Sanionins: anti-inflammatory and antibacterial agents with weak cytotoxicity from the Antarctic moss Sanionia georgico-uncinata

Sanionins A (1) and B (2) were isolated from the moss Sanionia georgico-uncinata, collected on the Antarctic Livingston Island. The compounds 1 and 2 were purified by solvent extraction, silica gel column chromatography, and preparative HPLC, consecutively. The structures of the both compounds were elucidated by 1D and 2D NMR experiments and mass spectrometric investigations. These compounds showed activity against important Gram-positive pathogens, such as mycobacteria, multiresistant staphylococci, and vancomycin resistant enterococci. This activity is combined with antiinflammatoric activity and low cytotoxicity.     

Influence of Nonenzymatic Posttranslational Modifications on Constitution,Oligomerization and Receptor Binding of S100A12

This study examined the effect of methylglyoxal (MGO)-derived nonenzymatic posttranslational modifications (nePTMs) on the binding affinity of S100A12 to its natural receptor for advanced glycation end-products (RAGE). Binding of MGO-modified S100A12 to RAGE decreased significantly with increasing MGO concentration and incubation time. Ca²⁺-induced S100A12 hexamerization was impaired only at higher MGO concentrations indicating that the loss of affinity is not predominantly caused by disturbance of ligand oligomerization. nePTM mapping showed carboxyethylation of lysine (CEL) and the N-terminus without preferential modification sites. Besides, hydroimidazolone, hemiaminals, argpyrimidine, and tetrahydropyrimidine rapidly formed at R21. Even at the highest modification rate, hexamerization of synthesized CEL-S100A12 was unaffected and RAGE-binding only slightly impaired. Thus, nePTMs at R21 seem to be the major cause of MGO-induced impairment of S100A12 oligomerization and RAGE binding.     

Mutations of the EPHB6 Receptor Tyrosine Kinase Induce a Pro-Metastatic Phenotype in Non-Small Cell Lung Cancer

Alterations of Eph receptor tyrosine kinases are frequent events in human cancers. Genetic variations of EPHB6 have been described but the functional outcome of these alterations is unknown. The current study was conducted to screen for the occurrence and to identify functional consequences of EPHB6 mutations in non-small cell lung cancer. Here, we sequenced the entire coding region of EPHB6 in 80 non-small cell lung cancer patients and 3 tumor cell lines. Three potentially relevant mutations were identified in primary patient samples of NSCLC patients (3.8%). Two point mutations led to instable proteins. An in frame deletion mutation (del915-917) showed enhanced migration and accelerated wound healing in vitro. Furthermore, the del915-917 mutation increased the metastatic capability of NSCLC cells in an in vivo mouse model. Our results suggest that EPHB6 mutations promote metastasis in a subset of patients with non-small cell lung cancer.     

Impacts of a national strategy to reduce population salt intake in England: serial cross sectional study

Background

The UK introduced an ambitious national strategy to reduce population levels of salt intake in 2003. The aim of this study was to evaluate the impact of this strategy on salt intake in England, including potential effects on health inequalities.

Methods

Secondary analysis of data from the Health Survey for England. Our main outcome measure was trends in estimated daily salt intake from 2003–2007, as measured by spot urine. Secondary outcome measures were knowledge of government guidance and voluntary use of salt in food preparation over this time period.

Results

There were significant reductions in salt intake between 2003 and 2007 (−0.175grams per day per year, p<0.001). Intake decreased uniformly across all other groups but remained significantly higher in younger persons, men, ethnic minorities and lower social class groups and those without hypertension in 2007. Awareness of government guidance on salt use was lowest in those groups with the highest intake (semi-skilled manual v professional; 64.9% v 71.0% AOR 0.76 95% CI 0.58–0.99). Self reported use of salt added at the table reduced significantly during the study period (56.5% to 40.2% p<0.001). Respondents from ethnic minority groups remained significantly more likely to add salt during cooking (white 42.8%, black 74.1%, south Asian 88.3%) and those from lower social class groups (unskilled manual 46.6%, professional 35.2%) were more likely to add salt at the table.

Conclusions

The introduction a national salt reduction strategy was associated with uniform but modest reductions in salt intake in England, although it is not clear precisely which aspects of the strategy contributed to this. Knowledge of government guidance was lower and voluntary salt use and total salt intake was higher among occupational and ethnic groups at greatest risk of cardiovascular disease.     

Peptide-coated nanotube-based biosensor for the detection of disease-specific autoantibodies in human serum

We demonstrate a label-free peptide-coated carbon nanotube-based immunosensor for the direct assay of human serum. A rheumatoid arthritis (RA)-specific (cyclic citrulline-containing) peptide, was immobilized to functionalized single-walled carbon nanotubes deposited on a quartz crystal microbalance (QCM) sensing crystal. Serum from RA patients was used to probe these nanotube-based sensors, and antibody binding was detected by QCM sensing. Specific antibody binding was also determined by comparing the assay of two serum control groups (normal and diseased sera), and the native unmodified peptide. The sensitivity of the nanotube-based sensor (detection in the femtomol range) was higher than that of the established ELISA and recently described microarray assay systems, detecting 34.4 and 37.5% more RA patients with anti-citrullinated peptide antibodies than those found by ELISA and microarray, respectively. There was also an 18.4 and 19.6% greater chance of a negative test being a true indicator of a person not having RA than by either ELISA or microarray, respectively. The performance of our label-free biosensor enables its application in the direct assay of sera in research and diagnostics.     

An assembly chaperone collaborates with the SMN complex to generate spliceosomal SnRNPs

Spliceosomal small nuclear ribonucleoproteins (snRNPs) are essential components of the nuclear pre-mRNA processing machinery. A hallmark of these particles is a ring-shaped core domain generated by the binding of Sm proteins onto snRNA. PRMT5 and SMN complexes mediate the formation of the core domain in vivo. Here, we have elucidated the mechanism of this reaction by both biochemical and structural studies. We show that pICln, a component of the PRMT5 complex, induces the formation of an otherwise unstable higher-order Sm protein unit. In this state, the Sm proteins are kinetically trapped, preventing their association with snRNA. The SMN complex subsequently binds to these Sm protein units, dissociates pICln, and catalyzes ring closure on snRNA. Our data identify pICln as an assembly chaperone and the SMN complex as a catalyst of spliceosomal snRNP formation. The mode of action of this combined chaperone/catalyst system is reminiscent of the mechanism employed by DNA clamp loaders.