The known unknowns of the Hsp90 chaperone

Molecular chaperones are vital proteins that maintain protein homeostasis by assisting in protein folding, activation, degradation, and stress protection. Among them, heat-shock protein 90 (Hsp90) stands out as an essential proteostasis hub in eukaryotes, chaperoning hundreds of "clients" (substrates). After decades of research, several "known unknowns" about the molecular function of Hsp90 remain unanswered, hampering rational drug design for the treatment of cancers, neurodegenerative and other diseases. We highlight three fundamental open questions, reviewing the current state of the field for each, and discuss new opportunities, including single-molecule technologies, to answer the known unknowns of the Hsp90 chaperone.Comment: 29 pages, 4 figure

A comprehensive study of reported high metallicity giant HII regions. I. Detailed abundance analysis

We present long-slit observations in the optical and near infrared of fourteen HII regions in the spiral galaxies: NGC 628, NGC 925, NGC 1232 and NGC 1637, all of them reported to have solar or oversolar abundances according to empirical calibrations. For seven of the observed regions, ion-weighted temperatures from optical forbidden auroral to nebular line ratios have been obtained and for six of them, the oxygen abundances derived by standard methods turn out to be significantly lower than solar. The other one, named CDT1 in NGC 1232, shows an oxygen abundance of 12+log(O/H) = 8.95+-0.20 and constitutes, to the best of our knowledge, the first high metallicity HII region for which accurate line temperatures, and hence elemental abundances, have been derived. For the rest of the regions no line temperature measurements could be made and the metallicity has been determined by means of both detailed photoionisation modelling and the sulphur abundance parameter S_23. Only one of these regions shows values of O_23 and S_23 implying a solar or oversolar metallicity. According to our analysis, only two of the observed regions can therefore be considered as of high metallicity. The two of them fit the trends previously found in other high metallicity HII regions, i.e. N/O and S/O abundance ratios seem to be higher and lower than solar respectively.Comment: Accepted for publication by MNRA

Cellular Immune Responses Induced with Dose-Sparing Intradermal Administration of HIV Vaccine to HIV-Uninfected Volunteers in the ANRS VAC16 Trial

The objective was to compare the safety and cellular immunogenicity of intradermal versus intramuscular immunization with an HIV-lipopeptide candidate vaccine (LIPO-4) in healthy volunteers.A randomized, open-label trial with 24 weeks of follow-up was conducted in France at six HIV-vaccine trial sites. Sixty-eight healthy 21- to 55-year-old HIV-uninfected subjects were randomized to receive the LIPO-4 vaccine (four HIV lipopeptides linked to a T-helper-stimulating epitope of tetanus-toxin protein) at weeks 0, 4 and 12, either intradermally (0.1 ml, 100 microg of each peptide) or intramuscularly (0.5 ml, 500 microg of each peptide). Comparative safety of both routes was evaluated. CD8+ T-cell immune responses to HIV epitopes (ELISpot interferon-gamma assay) and tetanus toxin-specific CD4+ T-cell responses (lymphoproliferation) were assessed at baseline, two weeks after each injection, and at week 24.No severe, serious or life-threatening adverse events were observed. Local pain was significantly more frequent after intramuscular injection, but local inflammatory reactions were more frequent after intradermal immunization. At weeks 2, 6, 14 and 24, the respective cumulative percentages of induced CD8+ T-cell responses to at least one HIV peptide were 9, 33, 39 and 52 (intradermal group) or 14, 20, 26 and 37 (intramuscular group), and induced tetanus toxin-specific CD4+ T-cell responses were 6, 27, 33 and 39 (intradermal), or 9, 46, 54 and 63 (intramuscular). In conclusion, intradermal LIPO-4 immunization was well tolerated, required one-fifth of the intramuscular dose, and induced similar HIV-specific CD8+ T-cell responses. Moreover, the immunization route influenced which antigen-specific T-cells (CD4+ or CD8+) were induced.ClinicalTrials.gov NCT00121121

Paradigmas y enfoques teóricos en la sociología de la música

The aim of this paper is to present the state of affairs on the theoretical currents in the sociology of contemporary music. Internationally, the sociology of music has been productive in empirical research, especially in the European tradition. The theoretical scenario found in the sociology of music is based on a pluralistic paradigm which follows general trends in sociology. This shows in a variety of approaches, which we will present here, which differ according to the plane in which they operate: macro, meso and micro. We provide a summary of classic proposals like Weber, Adorno, Bourdieu and DeNora, and include new methodological proposals from social network analysis, ethnography and cultural studies. We consider that in order to consolidate a theoretical framework we must avoid the postmodern trap, which avoids sociological criticism, and recognize the need for doing true social theory.<br><br>El objetivo de este artículo es plantear un estado de la cuestión sobre las corrientes teóricas en la sociología de la música actual. A escala internacional, la sociología de la música ha sido un campo pródigo en teorías más que en investigación empírica, sobre todo en la tradición europea. El escenario teórico que encontramos en la sociología de la música sigue el pluralismo paradigmático de la sociología general. Esto se refleja en una variedad de enfoques, que presentaremos aquí, y que diferenciamos según el plano en el que operan: macro, meso y micro. Ofrecemos una síntesis de las propuestas de clásicos como Weber, Adorno, DeNora y Bourdieu, e incluimos nuevas propuestas metodológicas desde el análisis de redes sociales, la etnografía y los estudios culturales. Para consolidar un marco teórico de referencia debemos huir de la trampa postmoderna, que renuncia a la crítica sociológica, y reconoceremos el carácter necesario de una verdadera teoría social

Prévention des infections à papillomavirus et du zona : nouveaux vaccins

Deux nouveaux vaccins ont obtenu récemment l’autorisation de mise sur le marché : un vaccin quadrivalent contre les infections à papillomavirus humains (HPV) 6, 11, 16 et 18, indiqué chez l’enfant à partir de 9 ans et le jeune adulte jusqu’à 26 ans, et un vaccin contre le zona pour l’adulte de 60 ans et plus. Un vaccin bivalent contre les infections à HPV 16 et 18 sera prochainement disponible. Les vaccins HPV représentent une avancée majeure dans le domaine de la vaccinologie car ces vaccins sont susceptibles d’être efficaces dans la prévention du cancer du col de l’utérus. Leur utilisation doit s’associer à la poursuite du dépistage par frottis du cancer du col de l’utérus et aux mesures de prévention des autres infections sexuellement transmissibles. Le vaccin zona permet de réduire l’incidence du zona et des douleurs post-zostériennes. Actuellement réservé aux sujets de plus de 60 ans, il est susceptible d’être plus largement utilisé et doit permettre de réduire significativement la morbidité liée à cette complication tardive de l’infection par le virus de la varicelle-zona

The known unknowns of the Hsp90 chaperone

Molecular chaperones are vital proteins that maintain protein homeostasis by assisting in protein folding, activation, degradation, and stress protection. Among them, heat-shock protein 90 (Hsp90) stands out as an essential proteostasis hub in eukaryotes, chaperoning hundreds of ‘clients’ (substrates). After decades of research, several ‘known unknowns’ about the molecular function of Hsp90 remain unanswered, hampering rational drug design for the treatment of cancers, neurodegenerative, and other diseases. We highlight three fundamental open questions, reviewing the current state of the field for each, and discuss new opportunities, including single-molecule technologies, to answer the known unknowns of the Hsp90 chaperone