A transgenic insertion upstream of sox9 is associated with dominant XX sex reversal in the mouse

In most mammals, male development is triggered by the transient expression of the Y-chromosome gene, Sry, which initiates a cascade of gene interactions ultimately leading to the formation of a testis from the indifferent fetal gonad. Several genes, in particular Sox9, have a crucial role in this pathway. Despite this, the direct downstream targets of Sry and the nature of the pathway itself remain to be clearly established. We report here a new dominant insertional mutation, Odsex (Ods), in which XX mice carrying a 150-kb deletion (approximately 1 Mb upstream of Sox9) develop as sterile XX males lacking Sry. During embryogenesis, wild-type XX fetal gonads downregulate Sox9 expression, whereas XY and XX Ods/+ fetal gonads upregulate and maintain its expression. We propose that Ods has removed a long-range, gonad-specific regulatory element that mediates the repression of Sox9 expression in XX fetal gonads. This repression would normally be antagonized by Sry protein in XY embryos. Our data are consistent with Sox9 being a direct downstream target of Sry and provide genetic evidence to support a general repressor model of sex determination in mammals.     

Dexamethasone enhances CTLA-4 expression during T cell activation

T cell activation is enhanced by the costimulatory interaction of B7 on antigen-presenting cells and CD28 on T cells, resulting in long-term T cell proliferation, differentiation and production of large amounts of cytokines, such as interleukin (IL)-2. CTLA-4 is a co-stimulation receptor that shares 31% homology with CD28 and binds B7 family members with higher affinity. CTLA-4 is transiently expressed intracellularly and on the cell surface following activation of T cells. We have studied the kinetics of CTLA-4 expression and the effects of dexamethasone on CTLA-4 expression during T cell activation in cultures of mouse spleen cells stimulated by a mixture of immobilized anti-CD3 and anti-CD28 monoclonal antibodies (anti-CD3/CD28 mAb) or concanavalin A (ConA). CTLA-4 expression peaked on day 2 and returned to background levels after 7 days. Dexamethasone was found to potentiate CTLA-4 expression in a dose-dependent manner with an EC₅₀ effective concentration 50%) of about 10⁻⁸ M. In contrast, other immunosuppressive agents, such as rapamycin or cyclosporin A had no or an inhibitory effect on CTLA-4 expression, respectively. Dexamethasone also stimulated CD28 expression, but inhibited IL-2R expression during anti-CD3/CD28 mAb-induced mouse splenic T cell activation. Western blot analyses of lysates of activated mouse T cells showed that dexamethasone increased CTLA-4 protein levels twofold during anti-CD3/CD28 mAb-induced activation. Dexamethasone also enhanced CTLA-4 messenger RNA twofold as quantified by ribonuclease protection assay. The effects of dexamethasone on CTLA-4 expression were glucocorticoid-specific and completely inhibited by the glucocorticoid receptor antagonist mifepristone (RU486), indicating that the effect of dexamethasone on CTLA-4 expression is mediated through the glucocorticoid receptor. In conclusion, the immunosuppressive agent dexamethasone actually stimulates CTLA-4 expression, which is involved in downregulation of T cell activation. Received 19 May 1999; received after revision 13 July 1999; accepted 13 July 1999     

Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus.

The metabolic pathways that produce 11-cis retinal are important for vision because this retinoid is the chromophore residing in rhodopsin and the cone opsins. The all-trans retinal that is generated after cone and rod photopigments absorb photons of light is recycled back to 11-cis retinal by the retinal pigment epithelium and Müller cells of the retina. Several of the enzymes involved have recently been purified and molecularly cloned; here we focus on 11-cis retinol dehydrogenase (encoded by the gene RDH5; chromosome 12q13-14; ref. 4), the first cloned enzyme in this pathway. This microsomal enzyme is abundant in the retinal pigment epithelium, where it has been proposed to catalyse the conversion of 11-cis retinol to 11-cis retinal. We evaluated patients with hereditary retinal diseases featuring subretinal spots (retinitis punctata albescens and fundus albipunctatus) and patients with typical dominant or recessive retinitis pigmentosa for mutations in RDH5. Mutations were found only in two unrelated patients, both with fundus albipunctatus; they segregated with disease in the respective families. Recombinant mutant 11-cis retinol dehydrogenases had reduced activity compared with recombinant enzyme with wild-type sequence. Our results suggest that mutant alleles in RDH5 are a cause of fundus albipunctatus, a rare form of stationary night blindness characterized by a delay in the regeneration of cone and rod photopigments.     

