Synthesis and Biochemical Evaluation of Warhead-Decorated Psoralens as (Immuno)Proteasome Inhibitors

The immunoproteasome is a multicatalytic protease that is predominantly expressed in cells of hematopoietic origin. Its elevated expression has been associated with autoimmune diseases, various types of cancer, and inflammatory diseases. Selective inhibition of its catalytic activities is therefore a viable approach for the treatment of these diseases. However, the development of immunoproteasome-selective inhibitors with non-peptidic scaffolds remains a challenging task. We previously reported 7H-furo[3,2-g]chromen-7-one (psoralen)-based compounds with an oxathiazolone warhead as selective inhibitors of the chymotrypsin-like (β5i) subunit of immunoproteasome. Here, we describe the influence of the electrophilic warhead variations at position 3 of the psoralen core on the inhibitory potencies. Despite mapping the chemical space with different warheads, all compounds showed decreased inhibition of the β5i subunit of immunoproteasome in comparison to the parent oxathiazolone-based compound. Although suboptimal, these results provide crucial information about structure–activity relationships that will serve as guidance for the further design of (immuno)proteasome inhibitors.     

Cosmetic Formulations with Melaleuca alternifolia Essential Oil for the Improvement of Photoaged Skin: A Double-Blind,Randomized, Placebo-Controlled Clinical Study

This aim of this study was to evaluate the penetration depth, antioxidant capacity and the clinical efficacy of Melaleuca alternifolia pure essential oil and in a nanoemulsion to prevent skin photoaging. For this, 2% of pure essential oil or 2% of this essential oil in a nanoemulsion were vehiculated in a formulation. The skin penetration was evaluated using confocal Raman microspectroscopy. The radical protection factor was evaluated using electron paramagnetic resonance spectroscopy. For a clinical study, 40 male participants, aged 18–28 years, were enrolled, being divided into three groups: vehicle formulation, M. alternifolia pure essential oil and M. alternifolia Nanoemulsion. All the participants also received a sunscreen SPF 50 to use during the day. Before and after 90 days of study, skin hydrolipidics and morphological characteristics were performed by skin imaging and biophysical techniques. The nanoemulsion presented a lower antioxidant capacity and a higher penetration through the stratum corneum, reaching the viable epidermis, improving the stratum granulosum morphology. The groups presented an increase in the papillary depth, improving in the dermis echogenicity and the collagen fibers. Melaleuca alternifolia essential provides the potential to improve photoaged skin, being the application of nanoemulsion able to reach deeper skin layers.     

Mechanically Activated Solid-State Radical Polymerization and Cross-Linking via Piezocatalysis

Piezocatalysis offers a means to transduce mechanical energy into chemical potential, harnessing physical force to drive redox reactions. Working in the solid state, we show here that piezoelectric BaTiO₃ nanoparticles can transduce mechanical load into a flux of reactive radical species capable of initiating solid state free radical polymerization. Activation of a BaTiO₃ powder by ball milling, striking with a hammer, or repeated compressive loading generates highly reactive hydroxyl radicals (⋅OH), which readily initiate radical chain growth and crosslinking of solid acrylamide, acrylate, methacrylate and styrenic monomers. Control experiments indicate a critical role for chemisorbed water on the BaTiO₃ nanoparticle surface, which is oxidized to ⋅OH via mechanoredox catalysis. The force-induced production of radicals by compressing dry piezoelectric materials represents a promising new route to harness mechanical energy for solid state radical synthesis.     

Determination of physiological noble metals in human urine using liquid-liquid extraction and Zeeman electrothermal atomic absorption spectrometry

An extremely sensitive, reliable and simple procedure is described for the determination of physiological palladium, platinum and gold in human urine. The urine samples were adjusted to pH 4 (Pd, Au) or pH 5 (Pt), followed by conversion of the analytes to their pyrrolidinedithiocarbamate complexes. These complexes were separated from the matrix by liquid-liquid extraction into 4-methyl-2-pentanone resulting in a 25-fold enrichment. Determination was by electrothermal atomic absorption spectrometry (ET-AAS) using longitudinal inverse alternating current Zeeman-effect background correction. The limits of detection calculated from three standard deviations of the blank values were 20 ng l⁻¹ for Pd and Au and 70 ng l⁻¹ Pt. Within-day precision (n = 10, 5 μg l⁻¹) ranged 5.2%–7.7%. The procedure is successfully applied to determine urinary palladium, platinum and gold in nine unexposed persons. Palladium levels in urine ranged < 20–80 ng l⁻¹ (arithmetical MEAN=38.7 ng l⁻¹), while gold levels ranged < 20–130 ng l⁻¹ (36.0 ng l⁻¹). Physiological platinum levels in urine were all < 70 ng l⁻¹. The accuracy of the procedure was checked by analyzing a series of urine samples by a second independent method (magnetic sector field inductively-coupled plasma-mass spectrometry) in combination with UV photolysis.     

