•Adenine accumulates in LPS and IL-4 stimulated M-CSF human macrophages.•Inflammation is suppressed in adenine treated M-CSF and GM-CSF human macrophages.•Adenine drives human macrophages towards ...metabolic quiescence.•AKT, AMPK and p38 MAPK pathways are not involved in adenine signalling.
Immunometabolism has been unveiled in the last decade to play a major role in controlling macrophage metabolism and inflammation. There has been a constant effort to understand the immunomodulating properties of regulated metabolites during inflammation with the aim of controlling and re-wiring aberrant macrophages in inflammatory diseases. M-CSF and GM-CSF-differentiated macrophages play a key role in mounting successful innate immune responses. When a resolution phase is not achieved however, GM-CSF macrophages contribute substantially more towards an adverse inflammatory milieu than M-CSF macrophages, consequently driving disease progression. Whether there are specific immunometabolites that determine the homoeostatic or inflammatory nature of M-CSF and GM-CSF-differentiated macrophages is still unknown. As such, we performed metabolomics analysis on LPS and IL-4-stimulated M-CSF and GM-CSF-differentiated human macrophages to identify differentially accumulating metabolites. Adenine was distinguished as a metabolite significantly higher in M-CSF-differentiated macrophages after both LPS or IL-4 stimulation. Human macrophages treated with adenine before LPS stimulation showed a reduction in inflammatory gene expression, cytokine secretion and surface marker expression. Adenine caused macrophages to become more quiescent by lowering glycolysis and OXPHOS which resulted in reduced ATP production. Moreover, typical metabolite changes seen during LPS-induced macrophage metabolic reprogramming were absent in the presence of adenine. Phosphorylation of metabolic signalling proteins AMPK, p38 MAPK and AKT were not responsible for the suppressed metabolic activity of adenine-treated macrophages. Altogether, in this study we highlight the immunomodulating capacity of adenine in human macrophages and its function in driving cellular quiescence.
Homozygosity mapping and linkage analysis in a Turkish family with autosomal recessive prelingual sensorineural hearing loss revealed a 15-cM critical region at 17q25.1-25.3 flanked by the ...polymorphic markers D17S1807 and D17S1806. The maximum two-point lod score was 4.07 at theta=0.0 for the marker D17S801. The linkage interval contains the Usher syndrome 1G gene (USH1G) that is mutated in patients with Usher syndrome (USH) type 1g and encodes the SANS protein. Mutation analysis of USH1G led to the identification of a homozygous missense mutation D458V at the -3 position of the PDZ binding motif of SANS. This mutation was also present homozygously in one out of 64 additional families from Turkey with autosomal recessive nonsyndromic hearing loss and heterozygously in one out of 498 control chromosomes. By molecular modeling, we provide evidence that this mutation impairs the interaction of SANS with harmonin. Ophthalmologic examination and vestibular evaluation of patients from both families revealed mild retinitis pigmentosa and normal vestibular function. These results suggest that these patients suffer from atypical USH.
Coherent processing of radio-echo sounding data of polar ice sheets is known to provide an indication of bedrock properties and detection of internal layers. We investigate the benefits of coherent ...processing of a large azimuth beamwidth to retrieve and characterize the orientation and angular backscattering properties of the surface and subsurface features. MCRDS data acquired over two distinct test areas in Greenland are used to demonstrate the specular backscattering properties of the ice surface and of the internal layers, as well as the much wider angular response of the bedrock. The coupling of internal layers' orientation with the bed topography is shown to increase with depth. Spectral filtering can be used to increase the SNR of the internal layers and mitigate the surface multiple. The variance of the bed backscattering can be used to characterize the bed return specularity. The use of the SAR-focused RES data ensures the correct azimuth positioning of the internal layers for the subsequent slope estimation.
Hereditary hearing impairment is a genetically heterogeneous disorder. To date, 49 autosomal recessive nonsyndromic hearing impairment (ARNSHI) loci have been described, and there are more than 16 ...additional loci announced. In 25 of the known loci, causative genes have been identified. A genome scan and fine mapping revealed a novel locus for ARNSHI (DFNB63) on chromosome 11q13.2-q13.4 in a five-generation Turkish family (TR57). The homozygous linkage interval is flanked by the markers D11S1337 and D11S2371 and spans a 5.3-Mb interval. A maximum two-point log of odds score of 6.27 at a recombination fraction of theta = 0.0 was calculated for the marker D11S4139. DFNB63 represents the eighth ARNSHI locus mapped to chromosome 11, and about 3.33 Mb separate the DFNB63 region from MYO7A (DFNB2/DFNB11). Sequencing of coding regions and exon-intron boundaries of 13 candidate genes, namely SHANK2, CTTN, TPCN2, FGF3, FGF4, FGF19, FCHSD2, PHR1, TMEM16A, RAB6A, MYEOV, P2RY2 and KIAA0280, in genomic DNA from an affected individual of family TR57 revealed no disease-causing mutations.
First look at the physics case of TLEP Bicer, M.; Duran Yildiz, H.; Coignet, G. ...
The journal of high energy physics,
01/2014, Letnik:
2014, Številka:
1
Journal Article
Recenzirano
Odprti dostop
A
bstract
The discovery by the ATLAS and CMS experiments of a new boson with mass around 125 GeV and with measured properties compatible with those of a Standard-Model Higgs boson, coupled with the ...absence of discoveries of phenomena beyond the Standard Model at the TeV scale, has triggered interest in ideas for future Higgs factories. A new circular e
+
e
−
collider hosted in a 80 to 100 km tunnel, TLEP, is among the most attractive solutions proposed so far. It has a clean experimental environment, produces high luminosity for top-quark, Higgs boson, W and Z studies, accommodates multiple detectors, and can reach energies up to the
threshold and beyond. It will enable measurements of the Higgs boson properties and of Electroweak Symmetry-Breaking (EWSB) parameters with unequalled precision, offering exploration of physics beyond the Standard Model in the multi-TeV range. Moreover, being the natural precursor of the VHE-LHC, a 100 TeV hadron machine in the same tunnel, it builds up a long-term vision for particle physics. Altogether, the combination of TLEP and the VHE-LHC offers, for a great cost effectiveness, the best precision and the best search reach of all options presently on the market. This paper presents a first appraisal of the salient features of the TLEP physics potential, to serve as a baseline for a more extensive design study.
Although most components of the mitochondrial translation apparatus are encoded by nuclear genes, all known molecular defects associated with impaired mitochondrial translation are due to mutations ...in mitochondrial DNA. We investigated two siblings with a severe defect in mitochondrial translation, reduced levels of oxidative phosphorylation complexes containing mitochondrial DNA (mtDNA)-encoded subunits, and progressive hepatoencephalopathy. We mapped the defective gene to a region on chromosome 3q containing elongation factor G1 (EFG1), which encodes a mitochondrial translation factor. Sequencing of EFG1 revealed a mutation affecting a conserved residue of the guanosine triphosphate (GTP)-binding domain. These results define a new class of gene defects underlying disorders of oxidative phosphorylation.
PDF
