Lysosomal multienzyme complex: pros and cons of working together

The ubiquitous distribution of lysosomes and their heterogeneous protein composition reflects the versatility of these organelles in maintaining cell homeostasis and their importance in tissue differentiation and remodeling. In lysosomes, the degradation of complex, macromolecular substrates requires the synergistic action of multiple hydrolases that usually work in a stepwise fashion. This catalytic machinery explains the existence of lysosomal enzyme complexes that can be dynamically assembled and disassembled to efficiently and quickly adapt to the pool of substrates to be processed or degraded, adding extra tiers to the regulation of the individual protein components. An example of such a complex is the one composed of three hydrolases that are ubiquitously but differentially expressed: the serine carboxypeptidase, protective protein/cathepsin A (PPCA), the sialidase, neuraminidase-1 (NEU1), and the glycosidase β-galactosidase (β-GAL). Next to this ‘core’ complex, the existence of sub-complexes, which may contain additional components, and function at the cell surface or extracellularly, suggests as yet unexplored functions of these enzymes. Here we review how studies of basic biological processes in the mouse models of three lysosomal storage disorders, galactosialidosis, sialidosis, and GM1-gangliosidosis, revealed new and unexpected roles for the three respective affected enzymes, Ppca, Neu1, and β-Gal, that go beyond their canonical degradative activities. These findings have broadened our perspective on their functions and may pave the way for the development of new therapies for these lysosomal storage disorders.     

Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells

Immunoglobulin-A has an irreplaceable role in the mucosal defence against infectious microbes. In human and mouse, IgA-producing plasma cells comprise approximately 20% of total plasma cells of peripheral lymphoid tissues, whereas more than 80% of plasma cells produce IgA in mucosa-associated lymphoid tissues (MALT). One of the most biologically important and long-standing questions in immunology is why this 'biased' IgA synthesis takes place in the MALT but not other lymphoid organs. Here we show that IgA class-switch recombination (CSR) is impaired in inducible-nitric-oxide-synthase-deficient (iNOS-/-; gene also called Nos2) mice. iNOS regulates the T-cell-dependent IgA CSR through expression of transforming growth factor-beta receptor, and the T-cell-independent IgA CSR through production of a proliferation-inducing ligand (APRIL, also called Tnfsf13) and a B-cell-activating factor of the tumour necrosis factor (TNF) family (BAFF, also called Tnfsf13b). Notably, iNOS is preferentially expressed in MALT dendritic cells in response to the recognition of commensal bacteria by toll-like receptor. Furthermore, adoptive transfer of iNOS+ dendritic cells rescues IgA production in iNOS-/- mice. Further analysis revealed that the MALT dendritic cells are a TNF-alpha/iNOS-producing dendritic-cell subset, originally identified in mice infected with Listeria monocytogenes. The presence of a naturally occurring TNF-alpha/iNOS-producing dendritic-cell subset may explain the predominance of IgA production in the MALT, critical for gut homeostasis.     

The mathematician Rehuel Lobatto advocates life insurances in The Netherlands in the period 1830–1860

In 1807 the first life insurance society was established in The Netherlands. In the second half of the century, life insurance societies underwent considerable expansion. During the intervening period, the lines had to be laid along which this new phenomenon was to develop in the future: between 1827 and 1830, the government started discussing the nature of its responsibility in this field and the kind of policy to be developed, and in 1830, a book on the organization of life insurance societies, the calculation of life annuities and widows' fund premiums was published, written by the mathematician Rehuel Lobatto. This book played an important role in the government's discussion. Royal Decrees which prescribed government approval for the establishment of life assurance societies were promulgated in 1830, 1833 and 1840. In 1832, Lobatto became the government's scientific adviser on the assessment of the calculations performed by these societies, and in the same year, he was also appointed adviser to the first life insurance society. From 1832 until his death in 1866 he advised the company on the use of life tables for life as well as for reversionary annuities, and he calculated the premiums based on these life tables. Another decree was promulgated in 1864 prescribing exactly which life tables were to be used. Because Lobatto probably played a part in this decree, he was responsible for a very ‘conservative’ government policy, which was no longer adequate in the second half of the century.     

An open environment for cooperative equational solving

We describe a system called CFLP which aims at the integration of the best features of functional logic programming (FLP), cooperative constraint solving (CCS), and distributed computing. FLP provides support for defining one’s own abstractions over a constraint domain in an easy and comfortable way, whereas CCS is employed to solve systems of mixed constraints by iterating specialized constraint solving methods in accordance with a well defined strategy. The system is a distributed implementation of a cooperative constraint functional logic programming scheme that combines higher-order lazy narrowing with cooperative constraint solving. The model takes advantage of the existence of several constraint solving resources located in a distributed environment (e. g., a network of computers), which communicate asynchronously via message passing. To increase the openness of the system, we are redesigning CFLP based on CORBA. We discuss some design and implementation issues of the system.     

Neuropeptides and the microcircuitry of the enteric nervous system

Summary The discovery of neuropeptides in enteric neurons has revolutionized the study of the microcircuitry of the enteric nervous system. Form immunohistochemistry, it is now clear that some individual enteric neurons contain several different neuropeptides with or without other transmitter-specific markers and that these markers occur in various combinations. There is evidence from experiments in which nerve pathways are interrupted that populations of enteric neurons with different combinations of markers have different projection patterns, sending their processes to distinct targets using different routes. Correlations between the neurochemistry of enteric neurons and the types of synaptic inputs they receive are also beginning to emerge from electrophysiological studies. These findings imply that enteric neurons are chemically coded by the combinations of peptides and other transmitter-related substances they contain and that the coding of each population correlates with its role in the neuronal pathways that control gastrointestinal function.     

Reduction of ferricytochrome c by human red cells

Summary Human red cells reduced extracellular ferricytochrome c to ferrocytochrome c under various conditions, suggesting that ferricytochrome c reducing systems are present at the outer surface of the red cell membrane.     

Genome sequencing and analysis of Aspergillus oryzae

The genome of Aspergillus oryzae, a fungus important for the production of traditional fermented foods and beverages in Japan, has been sequenced. The ability to secrete large amounts of proteins and the development of a transformation system have facilitated the use of A. oryzae in modern biotechnology. Although both A. oryzae and Aspergillus flavus belong to the section Flavi of the subgenus Circumdati of Aspergillus, A. oryzae, unlike A. flavus, does not produce aflatoxin, and its long history of use in the food industry has proved its safety. Here we show that the 37-megabase (Mb) genome of A. oryzae contains 12,074 genes and is expanded by 7-9 Mb in comparison with the genomes of Aspergillus nidulans and Aspergillus fumigatus. Comparison of the three aspergilli species revealed the presence of syntenic blocks and A. oryzae-specific blocks (lacking synteny with A. nidulans and A. fumigatus) in a mosaic manner throughout the genome of A. oryzae. The blocks of A. oryzae-specific sequence are enriched for genes involved in metabolism, particularly those for the synthesis of secondary metabolites. Specific expansion of genes for secretory hydrolytic enzymes, amino acid metabolism and amino acid/sugar uptake transporters supports the idea that A. oryzae is an ideal microorganism for fermentation.