Interindividual methylomic variation across blood, cortex, and cerebellum: implications for epigenetic studies of neurological and neuropsychiatric phenotypes

Given the tissue-specific nature of epigenetic processes, the assessment of disease-relevant tissue is an important consideration for epigenome-wide association studies (EWAS). Little is known about whether easily accessible tissues, such as whole blood, can be used to address questions about interindividual epigenomic variation in inaccessible tissues, such as the brain. We quantified DNA methylation in matched DNA samples isolated from whole blood and 4 brain regions (prefrontal cortex, entorhinal cortex, superior temporal gyrus, and cerebellum) from 122 individuals. We explored co-variation between tissues and the extent to which methylomic variation in blood is predictive of interindividual variation identified in the brain. For the majority of DNA methylation sites, interindividual variation in whole blood is not a strong predictor of interindividual variation in the brain, although the relationship with cortical regions is stronger than with the cerebellum. Variation at a subset of probes is strongly correlated across tissues, even in instances when the actual level of DNA methylation is significantly different between them. A substantial proportion of this co-variation, however, is likely to result from genetic influences. Our data suggest that for the majority of the genome, a blood-based EWAS for disorders where brain is presumed to be the primary tissue of interest will give limited information relating to underlying pathological processes. These results do not, however, discount the utility of using a blood-based EWAS to identify biomarkers of disease phenotypes manifest in the brain. We have generated a searchable database for the interpretation of data from blood-based EWAS analyses (http://epigenetics.essex.ac.uk/ bloodbrain/)

Bacteria isolated from Bengal cat (Felis catus × Prionailurus bengalensis) anal sac secretions produce volatile compounds potentially associated with animal signaling.

In social animals, scent secretions and marking behaviors play critical roles in communication, including intraspecific signals, such as identifying individuals and group membership, as well as interspecific signaling. Anal sacs are an important odor producing organ found across the carnivorans (species in the mammalian Order Carnivora). Secretions from the anal sac may be used as chemical signals by animals for behaviors ranging from defense to species recognition to signaling reproductive status. In addition, a recent study suggests that domestic cats utilize short-chain free fatty acids in anal sac secretions for individual recognition. The fermentation hypothesis is the idea that symbiotic microorganisms living in association with animals contribute to odor profiles used in chemical communication and that variation in these chemical signals reflects variation in the microbial community. Here we examine the fermentation hypothesis by characterizing volatile organic compounds (VOC) and bacteria isolated from anal sac secretions collected from a male Bengal cat (Felis catus × Prionailurus bengalensis), a cross between the domestic cat and the leopard cat. Both left and right anal sacs of a male Bengal cat were manually expressed (emptied) and collected. Half of the material was used to culture bacteria or to extract bacterial DNA and the other half was used for VOC analysis. DNA was extracted from the anal sac secretions and used for a 16S rRNA gene PCR amplification and sequencing based characterization of the microbial community. Additionally, some of the material was plated out in order to isolate bacterial colonies. Three taxa (Bacteroides fragilis, Tessaracoccus, and Finegoldia magna) were relatively abundant in the 16S rRNA gene sequence data and also isolated by culturing. Using Solid Phase Microextraction (SPME) gas chromatography-mass spectrometry (GC-MS), we tentatively identified 52 compounds from the Bengal cat anal sac secretions and 67 compounds from cultures of the three bacterial isolates chosen for further analysis. Among 67 compounds tentatively identified from bacterial isolates, 51 were also found in the anal sac secretion. We show that the bacterial community in the anal sac consists primarily of only a few abundant taxa and that isolates of these taxa produce numerous volatiles that are found in the combined anal sac volatile profile. Several of these volatiles are found in anal sac secretions from other carnivorans, and are also associated with known bacterial biosynthesis pathways. This is consistent with the fermentation hypothesis and the possibility that the anal sac is maintained at least in part to house bacteria that produce volatiles for the host

Wind-induced interannual variability of sea level slope, along-shelf flow, and surface salinity on the Northwest Atlantic shelf

Author Posting. © American Geophysical Union, 2014. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research: Oceans 119 (2014): 2462–2479, doi:10.1002/2013JC009385.In this study, we examine the importance of regional wind forcing in modulating advective processes and hydrographic properties along the Northwest Atlantic shelf, with a focus on the Nova Scotian Shelf (NSS)-Gulf of Maine (GoM) region. Long-term observational data of alongshore wind stress, sea level slope, and along-shelf flow are analyzed to quantify the relationship between wind forcing and hydrodynamic responses on interannual time scales. Additionally, a simplified momentum balance model is used to examine the underlying mechanisms. Our results show significant correlation among the observed interannual variability of sea level slope, along-shelf flow, and alongshore wind stress in the NSS-GoM region. A mechanism is suggested to elucidate the role of wind in modulating the sea level slope and along-shelf flow: stronger southwesterly (northeastward) winds tend to weaken the prevailing southwestward flow over the shelf, building sea level in the upstream Newfoundland Shelf region, whereas weaker southwesterly winds allow stronger southwestward flow to develop, raising sea level in the GoM region. The wind-induced flow variability can influence the transport of low-salinity water from the Gulf of St. Lawrence to the GoM, explaining interannual variations in surface salinity distributions within the region. Hence, our results offer a viable mechanism, besides the freshening of remote upstream sources, to explain interannual patterns of freshening in the GoM.This work was supported by NOAA’s Fisheries and the Environment Program, Grant #12-03 and through NOAA Cooperative Agreement NA09OAR4320129.2014-10-1

