CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes

A long-standing paradox in cellular immunology concerns the conditional requirement for CD4+ T-helper (T(H)) cells in the priming of cytotoxic CD8+ T lymphocyte (CTL) responses in vivo. Whereas CTL responses against certain viruses can be primed in the absence of CD4+ T cells, others, such as those mediated through 'cross-priming' by host antigen-presenting cells, are dependent on T(H) cells. A clearer understanding of the contribution of T(H) cells to CTL development has been hampered by the fact that most T(H)-independent responses have been demonstrated ex vivo as primary cytotoxic effectors, whereas T(H)-dependent responses generally require secondary in vitro re-stimulation for their detection. Here, we have monitored the primary and secondary responses of T(H)-dependent and T(H)-independent CTLs and find in both cases that CD4+ T cells are dispensable for primary expansion of CD8+ T cells and their differentiation into cytotoxic effectors. However, secondary CTL expansion (that is, a secondary response upon re-encounter with antigen) is wholly dependent on the presence of T(H) cells during, but not after, priming. Our results demonstrate that T-cell help is 'programmed' into CD8+ T cells during priming, conferring on these cells a hallmark of immune response memory: the capacity for functional expansion on re-encounter with antigen.     

Engineering evolution to study speciation in yeasts

The Saccharomyces 'sensu stricto' yeasts are a group of species that will mate with one another, but interspecific pairings produce sterile hybrids. A retrospective analysis of their genomes revealed that translocations between the chromosomes of these species do not correlate with the group's sequence-based phylogeny (that is, translocations do not drive the process of speciation). However, that analysis was unable to infer what contribution such rearrangements make to reproductive isolation between these organisms. Here, we report experiments that take an interventionist, rather than a retrospective approach to studying speciation, by reconfiguring the Saccharomyces cerevisiae genome so that it is collinear with that of Saccharomyces mikatae. We demonstrate that this imposed genomic collinearity allows the generation of interspecific hybrids that produce a large proportion of spores that are viable, but extensively aneuploid. We obtained similar results in crosses between wild-type S. cerevisiae and the naturally collinear species Saccharomyces paradoxus, but not with non-collinear crosses. This controlled comparison of the effect of chromosomal translocation on species barriers suggests a mechanism for the generation of redundancy in the S. cerevisiae genome.     

Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin,a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1)

Hermansky-Pudlak syndrome (HPS; MIM 203300) is a genetically heterogeneous disorder characterized by oculocutaneous albinism, prolonged bleeding and pulmonary fibrosis due to abnormal vesicle trafficking to lysosomes and related organelles, such as melanosomes and platelet dense granules. In mice, at least 16 loci are associated with HPS, including sandy (sdy; ref. 7). Here we show that the sdy mutant mouse expresses no dysbindin protein owing to a deletion in the gene Dtnbp1 (encoding dysbindin) and that mutation of the human ortholog DTNBP1 causes a novel form of HPS called HPS-7. Dysbindin is a ubiquitously expressed protein that binds to alpha- and beta-dystrobrevins, components of the dystrophin-associated protein complex (DPC) in both muscle and nonmuscle cells. We also show that dysbindin is a component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1; refs. 9-11), which regulates trafficking to lysosome-related organelles and includes the proteins pallidin, muted and cappuccino, which are associated with HPS in mice. These findings show that BLOC-1 is important in producing the HPS phenotype in humans, indicate that dysbindin has a role in the biogenesis of lysosome-related organelles and identify unexpected interactions between components of DPC and BLOC-1.     

南极拉斯曼丘陵变质岩中氟磷镁石新多型(wagnerite-Ma5bc)的岩石学意义

通过详细的镜下矿物组合观察、单晶结构和电子探针成分测定,确定了南极拉斯曼丘陵与条带状堇青石-柱晶石片麻岩互层的片麻岩中产出的氟磷镁石Ma5bc新多型,氟磷镁石与磷灰石共生并以造岩矿物出现.贫钙不是氟磷镁石形成的必要条件,关键在于F,P和Mg供应充分,而钙对镁的活动相对不足,否则,将只能形成磷灰石.本区强烈发育的深熔作用可以造成浅、暗组分的分异和分别集中,F,P易集中于暗色富镁铁组分中,达一定浓度时即形成氟磷镁石.成分因素可能决定了氟磷镁石的出现与否,温压条件则导致氟磷镁石多型的变化:较高温环境下为无序多型,之后经历较缓慢的降温冷却过程后转变为有序多型,本区即Ma5bc多型.     

Science,sensitivity and the sociozoological scale: Constituting and complicating the human-animal boundary at the 1875 Royal Commission on Vivisection and beyond

Arnold Arluke and Clinton Sanders (1996) have argued that human societies index both humans and animals as belonging to particular rungs of the social hierarchy. They term this multispecies ranking the “sociozoological scale”. This paper will investigate how claims at the 1875 Royal Commission on Vivisection about the sensitivity of particular species and breeds not only reflected assumptions about human social hierarchy but also blurred the boundaries between the human and the animal in the process. It will further be shown how these claims were informed by 18th and 19th century humanitarianism, classism, scientific racism and evolutionary theory, and how these influences combined in claims-making about the relative capacity of particular animals to sense pain and ethical duties towards them that followed from this sensitivity. Particular attention will be given to the opposing efforts of commissioners Thomas Henry Huxley and Richard Holt Hutton to demarcate human and animal sensitivity and exempt companion animals from vivisection respectively. The paper concludes by considering the sociozoological orders constituted by the 1876 Cruelty to Animals Act, particularly through its focus on calculating pain, and the legacy and limitations of this constitution.     

Glutamine deprivation initiates reversible assembly of mammalian rods and rings

Rods and rings (RR) are protein assemblies composed of cytidine triphosphate synthetase type 1 (CTPS1) and inosine monophosphate dehydrogenase type 2 (IMPDH2), key enzymes in CTP and GTP biosynthesis. Small-molecule inhibitors of CTPS1 or IMPDH2 induce RR assembly in various cancer cell lines within 15 min to hours. Since glutamine is an essential amide nitrogen donor in these nucleotide biosynthetic pathways, glutamine deprivation was examined to determine whether it leads to RR formation. HeLa cells cultured in normal conditions did not show RR, but after culturing in media lacking glutamine, short rods (<2 μm) assembled after 24 h, and longer rods (>5 μm) formed after 48 h. Upon supplementation with glutamine or guanosine, these RR underwent almost complete disassembly within 15 min. Inhibition of glutamine synthetase with methionine sulfoximine also increased RR assembly in cells deprived of glutamine. Taken together, our data support the hypothesis that CTP/GTP biosynthetic enzymes polymerize to form RR in response to a decreased intracellular level of glutamine. We speculate that rod and ring formation is an adaptive metabolic response linked to disruption of glutamine homeostasis.