Genetic Deletion of Mst1 Alters T Cell Function and Protects against Autoimmunity

Mammalian sterile 20-like kinase 1 (Mst1) is a MAPK kinase kinase kinase which is involved in a wide range of cellular responses, including apoptosis, lymphocyte adhesion and trafficking. The contribution of Mst1 to Ag-specific immune responses and autoimmunity has not been well defined. In this study, we provide evidence for the essential role of Mst1 in T cell differentiation and autoimmunity, using both genetic and pharmacologic approaches. Absence of Mst1 in mice reduced T cell proliferation and IL-2 production in vitro, blocked cell cycle progression, and elevated activation-induced cell death in Th1 cells. Mst1 deficiency led to a CD4⁺ T cell development path that was biased toward Th2 and immunoregulatory cytokine production with suppressed Th1 responses. In addition, Mst1^−/− B cells showed decreased stimulation to B cell mitogens in vitro and deficient Ag-specific Ig production in vivo. Consistent with altered lymphocyte function, deletion of Mst1 reduced the severity of experimental autoimmune encephalomyelitis (EAE) and protected against collagen-induced arthritis development. Mst1^−/− CD4⁺ T cells displayed an intrinsic defect in their ability to respond to encephalitogenic antigens and deletion of Mst1 in the CD4⁺ T cell compartment was sufficient to alleviate CNS inflammation during EAE. These findings have prompted the discovery of novel compounds that are potent inhibitors of Mst1 and exhibit desirable pharmacokinetic properties. In conclusion, this report implicates Mst1 as a critical regulator of adaptive immune responses, Th1/Th2-dependent cytokine production, and as a potential therapeutic target for immune disorders.     

Influence of wine-like conditions on arginine utilization by lactic acid bacteria

Wine can contain trace amounts of ethyl carbamate (EC), a carcinogen formed when ethanol reacts with carbamyl compounds such as citrulline. EC is produced from arginine by lactic acid bacteria (LAB), e.g., Lactobacillus and Pediococcus. Although the amounts of EC in wine are usually negligible, over the last few years there has been a slight but steady increase, as climate change has increased temperatures and alcohol levels have become proportionately higher, both of which favor EC formation. In this study, resting cells of LAB were used to evaluate the effects of ethanol, glucose, malic acid, and low pH on the ability of non-oenococcal strains of these bacteria to degrade arginine and excrete citrulline. Malic acid was found to clearly inhibit arginine consumption in all strains. The relation between citrulline produced and arginine consumed was clearly higher in the presence of ethanol (10-12%) and at low pH (3.0), which is consistent with both the decreased amount of ornithine produced from arginine and the reduction in arginine degradation. In L. brevis and L. buchneri strains isolated from wine and beer, respectively, the synthesis of citrulline from arginine was highest.     

The response of sorghum and sunflower to short-term waterlogging

Summary Sorghum and sunflower were waterlogged for nine days during the vegetative, floral initiation/buds-visible or anthesis stage of growth under glasshouse conditions to observe the effects on root growth and development. In addition, some plants were waterlogged at all three stages to observe any adaptations induced by waterlogging. The most marked effects occurred at the initiation/buds-visible stage where a 30% reduction in root length and a 40% reduction in root dry weight of sorghum occurred with comparable figures for sunflower being 50 and 60% respectively. Generally, sorghum roots had a higher porosity than sunflower which may contribute to its greater tolerance to waterlogging. The observed changes in root growth are discussed in relation to previously documented effects of waterlogging on growth of the two species and changes which occur in the soil environment.     

Invasive cane toads might initiate cascades of direct and indirect effects in a terrestrial ecosystem

Understanding the impacts that invasive vertebrates have on terrestrial ecosystems extends primarily to invaders’ impacts on species with which they interact directly through mechanisms such as predation, competition and habitat modification. In addition to direct effects, invaders can also initiate ecological cascades via indirect population level effects on species with which they do not directly interact. However, evidence that invasive vertebrates initiate ecological cascades in terrestrial ecosystems remains scarce. Here, we ask whether the invasion of the cane toad, a vertebrate invader that is toxic to many of Australia’s vertebrate predators, has induced ecological cascades in a semi-arid rangeland. We compared activity of a large predatory lizard, the sand-goanna, and abundances of smaller lizards preyed upon by goannas in areas of high toad activity near toads’ dry season refuges and areas of low toad activity distant from toads’ dry season refuges. Consistent with the hypothesis that toad invasion has led to declines of native predators susceptible to poisoning, goanna activity was lower in areas of high toad activity. Consistent with the hypothesis that toad-induced goanna decline lead to increases in abundance the prey of goannas, smaller lizards were more abundant in areas of high toad activity. Structural equation modelling showed a positive correlation between goanna activity and distance from dry season refuge habitats used by toads. The abundances of small lizards was correlated negatively with goanna activity and distance from dry season refuges of toads. Our findings provide support for the notion that invasions by terrestrial vertebrates can trigger ecological cascades.     

Deletion mapping of gliomas suggest the presence of two small regions for candidate tumor-suppressor genes in a 17-cM interval on chromosome 10q.

The loss of genetic material on chromosome 10q is frequent in different tumors and particularly in malignant gliomas. We analyzed 90 of these tumors and found loss of heterozygosity (LOH) in >90% of the informative loci in glioblastoma multiforme (GBM). Initial studies restricted the common LOH region to 10q24-qter. Subsequently, the study of a pediatric GBM suggested D10S221 and D10S209, respectively, as centromeric and telomeric markers of a 4-cM LOH region. It is interesting to note that, in one subset of cells from this tumor, locus D10S209 seems involved in the allelic imbalance of a larger region, with D10S214 as telomeric marker. This 17-cM region contains the D10S587-D10S216 interval of common deletion recently defined on another set of gliomas.     

Substitution reaction mechanisms of dihydrido-ruthenium(II) phosphine complexes: hydribe basicity and molecular hydrogen intermediates

Kinetic and activation parameter data for the reactions of cct-Ru(H)₂(CO)₂(PPh₃)₂ (1) (cct = cis, cis, trans) in THF with thiols, CO and PPh₃ to give cct-RuH(SR)(CO)₂(PPh₃)₂, Ru(CO)₃(PPh₃)₂ and Ru(CO)₂(PPh₃)₂, respectively, reveal a common, rate-determining step, the initial dissociation of H₂ from 1; the activated complex probably resembles the corresponding Ru(η²-H₂) species. Reaction of Ru(H)₂(dppm)₂ (2) (as a cis/trans mixture, DPPM = bis(diphenylphosphino)methane) with thiols initially generated cis- and trans- RuH(SR) (dppm)₂ with a rate that depends on both the type and concentration of thiol. The higher basicity of the hydride ligands in 2 (versus 1), which is demonstrated by deuterium exchange with CD₃OD, gives rise in the thiol reaction to an initial protonation step prior to loss of H₂. A species detected in the thiol reaction is possibly [RuH(η²-H₂ (dppm)₂]², the anticipated intermediate for this reaction and for the hydrogen exchange with alcohol. A longer reaction of 2 with PhCH₂SH gives solely cis-Ru(SCH₂Ph)₂(dppm)₂.