A RING-type ubiquitin ligase family member required to repress follicular helper T cells and autoimmunity

Despite the sequencing of the human and mouse genomes, few genetic mechanisms for protecting against autoimmune disease are currently known. Here we systematically screen the mouse genome for autoimmune regulators to isolate a mouse strain, sanroque, with severe autoimmune disease resulting from a single recessive defect in a previously unknown mechanism for repressing antibody responses to self. The sanroque mutation acts within mature T cells to cause formation of excessive numbers of follicular helper T cells and germinal centres. The mutation disrupts a repressor of ICOS, an essential co-stimulatory receptor for follicular T cells, and results in excessive production of the cytokine interleukin-21. sanroque mice fail to repress diabetes-causing T cells, and develop high titres of autoantibodies and a pattern of pathology consistent with lupus. The causative mutation is in a gene of previously unknown function, roquin (Rc3h1), which encodes a highly conserved member of the RING-type ubiquitin ligase protein family. The Roquin protein is distinguished by the presence of a CCCH zinc-finger found in RNA-binding proteins, and localization to cytosolic RNA granules implicated in regulating messenger RNA translation and stability.     

Closing the spin gap in the Kondo insulator Ce3Bi4Pt3 at high magnetic fields

Kondo insulator materials--such as CeRhAs, CeRhSb, YbB12, Ce3Bi4Pt3 and SmB6--are 3d, 4f and 5f intermetallic compounds that have attracted considerable interest in recent years. At high temperatures, they behave like metals. But as temperature is reduced, an energy gap opens in the conduction band at the Fermi energy and the materials become insulating. This contrasts with other f-electron compounds, which are metallic at all temperatures. The formation of the gap in Kondo insulators has been proposed to be a consequence of hybridization between the conduction band and the f-electron levels, giving a 'spin' gap. If this is indeed the case, metallic behaviour should be recovered when the gap is closed by changing external parameters, such as magnetic field or pressure. Some experimental evidence suggests that the gap can be closed in SmB6 (refs 5, 8) and YbB12 (ref. 9). Here we present specific-heat measurements of Ce3Bi4Pt3 in d.c. and pulsed magnetic fields up to 60 tesla. Numerical results and the analysis of our data using the Coqblin-Schrieffer model demonstrate unambiguously a field-induced insulator-to-metal transition.     

Atom transfer mechanisms in oxidation processes

The emphasis placed on electron transfer in connection with oxidation reactions has often resulted in these processes being considered as a group apart from the main class of chemical reactions. Although some oxidations, for example certain exchange reactions between ions in solution, can be reasonably described as electron transfer processes, there are very many other oxidations, whose mechanisms are much better described in the familiar terms of modern organic chemistry.The use of isotopes as tracers has shown, that many oxidations proceed with transfer of atoms or groups from oxidant to reductant andvice versa; the use of the kinetic isotope effect has shown that such transfer is seldom an incidental process, but is almost always a part of the slow step of the reaction. In this paper, oxidations involving the transfer of such species as oxygen atoms, hydride ions, hydrogen atoms, chlorine atoms, and hydroxyl radicals are discussed in terms of mechanism. An attempt is made to show that a graded series of mechanisms is possible ranging from what appear to be pure electron transfer processes at one end to certain atom transfer processes at the other. The latter group belong, in fact, in the familiar realm of ordinary chemical raactions, in which strong bonds are being broken and formed in the activated complex.Contribution from Department of Chemistry, University of British Columbia, Vancouver. — Presented at the Organic Chemistry Symposium of the Chemical Institute of Canada, Ottawa, Dec. 8–9, 1958.     

Atypical mast cell degranulation and focal hydropic degeneration of venular endothelium in diffuse fibrosing alveolitis

Atypical scroll-like and tubular degranulation of mast cells closely associated with focal endothelial hydropic degeneration is reported in human lung from 4 patients with diffuse fibrosing alveolitis in which the predominant abnormality was hyperplasia and desquamation of type 2 pneumocytes.     

Plutonium-based superconductivity with a transition temperature above 18 K

Plutonium is a metal of both technological relevance and fundamental scientific interest. Nevertheless, the electronic structure of plutonium, which directly influences its metallurgical properties, is poorly understood. For example, plutonium's 5f electrons are poised on the border between localized and itinerant, and their theoretical treatment pushes the limits of current electronic structure calculations. Here we extend the range of complexity exhibited by plutonium with the discovery of superconductivity in PuCoGa5. We argue that the observed superconductivity results directly from plutonium's anomalous electronic properties and as such serves as a bridge between two classes of spin-fluctuation-mediated superconductors: the known heavy-fermion superconductors and the high-T(c) copper oxides. We suggest that the mechanism of superconductivity is unconventional; seen in that context, the fact that the transition temperature, T(c) approximately 18.5 K, is an order of magnitude greater than the maximum seen in the U- and Ce-based heavy-fermion systems may be natural. The large critical current displayed by PuCoGa5, which comes from radiation-induced self damage that creates pinning centres, would be of technological importance for applied superconductivity if the hazardous material plutonium were not a constituent.     

A physical map of the mouse genome

A physical map of a genome is an essential guide for navigation, allowing the location of any gene or other landmark in the chromosomal DNA. We have constructed a physical map of the mouse genome that contains 296 contigs of overlapping bacterial clones and 16,992 unique markers. The mouse contigs were aligned to the human genome sequence on the basis of 51,486 homology matches, thus enabling use of the conserved synteny (correspondence between chromosome blocks) of the two genomes to accelerate construction of the mouse map. The map provides a framework for assembly of whole-genome shotgun sequence data, and a tile path of clones for generation of the reference sequence. Definition of the human-mouse alignment at this level of resolution enables identification of a mouse clone that corresponds to almost any position in the human genome. The human sequence may be used to facilitate construction of other mammalian genome maps using the same strategy.     

Dominant role of the niche in melanocyte stem-cell fate determination

Stem cells which have the capacity to self-renew and generate differentiated progeny are thought to be maintained in a specific environment known as a niche. The localization of the niche, however, remains largely obscure for most stem-cell systems. Melanocytes (pigment cells) in hair follicles proliferate and differentiate closely coupled to the hair regeneration cycle. Here we report that stem cells of the melanocyte lineage can be identified, using Dct-lacZ transgenic mice, in the lower permanent portion of mouse hair follicles throughout the hair cycle. It is only the population in this region that fulfils the criteria for stem cells, being immature, slow cycling, self-maintaining and fully competent in regenerating progeny on activation at early anagen (the growing phase of hair follicles). Induction of the re-pigmentation process in K14-steel factor transgenic mice demonstrates that a portion of amplifying stem-cell progeny can migrate out from the niche and retain sufficient self-renewing capability to function as stem cells after repopulation into vacant niches. Our data indicate that the niche has a dominant role in the fate determination of melanocyte stem-cell progeny.