Mechanisms of Intramolecular Communication in a Hyperthermophilic Acylaminoacyl Peptidase: A Molecular Dynamics Investigation

Protein dynamics and the underlying networks of intramolecular interactions and communicating residues within the three-dimensional (3D) structure are known to influence protein function and stability, as well as to modulate conformational changes and allostery. Acylaminoacyl peptidase (AAP) subfamily of enzymes belongs to a unique class of serine proteases, the prolyl oligopeptidase (POP) family, which has not been thoroughly investigated yet. POPs have a characteristic multidomain three-dimensional architecture with the active site at the interface of the C-terminal catalytic domain and a β-propeller domain, whose N-terminal region acts as a bridge to the hydrolase domain. In the present contribution, protein dynamics signatures of a hyperthermophilic acylaminoacyl peptidase (AAP) of the prolyl oligopeptidase (POP) family, as well as of a deletion variant and alanine mutants (I12A, V13A, V16A, L19A, I20A) are reported. In particular, we aimed at identifying crucial residues for long range communications to the catalytic site or promoting the conformational changes to switch from closed to open ApAAP conformations. Our investigation shows that the N-terminal α1-helix mediates structural intramolecular communication to the catalytic site, concurring to the maintenance of a proper functional architecture of the catalytic triad. Main determinants of the effects induced by α1-helix are a subset of hydrophobic residues (V16, L19 and I20). Moreover, a subset of residues characterized by relevant interaction networks or coupled motions have been identified, which are likely to modulate the conformational properties at the interdomain interface

Centrioles: active players or passengers during mitosis?

Centrioles are cylinders made of nine microtubule (MT) triplets present in many eukaryotes. Early studies, where centrosomes were seen at the poles of the mitotic spindle led to their coining as “the organ for cell division”. However, a variety of subsequent observational and functional studies showed that centrosomes might not always be essential for mitosis. Here we review the arguments in this debate. We describe the centriole structure and its distribution in the eukaryotic tree of life and clarify its role in the organization of the centrosome and cilia, with an historical perspective. An important aspect of the debate addressed in this review is how centrioles are inherited and the role of the spindle in this process. In particular, germline inheritance of centrosomes, such as their de novo formation in parthenogenetic species, poses many interesting questions. We finish by discussing the most likely functions of centrioles and laying out new research avenues

Present and future evolution of advanced breast cancer therapy

Although the introduction of novel therapies and drug combinations has improved the prognosis of metastatic breast cancer, the disease remains incurable. Increased knowledge of the biology and the molecular alterations in breast cancer has facilitated the design of targeted therapies. These agents include receptor and nonreceptor tyrosine kinase inhibitors (epidermal growth factor receptor family), intracellular signaling pathways (phosphatidylinositol-3-kinase, AKT, mammalian target of rapamycin) angiogenesis inhibitors and agents that interfere with DNA repair (poly(ADP-ribose) polymerase inhibitors). In the present review, we present the most promising studies of these new targeted therapies and novel combinations of targeted therapies with cytotoxic agents

B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction.

Acute myocardial infarction is a severe ischemic disease responsible for heart failure and sudden death. Here, we show that after acute myocardial infarction in mice, mature B lymphocytes selectively produce Ccl7 and induce Ly6C(hi) monocyte mobilization and recruitment to the heart, leading to enhanced tissue injury and deterioration of myocardial function. Genetic (Baff receptor deficiency) or antibody-mediated (CD20- or Baff-specific antibody) depletion of mature B lymphocytes impeded Ccl7 production and monocyte mobilization, limited myocardial injury and improved heart function. These effects were recapitulated in mice with B cell-selective Ccl7 deficiency. We also show that high circulating concentrations of CCL7 and BAFF in patients with acute myocardial infarction predict increased risk of death or recurrent myocardial infarction. This work identifies a crucial interaction between mature B lymphocytes and monocytes after acute myocardial ischemia and identifies new therapeutic targets for acute myocardial infarction.This work was supported by Inserm, British Heart Foundation (Z.M.), European Research Council (Z.M.), Fondation Coeur et Recherche (Z.M., T.S., N.D.), Fondation pour la Recherche Medicale (J.S.S.), European Union Seven Framework programme TOLERAGE (Z.M.), Fondation Leducq transatlantic network (C.J.B., D.T., A.T., J.S.S., Z.M.), National Institutes of Health grants AI56363 and AI057157, and a grant from The Lymphoma Research Foundation (T.F.T).This is the author accepted manuscript. The final version is available from Nature Publishing Group at http://dx.doi.org/10.1038/nm.3284

