Structural investigation of nucleophosmin interaction with the tumor suppressor Fbw7γ

Nucleophosmin (NPM1) is a multifunctional nucleolar protein implicated in ribogenesis, centrosome duplication, cell cycle control, regulation of DNA repair and apoptotic response to stress stimuli. The majority of these functions are played through the interactions with a variety of protein partners. NPM1 is frequently overexpressed in solid tumors of different histological origin. Furthermore NPM1 is the most frequently mutated protein in acute myeloid leukemia (AML) patients. Mutations map to the C-terminal domain and lead to the aberrant and stable localization of the protein in the cytoplasm of leukemic blasts. Among NPM1 protein partners, a pivotal role is played by the tumor suppressor Fbw7γ, an E3-ubiquitin ligase that degrades oncoproteins like c-MYC, cyclin E, Notch and c-jun. In AML with NPM1 mutations, Fbw7γ is degraded following its abnormal cytosolic delocalization by mutated NPM1. This mechanism also applies to other tumor suppressors and it has been suggested that it may play a key role in leukemogenesis. Here we analyse the interaction between NPM1 and Fbw7γ, by identifying the protein surfaces implicated in recognition and key aminoacids involved. Based on the results of computational methods, we propose a structural model for the interaction, which is substantiated by experimental findings on several site-directed mutants. We also extend the analysis to two other NPM1 partners (HIV Tat and CENP-W) and conclude that NPM1 uses the same molecular surface as a platform for recognizing different protein partners. We suggest that this region of NPM1 may be targeted for cancer treatment

Violation of area-law scaling for the entanglement entropy in spin 1/2 chains

Entanglement entropy obeys area law scaling for typical physical quantum systems. This may naively be argued to follow from locality of interactions. We show that this is not the case by constructing an explicit simple spin chain Hamiltonian with nearest neighbor interactions that presents an entanglement volume scaling law. This non-translational model is contrived to have couplings that force the accumulation of singlet bonds across the half chain. Our result is complementary to the known relation between non-translational invariant, nearest neighbor interacting Hamiltonians and QMA complete problems.Comment: 9 pages, 4 figure

Fluorescence and Morphology of Self-Assembled Nucleobases and Their Diphenylalanine Hybrid Aggregates

Studies carried out in recent decades have revealed that the ability to self-assemble is a widespread property among biomolecules. Small nucleic acid moieties or very short peptides are able to generate intricate assemblies endowed with remarkable structural and spectroscopic properties. Herein, the structural/spectroscopic characterization of aggregates formed by nucleobases and peptide nucleic acid (PNA)-peptide conjugates are reported. At high concentration, all studied nucleobases form aggregates characterized by previously unreported fluorescence properties. The conjugation of these bases, as PNA derivatives, to the dipeptide Phe-Phe leads to the formation of novel hybrid assemblies, which are characterized by an amyloid-like association of the monomers. Although these compounds share the same basic cross-\u3b2 motif, the nature and number of PNA units have an important impact on both the level of structural order and the intrinsic fluorescence of the self-assembled nanostructure

Is the treatment of the tear trough deformity with hyaluronic acid injections a safe procedure? A systematic review

Among the various therapeutic options for the treatment of tear trough deformities, the use of hyaluronic acid-based fillers has constantly been increasing. The aim of this research is to conduct a systematic review of the published literature related to the use of hyaluronic acid-based dermal fillers for the treatment of tear trough deformities and possible related complications. A search of the published literature was conducted following the PRISMA guidelines, including PubMed, Cochrane Library, and Ovid databases. Text words and Medical Search Headings (MeSH terms) were used to identify nine articles included in our analysis. The most used filler was Restylane (Galderma). The injection technique was performed through the use of a cannula or, more frequently, with a needle, through the execution of boluses or retrograde release. The injection plane was predominantly the supra-periosteal layer. The most observed side effects were mild and included redness, edema, contour irregularities, bruising, and blue-gray dyschromia. The degree of patient satisfaction was high, with an optimal aesthetic result that was maintained for 6 to 12 months. Although the duration of treatment of tear trough deformities with HA fillers is not comparable to surgical treatment, this is a minimally invasive, safe procedure, quick to perform, and with a high degree of patient satisfaction

