to analyze in detail the evolution of a theta aurora, in one case crossing the entire polar region. No sign change in B-z is needed for theta aurora formation.
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| 10. |
- Ogony, Joshua, et al.
(författare)
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Towards defining morphologic parameters of normal parous and nulliparous breast tissues by artificial intelligence
- 2022
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Ingår i: Breast Cancer Research. - : BMC. - 1465-5411 .- 1465-542X. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Breast terminal duct lobular units (TDLUs), the source of most breast cancer (BC) precursors, are shaped by age-related involution, a gradual process, and postpartum involution (PPI), a dramatic inflammatory process that restores baseline microanatomy after weaning. Dysregulated PPI is implicated in the pathogenesis of postpartum BCs. We propose that assessment of TDLUs in the postpartum period may have value in risk estimation, but characteristics of these tissues in relation to epidemiological factors are incompletely described. Methods Using validated Artificial Intelligence and morphometric methods, we analyzed digitized images of tissue sections of normal breast tissues stained with hematoxylin and eosin from donors <= 45 years from the Komen Tissue Bank (180 parous and 545 nulliparous). Metrics assessed by AI, included: TDLU count; adipose tissue fraction; mean acini count/TDLU; mean dilated acini; mean average acini area; mean "capillary" area; mean epithelial area; mean ratio of epithelial area versus intralobular stroma; mean mononuclear cell count (surrogate of immune cells); mean fat area proximate to TDLUs and TDLU area. We compared epidemiologic characteristics collected via questionnaire by parity status and race, using a Wilcoxon rank sum test or Fishers exact test. Histologic features were compared between nulliparous and parous women (overall and by time between last birth and donation [recent birth: <= 5 years versus remote birth: > 5 years]) using multivariable regression models. Results Normal breast tissues of parous women contained significantly higher TDLU counts and acini counts, more frequent dilated acini, higher mononuclear cell counts in TDLUs and smaller acini area per TDLU than nulliparas (all multivariable analyses p < 0.001). Differences in TDLU counts and average acini size persisted for > 5 years postpartum, whereas increases in immune cells were most marked <= 5 years of a birth. Relationships were suggestively modified by several other factors, including demographic and reproductive characteristics, ethanol consumption and breastfeeding duration. Conclusions Our study identified sustained expansion of TDLU numbers and reduced average acini area among parous versus nulliparous women and notable increases in immune responses within five years following childbirth. Further, we show that quantitative characteristics of normal breast samples vary with demographic features and BC risk factors.
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| 11. |
- Cumnock, Judy, et al.
(författare)
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POLAR UVI Observations of Auroral Oval Intensifications During a Transpolar Arc Event on December 7, 1996
- 2000
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- The evolution of the northern hemisphere aurora is examined during a time when the IMF makes three brief southward excursions after a change in the sign of By during an extended period of northward IMF. POLAR UVI provides images of the aurora while DMSP F13 and F14 provide in situ measurements of precipitating particles, ionospheric plasma flows and ion density. Three different intensifications located in the nightside auroral oval occur during northward turnings of the IMF after brief periods of southward IMF. Spatial expansion, intensity of emissions and their duration are related to the length of time the IMF is southward prior to the northward turning. Thus the longer the period of enhanced magnetospheric convection the more intense the ionospheric response. Observations of a transpolar arc indicate that when the transpolar arc reaches highest latitudes it is located on a spatially narrow region of closed field lines, which extends along the noon-midnight meridian. UV observations indicate a connection between the transpolar arc and the nightside auroral enhancements. Precipitating particles associated with both features are attributed to a plasma sheet boundary layer source in the magnetotail implying a magnetospheric connection between the transpolar arc and the nightside auroral oval intensification.
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| 12. |
- Fonseca, Gregory J, et al.
(författare)
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Diverse motif ensembles specify non-redundant DNA binding activities of AP-1 family members in macrophages.
