7,599 research outputs found
Methylation of the imprinted GNAS1 gene in cell-free plasma DNA : equal steady-state quantities of methylated and unmethylated DNA in plasma
Background
Genomic DNA sequences in cell-free plasma are biomarkers of cancer prognosis, where characteristic changes in methylation of tumour suppressor or oncogene DNA regions are indicative of changes in gene activity. Also, cell-free fetal DNA can be distinguished, by its methylation status, from the maternal DNA in the plasma of pregnant women, hence providing DNA biomarkers for the proposed minimally-invasive diagnosis of fetal aneuploidies, including Down's syndrome. However, the production and clearance of cell-free DNA from plasma in relation to its methylation status, are poorly understood processes.
Methods
We studied the methylation status of DNA derived from the imprinted GNAS1 locus, in cell-free plasma DNA of healthy adults. Heterozygotes were identified that carried the SNP rs1800905 in the imprinted region. The parent-of-origin-dependent DNA methylation was analysed by bisulfite conversion, followed by cloning and sequencing.
Results
Genomic DNA molecules derived from both the methylated, maternal, allele and the unmethylated, paternal, allele were found in plasma. Methylated and unmethylated DNA molecules were present in equal numbers.
Conclusions
Our data indicate that the methylation status of a DNA sequence has no effect on its steady state concentration in the cell-free DNA component of plasma, in healthy adults
A two-step learning approach for solving full and almost full cold start problems in dyadic prediction
Dyadic prediction methods operate on pairs of objects (dyads), aiming to
infer labels for out-of-sample dyads. We consider the full and almost full cold
start problem in dyadic prediction, a setting that occurs when both objects in
an out-of-sample dyad have not been observed during training, or if one of them
has been observed, but very few times. A popular approach for addressing this
problem is to train a model that makes predictions based on a pairwise feature
representation of the dyads, or, in case of kernel methods, based on a tensor
product pairwise kernel. As an alternative to such a kernel approach, we
introduce a novel two-step learning algorithm that borrows ideas from the
fields of pairwise learning and spectral filtering. We show theoretically that
the two-step method is very closely related to the tensor product kernel
approach, and experimentally that it yields a slightly better predictive
performance. Moreover, unlike existing tensor product kernel methods, the
two-step method allows closed-form solutions for training and parameter
selection via cross-validation estimates both in the full and almost full cold
start settings, making the approach much more efficient and straightforward to
implement
Deletion of the GABAA α2-subunit does not alter self dministration of cocaine or reinstatement of cocaine seeking
Rationale
GABAA receptors containing α2-subunits are highly represented in brain areas that are involved in motivation and reward, and have been associated with addiction to several drugs, including cocaine. We have shown previously that a deletion of the α2-subunit results in an absence of sensitisation to cocaine.
Objective
We investigated the reinforcing properties of cocaine in GABAA α2-subunit knockout (KO) mice using an intravenous self-administration procedure.
Methods
α2-subunit wildtype (WT), heterozygous (HT) and KO mice were trained to lever press for a 30 % condensed milk solution. After implantation with a jugular catheter, mice were trained to lever press for cocaine (0.5 mg/kg/infusion) during ten daily sessions. Responding was extinguished and the mice tested for cue- and cocaine-primed reinstatement. Separate groups of mice were trained to respond for decreasing doses of cocaine (0.25, 0.125, 0.06 and 0.03 mg/kg).
Results
No differences were found in acquisition of lever pressing for milk. All genotypes acquired self-administration of cocaine and did not differ in rates of self-administration, dose dependency or reinstatement. However, whilst WT and HT mice showed a dose-dependent increase in lever pressing during the cue presentation, KO mice did not.
Conclusions
Despite a reported absence of sensitisation, motivation to obtain cocaine remains unchanged in KO and HT mice. Reinstatement of cocaine seeking by cocaine and cocaine-paired cues is also unaffected. We postulate that whilst not directly involved in reward perception, the α2-subunit may be involved in modulating the “energising” aspect of cocaine’s effects on reward-seeking
Ligand binding site superposition and comparison based on Atomic Property Fields: identification of distant homologues, convergent evolution and PDB-wide clustering of binding sites
A new binding site comparison algorithm using optimal superposition of the continuous pharmacophoric property distributions is reported. The method demonstrates high sensitivity in discovering both, distantly homologous and convergent binding sites. Good quality of superposition is also observed on multiple examples. Using the new approach, a measure of site similarity is derived and applied to clustering of ligand binding pockets in PDB
Clostridium difficile ribotype diversity at six health care institutions in the United States
Capillary-based PCR ribotyping was used to quantify the presence/absence and relative abundance of 98 Clostridium difficile ribotypes from clinical cases of disease at health care institutions in six states of the United States. Regionally important ribotypes were identified, and institutions in close proximity did not necessarily share more ribotype diversity than institutions that were farther apart
The Many Manifestations of Downsizing: Hierarchical Galaxy Formation Models confront Observations
[abridged] It has been widely claimed that several lines of observational
evidence point towards a "downsizing" (DS) of the process of galaxy formation
over cosmic time. This behavior is sometimes termed "anti-hierarchical", and
contrasted with the "bottom-up" assembly of the dark matter structures in Cold
Dark Matter models. In this paper we address three different kinds of
observational evidence that have been described as DS: the stellar mass
assembly, star formation rate and the ages of the stellar populations in local
galaxies. We compare a broad compilation of available data-sets with the
predictions of three different semi-analytic models of galaxy formation within
the Lambda-CDM framework. In the data, we see only weak evidence at best of DS
in stellar mass and in star formation rate. We find that, when observational
errors on stellar mass and SFR are taken into account, the models acceptably
reproduce the evolution of massive galaxies, over the entire redshift range
that we consider. However, lower mass galaxies are formed too early in the
models and are too passive at late times. Thus, the models do not correctly
reproduce the DS trend in stellar mass or the archaeological DS, while they
qualitatively reproduce the mass-dependent evolution of the SFR. We demonstrate
that these discrepancies are not solely due to a poor treatment of satellite
galaxies but are mainly connected to the excessively efficient formation of
central galaxies in high-redshift haloes with circular velocities ~100-200
km/s. [abridged]Comment: MNRAS accepted, 16 pages, 10 figure
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