Phosphopeptide selective coordination complexes as promising SRC homology 2 domain mimetics

Src Homology 2 (SH2) domains are the paradigm of phosphotyrosine (pY) protein recognition modules and mediate numerous cancer-promoting protein-protein complexes. Effective SH2 domain mimicry with pY-binding coordination complexes offers a promising route to new and selective disruptors of pY-mediated protein-protein interactions. We herein report the synthesis and in vitro characterization of a library of coordination complex SH2 domain proteomimetics. Compounds were designed to interact with phosphopeptides via a two-point interaction, principally with pY, and to make secondary interactions with pY+2/3, thereby achieving sequence-selective discrimination. Here, we report that lead mimetics demonstrated high target phosphopeptide affinity (K(a) ～ 10(7) M(-1)) and selectivity. In addition, biological screening in various tumor cells for anticancer effects showed a high degree of variability in cytotoxicity among receptors, which supported the proposed two-point binding mode. Several receptors potently disrupted cancer cell viability in breast cancer, prostate cancer, and acute myeloid leukemia cell lines.     

Rank Tests Based on Exceeding Observations

Rank tests based on the maximum number of exceeding observations for several standard nonparametric hypotheses are proposed. An approach to constructing nonparametric rank tests via metrics on the permutation group is used. The test statistics are based on a metric induced by Chebyshev's norm.     

Exploring Microfluidic Routes to Microgels of Biological Polymers

Polymer microgels in the size range from several micrometers to hundreds of micrometers are used in the pharmaceutical, cosmetics, nutrition, pesticide, and food industries, as well as in the encapsulation of cells. To date, a broad range of strategies for the generation of polymer microgels exist, however, these methods involve multistage processes, do not utilize biocompatible components or do not allow precise control of the dimensions and internal structure of the microgels. Recently, microfluidic strategies for the production of polymer particles have offered precise control over the shapes, morphologies, and size distributions of polymer colloids. This paper discusses the most recent results obtained by the authors in the area of the microfluidic production of biopolymer microgels. It provides a brief review of the microfluidic methods for the continuous synthesis and fabrication of microgels, sets the criteria for the successful microfluidic generation of biomicrogels, and describes two methods for the preparation of microgels by microfluidic means. The article concludes with a summary and an outlook.

     

Dually Responsive Poly(N-vinylcaprolactam)-b-poly(dimethylsiloxane)-b-poly(N-vinylcaprolactam) Polymersomes for Controlled Delivery

Limited tissue selectivity and targeting of anticancer therapeutics in systemic administration can produce harmful side effects in the body. Various polymer nano-vehicles have been developed to encapsulate therapeutics and prevent premature drug release. Dually responsive polymeric vesicles (polymersomes) assembled from temperature-/pH-sensitive block copolymers are particularly interesting for the delivery of encapsulated therapeutics to targeted tumors and inflamed tissues. We have previously demonstrated that temperature-responsive poly(N-vinylcaprolactam) (PVCL)-b-poly(dimethylsiloxane) (PDMS)-b-PVCL polymersomes exhibit high loading efficiency of anticancer therapeutics in physiological conditions. However, the in-vivo toxicity of these polymersomes as biocompatible materials has not yet been explored. Nevertheless, developing an advanced therapeutic nanocarrier must provide the knowledge of possible risks from the material’s toxicity to support its future clinical research in humans. Herein, we studied pH-induced degradation of PVCL₁₀-b-PDMS₆₅-b-PVCL₁₀ vesicles in-situ and their dually (pH- and temperature-) responsive release of the anticancer drug, doxorubicin, using NMR, DLS, TEM, and absorbance spectroscopy. The toxic potential of the polymersomes was evaluated in-vivo by intravenous injection (40 mg kg⁻¹ single dose) of PVCL₁₀-PDMS₆₅-PVCL₁₀ vesicles to mice. The sub-acute toxicity study (14 days) included gravimetric, histological, and hematological analyses and provided evidence for good biocompatibility and non-toxicity of the biomaterial. These results show the potential of these vesicles to be used in clinical research.     

Spectrum of partial automorphisms of regular rooted tree

Semigroup Forum - We study properties of eigenvalues of a matrix associated with a randomly chosen partial automorphism of a regular rooted tree. We show that asymptotically, as the level number...     

Existence and uniqueness of solutions in H1(Δ) of a general class of non-linear functional equations

A functional analytic method is used to prove the existence and the uniqueness of a solution in the Banach space H₁(Δ) of a general class of non-linear functional equations. This general class includes some specific functional equations studied recently. Our results simplify and improve the existing results for these specific equations. Moreover, for one of them, we give an answer to an open problem.     

Asymptotically sharp uniform estimates in a scalar spectral stiff problemEstimations asymptotiques uniformes pour le spectre d'un problème scalaire raide

Estimates of convergence rates for rescaled eigenvalues of the stiff Neumann problem for the Laplacian are obtained. The bounds are expressed in terms of the stiffness ratio and properties of the limit spectrum both for low and middle frequency ranges. To cite this article: M. Lobo et al., C. R. Mecanique 331 (2003).     

A “discretization” technique for the solution of ODEs

A functional-analytic technique was developed in the past for the establishment of unique solutions of ODEs in H₂(D) and H₁(D) and of difference equations in ?₂ and ?₁. This technique is based on two isomorphisms between the involved spaces. In this paper, the two isomorphisms are combined in order to find discrete equivalent counterparts of ODEs, so as to obtain eventually the solution of the ODEs under consideration. As an application, the Duffing equation and the Lorenz system are studied. The results are compared with numerical ones obtained using the 4th order Runge-Kutta method. The advantages of the present method are that, it is accurate, the only errors involved are the round-off errors, it does not depend on the grid used and the obtained solution is proved to be unique.