Revisiting Proteasome Inhibitors: Molecular Underpinnings of Their Development,Mechanisms of Resistance and Strategies to Overcome Anti-Cancer Drug Resistance

Proteasome inhibitors have shown relevant clinical activity in several hematological malignancies, namely in multiple myeloma and mantle cell lymphoma, improving patient outcomes such as survival and quality of life, when compared with other therapies. However, initial response to the therapy is a challenge as most patients show an innate resistance to proteasome inhibitors, and those that respond to the therapy usually develop late relapses suggesting the development of acquired resistance. The mechanisms of resistance to proteasome inhibition are still controversial and scarce in the literature. In this review, we discuss the development of proteasome inhibitors and the mechanisms of innate and acquired resistance to their activity—a major challenge in preclinical and clinical therapeutics. An improved understanding of these mechanisms is crucial to guiding the design of new and more effective drugs to tackle these devastating diseases. In addition, we provide a comprehensive overview of proteasome inhibitors used in combination with other chemotherapeutic agents, as this is a key strategy to combat resistance.     

Thermodynamic Signatures of Structural Transitions and Dissociation of Charged Colloidal Clusters: A Parallel Tempering Monte Carlo Study

Computational simulation of colloidal systems make use of empirical interaction potentials that are founded in well-established theory. In this work, we have performed parallel tempering Monte Carlo (PTMC) simulations to calculate heat capacity and to assess structural transitions, which may occur in charged colloidal clusters whose effective interactions are described by a sum of pair potentials with attractive short-range and repulsive long-range components. Previous studies on these systems have shown that the global minimum structure varies from spherical-type shapes for small-size clusters to Bernal spiral and “beaded-necklace” shapes at intermediate and larger sizes, respectively. In order to study both structural transitions and dissociation, we have organized the structures appearing in the PTMC calculations by three sets according to their energy: (i) low-energy structures, including the global minimum; (ii) intermediate-energy “beaded-necklace” motifs; (iii) high-energy linear and branched structures that characterize the dissociative clusters. We observe that, depending on the cluster, either peaks or shoulders on the heat–capacity curve constitute thermodynamics signatures of dissociation and structural transitions. The dissociation occurs at T=0.20 for all studied clusters and it is characterized by the appearance of a significant number of linear structures, while the structural transitions corresponding to unrolling the Bernal spiral are quite dependent on the size of the colloidal system.     

Modelling of optical absorption of silver NP’s produced by UV radiation embedded in mesostructured silica films

Hexagonal mesostructured films containing silver ions were obtained by sol–gel method. Brij 58 was used to produce channels into the film, which house these ions. The films were exposure to UV radiation to produced silver metallic nanoparticles. The presence of the metallic nanoparticles was determined by infrared spectroscopy and optical absorption. Besides, these nanoparticles and core–shell structures of silver–silver oxide nanoparticles were identified by high-resolution transmission electronic microscopy. From these measurements, the obtained size range for silver nanoparticles was 6.1 nm. The absorption spectrum located at 440 nm was modelled and well fitted with the Gans theory considering refractive index higher than the one coming from host matrix. This index is explained because the silver oxide shell modifies the local surrounding medium of the metallic nanoparticles.     

Three-parameter Lorentz-violating texture for neutrino mixing

A three-parameter model of neutrino oscillations based on a simple Lorentz- and CPT-violating texture is presented. The model is consistent with established data and naturally generates low-energy and neutrino–antineutrino anomalies of the MiniBooNE type. A one-parameter extension incorporates the MINOS anomaly, while a simple texture enhancement accommodates the LSND signal.     

Improvement of the dynamic range of a fiber specklegram sensor based on volume speckle recording in photorefractive materials

In this work, the improvement of the dynamic range of a micro displacement sensor based on fiber specklegrams holographically stored in a photorefractive BSO (Bi₁₂SiO₂₀) crystal is reported. In our experimental setup, a plastic optical fiber (POF) was used to generate a subjective speckle pattern that was recorded in the crystal using a two-wave mixing arrangement. The speckle size was controlled by modifying the diameter of a pupil aperture adjacent to a lens producing the image of the speckle. Fringe patterns were obtained at the output of the system by producing micro displacements of the fiber output end. An increase in the visibility of the fringe patterns was appreciated when the pupil aperture diameter decreased even without controlling the average modulation of the intensity of the light pattern, i.e. when the speckle length increased and the average light modulation simultaneously decreased. This behavior allowed recovering the autocorrelation functions of fringe patterns associated with displacements that initially led to decorrelation, and therefore, significantly to improve the dynamic range of the metrological system. To the best of our knowledge this is the first report about the influence of speckle size on the dynamic range of fiber specklegrams sensors recorded on photorefractive materials.     

Free-space fluorescence molecular tomography utilizing 360 degrees geometry projections

Fluorescence tomography of diffuse media can yield optimal three-dimensional imaging when multiple projections over 360 degrees geometries are captured, compared with limited projection angle systems such as implementations in the slab geometry. We demonstrate how it is possible to perform noncontact, 360 degrees projection fluorescence tomography of mice using CCD-camera-based detection in free space, i.e., in the absence of matching fluids. This approach achieves high spatial sampling of photons propagating through tissue and yields a superior information content data set compared with fiber-based 360 degrees implementations. Reconstruction feasibility using 36 projections in 10 degrees steps is demonstrated in mice.     

Anisotropic Local Hardy Spaces

In this paper we introduce and study the anisotropic local Hardy spaces h_A^p(\mathbbRⁿ)h_{A}^{p}(\mathbb{R}^{n}) 0<p≤1, associated with the expansive matrix A. We obtain an atomic characterization of the distributions in h_A^p(\mathbbRⁿ)h_{A}^{p}(\mathbb{R}^{n}). Also we describe the dual spaces of our local Hardy anisotropic spaces as anisotropic Campanato type spaces.     

The extended loop group: An infinite dimensional manifold associated with the loop space

A set of coordinates in the non-parametric loop-space is introduced. We show that these coordinates transform under infinite dimensional linear representations of the diffeomorphism group. An extension of the group of loops in terms of these objects is proposed. The enlarged group behaves locally as an infinite dimensional Lie group. Ordinary loops form a subgroup of this group. The algebraic properties of this new mathematical structure are analyzed in detail. Applications of the formalism to field theory, quantum gravity and knot theory are considered.     

Stealth scalar field overflying a 2+1 black hole

A nontrivial scalar field configuration of vanishing energy-momentum is reported. These matter configurations have no influence on the metric and therefore they are not be “detected" gravitationally. This phenomenon occurs for a time–dependent nonminimally coupled and self-interacting scalar field on the 2+1 (BTZ) black hole geometry. We conclude that such stealth configurations exist for the static 2+1 black hole for any value of the nonminimal coupling parameter ζ≠0 with a fixed self-interaction potential U _ζ(Φ). For the range 0 < ζ≤1/2 potentials are bounded from below and for the range 0 < ζ < 1/4 the stealth field falls into the black hole and is swallowed by it at an exponential rate, without any consequence for the black hole.