Influence of the neonatal (clomiphene) inhibition of estradiol imprinting on gonadal development and gonadal and thyroid hormone production later in life

Treatment of newborn rats with clomiphene citrate during the first 5 days of life gave rise to a marked decrease in body mass and to a still greater decrease in gonadal mass. A decrease was also observed in the testicular diameter of the males. The females showed a 43% increase in their estradiol levels over the control and an increase in the sensitivity to gonadotropins. Thyroxine level, which was also determined in view of the known gonadotropin-thyrotropin overlap, showed no change 6 weeks after pretreatment with clomiphene, while the thyroid gland responded to gonadotropin in the same manner as to thyrotropin.     

Attempts to control sand flies by insecticide-sprayed strips along the periphery of a village.

The customary method for controlling leishmaniasis and sand fly bites in Israel is the spraying of large quantities of residual insecticides on walls of houses and neighboring surfaces. However, the high summer temperatures, strong radiation, and dust limit the efficacy of the method. The sand fly vectors of Leishmania appeared to come uphill to the village of Kfar Adumim. Therefore, to block their path and improve control, beta-cyfluthrine or DDT were repeatedly sprayed on a strip of cloth that was stretched on the ground along and near the peripheral houses. The efficacy of the treatments was examined by comparing the proportions of sand flies that had been caught before and after the treatments, below and above the belt. The capture near the houses of sand flies that had been marked by colored sugar baits below the protective belt indicated that they were moving uphill and crossing the strip. The catches showed a gradual uphill decrease, up to the houses, in the number of sand flies. However, the proportions of sand flies caught in the different sites were similar before and after insecticide treatments showing that the belt was ineffective. Laboratory tests of pieces of the sprayed strip and exposure of sand flies to similar pieces indicated that the lack of effect was not caused by deficiency of insecticides.     

Conversion of normal human lymphocytes to tumor-specific immunoreactivity by xenogeneic Immune RNA: Blastogenic responses to soluble tumor antigens

Summary Lymphocyte blastogenesis was used as an assay of Immune RNA (I-RNA) activity. Normal, non-immune human lymphocytes following incubation with xenogeneic antitumor I-RNA extracted from the lymphoid organs of specifically immunized sheep underwent blastogenesis when exposed to solubilized human tumor antigens in vitro. Blastogenic responses were, unexpectedly, relatively specific for the tumor type used to immunize the I-RNA donor sheep. No significant blastogenic responses were elicited by the I-RNA extracts or by the antigen preparations themselves. This study suggests that normal, human lymphocytes incubated (sensitized) with I-RNA, in vitro, behave, in terms of antigen recognition, like lymphocytes which have previously been sensitized to tumor antigens and demonstrates that xenogeneic Immune RNA will mediate afferent limb immune responses to human tumor antigens.Supported, in part, by Public Health Service Grant CA-18321 from the National Institute of Health     

Seed and gland morphology in Euphorbia (Euphorbiaceae) with focus on their systematic and phylogenetic importance, a case study in Iranian highlands

A comprehensive study based on gland and seed micromorphology in Euphorbia (Euphorbiaceae) for species distributed in Iranian highlands is presented. A total of 86 species were studied. The gland structure was examined by direct field observations. Taxonomically important characters of glands were observed and measured: size, texture, shape, color, and horns. For species out of Iran herbarium materials were studied. Seed characteristics were examined using scanning electron microscopy (SEM) as well as dissecting light microscopy. Significant features are: seed size, seed shape, presence of caruncle, shape of caruncle, and seed surface ornamentation. A phylogenetic study using Maximum Parsimony (MP) and Bayesian Inference (BI) was performed based on sequences of nuclear DNA internal transcribed spacers (ITS) for selected species representing the main clades known in Euphorbia and with special focus on the species distributed in Iranian highlands. ITS sequences for 20 accessions representing 19 species are provided for the first time, and 48 accessions of 47 species were used from GenBank. The topologies of both analyses were congruent. The results indicate: (1) four main clades with high supports in subgen. Esula which are appropriate to be recognized at sectional rank. (2) E. larica is nested within clade A including few members of subgen. Rhizanthium and is closely related to sect. Balsamis, which is suggested here to be transferred from subgen. Esula into subgen. Rhizanthium. (3) E. osyridea of the monotypic subsect. Osyrideae is closely related to E. buhsei and to the members of sect. Esula. Tracing morphological characters on the phylogenetic tree shows that several morphological characters, such as seed ornamentation applied in previous subgeneric classification of the subgen. Esula, are homoplasious, but the gland structure and capsule surface characters are more reliable for classification purposes.     

