Sofosbuvir Selects for Drug-Resistant Amino Acid Variants in the Zika Virus RNA-Dependent RNA-Polymerase Complex In Vitro

The nucleotide analog sofosbuvir, licensed for the treatment of hepatitis C, recently revealed activity against the Zika virus (ZIKV) in vitro and in animal models. However, the ZIKV genetic barrier to sofosbuvir has not yet been characterized. In this study, in vitro selection experiments were performed in infected human hepatoma cell lines. Increasing drug pressure significantly delayed viral breakthrough (p = 0.029). A double mutant in the NS5 gene (V360L/V607I) emerged in 3 independent experiments at 40–80 µM sofosbuvir resulting in a 3.9 ± 0.9-fold half- maximal inhibitory concentration (IC₅₀) shift with respect to the wild type (WT) virus. A triple mutant (C269Y/V360L/V607I), detected in one experiment at 80 µM, conferred a 6.8-fold IC₅₀ shift with respect to the WT. Molecular dynamics simulations confirmed that the double mutant V360L/V607I impacts the binding mode of sofosbuvir, supporting its role in sofosbuvir resistance. Due to the distance from the catalytic site and to the lack of reliable structural data, the contribution of C269Y was not investigated in silico. By a combination of sequence analysis, phenotypic susceptibility testing, and molecular modeling, we characterized a double ZIKV NS5 mutant with decreased sofosbuvir susceptibility. These data add important information to the profile of sofosbuvir as a possible lead for anti-ZIKV drug development.     

Nondegradative microextrusion of resorbable polyesters for pharmaceutical and biomedical applications: The cases of poly‐lactic‐acid and poly‐caprolactone

In recent years biodegradable polymers, particularly polyesters such as the poly(lactic acid) (PLA) and polycaprolactone (PCL), have gained high interests for their applicability in the biomedical and pharmaceutical fields where they're used for manufacturing various different resorbable devices, from tissue engineering scaffolds to controlled drug release systems. Despite many positive characteristics, processability of these materials still remains a critical issue as they easily tend to degrade during manufacturing. In this article we aimed to assess microextrusion as a nondegradative process for manufacturing PLA and PCL. The results we experimentally obtained, that are hereby presented, set a new point in the on‐going debate on degradation during processing of resorbable polymers as they allow to affirm that microextrusion leaves unmodified molecular weight distributions without producing any evident reductions in mean molecular weight. Microextrusion thus represents a risk‐free high molecular weight polymer processing solution for obtaining nondegraded products within pharmaceutical and biomedical production lines, such as for scaffolds for tissue engineering applications or drug delivery. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Measuring the load eccentricity in helical compression springs

An experimental device able to detect the load eccentricity in helical compression springs is described. The theory underlying the resolution of measured bending strains of the apparatus into effective load eccentricity is discussed. Laboratory results are offered for heavy duty springs and compared to theoretical estimates retrieved from the literature.     

BRAF Gene and Melanoma: Back to the Future

As widely acknowledged, 40–50% of all melanoma patients harbour an activating BRAF mutation (mostly BRAF V600E). The identification of the RAS–RAF–MEK–ERK (MAP kinase) signalling pathway and its targeting has represented a valuable milestone for the advanced and, more recently, for the completely resected stage III and IV melanoma therapy management. However, despite progress in BRAF-mutant melanoma treatment, the two different approaches approved so far for metastatic disease, immunotherapy and BRAF+MEK inhibitors, allow a 5-year survival of no more than 60%, and most patients relapse during treatment due to acquired mechanisms of resistance. Deep insight into BRAF gene biology is fundamental to describe the acquired resistance mechanisms (primary and secondary) and to understand the molecular pathways that are now being investigated in preclinical and clinical studies with the aim of improving outcomes in BRAF-mutant patients.     

Designing N‐PolyVector Fields with Complex Polynomials

We introduce N‐PolyVector fields, a generalization of N‐RoSy fields for which the vectors are neither necessarily orthogonal nor rotationally symmetric. We formally define a novel representation for N‐PolyVectors as the root sets of complex polynomials and analyze their topological and geometric properties. A smooth N‐PolyVector field can be efficiently generated by solving a sparse linear system without integer variables. We exploit the flexibility of N‐PolyVector fields to design conjugate vector fields, offering an intuitive tool to generate planar quadrilateral meshes.     

