Stabilizer‐Guided Inhibition of Protein–Protein Interactions

The discovery of novel protein–protein interaction (PPI) modulators represents one of the great molecular challenges of the modern era. PPIs can be modulated by either inhibitor or stabilizer compounds, which target different though proximal regions of the protein interface. In principle, protein–stabilizer complexes can guide the design of PPI inhibitors (and vice versa). In the present work, we combine X‐ray crystallographic data from both stabilizer and inhibitor co‐crystal complexes of the adapter protein 14‐3‐3 to characterize, down to the atomic scale, inhibitors of the 14‐3‐3/Tau PPI, a potential drug target to treat Alzheimer’s disease. The most potent compound notably inhibited the binding of phosphorylated full‐length Tau to 14‐3‐3 according to NMR spectroscopy studies. Our work sets a precedent for the rational design of PPI inhibitors guided by PPI stabilizer–protein complexes while potentially enabling access to new synthetically tractable stabilizers of 14‐3‐3 and other PPIs.     

Quantitative Proteomic Analysis of Optimal Cutting Temperature (OCT) Embedded Core-Needle Biopsy of Lung Cancer

With recent advances in understanding the genomic underpinnings and oncogenic drivers of pathogenesis in different subtypes, it is increasingly clear that proper pretreatment diagnostics are essential for the choice of appropriate treatment options for non-small cell lung cancer (NSCLC). Tumor tissue preservation in optimal cutting temperature (OCT) compound is commonly used in the surgical suite. However, proteins recovered from OCT-embedded specimens pose a challenge for LC-MS/MS experiments, due to the large amounts of polymers present in OCT. Here we present a simple workflow for whole proteome analysis of OCT-embedded NSCLC tissue samples, which involves a simple trichloroacetic acid precipitation step. Comparisons of protein recovery between frozen versus OCT-embedded tissue showed excellent consistency with more than 9200 proteins identified. Using an isobaric labeling strategy, we quantified more than 5400 proteins in tumor versus normal OCT-embedded core needle biopsy samples. Gene ontology analysis indicated that a number of proliferative as well as squamous cell carcinoma (SqCC) marker proteins were overexpressed in the tumor, consistent with the patient’s pathology based diagnosis of “poorly differentiated SqCC”. Among the most downregulated proteins in the tumor sample, we noted a number of proteins with potential immunomodulatory functions. Finally, interrogation of the aberrantly expressed proteins using a candidate approach and cross-referencing with publicly available databases led to the identification of potential druggable targets in DNA replication and DNA damage repair pathways. We conclude that our approach allows LC-MS/MS proteomic analyses on OCT-embedded lung cancer specimens, opening the way to bring powerful proteomics into the clinic.

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Finding Adam in random growing trees

We investigate algorithms to find the first vertex in large trees generated by either the uniform attachment or preferential attachment model. We require the algorithm to output a set of K vertices, such that, with probability at least , the first vertex is in this set. We show that for any ε, there exist such algorithms with K independent of the size of the input tree. Moreover, we provide almost tight bounds for the best value of K as a function of ε. In the uniform attachment case we show that the optimal K is subpolynomial in , and that it has to be at least superpolylogarithmic. On the other hand, the preferential attachment case is exponentially harder, as we prove that the best K is polynomial in . We conclude the paper with several open problems. © 2016 Wiley Periodicals, Inc. Random Struct. Alg., 50, 158–172, 2017     

The graph structure of a deterministic automaton chosen at random

An n‐state deterministic finite automaton over a k‐letter alphabet can be seen as a digraph with n vertices which all have k labeled out‐arcs. Grusho (Publ Math Inst Hungarian Acad Sci 5 (1960), 17–61). proved that whp in a random k‐out digraph there is a strongly connected component of linear size, i.e., a giant, and derived a central limit theorem. We show that whp the part outside the giant contains at most a few short cycles and mostly consists of tree‐like structures, and present a new proof of Grusho's theorem. Among other things, we pinpoint the phase transition for strong connectivity. © 2016 Wiley Periodicals, Inc. Random Struct. Alg., 51, 428–458, 2017     

An algebraic interpretation of the multivariate <Emphasis Type="Italic">q</Emphasis>-Krawtchouk polynomials

The multivariate quantum q-Krawtchouk polynomials are shown to arise as matrix elements of “q-rotations” acting on the state vectors of many q-oscillators. The focus is put on the two-variable case. The algebraic interpretation is used to derive the main properties of the polynomials: orthogonality, duality, structure relations, difference equations, and recurrence relations. The extension to an arbitrary number of variables is presented.     

