A role for Src kinase in progestin facilitation of estrous behavior in estradiol-primed female rats

This study tested the hypothesis that the Src/Raf/MAPK signaling pathway is involved in the facilitation of the lordosis and proceptive behaviors induced by progesterone (P) and its ring A-reduced metabolites in ovariectomized, estradiol-primed rats. Intraventricular (icv) infusion of PP2 (7.5, 15 and 30 µg), a Src kinase inhibitor, significantly depressed P-dependent estrous behavior (lordosis and proceptivity) in estradiol-primed rats. Icv infusion of 30 µg of PP2 also significantly attenuated estrous behavior induced by the ring A-reduced P metabolites 5α-dihydroprogesterone (5α-DHP) and 5α-pregnan-3α-ol-20-one (allopregnanolone). PP2 did not inhibit estrous behavior induced by administration of high doses of estradiol alone to ovariectomized rats. We also assessed if the ventromedial hypothalamus (VMH) is one of the neural sites at which progestins activate Src signaling to facilitate estrous behavior. Bilateral administration of 15 µg of PP2 into the VMH inhibited the stimulation of both lordosis and proceptive behaviors elicited by subcutaneous P administration to estradiol-primed rats. These results suggest that progestins act through Src/Raf/MAPK signaling to initiate estrous behaviors in estrogen-primed rats. This event is one component of the cellular pathways leading to the display of estrous behaviors induced by P and its ring A-reduced metabolites in female rats.     

Iron(III) and aluminum(III) complexes with hydroxypyrone ligands aimed to design kojic acid derivatives with new perspectives

With the aim to design new chelators for the clinical treatment of different diseases involving the trivalent metal ions Fe(III) and Al(III), we present the equilibria of kojic acid and its derivative 6-[5-hydroxy-2-hydroxymethyl-pyran-4-one]-5-hydroxy-2-hydroxymethyl-pyran-4-one with these two metal ions. Potentiometric and spectrophotometric techniques for iron, and potentiometry and ¹H NMR for aluminum were used, supported by X-ray, electrospray ionization-mass spectrometry (ESI-MS), calorimetry and quantum chemical calculations. In this work, evidence is given on the formation of MeL, MeL₂, and MeL₃ complexes of both metal ions with kojic acid, confirmed by the X-ray structure of the FeL₃ complex, and of variously protonated Me₂L₂ and MeL₂ complexes of 6-[5-hydroxy-2-hydroxymethyl-pyran-4-one]-5-hydroxy-2-hydroxymethyl-pyran-4-one. The extremely good pFe value for this second ligand gives confidence to, and opens perspectives for, the search of new kojic acid derivatives.     

Missing link in the Southern Ocean: sampling the marine benthic fauna of remote Bouvet Island

Bouvet (Bouvetøya) is a geologically young and very remote island just south of the Polar Front. Here we report samples taken during the RV “Polarstern" cruise ANTXXI/2 on 3 days in November 2003 and January 2004. This work was part of SCAR’s EASIZ programme and intended, by providing data on the marine fauna of this “white gap" in the Atlantic sector of the Southern Ocean, to contribute to identifying the role of Bouvet in the faunal exchange between the Sub- and high Antarctic. While this goal demands extensive molecular analysis of the material sampled (future work), a checklist of the samples and data at hand widens the faunal and environmental inventory substantially. We suggest some preliminary conclusions on the relationship of Bouvet Island’s fauna with that of other regions, such as Magellanic South America, the Antarctic Peninsula, and the high Antarctic Weddell Sea, which have been sampled previously. There seem to be different connections for individual higher taxa rather than a generally valid consistent picture.     

