Characterization of endocrine gland-derived vascular endothelial growth factor signaling in adrenal cortex capillary endothelial cells.

Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) has been recently identified as a mitogen specific for the endothelium of steroidogenic glands. Here we report a characterization of the signal transduction of EG-VEGF in a responsive cell type, bovine adrenal cortex-derived endothelial (ACE) cells. EG-VEGF led to a time- and dose-dependent phosphorylation of p44/42 MAPK. This effect was blocked by pretreatment with pertussis toxin, suggesting that G alpha(i) plays an important role in mediating EG-VEGF-induced activation of MAPK signaling. The inhibitor of p44/42 MAPK phosphorylation PD 98059 resulted in suppression of both proliferation and migration in response to EG-VEGF. EG-VEGF also increased the phosphorylation of Akt in a phosphatidylinositol 3-kinase-dependent manner. Consistent with such an effect, EG-VEGF was a potent survival factor for ACE cells. We also identified endothelial nitric-oxide synthase as one of the downstream targets of Akt activation. Phosphorylation of endothelial nitric-oxide synthase in ACE cells was stimulated by EG-VEGF with a time course correlated to the Akt phosphorylation. Our data demonstrate that EG-VEGF, possibly through binding to a G-protein coupled receptor, results in the activation of MAPK p44/42 and phosphatidylinositol 3-kinase signaling pathways, leading to proliferation, migration, and survival of responsive endothelial cells.     

Increased expression of the neuropeptide Y receptor Y1 gene in the medial amygdala of transgenic mice induced by long-term treatment with progesterone or allopregnanolone

The neurosteroid allopregnanolone, a reduced metabolite of progesterone, induces anxiolytic effects by enhancing GABA(A) receptor function. Neuropeptide Y (NPY) and GABA are thought to interact functionally in the amygdala, and this interaction may be important in the regulation of anxiety. By using Y(1)R/LacZ transgenic mice, which harbour a fusion construct comprising the promoter of the mouse gene for the Y(1) receptor for NPY linked to the lacZ gene, we previously showed that long-term treatment with benzodiazepine receptor ligands modulates Y(1) receptor gene expression in the medial amygdala. We have now investigated the effects of prolonged treatment with progesterone or allopregnanolone on Y(1)R/LacZ transgene expression, as determined by quantitative histochemical analysis of beta-galactosidase activity. Progesterone increased both the cerebrocortical concentration of allopregnanolone and beta-galactosidase expression in the medial amygdala. Finasteride, a 5alpha-reductase inhibitor, prevented both of these effects. Long-term administration of allopregnanolone also increased both the cortical concentration of this neurosteroid and transgene expression in the medial amygdala. Treatment with neither progesterone nor allopregnanolone affected beta-galactosidase activity in the medial habenula. These data suggest that allopregnanolone regulates Y(1) receptor gene expression through modulation of GABA(A) receptor function, and they provide further support for a functional interaction between GABA and neuropeptide Y in the amygdala.     

Measuring Emotional Contagion in Social Media

Social media are used as main discussion channels by millions of individuals every day. The content individuals produce in daily social-media-based micro-communications, and the emotions therein expressed, may impact the emotional states of others. A recent experiment performed on Facebook hypothesized that emotions spread online, even in absence of non-verbal cues typical of in-person interactions, and that individuals are more likely to adopt positive or negative emotions if these are over-expressed in their social network. Experiments of this type, however, raise ethical concerns, as they require massive-scale content manipulation with unknown consequences for the individuals therein involved. Here, we study the dynamics of emotional contagion using a random sample of Twitter users, whose activity (and the stimuli they were exposed to) was observed during a week of September 2014. Rather than manipulating content, we devise a null model that discounts some confounding factors (including the effect of emotional contagion). We measure the emotional valence of content the users are exposed to before posting their own tweets. We determine that on average a negative post follows an over-exposure to 4.34% more negative content than baseline, while positive posts occur after an average over-exposure to 4.50% more positive contents. We highlight the presence of a linear relationship between the average emotional valence of the stimuli users are exposed to, and that of the responses they produce. We also identify two different classes of individuals: highly and scarcely susceptible to emotional contagion. Highly susceptible users are significantly less inclined to adopt negative emotions than the scarcely susceptible ones, but equally likely to adopt positive emotions. In general, the likelihood of adopting positive emotions is much greater than that of negative emotions.     

Rat pheochromocytoma tyrosine hydroxylase is phosphorylated on serine 40 by an associated protein kinase

Tyrosine hydroxylase, a key enzyme in the biosynthesis of catecholamines, was previously shown to be phosphorylated on four distinct serine residues in PC12 cell cultures, each one being specific for the kinase system involved (McTigue, M., Cremins, J., and Halegoua, S. (1985) J. Biol. Chem. 260, 9047-9056). A cAMP- and Ca2+-independent protein kinase was found to be associated with tyrosine hydroxylase purified from rat pheochromocytoma tumor. The use of this activity and the availability of a large amount of purified tyrosine hydroxylase allowed identification of the site phosphorylated by this kinase activity. A peptide of 1.5 kDa (about 12 residues long), carrying the phosphorylation site, was released from 32P-labeled tyrosine hydroxylase by limited proteolysis with trypsin. This peptide was isolated from trypsinized tyrosine hydroxylase by sequential gel filtration and ion exchange chromatographies. Analysis by thin layer chromatography of an acid hydrolysate of the peptide revealed that it contained phosphoserine. The sequence determination of the peptide showed that it corresponded to the residues 38-45 in the tyrosine hydroxylase primary structure (Arg-Gln-Ser(P)-Leu-Ile-Glu-Asp-Ala). Thus, the associated kinase phosphorylated Ser-40, one of the phosphorylation sites for the cAMP-dependent protein kinase also found in rat pheochromocytoma tumors. These results are compared to those recently appearing in a report by Campbell et al. (Campbell, D. G., Hardie, D. G., and Vulliet, P. R. (1986) J. Biol. Chem. 261, 10489-10492).     