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Mechanisms by which members of the AP-1 family of transcription factors play non-redundant biological roles despite recognizing the same DNA sequence remain poorly understood. To address this question, here we investigate the molecular functions and genome-wide DNA binding patterns of AP-1 family members in primary and immortalized mouse macrophages. ChIP-sequencing shows overlapping and distinct binding profiles for each factor that were remodeled following TLR4 ligation. Development of a machine learning approach that jointly weighs hundreds of DNA recognition elements yields dozens of motifs predicted to drive factor-specific binding profiles. Machine learning-based predictions are confirmed by analysis of the effects of mutations in genetically diverse mice and by loss of function experiments. These findings provide evidence that non-redundant genomic locations of different AP-1 family members in macrophages largely result from collaborative interactions with diverse, locus-specific ensembles of transcription factors and suggest a general mechanism for encoding functional specificities of their common recognition motif.
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| 13. |
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| 14. |
- Germany, G A, et al.
(författare)
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Remote determination of auroral energy characteristics during substorm activity
- 1997
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Ingår i: Geophysical Research Letters. - 0094-8276 .- 1944-8007. ; 24, s. 995-998
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Tidskriftsartikel (refereegranskat)abstract
- Ultraviolet auroral images from the Ultraviolet Imager (UVI) onboard the POLAR satellite can be used as quantitative remote diagnostics of the auroral regions, yielding estimates of incident energy characteristics, compositional changes, and other higher order data products. Here incident energy estimates derived from UVI are compared with in situ measurements of the same parameters from an overflight by the DMSP F12 satellite coincident with the UVI image times during substorm activity occurring on May 19, 1996. This event was simultaneously observed by WIND, GEOTAIL, INTERBALL, DMSP and NOAA spacecraft as well as by POLAR.
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| 15. |
- Link, Verena M, et al.
(författare)
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Analysis of Genetically Diverse Macrophages Reveals Local and Domain-wide Mechanisms that Control Transcription Factor Binding and Function.
- 2018
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Ingår i: Cell. - Cambridge, United States : Cell Press. - 0092-8674 .- 1097-4172. ; 173:7, s. 1796-1809.e17
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Tidskriftsartikel (refereegranskat)abstract
- Non-coding genetic variation is a major driver of phenotypic diversity and allows the investigation of mechanisms that control gene expression. Here, we systematically investigated the effects of >50 million variations from five strains of mice on mRNA, nascent transcription, transcription start sites, and transcription factor binding in resting and activated macrophages. We observed substantial differences associated with distinct molecular pathways. Evaluating genetic variation provided evidence for roles of ∼100 TFs in shaping lineage-determining factor binding. Unexpectedly, a substantial fraction of strain-specific factor binding could not be explained by local mutations. Integration of genomic features with chromatin interaction data provided evidence for hundreds of connected cis-regulatory domains associated with differences in transcription factor binding and gene expression. This system and the >250 datasets establish a substantial new resource for investigation of how genetic variation affects cellular phenotypes.
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| 16. |
- Oishi, Yumiko, et al.
(författare)
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SREBP1 Contributes to Resolution of Pro-inflammatory TLR4 Signaling by Reprogramming Fatty Acid Metabolism
- 2017
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Ingår i: Cell Metabolism. - Cambridge, MA, United States : Cell Press. - 1550-4131 .- 1932-7420. ; 25:2, s. 412-427
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Tidskriftsartikel (refereegranskat)abstract
- Macrophages play pivotal roles in both the induction and resolution phases of inflammatory processes. Macrophages have been shown to synthesize anti-inflammatory fatty acids in an LXR-dependent manner, but whether the production of these species contributes to the resolution phase of inflammatory responses has not been established. Here, we identify a biphasic program of gene expression that drives production of anti-inflammatory fatty acids 12-24 hr following TLR4 activation and contributes to downregulation of mRNAs encoding pro-inflammatory mediators. Unexpectedly, rather than requiring LXRs, this late program of anti-inflammatory fatty acid biosynthesis is dependent on SREBP1 and results in the uncoupling of NFκB binding from gene activation. In contrast to previously identified roles of SREBP1 in promoting production of IL1β during the induction phase of inflammation, these studies provide evidence that SREBP1 also contributes to the resolution phase of TLR4-induced gene activation by reprogramming macrophage lipid metabolism.
