Age-related cognitive impairment is multifactorial, with numerous underlying and frequently co-morbid pathological correlates. Amyloid beta (Aβ) plays a major role in Alzheimer's type age-related ...cognitive impairment, in addition to other etiopathologies such as Aβ-independent hyperphosphorylated tau, cerebrovascular disease, and myelin damage, which also warrant further investigation. Classical methods, even in the setting of the gold standard of postmortem brain assessment, involve semi-quantitative ordinal staging systems that often correlate poorly with clinical outcomes, due to imperfect cognitive measurements and preconceived notions regarding the neuropathologic features that should be chosen for study. Improved approaches are needed to identify histopathological changes correlated with cognition in an unbiased way. We used a weakly supervised multiple instance learning algorithm on whole slide images of human brain autopsy tissue sections from a group of elderly donors to predict the presence or absence of cognitive impairment (n = 367 with cognitive impairment, n = 349 without). Attention analysis allowed us to pinpoint the underlying subregional architecture and cellular features that the models used for the prediction in both brain regions studied, the medial temporal lobe and frontal cortex. Despite noisy labels of cognition, our trained models were able to predict the presence of cognitive impairment with a modest accuracy that was significantly greater than chance. Attention-based interpretation studies of the features most associated with cognitive impairment in the top performing models suggest that they identified myelin pallor in the white matter. Our results demonstrate a scalable platform with interpretable deep learning to identify unexpected aspects of pathology in cognitive impairment that can be translated to the study of other neurobiological disorders.
CpG‐related single nucleotide polymorphisms (CGS) have the potential to perturb DNA methylation; however, their effects on Alzheimer disease (AD) risk have not been evaluated systematically. We ...conducted a genome‐wide association study using a sliding‐window approach to measure the combined effects of CGSes on AD risk in a discovery sample of 24 European ancestry cohorts (12,181 cases, 12,601 controls) from the Alzheimer's Disease Genetics Consortium (ADGC) and replication sample of seven European ancestry cohorts (7,554 cases, 27,382 controls) from the International Genomics of Alzheimer's Project (IGAP). The potential functional relevance of significant associations was evaluated by analysis of methylation and expression levels in brain tissue of the Religious Orders Study and the Rush Memory and Aging Project (ROSMAP), and in whole blood of Framingham Heart Study participants (FHS). Genome‐wide significant (p < 5 × 10−8) associations were identified with 171 1.0 kb‐length windows spanning 932 kb in the APOE region (top p < 2.2 × 10−308), five windows at BIN1 (top p = 1.3 × 10−13), two windows at MS4A6A (top p = 2.7 × 10−10), two windows near MS4A4A (top p = 6.4 × 10−10), and one window at PICALM (p = 6.3 × 10‐9). The total number of CGS‐derived CpG dinucleotides in the window near MS4A4A was associated with AD risk (p = 2.67 × 10−10), brain DNA methylation (p = 2.15 × 10−10), and gene expression in brain (p = 0.03) and blood (p = 2.53 × 10−4). Pathway analysis of the genes responsive to changes in the methylation quantitative trait locus signal at MS4A4A (cg14750746) showed an enrichment of methyltransferase functions. We confirm the importance of CGS in AD and the potential for creating a functional CpG dosage‐derived genetic score to predict AD risk.
CpG‐related single nucleotide polymorphisms (CGS) have the potential to perturb DNA methylation. We conducted a genome‐wide sliding window screen to assess the combined effects of multiple CGSes on the risk of Alzheimer disease (AD) in 12,181 cases, and 12,601 controls during discovery and top windows were followed with replication and functional analysis. We found that the CGSes in MS4 region has a dosage effect on AD risk, DNA methylation, and gene expression in human blood and brain.
Chromatin remodeling complexes (remodelers) are a set of diverse multi-protein machines
that reposition and restructure nucleosomes. Remodelers are specialized, containing unique proteins
that assist ...in targeting, interaction with modified nucleosomes, and performing specific chromatin
tasks. However, all remodelers contain an ATPase domain that is highly similar to known DNA translocases/helicases,
suggesting that DNA translocation is a property common to all remodelers. Here we examine the
different reactions they perform in vitro, focusing on the SWI/SNF and the ISWI complexes, and explore
how DNA translocation might be utilized to execute various remodeling processes.
In the fall of 2017, an airborne field campaign was conducted from the NASA Armstrong Flight Research Center in Palmdale, California, to advance the remote sensing of aerosols and clouds with ...multi-angle polarimeters (MAP) and lidars. The Aerosol Characterization from Polarimeter and Lidar (ACEPOL) campaign was jointly sponsored by NASA and the Netherlands Institute for Space Research (SRON). Six instruments were deployed on the ER-2 high-altitude aircraft. Four were MAPs: the Airborne Hyper Angular Rainbow Polarimeter (AirHARP), the Airborne Multiangle SpectroPolarimetric Imager (AirMSPI), the Airborne Spectrometer for Planetary EXploration (SPEX airborne), and the Research Scanning Polarimeter (RSP). The remainder were lidars, including the Cloud Physics Lidar (CPL) and the High Spectral Resolution Lidar 2 (HSRL-2). The southern California base of ACEPOL enabled observation of a wide variety of scene types, including urban, desert, forest, coastal ocean, and agricultural areas, with clear, cloudy, polluted, and pristine atmospheric conditions. Flights were performed in coordination with satellite overpasses and ground-based observations, including the Ground-based Multiangle SpectroPolarimetric Imager (GroundMSPI), sun photometers, and a surface reflectance spectrometer.
We have studied the structure and expression of histone H2B mRNAs and genes in the parasitic protozoan Leishmania enriettii, A genomic clone containing three tandemly repeated genes has been ...sequenced and shown to encode three identical histone proteins and two types of closely related mRNA sequence. We have also sequenced three independent cDNA clones and demonstrated that the Leishmania H2B mRNAs are polyadenylated, similar to the basal histone mRNAs of higher eucaryotes and the histone mRNAs of yeast. In addition, the Leishmania mRNAs contain inverted repeats near the poly(A) tail which could form stem-loops similar in secondary structure, but not in sequence, to the 3′ stem-loops of nonpolyadenylated replication-dependent histones of higher eucaryotes. Unlike the replication-dependent histones, the Leishmania histone H2B mRNAs do not decrease in abundance following treatment with inhibitors of DNA synthesis. The histone mRNAs are differentially expressed during the parasite life cycle and accumulate to a higher level in the extracellular promastigotes (the form which in nature lives within the gut of the insect vector) than in the intracellular amastigotes (the form that lives within the mammalian host macrophages).
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