In Vitro Antiplasmodial and Cytotoxic Activities of Compounds from the Roots of Eriosema montanum Baker f. (Fabaceae)

Malaria remains one of the leading causes of death in sub-Saharan Africa, ranked in the top three infectious diseases in the world. Plants of the Eriosema genus have been reported to be used for the treatment of this disease, but scientific evidence is still missing for some of them. In the present study, the in vitro antiplasmodial activity of the crude extract and compounds from Eriosema montanum Baker f. roots were tested against the 3D7 strain of Plasmodium falciparum and revealed using the SYBR Green, a DNA intercalating compound. The cytotoxicity effect of the compounds on a human cancer cell line (THP-1) was assessed to determine their selectivity index. It was found that the crude extract of the plant displayed a significant antiplasmodial activity with an IC₅₀ (µg/mL) = 17.68 ± 4.030 and a cytotoxic activity with a CC₅₀ (µg/mL) = 101.5 ± 12.6, corresponding to a selective antiplasmodial activity of 5.7. Bioactivity-guided isolation of the major compounds of the roots’ crude extract afforded seven compounds, including genistein, genistin and eucomic acid. Under our experimental conditions, using Artemisinin as a positive control, eucomic acid showed the best inhibitory activity against the P. falciparum 3D7, a well-known chloroquine-sensitive strain. The present results provide a referential basis to support the traditional use of Eriosema species in the treatment of malaria.     

Magnetic Hyperthermia Enhancement in Iron-based Materials Driven by Carbon Support Interactions

Magnetic hyperthermia (MH) shows great potential in clinical applications because of its very localized action and minimal side effects. Because of their high saturation magnetization values, reduced forms of iron are promising candidates for MH. However, they must be protected in order to overcome their toxicity and instability (i. e., oxidation) under biological conditions. In this work, a novel methodology for the protection of iron nanoparticles through confinement within graphitic carbon layers after thermal treatment of preformed nanoparticles supported on carbon is reported. We demonstrate that the size and composition of the nascent confined iron nanoparticles, as well as the thickness of their protective carbon layer can be controlled by selecting the nature of the carbon support. Our findings reveal that a higher nanoparticle–carbon interaction, mediated by the presence of oxygen-containing groups, induces the formation of small and well-protected α-Fe-based nanoparticles that exhibit promising results towards MH based on their enhanced specific absorption rate values.     

The constitutive equations of finite strain poroelasticity in the light of a micro-macro approach

After recalling the constitutive equations of finite strain poroelasticity formulated at the macroscopic level, we adopt a microscopic point of view which consists of describing the fluid-saturated porous medium at a space scale on which the fluid and solid phases are geometrically distinct. The constitutive equations of poroelasticity are recovered from the analysis conducted on a representative elementary volume of porous material open to fluid mass exchange. The procedure relies upon the solution of a boundary value problem defined on the solid domain of the representative volume undergoing large elastic strains. The macroscopic potential, computed as the integral of the free energy density over the solid domain, is shown to depend on the macroscopic deformation gradient and the porous space volume as relevant variables. The corresponding stress-type variables obtained through the differentiation of this potential turn out to be the macroscopic Boussinesq stress tensor and the pore pressure. Furthermore, such a procedure makes it possible to establish the necessary and sufficient conditions to ensure the validity of an ‘effective stress’ formulation of the constitutive equations of finite strain poroelasticity. Such conditions are notably satisfied in the important case of an incompressible solid matrix.     

On a Volume‐Constrained Variational Problem

. Existence of minimizers for a volume-constrained energy $ E(u) := \int_{\Omega} W(\nabla u)\, dx Existence of minimizers for a volume-constrained energy E(u) : = ò_W W(?u) dx E(u) := \int_{\Omega} W(\nabla u)\, dx where L^N({u = z_i}) = a_i, i = 1, ?, P, {\cal L}^N(\{u = z_i\}) = \alpha_i, i = 1, \ldots, P, is proved for the case in which z_iz_i are extremal points of a compact, convex set in \Bbb R^d\Bbb R^d and under suitable assumptions on a class of quasiconvex energy densities W. Optimality properties are studied in the scalar-valued problem where d=1d=1, P=2P=2, W(x)=|x|²W(\xi)=|\xi|^2, and the &-limit as the sum of the measures of the 2 phases tends to \L(W)\L(\Omega) is identified. Minimizers are fully characterized when N=1N=1, and candidates for solutions are studied for the circle and the square in the plane.     

Porous polycrystals built up by uniformly and axisymmetrically oriented needles: homogenization of elastic propertiesPolycristaux poreux constitués d'aiguilles orientées de façon uniforme ou axisymétrique : homogénéisation des propriétés élastiques

Porous polycrystal-type microstructures built up of needle-like platelets or sheets are characteristic for a number of biological and man-made materials. Herein, we consider (i) uniform, (ii) axisymmetrical orientation distribution of linear elastic, isotropic as well as anisotropic needles. Axisymmetrical needle orientation requires derivation of the Hill tensor for arbitrarily oriented ellipsoidal inclusions with one axis tending towards infinity, embedded in a transversely isotropic matrix; therefore, Laws' integral expression of the Hill tensor is evaluated employing the theory of rational functions. For a porosity lower 0.4, the elastic properties of the polycrystal with uniformly oriented needles are quasi-identical to those of a polycrystal with solid spheres. However, as opposed to the sphere-based model, the needle-based model does not predict a percolation threshold. As regards axisymmetrical orientation distribution of needles, two effects are remarkable: Firstly, the sharper the cone of orientations the higher the anisotropy of the polycrystal. Secondly, for a given cone, the anisotropy increases with the porosity. Estimates for the polycrystal stiffness are hardly influenced by the anisotropy of the bone mineral needles. Our results also confirm the very high degree of orientation randomness of crystals building up mineral foams in bone tissues. To cite this article: A. Fritsch et al., C. R. Mecanique 334 (2006).