609 research outputs found
Cis and Trans Effects of Human Genomic Variants on Gene Expression
This work was funded by the Louis-Jeantet Foundation (http://www.jeantet.ch/), the European Research Council (Grant ID: 260927 http://erc.europa.eu/), the Swiss National Foundation (Grant ID: 130342 http://www.snf.ch), NCCR Frontiers In Genetics (http://www.frontiers-in-genetics.org), the UK Medical Research Council (http://www.mrc.ac.uk) and the Wellcome Trust (Grant ID: 092731).
Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses.
Hereditary multiple exostoses (EXT; MIM 133700) is an autosomal dominant bone disorder characterized by the presence of multiple benign cartilage-capped tumors (exostoses). Besides suffering complications caused by the pressure of these exostoses on the surrounding tissues, EXT patients are at an increased risk for malignant chondrosarcoma, which may develop from an exostosis. EXT is genetically heterogeneous, and three loci have been identified so far: EXT1, on chromosome 8q23-q24; EXT2, on 11p11-p12; and EXT3, on the short arm of chromosome 19. The EXT1 and EXT2 genes were cloned recently, and they were shown to be homologous. We have now analyzed the EXT1 and EXT2 genes, in 26 EXT families originating from nine countries, to identify the underlying disease-causing mutation. Of the 26 families, 10 families had an EXT1 mutation, and 10 had an EXT2 mutation. Twelve of these mutations have never been described before. In addition, we have reviewed all EXT1 and EXT2 mutations reported so far, to determine the nature, frequency, and distribution of mutations that cause EXT. From this analysis, we conclude that mutations in either the EXT1 or the EXT2 gene are responsible for the majority of EXT cases. Most of the mutations in EXT1 and EXT2 cause premature termination of the EXT proteins, whereas missense mutations are rare. The development is thus mainly due to loss of function of the EXT genes, consistent with the hypothesis that the EXT genes have a tumor- suppressor function
Signatures of arithmetic simplicity in metabolic network architecture
Metabolic networks perform some of the most fundamental functions in living
cells, including energy transduction and building block biosynthesis. While
these are the best characterized networks in living systems, understanding
their evolutionary history and complex wiring constitutes one of the most
fascinating open questions in biology, intimately related to the enigma of
life's origin itself. Is the evolution of metabolism subject to general
principles, beyond the unpredictable accumulation of multiple historical
accidents? Here we search for such principles by applying to an artificial
chemical universe some of the methodologies developed for the study of genome
scale models of cellular metabolism. In particular, we use metabolic flux
constraint-based models to exhaustively search for artificial chemistry
pathways that can optimally perform an array of elementary metabolic functions.
Despite the simplicity of the model employed, we find that the ensuing pathways
display a surprisingly rich set of properties, including the existence of
autocatalytic cycles and hierarchical modules, the appearance of universally
preferable metabolites and reactions, and a logarithmic trend of pathway length
as a function of input/output molecule size. Some of these properties can be
derived analytically, borrowing methods previously used in cryptography. In
addition, by mapping biochemical networks onto a simplified carbon atom
reaction backbone, we find that several of the properties predicted by the
artificial chemistry model hold for real metabolic networks. These findings
suggest that optimality principles and arithmetic simplicity might lie beneath
some aspects of biochemical complexity
The Effects of Cocaine on Different Redox Forms of Cysteine and Homocysteine, and on Labile, Reduced Sulfur in the Rat Plasma Following Active versus Passive Drug Injections
Received: 28 November 2012 / Revised: 19 April 2013 / Accepted: 6 May 2013 / Published online: 16 May 2013
The Author(s) 2013. This article is published with open access at Springerlink.comThe aim of the present studies was to evaluate
cocaine-induced changes in the concentrations of different
redox forms of cysteine (Cys) and homocysteine (Hcy),
and products of anaerobic Cys metabolism, i.e., labile,
reduced sulfur (LS) in the rat plasma. The above-mentioned
parameters were determined after i.p. acute and
subchronic cocaine treatment as well as following i.v.
cocaine self-administration using the yoked procedure.
