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Altered corticolimbic glutamate transmission is implicated in the origin of neuropsychiatric disorders. Homer proteins are a family of postsynaptic scaffolding proteins that regulate the synaptic localization of glutamate receptors. Dr. Karen Szumlinski University of California at Santa Barbara, Santa Barbara, Calif. ; in her talk "Homer regulations of corticolimbic glutamate: implications for neuropsychiatric disorders" presented a series of studies aimed at examining the role of Homer proteins in mesocortical glutamate transmission and behaviour. She showed that, in mice, deletion of Homer1 or Homer2 produces specific glutamatergic abnormalities that are associated with specific changes in behaviour, including changes in drug self-administration and drug-induced motor activation. The changes in glutamatergic function and behaviour are dependent on the type of Homer protein that is deleted. In addition, she showed that Homer1, but not Homer2, mutant mice exhibit abnormalities in cognitive and sensorimotor function that resemble those observed in schizophrenia, suggesting that Homer1 mutant mice may be used as a potential animal model of schizophrenia. Dr. Sheena Josselyn University of Toronto, Toronto ; talked about potential "Molecular mechanisms involved in fear learning" by placing special emphasis on the role of the CREB cyclic AMP response element binding protein ; family of transcription factors. CREB mutant mice have been shown to exhibit deficiencies in synaptic plasticity that correlate with deficits in several forms of long-term memory function, including auditory fear conditioning. By means of viralmediated gene transfer, Dr. Josselyn showed that "replacing" CREB directly in the amygdala of CREB mutant mice restores long-term memory for auditory conditioned fear, specifically. These data suggest that the amygdala is implicated in the storage of memory for auditory fear conditioning and that CREB-mediated mechanisms are involved in this process. Dr. Elena Chartoff Harvard University, Boston, Mass. ; talked about "Behavioral adaptations associated with nucleus accumbens CREB activation: Implications for depression." Increased CREB within the nucleus accumbens NA ; has been previously associated with aversive states in rats.
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FIG. 5. AR acetylation mutants convey contact-independent growth. A and B ; MTT assay of DU145 stable cell lines expressing either pcDNA3, wild-type AR, or AR acetylation site mutants. Equal numbers of cells were seeded into 96-well plates, treated with either DHT, TSA, or SAHA for 24 h, and the MTT assay was conducted, measuring absorbance at 570 nm. C and D ; DU145 cells stably expressing wild-type AR or AR acetylation site mutants were seeded in soft agar. Phase contrast image of the colonies from a representative experiment is shown magnification, 100 ; . Colony numbers and size percentage of colonies with 100 cells ; are shown at day 14. E and F ; Nude mice were implanted with 106 cells of stable lines expressing either wild-type AR or AR acetylation site mutants. The mean volume of DU145 tumors grown in nude mice were shown at each time point. G and H ; Apoptosis in implanted tumors was assessed by TUNEL staining for wild-type AR, ARK630Q, and ARK630T n 4.
Meda becomes a leading specialty pharma company in Europe through acquisition of Viatris, a German pharma group. Sale of the parallel trading operation implemented. The board proposes a new share issue with preferential rights for existing shareholders.
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In a previous study searching for highly effective antileishmanial drugs, we reported the in vitro activity of a series of mesoionic derivatives against Leishmania L. ; amazonensis . As a part of this program, we decided to assay some halogens groups of mesoionic derivatives against other two different species of Leishmania from the New World. As follow: Leishmania braziliensis that the usually caused mucocutaneous disease and is endemic in the state of Rio de Janeiro and Leishmania chagasi which is the causal agent of visceral leishmaniasis.These compounds, 4-phenyl-5- 4'and 3'halogen-cinnamoyl ; -1, 3, 4-thiadiazolium-2-phenylamine chlorides were assayed against L. braziliensis MCAN BR 98 R619 ; and L. chagasi MCAN BR 97 P142 ; promastigotes forms and the potential toxicity was also evaluated. Parasites were cultured with and without the drugs in Schneiders medium at 25C, using Pentamidine as reference drug. After 24 hours incubation, the drug activity was evaluated by counting the parasites in Neubauers chamber. The cytotoxicity effect of these halogens- derivatives was assayed on mice peritoneal macrophages with addition of MTT tetrazolium blue ; .The results showed that these compounds were less toxic than Pentamidine. In addition, mesoionic compounds such as 4'-F, 4'-Br and 3'-Cl were effective against both L. braziliensis 4'-F, LD50 5, 12, 5M; LD50 2, 930, 52M and 3'-Cl, and L. chagasi 4'-F, LD50 3, 420, 16M; LD50 1, 720, 49M ; LD50 9, 970, 08M and 3'-Cl, LD50 5, 170.47M ; . However, the data from our previous work showed that L. amazonensis promastigotes MHOM BR 77 LTB0016 ; had lower LD50 24h for these derivatives 4'-F, LD50 0, 380, 03M; 4'-Br, LD50 0, 410, 05M and 3'-Cl, LD50 0, 210.01M ; . The difference of effectiveness would be explained by the differences in the culture conditions such as higher concentration of fetal calf serum, resulting in a decrease in the drug availability. Besides, the metabolism from the three species should be different and this could be important for the treatment of leishmaniasis. Supported by CNPq PDTIS FIOCRUZ.
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