Postnatal expression profiles of atypical cadherin FAT1 suggest its role in autism

Genetic studies have linked FAT1 (FAT atypical cadherin 1) with autism spectrum disorder (ASD); however, the role that FAT1 plays in ASD remains unknown. In mice, the function of Fat1 has been primarily implicated in embryonic nervous system development with less known about its role in postnatal development. We show for the first time that FAT1 protein is expressed in mouse postnatal brains and is enriched in the cerebellum, where it localizes to granule neurons and Golgi cells in the granule layer, as well as inhibitory neurons in the molecular layer. Furthermore, subcellular characterization revealed FAT1 localization in neurites and soma of granule neurons, as well as being present in the synaptic plasma membrane and postsynaptic densities. Interestingly, FAT1 expression was decreased in induced pluripotent stem cell (iPSC)-derived neural precursor cells (NPCs) from individuals with ASD. These findings suggest a novel role for FAT1 in postnatal development and may be particularly important for cerebellum function. As the cerebellum is one of the vulnerable brain regions in ASD, our study warrants further investigation of FAT1 in the disease etiology

Comparative analysis of affinity-based 5-hydroxymethylation enrichment techniques

The epigenetic modification of 5-hydroxymethylcytosine (5hmC) is receiving great attention due to its potential role in DNA methylation reprogramming and as a cell state identifier. Given this interest, it is important to identify reliable and cost-effective methods for the enrichment of 5hmC marked DNA for downstream analysis. We tested three commonly used affinity-based enrichment techniques; (i) antibody, (ii) chemical capture and (iii) protein affinity enrichment and assessed their ability to accurately and reproducibly report 5hmC profiles in mouse tissues containing high (brain) and lower (liver) levels of 5hmC. The protein-affinity technique is a poor reporter of 5hmC profiles, delivering 5hmC patterns that are incompatible with other methods. Both antibody and chemical capture-based techniques generate highly similar genome-wide patterns for 5hmC, which are independently validated by standard quantitative PCR (qPCR) and glucosyl-sensitive restriction enzyme digestion (gRES-qPCR). Both antibody and chemical capture generated profiles reproducibly link to unique chromatin modification profiles associated with 5hmC. However, there appears to be a slight bias of the antibody to bind to regions of DNA rich in simple repeats. Ultimately, the increased specificity observed with chemical capture-based approaches makes this an attractive method for the analysis of locus-specific or genome-wide patterns of 5hm

Non-genotoxic carcinogen exposure induces defined changes in the 5-hydroxymethylome.

BACKGROUND: Induction and promotion of liver cancer by exposure to non-genotoxic carcinogens coincides with epigenetic perturbations, including specific changes in DNA methylation. Here we investigate the genome-wide dynamics of 5-hydroxymethylcytosine (5hmC) as a likely intermediate of 5-methylcytosine (5mC) demethylation in a DNA methylation reprogramming pathway. We use a rodent model of non-genotoxic carcinogen exposure using the drug phenobarbital. RESULTS: Exposure to phenobarbital results in dynamic and reciprocal changes to the 5mC/5hmC patterns over the promoter regions of a cohort of genes that are transcriptionally upregulated. This reprogramming of 5mC/5hmC coincides with characteristic changes in the histone marks H3K4me2, H3K27me3 and H3K36me3. Quantitative analysis of phenobarbital-induced genes that are involved in xenobiotic metabolism reveals that both DNA modifications are lost at the transcription start site, while there is a reciprocal relationship between increasing levels of 5hmC and loss of 5mC at regions immediately adjacent to core promoters. CONCLUSIONS: Collectively, these experiments support the hypothesis that 5hmC is a potential intermediate in a demethylation pathway and reveal precise perturbations of the mouse liver DNA methylome and hydroxymethylome upon exposure to a rodent hepatocarcinogen.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Longitudinal trajectories of amyloid deposition, cortical thickness, and tau in Down syndrome: A deep-phenotyping case report.

Introduction:Comorbid Alzheimer disease pathologies are frequently found in people with Down syndrome (DS). We report a deep phenotyping study undertaken over 7 years in a participant with DS who was nondemented at baseline but developed dementia after 5 years. Methods:Throughout the course of the study, the participant was seen 4 times (2010, 2013, 2015, and 2017). Multimodal neuroimaging, including three serial scans of [11C]-PiB-PET, four structural magnetic resonance imagings, as well as a [18F]-AV1451 scan, was interpreted alongside detailed neuropsychological assessments over the study period. Results:Amyloid beta accumulation preceded the onset of dementia and cognitive decline, which in turn corresponded to the predominant deposition of tau in temporoparietal cortices. Discussion:Until now, data on the longitudinal trajectories of amyloid accumulation, tau pathology, and brain atrophy over multiple time points remain scarce in DS. This case report highlights the potential for deep phenotyping imaging to elucidate the substrates of cognitive decline in DS, although further longitudinal studies are necessary to clarify the relative contributions of both amyloid and tau

Comparative analysis of affinity-based 5-hydroxymethylation enrichment techniques

