Cell-Permeable Succinate Rescues Mitochondrial Respiration in Cellular Models of Statin Toxicity

Statins are the cornerstone of lipid-lowering therapy. Although generally well tolerated, statin-associated muscle symptoms (SAMS) represent the main reason for treatment discontinuation. Mitochondrial dysfunction of complex I has been implicated in the pathophysiology of SAMS. The present study proposed to assess the concentration-dependent ex vivo effects of three statins on mitochondrial respiration in viable human platelets and to investigate whether a cell-permeable prodrug of succinate (complex II substrate) can compensate for statin-induced mitochondrial dysfunction. Mitochondrial respiration was assessed by high-resolution respirometry in human platelets, acutely exposed to statins in the presence/absence of the prodrug NV118. Statins concentration-dependently inhibited mitochondrial respiration in both intact and permeabilized cells. Further, statins caused an increase in non-ATP generating oxygen consumption (uncoupling), severely limiting the OXPHOS coupling efficiency, a measure of the ATP generating capacity. Cerivastatin (commercially withdrawn due to muscle toxicity) displayed a similar inhibitory capacity compared with the widely prescribed and tolerable atorvastatin, but did not elicit direct complex I inhibition. NV118 increased succinate-supported mitochondrial oxygen consumption in atorvastatin/cerivastatin-exposed platelets leading to normalization of coupled (ATP generating) respiration. The results acquired in isolated human platelets were validated in a limited set of experiments using atorvastatin in HepG2 cells, reinforcing the generalizability of the findings.     

A concise nodal-based derivation of the floating frame of reference formulation for displacement-based solid finite elements

Multibody System Dynamics - The Floating Frame of Reference Formulation (FFRF) is one of the most widely used methods to analyze flexible multibody systems subjected to large rigid-body motion but...     

EGGS: Sparsity-Specific Code Generation

Sparse matrix computations are among the most important computational patterns, commonly used in geometry processing, physical simulation, graph algorithms, and other situations where sparse data arises. In many cases, the structure of a sparse matrix is known a priori, but the values may change or depend on inputs to the algorithm. We propose a new methodology for compile-time specialization of algorithms relying on mixing sparse and dense linear algebra operations, using an extension to the widely-used open source Eigen package. In contrast to library approaches optimizing individual building blocks of a computation (such as sparse matrix product), we generate reusable sparsity-specific implementations for a given algorithm, utilizing vector intrinsics and reducing unnecessary scanning through matrix structures. We demonstrate the effectiveness of our technique on a benchmark of artificial expressions to quantitatively evaluate the benefit of our approach over the state-of-the-art library Intel MKL. To further demonstrate the practical applicability of our technique we show that our technique can improve performance, with minimal code changes, for mesh smoothing, mesh parametrization, volumetric deformation, optical flow, and computation of the Laplace operator.     

Aqueous‐Phase Reforming in a Microreactor: The Role of Surface Bubbles

In heterogeneous catalysis, the creation of gaseous products as bubbles in a liquid phase on the catalytic surface is associated with slip phenomena. In a microreactor, the slip length at the gas‐liquid interface is in the same order of magnitude as the reactor dimensions, which can affect fluid dynamics and transport phenomena. Here, the interplay of momentum, heat and mass transfer in a microreactor, when bubbles form on the catalytic surface, was investigated using two‐dimensional simulations. The effect of bubbles on the endothermic process of aqueous‐phase reforming of a glycerol solution was evaluated in terms of conversion and conversion and temperature in the reactor. Altogether, this study highlights the impact of bubbles, not only on the transport phenomena but also on the reactor performance.     

On the Barzilai-Borwein basic scheme in FFT-based computational homogenization

Building upon the equivalence of the basic scheme in the work of Moulinec and Suquet with gradient descent methods, we investigate the effect of using the celebrated Barzilai-Borwein step size selection technique in this context. We provide an overview of recent convergence theory and present efficient implementations in the context of computational micromechanics, with and without globalization. In contrast to polarization schemes and fast gradient methods, no lower bound on the eigenvalues of the material tangent is necessary for the Barzilai-Borwein scheme. We demonstrate the power of the proposed method for linear elastic and inelastic large scale problems with finite and infinite material contrast.     

Characteristics of Bi-metallic Interfaces Formed During Direct Energy Deposition Additive Manufacturing Processing

Metallurgical and Materials Transactions B - Various additive manufacturing processes are being evaluated to reduce the time and cost for fabrication of low volume, complex, and multifunctional...     

Room temperature R-curve and stable crack growth behaviour of ZrB2–SiC ceramic composites

ABSTRACT

R-curve and controlled stable crack growth behaviour of ZrB₂–17vol.-%SiC and ZrB₂–45vol.-%SiC ceramic composites was studied on V-notched samples using four-point bending at room temperature. The rising K_1R behaviour was determined as a function of the crack extension Δa with a crack bridging mechanism being dominant in such behaviour. Significant differences in crack growth rates were found within the same composition of ceramics simply as the crack length varied during crack growth processes. These differences are indicative of the significant influence of microstructural parameters of the ceramics on crack propagation. The peculiarities of stress intensity factor K₁ and the crack growth-specific behaviour in ZrB₂–SiC particulate ceramic composites are discussed.     

Click-Chemistry (CuAAC) Trimerization of an αvβ6 Integrin Targeting Ga-68-Peptide: Enhanced Contrast for in-Vivo PET Imaging of Human Lung Adenocarcinoma Xenografts

α_vβ₆ Integrin is an epithelial transmembrane protein that recognizes latency-associated peptide (LAP) and primarily activates transforming growth factor beta (TGF-β). It is overexpressed in carcinomas (most notably, pancreatic) and other conditions associated with α_vβ₆ integrin-dependent TGF-β dysregulation, such as fibrosis. We have designed a trimeric Ga-68-labeled TRAP conjugate of the α_vβ₆-specific cyclic pentapeptide SDM17 (cyclo[RGD-Chg-E]-CONH₂) to enhance α_vβ₆ integrin affinity as well as target-specific in-vivo uptake. Ga-68-TRAP(SDM17)₃ showed a 28-fold higher α_vβ₆ affinity than the corresponding monomer Ga-68-NOTA-SDM17 (IC₅₀ of 0.26 vs. 7.4 nM, respectively), a 13-fold higher IC₅₀-based selectivity over the related integrin α_vβ₈ (factors of 662 vs. 49), and a threefold higher tumor uptake (2.1 vs. 0.66 %ID/g) in biodistribution experiments with H2009 tumor-bearing SCID mice. The remarkably high tumor/organ ratios (tumor-to-blood 11.2; -to-liver 8.7; -to-pancreas 29.7) enabled high-contrast tumor delineation in PET images. We conclude that Ga-68-TRAP(SDM17)₃ holds promise for improved clinical PET diagnostics of carcinomas and fibrosis.