Higher-order Mechanics: Variational Principles and other topics

After reviewing the Lagrangian-Hamiltonian unified formalism (i.e, the Skinner-Rusk formalism) for higher-order (non-autonomous) dynamical systems, we state a unified geometrical version of the Variational Principles which allows us to derive the Lagrangian and Hamiltonian equations for these kinds of systems. Then, the standard Lagrangian and Hamiltonian formulations of these principles and the corresponding dynamical equations are recovered from this unified framework.Comment: New version of the paper "Variational principles for higher-order dynamical systems", which was presented in the "III Iberoamerican Meeting on Geometry, Mechanics and Control" (Salamanca, 2012). The title is changed. A detailed review is added. Sections containing results about variational principles are enlarged with additional comments, diagrams and summarizing results. Bibliography is update

Epigenetic and genetic landscape of uterine leiomyomas: a current view over a common gynecological disease

Purpose: Despite the numerous studies on the factors involved in the genesis and growth of uterine leiomyomas, the pathogenesis of these tumors remains unknown. Intrinsic abnormalities of the myometrium, abnormal myometrial receptors for estrogen, and hormonal changes or altered responses to ischemic damage during the menstrual period may be responsible for the initiation of (epi)genetic changes found in these tumors. Considering these elements, we aimed to offer an overview about epigenetic and genetic landscape of uterine leiomyomas. Methods: Narrative overview, synthesizing the findings of literature retrieved from searches of computerized databases. Results: Several studies showed that leiomyomas have a monoclonal origin. Accumulating evidence converges on the risk factors and mechanisms of tumorigenesis: the translocation t (12;14) and deletion of 7q were found in the highest percentages of recurrence; dysregulation of the HMGA2 gene has been mapped within the critical 12q14-q15 locus. Estrogen and progesterone are recognized as promoters of tumor growth, and the potential role of environmental estrogens has been poorly explored. The growth factors with mitogenic activity, such as transforming growth factor-β3, fibroblast growth factor, epidermal growth factor, and insulin-like growth factor-I are elevated in fibroids and may have a role as effectors of the tumor promotion. Conclusion: The new clues on genetics and epigenetics, as well as about the growth factors that control normal and pathological myometrial cellular biology may be of great help for the development of new effective and less invasive therapeutic strategies in the near future

From Atiyah Classes to Homotopy Leibniz Algebras

A celebrated theorem of Kapranov states that the Atiyah class of the tangent bundle of a complex manifold $X$ makes $T_X[-1]$ into a Lie algebra object in $D^+(X)$, the bounded below derived category of coherent sheaves on $X$. Furthermore Kapranov proved that, for a K\"ahler manifold $X$, the Dolbeault resolution $\Omega^{\bullet-1}(T_X^{1,0})$ of $T_X[-1]$ is an $L_\infty$ algebra. In this paper, we prove that Kapranov's theorem holds in much wider generality for vector bundles over Lie pairs. Given a Lie pair $(L,A)$, i.e. a Lie algebroid $L$ together with a Lie subalgebroid $A$, we define the Atiyah class $\alpha_E$ of an $A$-module $E$ (relative to $L$) as the obstruction to the existence of an $A$-compatible $L$-connection on $E$. We prove that the Atiyah classes $\alpha_{L/A}$ and $\alpha_E$ respectively make $L/A[-1]$ and $E[-1]$ into a Lie algebra and a Lie algebra module in the bounded below derived category $D^+(\mathcal{A})$, where $\mathcal{A}$ is the abelian category of left $\mathcal{U}(A)$-modules and $\mathcal{U}(A)$ is the universal enveloping algebra of $A$. Moreover, we produce a homotopy Leibniz algebra and a homotopy Leibniz module stemming from the Atiyah classes of $L/A$ and $E$, and inducing the aforesaid Lie structures in $D^+(\mathcal{A})$.Comment: 36 page

Averaging inhomogeneities in scalar-tensor cosmology

The backreaction of inhomogeneities on the cosmic dynamics is studied in the context of scalar-tensor gravity. Due to terms of indefinite sign in the non-canonical effective energy tensor of the Brans-Dicke-like scalar field, extra contributions to the cosmic acceleration can arise. Brans-Dicke and metric f(R) gravity are presented as specific examples. Certain representation problems of the formalism peculiar to these theories are pointed out.Comment: Comments and references added. 14 page