Метод определения дезоксирибонуклеазной активности с использованием бромистого этидия

дезоксирибонуклеазыэтиди

Nutrient Sensing by Tas1R Proteins is Required for Normal Bone Resorption

Current therapies for low bone mass consist of inhibiting osteoclast activity or increasing the PTH or Wnt signaling pathways. These approaches have significant drawbacks that limit their use in specific patient populations and/or negatively impact patient compliance with therapy. Developing improved therapies requires diversifying our understanding of the mechanisms underlying postnatal bone remodeling by examining lesser-known signaling pathways. One such pathway is the taste receptor type 1 (TAS1R) family of heterotrimeric G protein-coupled receptors, which participates in monitoring energy and nutrient status. Previous work reported that global deletion of TAS1R member 3 (TAS1R3), which is a bi-functional protein that recognizes amino acids or sweet molecules when dimerized with TAS1R member 1 (TAS1R1) or TAS1R member 2 (TAS1R2), respectively, leads to increased cortical bone mass. Here, we corroborate the increased thickness of cortical bone in Tas1R3 knockout mice and confirm that Tas1R3 is expressed in the bone environment. Quantification of serum bone turnover markers indicate that this phenotype is likely due to uncoupled bone remodeling, with levels of the bone resorption marker CTx being reduced greater than 60% in Tas1R3 mutant mice; no changes were observed in levels of the bone formation marker PINP. Consistent with this, Tas1R3 and its putative signaling partner Tas1R2 are expressed in primary osteoclasts and RAW264.7 cells following RANKL-mediated differentiation. These findings suggest that osteoclast function and/or differentiation may be altered in the absence of Tas1R3 expression. To test this, we quantified bone-specific expression of Rankl and determined the Rankl:Opg ratio; no differences were observed between control and Tas1R3 knockout mice in these analyses. In vitro studies examining further downstream effectors of TAS1R2:3 in response to saccharin and receptor antagonist gurmarin are currently underway. Collectively, our findings provide the first demonstration that nutrient monitoring by TAS1R3 is essential for normal bone resorption in vivo

Gene Transfer of Engineered Calmodulin Alleviates Ventricular Arrhythmias in a Calsequestrin-Associated Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmogenic syndrome characterized by sudden death. There are several genetic forms of CPVT associated with mutations in genes encoding the cardiac ryanodine receptor (RyR2) and its auxiliary proteins including calsequestrin (CASQ2) and calmodulin (CaM). It has been suggested that impairment of the ability of RyR2 to stay closed (ie, refractory) during diastole may be a common mechanism for these diseases. Here, we explore the possibility of engineering CaM variants that normalize abbreviated RyR2 refractoriness for subsequent viral-mediated delivery to alleviate arrhythmias in non-CaM-related CPVT

Morphing Ensemble Kalman Filters

A new type of ensemble filter is proposed, which combines an ensemble Kalman filter (EnKF) with the ideas of morphing and registration from image processing. This results in filters suitable for nonlinear problems whose solutions exhibit moving coherent features, such as thin interfaces in wildfire modeling. The ensemble members are represented as the composition of one common state with a spatial transformation, called registration mapping, plus a residual. A fully automatic registration method is used that requires only gridded data, so the features in the model state do not need to be identified by the user. The morphing EnKF operates on a transformed state consisting of the registration mapping and the residual. Essentially, the morphing EnKF uses intermediate states obtained by morphing instead of linear combinations of the states.Comment: 17 pages, 7 figures. Added DDDAS references to the introductio

SoK: Why Johnny Can't Fix PGP Standardization

Pretty Good Privacy (PGP) has long been the primary IETF standard for encrypting email, but suffers from widespread usability and security problems that have limited its adoption. As time has marched on, the underlying cryptographic protocol has fallen out of date insofar as PGP is unauthenticated on a per message basis and compresses before encryption. There have been an increasing number of attacks on the increasingly outdated primitives and complex clients used by the PGP eco-system. However, attempts to update the OpenPGP standard have failed at the IETF except for adding modern cryptographic primitives. Outside of official standardization, Autocrypt is a "bottom-up" community attempt to fix PGP, but still falls victim to attacks on PGP involving authentication. The core reason for the inability to "fix" PGP is the lack of a simple AEAD interface which in turn requires a decentralized public key infrastructure to work with email. Yet even if standards like MLS replace PGP, the deployment of a decentralized PKI remains an open issue