Helicobacter pylori CagA-dependent macrophage migration inhibitory factor produced by gastric epithelial cells binds to CD74 and stimulates procarcinogenic events

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that has recently been implicated in carcinogenesis. Helicobacter pylori, which is closely linked to gastric cancer, induces the gastric epithelium to produce proinflammatory cytokines, including MIF. MIF can bind to CD74, which we have previously shown to be highly expressed on the surface of gastric epithelial cells (GEC) during H. pylori infection. In this study, we sought to investigate the role of the H. pylori-induced MIF on epithelial proliferation and procarcinogenic events. Upon establishing a role for the H. pylori CagA virulence factor in MIF production, MIF binding to CD74 on GEC was confirmed. rMIF and H. pylori were shown to increase GEC proliferation, which was decreased when cagA- strains were used and when CD74 was blocked by mAbs. Apoptosis was also decreased by MIF, but increased by cagA- strains that induced much lower amounts of MIF than the wild-type bacteria. Furthermore, MIF binding to CD74 was also shown to decrease p53 phosphorylation and up-regulate Bcl-2 expression. This data describes a novel system in which an H. pylori virulence factor contributes to the production of a host factor that in turn up-regulates procarcinogenic events by the gastric epithelium.     

An evolutionary perspective on the resistance of Daphnia to the epizoic rotifer Brachionus rubens

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Seasonal seston stoichiometry: effects on zooplankton in cyanobacteria-dominated lakes

Seasonal dynamics in elemental composition [carbon (C), nitrogenand phosphorus (P)] of seston and zooplankton were studied overseveral years in three hypereutrophic Dutch lakes with persistentdominance and high biomass of cyanobacteria. In all three lakes,there was a strong pattern with decreased P-content and increasedC:P ratio in seston (<150 µm) coinciding with the increasein water temperature. The seston C:P ratios (at:at) were morethan doubled with the rising temperature, i.e. from 200 (at:at)in winter to 500 in summer. Sestonic C:P ratios increased overthe growing season, suggesting that seasonal dynamics amongautotrophs with high P-uptake in winter and support of subsequentphytoplankton growth by consumption of internal cellular P (P-quota)was the main cause of low sestonic P contents in late summer.This could, however, occur in concert with a physiologicallydriven decrease in cell-specific P at higher temperatures insummer. In contrast, the annual variation of C:P ratios of thezooplankton fraction was only 10% of that of seston. The variationsof C:P ratios of the zooplankton were, nevertheless, stronglycorrelated with those of seston. For most of the summer, sestonC:P ratios were far above the threshold ratio for P-limitationin Daphnia and other P-demanding species. This will pose furtherconstraints on growth performance of Daphnia in these lakes,thus adding to the fish predation pressure and the poor foodquality of cyanobacteria per se. The low grazing pressure causesa high biomass of low-quality autotrophs, promoting a stablestate with low trophic transfer efficiency.     

Inheritance of the group I rDNA intron in Tetrahymena pigmentosa

We have previously argued from phylogenetic sequence data that the group I intron in the rRNA genes of Tetrahymena was acquired by different Tetrahymena species at different times during evolution. We have now approached the question of intron mobility experimentally by crossing intron⁺ and intron^? strains looking for a strong polarity in the inheritance of the intron (intron homing). Based on the genetic analysis we find that the intron in T. pigmentosa is inherited as a neutral character and that intron⁺ and intron^? alleles segregate in a Mendelian fashion with no sign of intron homing. In an analysis of vegetatively growing cells containing intron⁺ and intron^? rDNA, initially in the same macronucleus, we similarly find no evidence of intron homing. During the course of this work, we observed to our surprise that progeny clones from some crosses contained three types of rDNA. One possible explanation is that T. pigmentosa has two rdn loci in contrast to the single locus found in T. thermophila. Some of the progeny clones from the genetic analysis were expanded for several hundred generations, and allelic assortment of the rDNA was demonstrated by subcloning analysis. © 1992 Wiley-Liss, Inc.     

Sex differences in the response to environmental cues regulating seasonal reproduction in birds

Although it is axiomatic that males and females differ in relation to many aspects of reproduction related to physiology, morphology and behaviour, relatively little is known about possible sex differences in the response to cues from the environment that control the timing of seasonal breeding. This review concerns the environmental regulation of seasonal reproduction in birds and how this process might differ between males and females. From an evolutionary perspective, the sexes can be expected to differ in the cues they use to time reproduction. Female reproductive fitness typically varies more as a function of fecundity selection, while male reproductive fitness varies more as a function sexual selection. Consequently, variation in the precision of the timing of egg laying is likely to have more serious fitness consequences for females than for males, while variation in the timing of recrudescence of the male testes and accompanying territory establishment and courtship are likely to have more serious fitness consequences for males. From the proximate perspective, sex differences in the control of reproduction could be regulated via the response to photoperiod or in the relative importance and action of supplementary factors (such as temperature, food supply, nesting sites and behavioural interactions) that adjust the timing of reproduction so that it is in step with local conditions. For example, there is clear evidence in several temperate zone avian species that females require both supplementary factors and long photoperiods in order for follicles to develop, while males can attain full gonadal size based on photoperiodic stimulation alone. The neuroendocrine basis of these sex differences is not well understood, though there are many candidate mechanisms in the brain as well as throughout the entire hypothalamo-pituitary-gonadal axis that might be important.     