A Poset Fiber Theorem for Doubly Cohen-Macaulay Posets and Its Applications

This paper studies topological properties of the lattices of non-crossing partitions of types A and B and of the poset of injective words. Specifically, it is shown that after the removal of the bottom and top elements (if existent) these posets are doubly Cohen-Macaulay. This strengthens the well-known facts that these posets are Cohen-Macaulay. Our results rely on a new poset fiber theorem which turns out to be a useful tool to prove double (homotopy) Cohen- Macaulayness of a poset. Applications to complexes of injective words are also included.     

Phase Field Modeling of Brittle and Ductile Fracture

The phase field modeling of brittle fracture was a topic of intense research in the last few years and is now well-established. We refer to the work [1-3], where a thermodynamically consistent framework was developed. The main advantage is that the phase-field-type diffusive crack approach is a smooth continuum formulation which avoids the modeling of discontinuities and can be implemented in a straightforward manner by multi-field finite element methods. Therefore complex crack patterns including branching can be resolved easily. In this paper, we extend the recently outlined phase field model of brittle crack propagation [1-3] towards the analysis of ductile fracture in elastic-plastic solids. In particular, we propose a formulation that is able to predict the brittle-to-ductile failure mode transition under dynamic loading that was first observed in experiments by Kalthoff and Winkler [4]. To this end, we outline a new thermodynamically consistent framework for phase field models of crack propagation in ductile elastic-plastic solids under dynamic loading, develop an incremental variational principle and consider its robust numerical implementation by a multi-field finite element method. The performance of the proposed phase field formulation of fracture is demonstrated by means of the numerical simulation of the classical Kalthoff-Winkler experiment that shows the dynamic failure mode transition. (© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)     

On Weak Solutions of Stochastic Differential Equations II

In the first part of this article a new method of proving existence of weak solutions to stochastic differential equations with continuous coefficients having at most linear growth was developed. In this second part, we show that the same method may be used even if the linear growth hypothesis is replaced with a suitable Lyapunov condition.     

Gradient type noises II - Systems of stochastic partial differential equations

The present paper is the second and main part of a study of partial differential equations under the influence of noisy perturbations. Existence and uniqueness of function solutions in the mild sense are obtained for a class of deterministic linear and semilinear parabolic boundary initial value problems. If the noise data are random, the results may be seen as a pathwise approach to SPDE's. For typical examples, such as spatially one-dimensional stochastic heat equations with additive or multiplicative perturbations of fractional Brownian type, we recover and extend known results. In addition, we propose to consider partial noises of low order.     

A priori estimates for rough PDEs with application to rough conservation laws

We introduce a general weak formulation for PDEs driven by rough paths, as well as a new strategy to prove well-posedness. Our procedure is based on a combination of fundamental a priori estimates with (rough) Gronwall-type arguments. In particular this approach does not rely on any sort of transformation formula (flow transformation, Feynman–Kac representation formula etc.) and is therefore rather flexible. As an application, we study conservation laws driven by rough paths establishing well–posedness for the corresponding kinetic formulation.     

Algebraic properties of classes of path ideals of posets

We consider path ideals associated to special classes of posets such as tree posets and cycles. We express their property of being sequentially Cohen–Macaulay in terms of the underlying poset. Moreover, monomial ideals, which arise in algebraic statistics from the Luce-decomposable model and the ascending model, can be viewed as path ideals of certain posets. We study invariants of these so-called Luce-decomposable monomial ideals and ascending ideals for diamond posets and products of chains. In particular, for these classes of posets, we explicitly compute their Krull dimension, their projective dimension, their Castelnuovo–Mumford regularity and their Betti numbers.