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| 17. |
- Sherman, Mark E., et al.
(författare)
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Serum hormone levels and normal breast histology among premenopausal women
- 2022
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Ingår i: Breast Cancer Research and Treatment. - New York, NY, United States : Springer. - 0167-6806 .- 1573-7217. ; 194, s. 149-158
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Breast terminal duct lobular units (TDLUs) are the main source of breast cancer (BC) precursors. Higher serum concentrations of hormones and growth factors have been linked to increased TDLU numbers and to elevated BC risk, with variable effects by menopausal status. We assessed associations of circulating factors with breast histology among premenopausal women using artificial intelligence (AI) and preliminarily tested whether parity modifies associations.Methods Pathology AI analysis was performed on 316 digital images of H&E-stained sections of normal breast tissues from Komen Tissue Bank donors ages ≤ 45 years to assess 11 quantitative metrics. Associations of circulating factors with AI metrics were assessed using regression analyses, with inclusion of interaction terms to assess effect modification.Results Higher prolactin levels were related to larger TDLU area (p<0.001) and increased presence of adipose tissue proximate to TDLUs (p<0.001), with less significant positive associations for acini counts (p = 0.012), dilated acini (p = 0.043), capillary area (p = 0.014), epithelial area (p = 0.007), and mononuclear cell counts (p = 0.017). Testosterone levels were associated with increased TDLU counts (p<0.001), irrespective of parity, but associations differed by adipose tissue content. AI data for TDLU counts generally agreed with prior visual assessments.Conclusion Among premenopausal women, serum hormone levels linked to BC risk were also associated with quantitative features of normal breast tissue. These relationships were suggestively modified by parity status and tissue composition. We conclude that the microanatomic features of normal breast tissue may represent a marker of BC risk.
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| 18. |
- Allgulander, C, et al.
(författare)
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A non-inferiority comparison of duloxetine and venlafaxine in the treatment of adult patients with generalized anxiety disorder
- 2008
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Ingår i: Journal of psychopharmacology (Oxford, England). - : SAGE Publications. - 0269-8811 .- 1461-7285. ; 22:4, s. 417-425
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Tidskriftsartikel (refereegranskat)abstract
- The present study is a non-inferiority comparison of duloxetine 60— 120 mg/day and venlafaxine extended-release (XR) 75—225 mg/day for the treatment of adults with generalized anxiety disorder (GAD). The non-inferiority test was a prespecified plan to pool data from two nearly identical 10-week, multicentre, randomized, placebo-controlled, double-blind studies of duloxetine 60-120 mg/day and venlafaxine 75—225 mg/ day for the treatment of GAD. An independent expert consensus panel provided six statistical and clinical criteria for determining non-inferiority between treatments. Response was defined as ≥50% reduction in Hamilton Anxiety Rating Scale (HAMA) total score. In the pooled sample, patients were randomly assigned to duloxetine ( n = 320), venlafaxine XR ( n = 333) or placebo ( n = 331). For the non-inferiority analysis, the per-protocol patients who were treated with duloxetine ( n = 239) or venlafaxine XR ( n = 262) improved significantly more (mean HAMA reductions were −15.4 and −15.2, respectively) than placebo-treated patients ( n = 267; −11.6, P ≤ 0.001, both comparisons). Response rates were 56%, 58% and 40%, respectively. Discontinuation rate because of AEs was significantly higher for duloxetine (13.4%, P ≤ 0.001) and venlafaxine XR (11.4%, P ≤ 0.01) groups compared with placebo (5.4%). Duloxetine 60—120 mg/day met all statistical and clinical criteria for non-inferiority and exhibited a similar tolerability profile compared with venlafaxine XR 75—225 mg/day for the treatment of adults with GAD.
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