Hypoxia effects on cell volume and ion uptake of cerebral microvascular endothelial cells

Increased transport of Na across an intact blood-brain barrier (BBB) contributes to cerebral edema formation in ischemic stroke. Our previous studies have shown that ischemic factors stimulate activity of a luminal BBB Na-K-Cl cotransporter, and we have hypothesized that during ischemia, the cotransporter together with the abluminal Na/K pump mediates increased transport of Na from blood into the brain. However, it is possible that elevated Na-K-Cl cotransporter activity could also cause cell swelling if it outpaces ion efflux pathways. The present study was conducted to evaluate the effects of hypoxia on intracellular volume of BBB cells. Cerebral microvascular endothelial cell (CMEC) monolayers were exposed to varying levels of hypoxia for 1 to 5 h in an O(2)-controlled glove box, and cell volume was assessed using 3-O-methyl-D-[(3)H]glucose and [(14)C]sucrose as markers of total and extracellular water space, respectively. Cells exposed to either 7.5%, 3%, or 1% O(2) showed gradual increases in volume (compared with 19% O(2) normoxic controls) that became significant after 3 or more hours. By ion chromatography methods, we also found that a 30-min exposure to 7.5% O(2) caused an increase in bumetanide-sensitive net Na uptake by the cells without increasing cell Na content. CMEC Na content was significantly increased, however, following 3 or more hours of exposure to 7.5% O(2). These findings are consistent with the hypothesis that during cerebral ischemia, the BBB Na-K-Cl cotransporter is stimulated to mediate transendothelial uptake of Na into the brain and that increased cotransporter activity also contributes to gradual swelling of the cells.     

Hsp90 recognizes a common surface on client kinases

Hsp90 is a highly abundant chaperone whose clientele includes hundreds of cellular proteins, many of which are central players in key signal transduction pathways and the majority of which are protein kinases. In light of the variety of Hsp90 clientele, the mechanism of selectivity of the chaperone toward its client proteins is a major open question. Focusing on human kinases, we have demonstrated that the chaperone recognizes a common surface in the amino-terminal lobe of kinases from diverse families, including two newly identified clients, NFkappaB-inducing kinase and death-associated protein kinase, and the oncoprotein HER2/ErbB-2. Surface electrostatics determine the interaction with the Hsp90 chaperone complex such that introduction of a negative charge within this region disrupts recognition. Compiling information on the Hsp90 dependence of 105 protein kinases, including 16 kinases whose relationship to Hsp90 is first examined in this study, reveals that surface features, rather than a contiguous amino acid sequence, define the capacity of the Hsp90 chaperone machine to recognize client kinases. Analyzing Hsp90 regulation of two major signaling cascades, the mitogen-activated protein kinase and phosphatidylinositol 3-kinase, leads us to propose that the selectivity of the chaperone to specific kinases is functional, namely that Hsp90 controls kinases that function as hubs integrating multiple inputs. These lessons bear significance to pharmacological attempts to target the chaperone in human pathologies, such as cancer.     

Contribution of the Atm protein to maintaining cellular homeostasis evidenced by continuous activation of the AP-1 pathway in Atm-deficient brains

Maintenance of genome stability is essential for keeping cellular homeostasis. The DNA damage response is a central component in maintaining genome integrity. Among of the most cytotoxic DNA lesions are double strand breaks (DSBs) caused by ionizing radiation or radiomimetic chemicals. ATM is missing or inactivated in patients with ataxia-telangiectasia. Ataxia-telangiectasia patients display a pleiotropic phenotype and suffer primarily from progressive ataxia caused by degeneration of cerebellar Purkinje and granule neurons. Additional features are immunodeficiency, genomic instability, radiation sensitivity, and cancer predisposition. Disruption of the mouse Atm locus creates a murine model of ataxia-telangiectasia that exhibits most of the clinical features of the human disease but very mild neuronal abnormality. The ATM protein is a multifunctional protein kinase, which serves as a master regulator of cellular responses to DSBs. There is growing evidence that ATM may be involved in addition to the DSB response in other processes that maintain processes in cellular homeostasis. For example, mounting evidence points to increased oxidative stress in the absence of ATM. Here we report that the AP-1 pathway is constantly active in the brains of Atm-deficient mice not treated with DNA damaging agents. A canonical activation (increased phosphorylation of mitogen-activated protein kinase kinase-4, c-Jun N-terminal kinase, and c-Jun) of the AP-1 pathway was found in Atm-deficient cerebra, whereas induction of the AP-1 pathway in Atm-deficient cerebella is likely to mediate elevated expression of c-Fos and c-Jun. Although Atm(+/+) mice are capable of responding to ionizing radiation by activating stress responses such as the AP-1 pathway, Atm-deficient mice display higher basal AP-1 activity but gradually lose their ability to activate AP-1 DNA-binding activity in response to ionizing radiation. Our results further demonstrate that inactivation of the ATM gene results in a state of constant stress.     

Seasonal effect of three desert halophytes on soil microbial functional diversity

The objective of this study was to evaluate the effect of some plant ecophysiological adaptations on soil microbial functional diversity in a Negev Desert ecosystem. Soil samples from the upper 0–10 cm layer were collected at the study site under three species of halophyte shrubs, Zygophyllum dumosum, Hammada scoparia, and Reaumuria negevensis. These halophytes represent the most typical cover of the Negev Desert and each of them develops complex strategies that enable greater adaptation and hence, survival. The microhabitat of the shrubs showed differences in trends and magnitude of organic matter content, electrical conductivity, total soluble nitrogen, microbial functional diversity, and C compound utilization. The trends are assumed to be driven by various mechanisms of shrub adaptation in order to be able to survive the harsh desert environment. This study provides evidence that ecophysiological strategies developed by halophytes force microbial communities (from the point of view of activity, composition, and substrate utilization) to adapt to a beneficial plant-microorganism relationship.