Additionally, Cys, Hcy, and LS levels were measured
during the 10-day extinction training in rats that underwent
i.v. cocaine administration. Acute i.p. cocaine treatment
increased the total and protein-bound Hcy contents,
decreased LS, and did not change the concentrations of Cys
fractions in the rat plasma. In turn, subchronic i.p. cocaine administration significantly increased free Hcy and lowered
the total and protein-bound Cys concentrations while
LS level was unchanged. Cocaine self-administration
enhanced the total and protein-bound Hcy levels, decreased
LS content, and did not affect the Cys fractions. On the
other hand, yoked cocaine infusions did not alter the concentration
of Hcy fractions while decreased the total and
protein-bound Cys and LS content. This extinction training
resulted in the lack of changes in the examined parameters
in rats with a history of cocaine self-administration while in
the yoked cocaine group an increase in the plasma free Cys
fraction and LS was seen. Our results demonstrate for the
first time that cocaine does evoke significant changes in
homeostasis of thiol amino acids Cys and Hcy, and in some
products of anaerobic Cys metabolism, which are dependent
on the way of cocaine administration
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
Lambda and Antilambda polarization from deep inelastic muon scattering
We report results of the first measurements of Lambda and Antilambda
polarization produced in deep inelastic polarized muon scattering on the
nucleon. The results are consistent with an expected trend towards positive
polarization with increasing x_F. The polarizations of Lambda and Antilambda
appear to have opposite signs. A large negative polarization for Lambda at low
positive x_F is observed and is not explained by existing models.A possible
interpretation is presented.Comment: 9 pages, 2 figure
Accurate and exact CNV identification from targeted high-throughput sequence data
<p>Abstract</p> <p>Background</p> <p>Massively parallel sequencing of barcoded DNA samples significantly increases screening efficiency for clinically important genes. Short read aligners are well suited to single nucleotide and indel detection. However, methods for CNV detection from targeted enrichment are lacking. We present a method combining coverage with map information for the identification of deletions and duplications in targeted sequence data.</p> <p>Results</p> <p>Sequencing data is first scanned for gains and losses using a comparison of normalized coverage data between samples. CNV calls are confirmed by testing for a signature of sequences that span the CNV breakpoint. With our method, CNVs can be identified regardless of whether breakpoints are within regions targeted for sequencing. For CNVs where at least one breakpoint is within targeted sequence, exact CNV breakpoints can be identified. In a test data set of 96 subjects sequenced across ~1 Mb genomic sequence using multiplexing technology, our method detected mutations as small as 31 bp, predicted quantitative copy count, and had a low false-positive rate.</p> <p>Conclusions</p> <p>Application of this method allows for identification of gains and losses in targeted sequence data, providing comprehensive mutation screening when combined with a short read aligner.</p
The 24-h Energy Intake of Obese Adolescents Is Spontaneously Reduced after Intensive Exercise: A Randomized Controlled Trial in Calorimetric Chambers
Background: Physical exercise can modify subsequent energy intake and appetite and may thus be of particular interest in terms of obesity treatment. However, it is still unclear whether an intensive bout of exercise can affect the energy consumption of obese children and adolescents. [br/]
Objective: To compare the impact of high vs. moderate intensity exercises on subsequent 24-h energy intake, macronutrient preferences, appetite sensations, energy expenditure and balance in obese adolescent. [br/]
Design: This randomized cross-over trial involves 15 obese adolescent boys who were asked to randomly complete three 24-h sessions in a metabolic chamber, each separated by at least 7 days: (1) sedentary (SED); (2) Low-Intensity Exercise (LIE) (40% maximal oxygen uptake, VO(2)max); (3) High-Intensity Exercise (HIE) (75% VO(2)max). Results: Despite unchanged appetite sensations, 24-h total energy intake following HIE was 6-11% lower compared to LIE and SED (p<0.05), whereas no differences appeared between SED and LIE. Energy intake at lunch was 9.4% and 8.4% lower after HIE compared to SED and LIE, respectively (p<0.05). At dinner time, it was 20.5% and 19.7% lower after HIE compared to SED and LIE, respectively (p<0.01). 24-h energy expenditure was not significantly altered. Thus, the 24-h energy balance was significantly reduced during HIE compared to SED and LIE (p<0.01), whereas those of SED and LIE did not differ. [br/]
Conclusions: In obese adolescent boys, HIE has a beneficial impact on 24-h energy balance, mainly due to the spontaneous decrease in energy intake during lunch and dinner following the exercise bout. Prescribing high-intensity exercises to promote weight loss may therefore provide effective results without affecting appetite sensations and, as a result, food frustrations
Quantitative imaging of concentrated suspensions under flow
We review recent advances in imaging the flow of concentrated suspensions,
focussing on the use of confocal microscopy to obtain time-resolved information
on the single-particle level in these systems. After motivating the need for
quantitative (confocal) imaging in suspension rheology, we briefly describe the
particles, sample environments, microscopy tools and analysis algorithms needed
to perform this kind of experiments. The second part of the review focusses on
microscopic aspects of the flow of concentrated model hard-sphere-like
suspensions, and the relation to non-linear rheological phenomena such as
yielding, shear localization, wall slip and shear-induced ordering. Both
Brownian and non-Brownian systems will be described. We show how quantitative
imaging can improve our understanding of the connection between microscopic
dynamics and bulk flow.Comment: Review on imaging hard-sphere suspensions, incl summary of
methodology. Submitted for special volume 'High Solid Dispersions' ed. M.
Cloitre, Vol. xx of 'Advances and Polymer Science' (Springer, Berlin, 2009);
22 pages, 16 fig
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