Effects of atmospheric pollution on human health

Most air pollutants do not lead to specific diseases. Depending on the pollutant, the concentration and the duration of exposure, some organs are more affected than others. The most frequent disorders are those caused by irritant gases and particulates on the mucous membranes and respiratory organs. The consequences are eye, nose and throat inflammations, diminished lung function, increased susceptability to respiratory infection and a higher incidence of chronic bronchitis. These disorders and diseases are, of course, influenced by other factors as well, such as immune deficiency, allergies, occupational exposure to pollutants, and particularly smoking. The effects of air pollutants are, therefore, multifactorially conditioned and nonspecific disorders are placed in the foreground. Evidence for an association of air pollution with adverse effects on human health is drawn from three sources: animal experiments, experimental human exposures, and epidemiologic studies of exposed human populations. The burden of atmospheric pollution must be reduced to protect human health by an adequate safety margin. In particular, the increased sensitivity of sick and aged people as well as children should be taken into account. In defining the maximum emmission levels, preventive aspects should have priority so as to keep the risk of damage to health and the harmful influences on the environment to a minimum.This article Effects of atmospheric pollution on human health by H. U. Wanner is a revised version of the same article that was first published in the Proceedings of the 1990 European Aerosol Conference; special issue of the J. Aerosol Sci., Vol. 21, Suppl. 1 (1990) 389–396.Reprinted with kind permission from Pergamon Press Ltd, Headington Hill Hall, Oxford OX3 0BW, Great Britain.     

Depletion and repletion of noradrenaline in adrenergic nerves of the rat after decaborane treatment

Zusammenfassung Mit Hilfe der Fluoreszenz-Technik werden die Veränderungen in sympathischen Fasern der Ratteniris nach Noradrenalin-Depletion durch Boron-Hydrid Decarboran (Dopa-Dekarboxylase-Hemmer) analysiert.

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This work has been supported by grants from the Swedish Medical Research Council under project No. B70-14x-97-06B, B70-14x-711-05B and Knut and Alice Wallenberg Foundation.     

Southern Ocean sea-ice extent, productivity and iron flux over the past eight glacial cycles

Sea ice and dust flux increased greatly in the Southern Ocean during the last glacial period. Palaeorecords provide contradictory evidence about marine productivity in this region, but beyond one glacial cycle, data were sparse. Here we present continuous chemical proxy data spanning the last eight glacial cycles (740,000 years) from the Dome C Antarctic ice core. These data constrain winter sea-ice extent in the Indian Ocean, Southern Ocean biogenic productivity and Patagonian climatic conditions. We found that maximum sea-ice extent is closely tied to Antarctic temperature on multi-millennial timescales, but less so on shorter timescales. Biological dimethylsulphide emissions south of the polar front seem to have changed little with climate, suggesting that sulphur compounds were not active in climate regulation. We observe large glacial-interglacial contrasts in iron deposition, which we infer reflects strongly changing Patagonian conditions. During glacial terminations, changes in Patagonia apparently preceded sea-ice reduction, indicating that multiple mechanisms may be responsible for different phases of CO2 increase during glacial terminations. We observe no changes in internal climatic feedbacks that could have caused the change in amplitude of Antarctic temperature variations observed 440,000 years ago.     

低强度瞬态电磁场下动物细胞的电穿孔效应

用低强度瞬态电磁场处理动物细胞后,一些胞内蛋白可以溢出细胞,荧光标记抗体蛋白（ＩｇＧ）可以进入细胞,通过扫描电镜观察到红细胞膜上有电致孔洞,证实了低强度瞬态电磁场作用能起电穿孔。