Stabilization of a compact conformation of monomeric GroEL at low temperature by adenine nucleotides

AbstractE. coli GroEL chaperonin monomers, isolated after urea-induced dissociation of GroEL14, undergo cold denaturation below 5° C. Above 5°C, these monomers undergo MgATP-dependent self-assembly. We have demonstrated a conformational transition at 0°C induced by interaction of monomeric GroEL with adenine nucleotides. This conformation has a dramatically decreased Stokes radius and enhanced resistance to trypsin but it is slightly less compact than the conformation of monomers at 23°C in the absence of MgATP and it is not capable of spontaneous self-assembly. A second, temperature-dependent conformational change with a transition at about 5°C is required for GroEL to undergo oligomerization

Consecuencias no deseadas de la acción colectiva empresaria: la Federación Agraria Argentina en la Mesa de Enlace. Un abordaje a partir de la sociología económica

La participación de la Federación Agraria Argentina en la Mesa de Enlace tendría serias implicancias para buena parte de sus asociados. Ahora bien, ¿por qué las corporaciones del empresariado desarrollan acciones que terminan por perjudicar los intereses de sus miembros? Es a través de la sociología económica que se reflexiona y se analiza la acción empresarial de la FAA en el desarrollo del conflicto agropecuario del año 2008.La participación de la Federación Agraria Argentina en la Mesa de Enlace tendría serias implicancias para buena parte de sus asociados. Ahora bien, ¿por qué las corporaciones del empresariado desarrollan acciones que terminan por perjudicar los intereses de sus miembros? Es a través de la sociología económica que se reflexiona y se analiza la acción empresarial de la FAA en el desarrollo del conflicto agropecuario del año 2008

Crisis de la Convertibilidad y salida posterior : El rol de los Bancos

Evitando concebir al Estado como mero instrumento de dominación de una sola clase o fracción, y aún entendiendo que en el interior del mismo se expresan contradicciones relativas a las distintas fracciones de clase que en él conviven (Poulantzas, 1979), podemos afirmar que el rumbo que elige tomar un gobierno guarda estrecha relación con las presiones de los actores económicos más poderosos. Esta influencia se hace más clara en los momentos en que se problematiza la estructura económica de un país (cuando el sistema vigente entra en crisis). Es en esos momentos donde las fracciones dominantes despliegan y utilizan diversos recursos de poder: económicos, políticos e ideológicos. Con respecto a estos últimos es importante señalar que en toda crisis se manifiesta una disputa más o menos ostensible por los “sentidos” de la misma. En otras palabras, se verifica una pugna (en lo ideológico) entre las distintas fracciones dominantes, sobre por qué se da la crisis, lo cual es relevante en tanto según el diagnóstico que triunfe se encauzará la salida de la crisis en determinado sentido y no en otro.Facultad de Humanidades y Ciencias de la Educació

Bioactivity of Isoflavones: Assessment through a Theoretical Model as a Way to Obtain a “Theoretical Efficacy Related to Estradiol (TERE)”

The increase of human life span will have profound implications in Public Health in decades to come. By 2030, there will be an estimated 1.2 billion women in post-menopause. Hormone Replacement Therapy with synthetic hormones is still full of risks and according to the latest developments, should be used for the shortest time possible. Searching for alternative drugs is inevitable in this scenario and science must provide physicians with other substances that can be used to treat the same symptoms with less side effects. Systematic research carried out on this field of study is focusing now on isoflavones but the randomised controlled trials and reviews of meta-analysis concerning post-menopause therapy, that could have an important impact on human health, are very controversial. The aim of the present work was to establish a theoretical calculation suitable for use as a way to estimate the “Theoretical Efficacy (TE)” of a mixture with different bioactive compounds as a way to obtain a “Theoretical Efficacy Related to Estradiol (TERE)”. The theoretical calculation that we propose in this paper integrates different knowledge about this subject and sets methodological boundaries that can be used to analyse already published data. The outcome should set some consensus for new clinical trials using isoflavones (isolated or included in mixtures) that will be evaluated to assess their therapeutically activity. This theoretical method for evaluation of a possible efficacy could probably also be applied to other herbal drug extracts when a synergistic or contradictory bio-effect is not verified. In this way, it we may contribute to enlighten and to the development of new therapeutic approaches

