The importance of sequence diversity in the aggregation and evolution of proteins

Incorrect folding of proteins, leading to aggregation and amyloid formation, is associated with a group of highly debilitating medical conditions including Alzheimer's disease and late-onset diabetes. The issue of how unwanted protein association is normally avoided in a living system is particularly significant in the context of the evolution of multidomain proteins, which account for over 70% of all eukaryotic proteins, where the effective local protein concentration in the vicinity of each domain is very high. Here we describe the aggregation kinetics of multidomain protein constructs of immunoglobulin domains and the ability of different homologous domains to aggregate together. We show that aggregation of these proteins is a specific process and that the efficiency of coaggregation between different domains decreases markedly with decreasing sequence identity. Thus, whereas immunoglobulin domains with more than about 70% identity are highly prone to coaggregation, those with less than 30-40% sequence identity do not detectably interact. A bioinformatics analysis of consecutive homologous domains in large multidomain proteins shows that such domains almost exclusively have sequence identities of less than 40%, in other words below the level at which coaggregation is likely to be efficient. We propose that such low sequence identities could have a crucial and general role in safeguarding proteins against misfolding and aggregation.     

Independent recruitment of a conserved developmental mechanism during leaf evolution

Vascular plants evolved in the Middle to Late Silurian period, about 420 million years ago. The fossil record indicates that these primitive plants had branched stems with sporangia but no leaves. Leaf-like lateral outgrowths subsequently evolved on at least two independent occasions. In extant plants, these events are represented by microphyllous leaves in lycophytes (clubmosses, spikemosses and quillworts) and megaphyllous leaves in euphyllophytes (ferns, gymnosperms and angiosperms). Our current understanding of how leaves develop is restricted to processes that operate during megaphyll formation. Because microphylls and megaphylls evolved independently, different mechanisms might be required for leaf formation. Here we show that this is not so. Gene expression data from a microphyllous lycophyte, phylogenetic analyses, and a cross-species complementation experiment all show that a common developmental mechanism can underpin both microphyll and megaphyll formation. We propose that this mechanism might have operated originally in the context of primitive plant apices to facilitate bifurcation. Recruitment of this pathway to form leaves occurred independently and in parallel in different plant lineages.     

Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells

The reduction of iron is an essential step in the transferrin (Tf) cycle, which is the dominant pathway for iron uptake by red blood cell precursors. A deficiency in iron acquisition by red blood cells leads to hypochromic, microcytic anemia. Using a positional cloning strategy, we identified a gene, six-transmembrane epithelial antigen of the prostate 3 (Steap3), responsible for the iron deficiency anemia in the mouse mutant nm1054. Steap3 is expressed highly in hematopoietic tissues, colocalizes with the Tf cycle endosome and facilitates Tf-bound iron uptake. Steap3 shares homology with F(420)H(2):NADP(+) oxidoreductases found in archaea and bacteria, as well as with the yeast FRE family of metalloreductases. Overexpression of Steap3 stimulates the reduction of iron, and mice lacking Steap3 are deficient in erythroid ferrireductase activity. Taken together, these findings indicate that Steap3 is an endosomal ferrireductase required for efficient Tf-dependent iron uptake in erythroid cells.     

Suppressed reduction of nitroblue tetrazolium by polymorphonuclear neutrophils from patients receiving steroids

Zusammenfassung Die Neutrophilen von Patienten mit Infektionskrankheiten zeigten verringerte Reduktion von NBT, wenn die Patienten zur gleichen Zeit Steroidhormone erhielten.     

Role of heavy water as solvent in the Antigen-Antibody precipitin reaction

Zusammenfassung Wenn die Lösung zu 50% aus schwerem Wasser bestand, blieb die Bildung von Antigen-Antikörperpräcipitat im Bereich des Antikörperüberschusses unverändert. Dies zeigt, dass die Substitution mit Deuterium die spezifischen Bindungseigenschaften nicht verändert. Dagegen fand sich eine erhöhte Niederschlagsmenge im Bereich des Antigenüberschusses, was auf eine Herabsetzung der Löslichkeit des normalerweise löslichen Antigen-Antikörperkomplexes hinweist.     

神经干细胞进展与移植

本书是由14位专家撰写的关于神经干细胞研究进展与移植方面的专著，介绍了发育与疾病中的神经干细胞模型，提供了有关的背景知识，讨论了干细胞谱系及决定其命运方面的内容，包括各个阶段特异性标志物及细胞命运标志物。传统来源及胚胎和神经干细胞特性在本书中也有所涉及。