The epigenetic modification of 5-hydroxymethylcytosine (5hmC) is receiving great attention due to its potential role in DNA methylation reprogramming and as a cell state identifier. Given this interest, it is important to identify reliable and cost-effective methods for the enrichment of 5hmC marked DNA for downstream analysis. We tested three commonly used affinity-based enrichment techniques; (i) antibody, (ii) chemical capture and (iii) protein affinity enrichment and assessed their ability to accurately and reproducibly report 5hmC profiles in mouse tissues containing high (brain) and lower (liver) levels of 5hmC. The protein-affinity technique is a poor reporter of 5hmC profiles, delivering 5hmC patterns that are incompatible with other methods. Both antibody and chemical capture-based techniques generate highly similar genome-wide patterns for 5hmC, which are independently validated by standard quantitative PCR (qPCR) and glucosyl-sensitive restriction enzyme digestion (gRES-qPCR). Both antibody and chemical capture generated profiles reproducibly link to unique chromatin modification profiles associated with 5hmC. However, there appears to be a slight bias of the antibody to bind to regions of DNA rich in simple repeats. Ultimately, the increased specificity observed with chemical capture-based approaches makes this an attractive method for the analysis of locus-specific or genome-wide patterns of 5hmC

The CANDELS/SHARDS multiwavelength catalog in GOODS-N : photometry, photometric redshifts, stellar masses, emission-line fluxes, and star formation rates

We present a WFC3 F160W (H-band) selected catalog in the CANDELS/GOODS-N field containing photometry from the ultraviolet (UV) to the far-infrared (IR), photometric redshifts, and stellar parameters derived from the analysis of the multiwavelength data. The catalog contains 35,445 sources over the 171 arcmin(2) of the CANDELS F160W mosaic. The 5 sigma detection limits (within an aperture of radius 0 ''.17) of the mosaic range between H = 27.8, 28.2, and 28.7 in the wide, intermediate, and deep regions, which span approximately 50%, 15%, and 35% of the total area. The multiwavelength photometry includes broadband data from the UV (U band from KPNO and LBC), optical (HST/ACS F435W, F606W, F775W, F814W, and F850LP), near-to-mid IR (HST/WFC3 F105W, F125W, F140W, and F160W; Subaru/MOIRCS Ks; CFHT/Megacam K; and Spitzer/IRAC 3.6, 4.5, 5.8, and 8.0 mu m), and far-IR (Spitzer/MIPS 24 mu m, HERSCHEL/PACS 100 and 160 mu m, SPIRE 250, 350 and 500 mu m) observations. In addition, the catalog also includes optical medium-band data (R similar to 50) in 25 consecutive bands, lambda = 500-950 nm, from the SHARDS survey and WFC3 IR spectroscopic observations with the G102 and G141 grisms (R similar to 210 and 130). The use of higher spectral resolution data to estimate photometric redshifts provides very high, and nearly uniform, precision from z = 0-2.5. The comparison to 1485 good-quality spectroscopic redshifts up to z similar to 3 yields Delta z/(1 + z(spec)) = 0.0032 and an outlier fraction of eta = 4.3%. In addition to the multiband photometry, we release value-added catalogs with emission-line fluxes, stellar masses, dust attenuations, UV- and IR-based star formation rates, and rest-frame colors

The 2001 Superoutburst of WZ Sagittae

We report the results of a worldwide campaign to observe WZ Sagittae during its 2001 superoutburst. After a 23-year slumber at V=15.5, the star rose within 2 days to a peak brightness of 8.2, and showed a main eruption lasting 25 days. The return to quiescence was punctuated by 12 small eruptions, of ~1 mag amplitude and 2 day recurrence time; these "echo outbursts" are of uncertain origin, but somewhat resemble the normal outbursts of dwarf novae. After 52 days, the star began a slow decline to quiescence. Periodic waves in the light curve closely followed the pattern seen in the 1978 superoutburst: a strong orbital signal dominated the first 12 days, followed by a powerful /common superhump/ at 0.05721(5) d, 0.92(8)% longer than P_orb. The latter endured for at least 90 days, although probably mutating into a "late" superhump with a slightly longer mean period [0.05736(5) d]. The superhump appeared to follow familiar rules for such phenomena in dwarf novae, with components given by linear combinations of two basic frequencies: the orbital frequency omega_o and an unseen low frequency Omega, believed to represent the accretion disk's apsidal precession. Long time series reveal an intricate fine structure, with ~20 incommensurate frequencies. Essentially all components occurred at a frequency n(omega_o)-m(Omega), with m=1, ..., n. But during its first week, the common superhump showed primary components at n (omega_o)-Omega, for n=1, 2, 3, 4, 5, 6, 7, 8, 9 (i.e., m=1 consistently); a month later, the dominant power shifted to components with m=n-1. This may arise from a shift in the disk's spiral-arm pattern, likely to be the underlying cause of superhumps. The great majority of frequency components ... . (etc., abstract continues)Comment: PDF, 54 pages, 4 tables, 21 figures, 1 appendix; accepted, in press, to appear July 2002, PASP; more info at http://cba.phys.columbia.edu