Quantitative fractographic analysis of impact fracture surfaces of steel R73

Macroscopic images offracture surfaces of Charpy test specimens of steel R73 were studied, where bright spots in images represent cleavage facets or ductile dimples, respectively, both in special orientations. Within image analysis, they may be taken for the most significant textural element. Being the brightest patches in the image, they can be extracted by thresholding. Their counts and area distribution are closely related to temperature and impact energy.Выполнены исследования макроизображений поверхностей разрушений образцов Шарпи из стали R73. При специальных условиях ориентации поверхностей разрушения видны яркие участки на изображениях, соответствующие граням скола или ямкам вязкого разрушения. Эти участки могут быть использованы в качестве основного элемента текстуры для обработки изображения. Поскольку эти участки на изображениях являются наиболее яркими, их можно отсеять путем настройки порогового уровня освещенности. Результаты расчета относительной доли их площади тесно коррелируют с температурой и энергией ударного разрушения

Keep off the grass?:Cannabis, cognition and addiction

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.In an increasing number of states and countries, cannabis now stands poised to join alcohol and tobacco as a legal drug. Quantifying the relative adverse and beneficial effects of cannabis and its constituent cannabinoids should therefore be prioritized. Whereas newspaper headlines have focused on links between cannabis and psychosis, less attention has been paid to the much more common problem of cannabis addiction. Certain cognitive changes have also been attributed to cannabis use, although their causality and longevity are fiercely debated. Identifying why some individuals are more vulnerable than others to the adverse effects of cannabis is now of paramount importance to public health. Here, we review the current state of knowledge about such vulnerability factors, the variations in types of cannabis, and the relationship between these and cognition and addiction.This work was supported by grants from the US National Institutes of Health to L.H.P. (AA020404, AA006420, AA022249 and AA017447) and by grants from the UK Medical Research Council to H.V.C. and C.J.A.M. (G0800268; MR/K015524/1)

Intracellular organelles mediate cytoplasmic pulling force for centrosome centration in the Caenorhabditis elegans early embryo

The centrosome is generally maintained at the center of the cell. In animal cells, centrosome centration is powered by the pulling force of microtubules, which is dependent on cytoplasmic dynein. However, it is unclear how dynein brings the centrosome to the cell center, i.e., which structure inside the cell functions as a substrate to anchor dynein. Here, we provide evidence that a population of dynein, which is located on intracellular organelles and is responsible for organelle transport toward the centrosome, generates the force required for centrosome centration in Caenorhabditis elegans embryos. By using the database of full-genome RNAi in C. elegans, we identified dyrb-1, a dynein light chain subunit, as a potential subunit involved in dynein anchoring for centrosome centration. DYRB-1 is required for organelle movement toward the minus end of the microtubules. The temporal correlation between centrosome centration and the net movement of organelle transport was found to be significant. Centrosome centration was impaired when Rab7 and RILP, which mediate the association between organelles and dynein in mammalian cells, were knocked down. These results indicate that minus end-directed transport of intracellular organelles along the microtubules is required for centrosome centration in C. elegans embryos. On the basis of this finding, we propose a model in which the reaction forces of organelle transport generated along microtubules act as a driving force that pulls the centrosomes toward the cell center. This is the first model, to our knowledge, providing a mechanical basis for cytoplasmic pulling force for centrosome centration

Smart Communities and Knowledge Sharing as Main Tools to Achieve Common Purposes

As reaction to globalization and the loosing of landmark caused by the huge data and information availability in the “net” and by the mass media proliferation, the research of an identity and the need of a feeling of belonging is stronger and stronger in today society. The information and communication technologies (ICT’s) - which initially helped to erase socio-territorial boundaries and to strengthen a feeling of belonging to a single community in which we are all interlinked and interdependent – have now become the main tools for building local, and smart, communities. These, in addition to being places of confrontation, are also and above all places for sharing subjective and objective knowledge (and therefore for continuous learning). There are several experiences going towards this direction (i.e. creating shared spaces built around shared values that emerge to deal with problems felt as “public”) ranging from analytical, investigative, critical and vindictive dimensions to proposals, monitoring, evaluation, deliberation, on the most varied topics: from the abandonment of public buildings (such as confis- cated property), to security and the protection of territories. These are thus defined spaces in which, through self-organization and civic hacking dynamics, problems that are perceived as public are discussed and public goods are co-produced. These last are intended not as goods produced or owned by a public administration, but as the result of a process of social interaction. Digital technologies in this contest are tools by which social practices of re-appropriation and collective redefinition of public goods are nourished