Hypoxia regulates glutamate receptor trafficking through an HIF‐independent mechanism

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102065/1/embj2011499-reviewer_comments.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/102065/2/embj2011499-sup-0001.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/102065/3/embj2011499.pd

Structural and kinetic basis for heightened immunogenicity of T cell vaccines

Analogue peptides with enhanced binding affinity to major histocompatibility class (MHC) I molecules are currently being used in cancer patients to elicit stronger T cell responses. However, it remains unclear as to how alterations of anchor residues may affect T cell receptor (TCR) recognition. We correlate functional, thermodynamic, and structural parameters of TCR–peptide–MHC binding and demonstrate the effect of anchor residue modifications of the human histocompatibility leukocyte antigens (HLA)–A2 tumor epitope NY–ESO-1157–165–SLLMWITQC on TCR recognition. The crystal structure of the wild-type peptide complexed with a specific TCR shows that TCR binding centers on two prominent, sequential, peptide sidechains, methionine–tryptophan. Cysteine-to-valine substitution at peptide position 9, while optimizing peptide binding to the MHC, repositions the peptide main chain and generates subtly enhanced interactions between the analogue peptide and the TCR. Binding analyses confirm tighter binding of the analogue peptide to HLA–A2 and improved soluble TCR binding. Recognition of analogue peptide stimulates faster polarization of lytic granules to the immunological synapse, reduces dependence on CD8 binding, and induces greater numbers of cross-reactive cytotoxic T lymphocyte to SLLMWITQC. These results provide important insights into heightened immunogenicity of analogue peptides and highlight the importance of incorporating structural data into the process of rational optimization of superagonist peptides for clinical trials

CD1b-restricted GEM T cell responses are modulated by Mycobacterium tuberculosis mycolic acid meromycolate chains

Tuberculosis, caused by Mycobacterium tuberculosis, remains a major human pandemic. Germline-encoded mycolyl lipid-reactive (GEM) T cells are donor-unrestricted and recognize CD1b-presented mycobacterial mycolates. However, the molecular requirements governing mycolate antigenicity for the GEM T cell receptor (TCR) remain poorly understood. Here, we demonstrate CD1b expression in tuberculosis granulomas and reveal a central role for meromycolate chains in influencing GEM-TCR activity. Meromycolate fine structure influences T cell responses in TB-exposed individuals, and meromycolate alterations modulate functional responses by GEM-TCRs. Computational simulations suggest that meromycolate chain dynamics regulate mycolate head group movement, thereby modulating GEM-TCR activity. Our findings have significant implications for the design of future vaccines that target GEM T cells

Specificity of bispecific T cell receptors and antibodies targeting peptide-HLA

Tumor-associated peptide–human leukocyte antigen complexes (pHLAs) represent the largest pool of cell surface–expressed cancer-specific epitopes, making them attractive targets for cancer therapies. Soluble bispecific molecules that incorporate an anti-CD3 effector function are being developed to redirect T cells against these targets using 2 different approaches. The first achieves pHLA recognition via affinity-enhanced versions of natural TCRs (e.g., immune-mobilizing monoclonal T cell receptors against cancer [ImmTAC] molecules), whereas the second harnesses an antibody-based format (TCR-mimic antibodies). For both classes of reagent, target specificity is vital, considering the vast universe of potential pHLA molecules that can be presented on healthy cells. Here, we made use of structural, biochemical, and computational approaches to investigate the molecular rules underpinning the reactivity patterns of pHLA-targeting bispecifics. We demonstrate that affinity-enhanced TCRs engage pHLA using a comparatively broad and balanced energetic footprint, with interactions distributed over several HLA and peptide side chains. As ImmTAC molecules, these TCRs also retained a greater degree of pHLA selectivity, with less off-target activity in cellular assays. Conversely, TCR-mimic antibodies tended to exhibit binding modes focused more toward hot spots on the HLA surface and exhibited a greater degree of crossreactivity. Our findings extend our understanding of the basic principles that underpin pHLA selectivity and exemplify a number of molecular approaches that can be used to probe the specificity of pHLA-targeting molecules, aiding the development of future reagents