Antimicrobial peptides in the venom of the European hornet, Vespa crabro, identified as mastoparan C and crabrolin

Amphibian skin secretions are rich sources of cationic amphipathic peptides which often possess potent and broad-spectrum antimicrobial activity. However, the venoms of other animals such as hymenopteran insects, also contain peptides with these characteristics and the literature is unclear as to their antimicrobial potential. Here we subjected the venom of the European hornet, Vespa crabro, to reverse phase HPLC fractionation followed by screening of aliquots of individual fractions in bacterial zonal inhibition assays. Two major peptides possessing activity in these assays were further purified by HPLC and subjected to MALDI-TOF MS analysis and MS/MS fragmentation using an ESI mass spectrometer. The peptides were identified as mastoparan C (LNLKALLAVAKKILamide) and crabrolin (FLPLILRKIVTALamide). Replicates of both peptides were synthesised by solid-phase methodology and mean inhibitory concentrations (MICs) established against Staphylococcus aureus and Escherichia coli. Mastoparan C was found to be a potent antimicrobial with MIC values of 2 µM and 4 µM against S. aureus and E. coli, respectively. Crabrolin was found to be less potent with MIC values of > 160 µM and 40 µM for S. aureus and E. coli. Hornet venom thus contains a potent antimicrobial peptide that has been unambiguously identified as mastoparan C, a peptide that is known to affect profound histamine release from mast cells and to generally activate membrane G protein-linked receptors. It is thus highly probable that its antimicrobial effects, like those previously documented, are a result of a generalized membrane interactive and disruptive function — perhaps reflective of the authentic role of amphibian skin antimicrobials.

Translocation of lipid-linked oligosaccharides across the ER membrane requires Rft1 protein

N-linked glycosylation of proteins in eukaryotic cells follows a highly conserved pathway. The tetradecasaccharide substrate (Glc3Man9GlcNAc2) is first assembled at the membrane of the endoplasmic reticulum (ER) as a dolichylpyrophosphate (Dol-PP)-linked intermediate, and then transferred to nascent polypeptide chains in the lumen of the ER. The assembly of the oligosaccharide starts on the cytoplasmic side of the ER membrane with the synthesis of a Man5GlcNAc2-PP-Dol intermediate. This lipid-linked intermediate is then translocated across the membrane so that the oligosaccharides face the lumen of the ER, where the biosynthesis of Glc3Man9GlcNAc2-PP-Dol continues to completion. The fully assembled oligosaccharide is transferred to selected asparagine residues of target proteins. The transmembrane movement of lipid-linked Man5GlcNAc2 oligosaccharide is of fundamental importance in this biosynthetic pathway, and similar processes involving phospholipids and glycolipids are essential in all types of cells. The process is predicted to be catalysed by proteins, termed flippases, which to date have remained elusive. Here we provide evidence that yeast RFT1 encodes an evolutionarily conserved protein required for the translocation of Man5GlcNAc2-PP-Dol from the cytoplasmic to the lumenal leaflet of the ER membrane.

ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth

The proto-oncogene c-Myc paradoxically activates both proliferation and apoptosis. In the pathogenic state, c-Myc-induced apoptosis is bypassed via a critical, yet poorly understood escape mechanism that promotes cellular transformation and tumorigenesis. The accumulation of unfolded proteins in the ER initiates a cellular stress program termed the unfolded protein response (UPR) to support cell survival. Analysis of spontaneous mouse and human lymphomas demonstrated significantly higher levels of UPR activation compared with normal tissues. Using multiple genetic models, we demonstrated that c-Myc and N-Myc activated the PERK/eIF2α/ATF4 arm of the UPR, leading to increased cell survival via the induction of cytoprotective autophagy. Inhibition of PERK significantly reduced Myc-induced autophagy, colony formation, and tumor formation. Moreover, pharmacologic or genetic inhibition of autophagy resulted in increased Myc-dependent apoptosis. Mechanistically, we demonstrated an important link between Myc-dependent increases in protein synthesis and UPR activation. Specifically, by employing a mouse minute (L24+/-) mutant, which resulted in wild-type levels of protein synthesis and attenuation of Myc-induced lymphomagenesis, we showed that Myc-induced UPR activation was reversed. Our findings establish a role for UPR as an enhancer of c-Myc-induced transformation and suggest that UPR inhibition may be particularly effective against malignancies characterized by c-Myc overexpression.

