Role of angiopoietin-like protein 3 in sugar-induced dyslipidemia in rhesus macaques: suppression by fish oil or RNAi.

Angiopoietin-like protein 3 (ANGPTL3) inhibits lipid clearance and is a promising target for managing cardiovascular disease. Here we investigated the effects of a high-sugar (high-fructose) diet on circulating ANGPTL3 concentrations in rhesus macaques. Plasma ANGPTL3 concentrations increased ∼30% to 40% after 1 and 3 months of a high-fructose diet (both P < 0.001 vs. baseline). During fructose-induced metabolic dysregulation, plasma ANGPTL3 concentrations were positively correlated with circulating indices of insulin resistance [assessed with fasting insulin and the homeostatic model assessment of insulin resistance (HOMA-IR)], hypertriglyceridemia, adiposity (assessed as leptin), and systemic inflammation [C-reactive peptide (CRP)] and negatively correlated with plasma levels of the insulin-sensitizing hormone adropin. Multiple regression analyses identified a strong association between circulating APOC3 and ANGPTL3 concentrations. Higher baseline plasma levels of both ANGPTL3 and APOC3 were associated with an increased risk for fructose-induced insulin resistance. Fish oil previously shown to prevent insulin resistance and hypertriglyceridemia in this model prevented increases of ANGPTL3 without affecting systemic inflammation (increased plasma CRP and interleukin-6 concentrations). ANGPTL3 RNAi lowered plasma concentrations of ANGPTL3, triglycerides (TGs), VLDL-C, APOC3, and APOE. These decreases were consistent with a reduced risk of atherosclerosis. In summary, dietary sugar-induced increases of circulating ANGPTL3 concentrations after metabolic dysregulation correlated positively with leptin levels, HOMA-IR, and dyslipidemia. Targeting ANGPTL3 expression with RNAi inhibited dyslipidemia by lowering plasma TGs, VLDL-C, APOC3, and APOE levels in rhesus macaques

A Useful Approximation to the Cooling Coefficient of Trace Elements

Radiative cooling is an important ingredient in hydrodynamical models involving evolution of high temperature plasmas. Unfortunately, calculating an accurate cooling coefficient generally requires the solution of over a hundred differential equations to follow the ionization. We discuss here a simple 2-parameter approximation for the cooling coefficient due to elements heavier than H and He, for the temperature range $T= 10^{4}-10^{8}$K. Tests of the method show that it successfully tracks the ionization level in severe dynamical environments, and accurately approximates the non-equilibrium cooling coefficient of the trace elements, usually to within 10% in all cases for which cooling is actually important. The error is large only when the temperature is dropping so rapidly due to expansion that radiative cooling is negligible, but even in this situation, the ionization level is followed sufficiently accurately. The current approximation is fully implemented in publicly available FORTRAN code. A second paper will discuss general approaches to approximation methods of this type, other realizations which could be even more accurate, and the potential for extension to calculations of non-equilibrium spectra.Comment: ApJLett, in press; Associated codes available at ftp://wisp5.physics.wisc.edu/pub/benjamin/BB

Neutralizing Antibody-Resistant Hepatitis C Virus Cell-to-Cell Transmission

Hepatitis C virus (HCV) can initiate infection by cell-free particle and cell-cell contact-dependent transmission. In this study we use a novel infectious coculture system to examine these alternative modes of infection. Cell-to-cell transmission is relatively resistant to anti-HCV glycoprotein monoclonal anti- bodies and polyclonal immunoglobulin isolated from infected individuals, providing an effective strategy for escaping host humoral immune responses. Chimeric viruses expressing the structural proteins rep- resenting the seven major HCV genotypes demonstrate neutralizing antibody-resistant cell-to-cell trans- mission. HCV entry is a multistep process involving numerous receptors. In this study we demonstrate that, in contrast to earlier reports, CD81 and the tight-junction components claudin-1 and occludin are all essential for both cell-free and cell-to-cell viral transmission. However, scavenger receptor BI (SR-BI) has a more prominent role in cell-to-cell transmission of the virus, with SR-BI-specific antibodies and small-molecule inhibitors showing preferential inhibition of this infection route. These observations highlight the importance of targeting host cell receptors, in particular SR-BI, to control viral infection and spread in the liver

In Vitro Tumor Models: Advantages, Disadvantages, Variables, and Selecting the Right Platform

In vitro tumor models have provided important tools for cancer research and serve as low-cost screening platforms for drug therapies; however, cancer recurrence remains largely unchecked due to metastasis, which is the cause of the majority of cancer related deaths. The need for an improved understanding of the progression and treatment of cancer has pushed for increased accuracy and physiological relevance of in vitro tumor models. As a result, in vitro tumor models have concurrently increased in complexity and their output parameters further diversified, since these models have progressed beyond simple proliferation, invasion, and cytotoxicity screens and have begun recapitulating critical steps in the metastatic cascade, such as intravasation, extravasation, angiogenesis, matrix remodeling, and tumor cell dormancy. Advances in tumor cell biology, 3D cell culture, tissue engineering, biomaterials, microfabrication, and microfluidics have enabled rapid development of new in vitro tumor models that often incorporate multiple cell types, extracellular matrix materials, and spatial and temporal introduction of soluble factors. Other innovations include the incorporation of perfusable microvessels to simulate the tumor vasculature and model intravasation and extravasation. The drive towards precision medicine has increased interest in adapting in vitro tumor models for patient-specific therapies, clinical management, and assessment of metastatic potential. Here, we review the wide range of current in vitro tumor models and summarize their advantages, disadvantages, and suitability in modeling specific aspects of the metastatic cascade and drug treatment

(E)-4-[(4-Nitro­phen­yl)diazen­yl]phenyl anthracene-9-carboxyl­ate

In the title compound, C27H17N3O4, the azo group displays a trans conformation and the dihedral angles between the central benzene ring and the pendant anthracene and nitro­benzene rings are 82.94 (7) and 7.30 (9)°, respectively. In the crystal structure, weak C—H⋯O hydrogen bonds, likely associated with a dipole moment present on the mol­ecule, help to consolidate the packing