Regulation of p53 activity through lysine methylation

p53 is a tumour suppressor that regulates the cellular response to genotoxic stresses. p53 is a short-lived protein and its activity is regulated mostly by stabilization via different post-translational modifications. Here we report a novel mechanism of p53 regulation through lysine methylation by Set9 methyltransferase. Set9 specifically methylates p53 at one residue within the carboxyl-terminus regulatory region. Methylated p53 is restricted to the nucleus and the modification positively affects its stability. Set9 regulates the expression of p53 target genes in a manner dependent on the p53-methylation site. The crystal structure of a ternary complex of Set9 with a p53 peptide and the cofactor product S-adenosyl-l-homocysteine (AdoHcy) provides the molecular basis for recognition of p53 by this lysine methyltransferase.     

Assay of aminoglycosides is influenced by tissue homogenization technique

Summary Recovery of neomycin from tissue homogenates was lower when glass/glass homogenizers were used due to the abrasion of glass which will bind to the drug. Glass homogenizers should be avoided for the determination of aminoglycoside levels in tissues.Acknowledgment. Supported by research grant NS-13792 and Program Project grant NS-05785 from the National Institutes of Health.     

Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders

Dietary fat is an important source of nutrition. Here we identify eight mutations in SARA2 that are associated with three severe disorders of fat malabsorption. The Sar1 family of proteins initiates the intracellular transport of proteins in COPII (coat protein)-coated vesicles. Our data suggest that chylomicrons, which vastly exceed the size of typical COPII vesicles, are selectively recruited by the COPII machinery for transport through the secretory pathways of the cell.     

Cell-specific mitotic defect and dyserythropoiesis associated with erythroid band 3 deficiency

Most eukaryotic cell types use a common program to regulate the process of cell division. During mitosis, successful partitioning of the genetic material depends on spatially coordinated chromosome movement and cell cleavage. Here we characterize a zebrafish mutant, retsina (ret), that exhibits an erythroid-specific defect in cell division with marked dyserythropoiesis similar to human congenital dyserythropoietic anemia. Erythroblasts from ret fish show binuclearity and undergo apoptosis due to a failure in the completion of chromosome segregation and cytokinesis. Through positional cloning, we show that the ret mutation is in a gene (slc4a1) encoding the anion exchanger 1 (also called band 3 and AE1), an erythroid-specific cytoskeletal protein. We further show an association between deficiency in Slc4a1 and mitotic defects in the mouse. Rescue experiments in ret zebrafish embryos expressing transgenic slc4a1 with a variety of mutations show that the requirement for band 3 in normal erythroid mitosis is mediated through its protein 4.1R-binding domains. Our report establishes an evolutionarily conserved role for band 3 in erythroid-specific cell division and illustrates the concept of cell-specific adaptation for mitosis.     

The consistency,coherence and calibration of holistic,decomposed and recomposed judgemental probability forecasts

In this paper we make an empirical investigation of the relationship between the consistency, coherence and validity of probability judgements in a real-world forecasting context. Our results indicate that these measures of the adequacy of an individual's probability assessments are not closely related as we anticipated. Twenty-nine of our thirty-six subjects were better calibrated in point probabilities than in odds and our subjects were, in general more coherent using point probabilities than odds forecasts. Contrary to our expectations we found very little difference in forecasting response and performance between simple and compound holistic forecasts. This result is evidence against the ‘divide-and-conquer’ rationale underlying most applications of normative decision theory. In addition, our recompositions of marginal and conditional assessments into compound forecasts were no better calibrated or resolved than their holistic counterparts. These findings convey two implications for forecasting. First, untrained judgemental forecasters should use point probabilities in preference to odds. Second, judgemental forecasts of complex compound probabilities may be as well assessed holistically as they are using methods of decomposition and recomposition. In addition, our study provides a paradigm for further studies of the relationship between consistency, coherence and validity in judgemental probability forecasting.