Alloreactive lymphocytes from T cell receptor (beta-chain) transgenic mice do not mediate a graft-versus-host reaction.

The injection of mature T cells into a tolerant or immunocompromised allogeneic host animal produces a graft versus host response (GVHR) that can result in splenomegaly, immunosuppression and death of the host animal. We demonstrate here that lymphocytes from T cell receptor beta-chain (TCR-beta) transgenic mice, in which the expression of the transgene inhibits endogenous beta- and gamma-gene rearrangements and thus causes abnormal T cell development, are unable to mediate a GVHR. The GVHR was measured after the injection of lymphocytes from transgenic mice into normal F1 mice and also after transplantation of bone marrow and lymphocytes from transgenic mice into lethally irradiated F1 recipients. In both systems, cells from transgenic mice failed to produce a significant GVHR. Cells from the transgenic mice were able to recognize the foreign histocompatibility Ag of the host in vitro and in vivo although the transgenic mice rejected skin grafts more slowly than controls. Thus, lymphocytes from transgenic mice were unable to produce a GVHR despite the presence of alloreactive T cells. These results suggest that lymphocytes from TCR-beta transgenic mice fail to mediate a GVHR either because lymphocytes with a single transgenic TCR-beta chain have a limited ability to recognize allogeneic cells in vivo or because the transgenic mice lack lymphocyte subsets that are important for the mediation of a GVHR.     

The merrit alloantigenic system of human B lymphocytes: evidence for thirteen possible factors including one six-member segregant series.

An analysis of the typing results of a 70-member chronic lymphatic leukemia B cell panel revealed evidence for 13 possible groups of the Merrit alloantigenic system. Six of these appeared possibly allelic and may represent a segregant series. The CLL panel was also fully typed for HLA and some degree of linkage dysequilibrium between Merrit and HLA seemed apparent from the data. Merrit antibodies can be absorbed out with selected surface membrane immunoglobulin (SMIG)-positive normal lymphocytes and less so or not at all with E rosette-forming T cells or Fc-positive SMIG-negative lymphocytes.     

Probing the structure and function of the estrogen receptor ligand binding domain by analysis of mutants with altered transactivation characteristics.

We have developed a genetic screen for the yeast Saccharomyces cerevisiae to isolate estrogen receptor (ER) mutants with altered transactivation characteristics. Use of a "reverse" ER, in which the mutagenized ligand binding domain was placed at the N terminus of the receptor, eliminated the isolation of truncated constitutively active mutants. A library was screened with a low-affinity estrogen, 2-methoxyestrone (2ME), at concentrations 50-fold lower than those required for activation of the unmutagenized ER. Several mutants displaying enhanced sensitivity to 2ME were isolated. We further characterized a mutant carrying the substitution L536P, which was located immediately N terminal to the AF-2-activating domain of the receptor. Amino acid 536 corresponds to a ligand contact residue in retinoic acid receptor gamma, suggesting that key contact points are conserved among receptors. Introduction of L536P into the original ER cDNA isolate HE0, which contains the substitution G400V, rendered the receptor more sensitive to a variety of agonists. When introduced into the wild-type ER HEG0, L536P also rendered the receptor more sensitive to agonists, and, in addition, induced high levels of constitutive activity that could be inhibited by antiestrogens. Estrogens containing a keto substitution in the steroid D ring, but not those containing a hydroxyl group, were full agonists of L536P-HEG0. Limited proteolytic analysis suggested that the L536P substitution, which is located immediately N terminal to the AF-2 domain, induces a conformational change in the ER that partially mimics binding by hormone. Both HEG0 and L536P-HEG0 formed complexes with hsp90 in vitro, indicating a lack of correlation between interaction with hsp90 in vitro and hormonal regulation of ER transactivation in vivo. This supports the idea that a factor(s) acting downstream of hsp90 is important for controlling activity of the hormone-free receptor.     

<Emphasis Type="Italic">Candida auris</Emphasis>: Antifungal Multi-Resistant Emerging Yeast

Purpose of Review

The purpose of this review is to contribute to the knowledge about the existence of Candida auris as an emerging pathogenic fungus, multi-resistant to antifungal, and causing health care-associated infections (HCAI).

Recent Findings

C. auris emerges as yeast with clonal transmission resistance to three families of commonly used antifungals, mainly azoles (fluconazole and voriconazole), diminishing therapeutic options for the treatment of fungal infections. In 2009, C. auris was isolated for the first time in Japan and by the time of this review, it has been reported in different countries in Africa, America, Asia, and Europe.

Summary

It is important to identify yeasts of the Candida genus up to species, to perform susceptibility tests and to implement surveillance, prevention, and control measures, to minimize the global spread of this fungus, due to its impact on public health.