Interaction of CheY2 and CheY2-P with the cognate CheA kinase in the chemosensory-signalling chain of Sinorhizobium meliloti

An unusual regulatory mechanism involving two response regulators, CheY1 and CheY2, but no CheZ phosphatase, operates in the chemotactic signalling chain of Sinorhizobium meliloti . Active CheY2-P, phosphorylated by the cognate histidine kinase, CheA, is responsible for flagellar motor control. In the absence of any CheZ phosphatase activity, the level of CheY2-P is quickly reset by a phospho-transfer from CheY2-P first back to CheA, and then to CheY1, which acts as a phosphate sink. In studying the mechanism of this phosphate shuttle, we have used GFP fusions to show that CheY2, but not CheY1, associates with CheA at a cell pole. Cross-linking experiments with the purified proteins revealed that both CheY2 and CheY2-P bind to an isolated P2 ligand-binding domain of CheA, but CheY1 does not. The dissociation constants of CheA–CheY2 and CheA–CheY2-P indicated that both ligands bind with similar affinity to CheA. Based on the NMR structures of CheY2 and CheY2-P, their interactions with the purified P2 domain were analysed. The interacting surface of CheY2 comprises its C-terminal β4-α4-β5-α5 structural elements, whereas the interacting surface of CheY2-P is shifted towards the loop connecting β5 and α5. We propose that the distinct CheY2 and CheY2-P surfaces interact with two overlapping sites in the P2 domain that selectively bind either CheY2 or CheY2-P, depending on whether CheA is active or inactive.     

A reassessment of the effect of activated Notch1 on CD4 and CD8 T cell development

The Notch signaling pathway plays an important role in the early steps of T cell development and in the generation of T cell tumors, but its role in the CD4 vs CD8 lineage decision is controversial. Notch1 is not essential for CD4 or CD8 T cell development; however, there are suggestions that multiple Notch family members may act in a redundant fashion during thymic development. In theory, expressing a constitutively activated form of Notch in CD4(+)CD8(+) thymocytes could provide clues about the normal role of Notch in developing CD4 and CD8 T cells. Unfortunately, two different studies of transgenic mice expressing activated forms of Notch1 (Notch1IC) led to conflicting conclusions. In this study, we re-examine the effect of the two Notch1IC transgenes on thymocyte development. We find that both Notch1IC transgenic lines display a decrease in CD4 single positive (SP) thymocytes and a corresponding increase in CD8 SP thymocytes. The enhanced development of CD8 SP thymocytes is dependent on either class I or II MHC. Thus, data from two different Notch1IC transgenic lines indicate that Notch activity promotes CD8 and inhibits CD4 SP development. We suggest that the discrepancies in previous reports of Notch1IC transgenic mice are due to differences in the propensity of the two different transgenic lines to develop tumors.     

Dual selection pressure by drugs and HLA class I-restricted immune responses on human immunodeficiency virus type 1 protease

To determine the influence of human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cells on the development of drug resistance mutations in the HIV-1 protease, we analyzed protease sequences from viruses from a human leukocyte antigen class I (HLA class I)-typed cohort of 94 HIV-1-positive individuals. In univariate statistical analyses (Fisher's exact test), minor and major drug resistance mutations as well as drug-associated polymorphisms showed associations with HLA class I alleles. All correlations with P values of 0.05 or less were considered to be relevant without corrections for multiple tests. A subset of these observed correlations was experimentally validated by enzyme-linked immunospot assays, allowing the definition of 10 new epitopes recognized by CD8+ T cells from patients with the appropriate HLA class I type. Several drug resistance-associated mutations in the protease acted as escape mutations; however, cells from many patients were still able to generate CD8+ T cells targeting the escape mutants. This result presumably indicates the usage of different T-cell receptors by CD8+ T cells targeting these epitopes in these patients. Our results support a fundamental role for HLA class I-restricted immune responses in shaping the sequence of the HIV-1 protease in vivo. This role may have important clinical implications both for the understanding of drug resistance pathways and for the design of therapeutic vaccines targeting drug-resistant HIV-1.