Toward the understanding of MNEI sweetness from hydration map surfaces

The binding mechanism of sweet proteins to their receptor, a G-protein-coupled receptor, is not supported by direct structural information. In principle, the key groups responsible for biological activity (glucophores) can be localized on a small structural unit (sweet finger) or spread on a larger surface area. A recently proposed model, called "wedge model", implies a large surface of interaction with the receptor. To explore this model in greater detail, it is necessary to examine the physicochemical features of the surfaces of sweet proteins, since their interaction with the receptor, with respect to that of small sweeteners, is more dependent on general physicochemical properties of the interface, such as electrostatic potential and hydration. In this study, we performed exhaustive molecular dynamics simulations in explicit water of the sweet protein MNEI and of its structural mutant G-16A, whose sweetness is one order of magnitude lower than that of MNEI. Solvent density and self-diffusion calculated from molecular dynamics simulations suggest a likely area of interaction delimited by four stretches arranged as a tetrahedron whose shape is complementary to that of a cavity on the surface of the receptor, in agreement with the wedge model. The suggested area of interaction is amazingly consistent with known mutagenesis data. In addition, the asymmetric hydration of the only helix in both proteins hints at a specific role for this secondary structure element in orienting the protein during the binding process.     

Protein interactions within the Set1 complex and their roles in the regulation of histone 3 lysine 4 methylation

Set1 is the catalytic subunit and the central component of the evolutionarily conserved Set1 complex (Set1C) that methylates histone 3 lysine 4 (H3K4). Here we have determined protein/protein interactions within the complex and related the substructure to function. The loss of individual Set1C subunits differentially affects Set1 stability, complex integrity, global H3K4 methylation, and distribution of H3K4 methylation along active genes. The complex requires Set1, Swd1, and Swd3 for integrity, and Set1 amount is greatly reduced in the absence of the Swd1-Swd3 heterodimer. Bre2 and Sdc1 also form a heteromeric subunit, which requires the SET domain for interaction with the complex, and Sdc1 strongly interacts with itself. Inactivation of either Bre2 or Sdc1 has very similar effects. Neither is required for complex integrity, and their removal results in an increase of H3K4 mono- and dimethylation and a severe decrease of trimethylation at the 5' end of active coding regions but a decrease of H3K4 dimethylation at the 3' end of coding regions. Cells lacking Spp1 have a reduced amount of Set1 and retain a fraction of trimethylated H3K4, whereas cells lacking Shg1 show slightly elevated levels of both di- and trimethylation. Set1C associates with both serine 5- and serine 2-phosphorylated forms of polymerase II, indicating that the association persists to the 3' end of transcribed genes. Taken together, our results suggest that Set1C subunits stimulate Set1 catalytic activity all along active genes.     

Gas1 is related to the glial cell-derived neurotrophic factor family receptors alpha and regulates Ret signaling

The growth arrest-specific gene 1 (Gas1) protein has been proposed to function during development as an inhibitor of growth and a mediator of cell death and is also re-expressed in adult neurons during excitotoxic insult. Here we have demonstrated that the Gas1 protein shows high structural similarity to the glial cell-derived neurotrophic factor (GDNF) family receptors alpha, which mediate GDNF responses through the receptor tyrosine kinase Ret. We found that Gas1 binds Ret in a ligand-independent manner and sequesters Ret in lipid rafts. Signaling downstream of Ret is thus modified through a mechanism that involves the adaptor protein Shc as well as ERK, eventually blocking Akt activation. Consequently, when Gas1 is induced, Ret-mediated GDNF-dependent survival effects are compromised.     

The success (or not) of HUGO nomenclature

Current usage of gene nomenclature is ambiguous and impairs the efficient handling of scientific information. Therefore it is important to propose guidelines to deal with this problem. This study attempts to evaluate the success of HUGO nomenclature for human genes. The results indicate that HUGO guidelines are not supported by the scientific community.     

An analysis of the Sargasso Sea resource and the consequences for database composition

Background  

The environmental sequencing of the Sargasso Sea has introduced a huge new resource of genomic information. Unlike the protein sequences held in the current searchable databases, the Sargasso Sea sequences originate from a single marine environment and have been sequenced from species that are not easily obtainable by laboratory cultivation. The resource also contains very many fragments of whole protein sequences, a side effect of the shotgun sequencing method.