Genetic variants of kinase suppressors of Ras (KSR1) to predict survival in patients with ERα-positive advanced breast cancer

In patients with breast cancer (BC), deregulation of estrogen receptor (ERα) activity may account for most resistance to endocrine therapies. Our previous study used a whole-human kinome siRNA screen to identify functional actors in ERα modulation and showed the implication of proteins kinase suppressors of ras (KSR1). From those findings we evaluated the clinical impact of KSR1 variants in patients with ERα+ BC treated with TAM. DNA was obtained from 222 patients with advanced ERα+ BC treated with TAM who had undergone surgery from 1981 to 2003. We selected three potentially functional relevant KSR1 polymorphisms; two within the 3'UTR (rs224190, rs1075952) and one in the coding exon 7 (rs2293180). The primary end points were overall survival (OS) and disease-free survival (DFS). After a 6.4-year median follow-up, patients carrying the rs2241906 TT genotype showed shorter DFS (2.1 vs 7.1 years, P=0.005) and OS (2.6 vs 8.4 years P=0.002) than those with the TC or TT genotypes. Those associations remained significant in the multivariable analysis adjusting age, lymph node status, LMTK3 and IGFR variants and HER2 status. The polymorphisms rs2241906 and rs1075952 were in linkage disequilibrium. No association was shown between rs2293180 and survival. Among the actors of ERα signaling, KSR1 rs2241906 variants may predict survival in patients with advanced ERα+ BC treated with adjuvant TAM.

Diálogo entre tradição e contemporaneidade na música erudita do século XX: a obra sinfónica do compositor chinês Zhu Jian-ER

O presente trabalho tem como objectivo estudar o processo dialógico que se manifesta entre a tradição e a contemporaneidade, nas culturas Oriental e Ocidental, em particular na nova música erudita chinesa do século XX. Evocando uma análise diversificada, e um estudo sobre a “individualidade do diálogo”, aprofundamos o nosso conhecimento sobre o compositor Zhu Jian-Er e a sua obra, enquanto manifesto individual das características e da determinação de um novo fazer artístico. Nesse estudo, trata-se, por um lado, de estudar de que forma a obra de Zhu espelha, e expressa, o espaço dialógico, examinando como a observação e a percepção individual se redimensionam nas diferentes vivências sócio-históricas e políticas do autor, e estas, na história da cultura chinesa do século XX. Procuramos ainda perceber como o auto-conhecimento e a personalidade de Zhu se declaram na sua última fase criativa, e a maneira como as diversas construções técnicoestéticas se edificam e interactuam num ponto de encontro único, e, por sua vez, se influenciam reciprocamente no processo dialógico. A estruturação do presente trabalho contém três partes, abrangendo a narração do contexto sócio-histórico da produção musical de Zhu Jian-Er, a pesquisa sobre a vida e obra do autor e, a análise detalhada da sua Décima Sinfonia. Desvendaremos ainda de que forma integra e interage com os diferentes elementos técnico, estilísticos e estéticos que obtém do contacto com diversas manifestações artísticas, não só da música erudita ocidental, como da música erudita oriental, em particular da tradição musical chinesa, determinando a forma como engloba os elementos que obtém na produção de arte. A maneira como constrói o diálogo entre as duas culturas, e que revela, posteriormente, na produção da sua Décima Sinfonia, constituirá, assim, o âmago deste trabalho.

新註便蒙演說日記故事Xin zhu bian meng yan shuo ri ji gu shi.Recueil d'exemples moraux pour les enfants ; autre titre : 新增註釋演說二十四孝故事Xin zeng zhu shi yan shuo er shi si xiao gu shi.Les vingt-quatre exemples de piété filiale expliqués et développés.

Comprenant les vingt-quatre traits de piété filiale avec gravures (livre 1), des exemples d'intelligence précoce (livre 2), de bonne éducation domestique (livre 3), de perfectionnement de soi-même (livre 4), de fidélité et de dévouement (livre 5).

繡像二十四孝圖Xiu xiang er shi si xiao tu.Les vingt-quatre exemples de piété filiale, illustrés.

Au début du volume, une chanson. Gravé à la salle Fu wen, à Canton.

睡畫二答Shui hua er da.Traité sur le sommeil et traité sur la peinture.

Par le P. Francesco Sambiaso (1582-1649). Publié par Sun Yuan hua, de Yun jian. Introduction de Li Zhi zao (1629). Gravé en 1629.

睡畫二答Shui hua er da.Traité sur le sommeil et traité sur la peinture.

Par le P. Francesco Sambiaso (1582-1649). Publié par Sun Yuan hua, de Yun jian. Introduction de Li Zhi zao (1629). Gravé en 1629.

Shui hua er da.

Même ouvrage.Édition un peu plus grande, peut-être postérieure.

Shui hua er da.

Double.