Implementation of the quadrature method of moments in CFD codes for aggregation-breakage problems

In this work the quadrature method of moments (QMOM) is implemented in a commercial computational fluid dynamics (CFD) code (FLUENT) for modeling simultaneous aggregation and breakage. Turbulent and Brownian aggregation kernels are considered in combination with different breakage kernels (power law and exponential) and various daughter distribution functions (symmetric, erosion, uniform). CFD predictions are compared with experimental data taken from other work in the literature and conclusions about CPU time required for the simulations and the advantages of this approach are drawn.     

Stay with the flow: How macroinvertebrate communities recover during the rewetting phase in Alpine streams affected by an exceptional drought

Droughts are affecting an increasing number of lotic ecosystems worldwide due to the combined effects of climatic and anthropogenic pressures. Unlike naturally intermittent rivers, where the drying phase is a part of the annual flow regime, water scarcity in Alpine rivers represents a relatively recent phenomenon and, therefore, a major threat for the biodiversity of these lotic ecosystems. However, Alpine stream community response to drought is still poorly investigated. Here, we assess the recovery of macroinvertebrates in two Alpine streams after a supraseasonal drought. As water returned, a total of 10 sampling sessions were carried out, and temporal patterns in diversity, density, and taxonomic composition of benthic communities, as well as in the percentage of functional feeding groups, were investigated. We found that the resistance of invertebrate communities in Alpine streams is generally low: drought markedly reduced the diversity and density of macroinvertebrates. Conversely, our results suggest that the passive dispersal by drift from the upstream river sections seems the most probable mechanism promoting the post‐drought recovery. Nevertheless, this resilience ability appears to be stream specific and influenced by intrinsic stream characteristics, including the flow permanence and distance from the nearest upstream perennial reach. This work sheds light on the ecological consequences of droughts on macroinvertebrate communities. As flow intermittency in Alpine areas is expected to intensify under current global change scenarios, results of this study provide important information to predict changes in the taxonomic composition and diversity of macroinvertebrate communities.     

Texture Mapping Real‐World Objects with Hydrographics

In the digital world, assigning arbitrary colors to an object is a simple operation thanks to texture mapping. However, in the real world, the same basic function of applying colors onto an object is far from trivial. One can specify colors during the fabrication process using a color 3D printer, but this does not apply to already existing objects. Paint and decals can be used during post‐fabrication, but they are challenging to apply on complex shapes. In this paper, we develop a method to enable texture mapping of physical objects, that is, we allow one to map an arbitrary color image onto a three‐dimensional object. Our approach builds upon hydrographics, a technique to transfer pigments printed on a sheet of polymer onto curved surfaces. We first describe a setup that makes the traditional water transfer printing process more accurate and consistent across prints. We then simulate the transfer process using a specialized parameterization to estimate the mapping between the planar color map and the object surface. We demonstrate that our approach enables the application of detailed color maps onto complex shapes such as 3D models of faces and anatomical casts.     

A Novel Particle/Photon Detector Based on a Superconducting Proximity Array of Nanodots

The current frontiers in the investigation of high-energy particles demand for new detection methods. Higher sensitivity to low-energy deposition, high-energy resolution to identify events and improve the background rejection, and large detector masses have to be developed to detect even an individual particle that weakly interacts with ordinary matter. Here, we will describe the concept and the layout of a novel superconducting proximity array which show dynamic vortex Mott insulator to metal transitions, as an ultra-sensitive compact radiation-particle detector.     

An element-based formulation for ES-FEM and FS-FEM models for implementation in standard solid mechanics finite element codes for 2D and 3D static analysis

Edge-based and face-based smoothed finite element methods (ES-FEM and FS-FEM, respectively) are modified versions of the finite element method allowing to achieve more accurate results and to reduce sensitivity to mesh distortion, at least for linear elements. These properties make the two methods very attractive. However, their implementation in a standard finite element code is nontrivial because it requires heavy and extensive modifications to the code architecture. In this article, we present an element-based formulation of ES-FEM and FS-FEM methods allowing to implement the two methods in a standard finite element code with no modifications to its architecture. Moreover, the element-based formulation permits to easily manage any type of element, especially in 3D models where, to the best of the authors' knowledge, only tetrahedral elements are used in FS-FEM applications found in the literature. Shape functions for non-simplex 3D elements are proposed in order to apply FS-FEM to any standard finite element.