SUMMARY Diabetes is a major risk factor for atherosclerosis. Although atherosclerosis is initiated by deposition of cholesterol-rich lipoproteins in the artery wall, the entry of inflammatory leukocytes into lesions fuels disease progression and impairs resolution. We show that diabetic mice have increased numbers of circulating neutrophils and Ly6-Chi monocytes, reflecting hyperglycemia-induced proliferation and expansion of bone marrow myeloid progenitors and release of monocytes into the circulation. Increased neutrophil production of S100A8/A9, via an interaction with the receptor for advanced glycation end products on common myeloid progenitor cells, leads to enhanced myelopoiesis. Treatment of hyperglycemia reduces monocytosis, entry of monocytes into atherosclerotic lesions and promotes regression. In patients with type I diabetes plasma S100A8/A9 levels correlate with leukocyte counts and coronary artery disease. Thus, hyperglycemia drives myelopoiesis and thus promotes atherogenesis in diabetes.

Ceramide is among a number of potential lipotoxic molecules that are thought to modulate cellular energy metabolism. The heart is one of the tissues thought to become dysfunctional due to excess lipid accumulation. Dilated lipotoxic cardiomyopathy, thought to be the result of diabetes and severe obesity, has been modeled in several genetically altered mice, including animals with cardiac-specific overexpression of glycosylphosphatidylinositol (GPI)-anchored human lipoprotein lipase (LpL GPI ). To test whether excess ceramide was implicated in cardiac lipotoxicity, de novo ceramide biosynthesis was inhibited pharmacologically by myriocin and genetically by heterozygous deletion of LCB1, a subunit of serine palmitoyltransferase (SPT). Inhibition of SPT, a rate-limiting enzyme in ceramide biosynthesis, reduced fatty acid and increased glucose oxidation in isolated perfused LpL GPI hearts, improved systolic function, and prolonged survival rates. Our results suggest a critical role for ceramide accumulation in the pathogenesis of lipotoxic cardiomyopathy.-Park, T

Methods GPI-LpL construct.A PCR-based strategy was used to ligate the DNA sequence encoding the last 37 amino acids of membrane decay accelerating factor (DAF) (9, 10) containing the GPI-anchoring sequence to a human LpL (hLpL) minigene (11) (see Figure 1a). This strategy required the elimination of the LpL termination codon

Polymer networks are complex systems consisting of molecular components. Whereas the properties of the individual components are typically well understood by most chemists, translating that chemical insight into polymer networks themselves is limited by the statistical and poorly defined nature of network structures. As a result, it is challenging, if not currently impossible, to extrapolate from the molecular behavior of components to the full range of performance and properties of the entire polymer network. Polymer networks therefore present an unrealized, important, and interdisciplinary opportunity to exert molecular-level, chemical control on material macroscopic properties. A barrier to sophisticated molecular approaches to polymer networks is that the techniques for characterizing the molecular structure of networks are often unfamiliar to many scientists. Here, we present a critical overview of the current characterization techniques available to understand the relation between the molecular properties and the resulting performance and behavior of polymer networks, in the absence of added fillers. We highlight the methods available to characterize the chemistry and molecular-level properties of individual polymer strands and junctions, the gelation process by which strands form networks, the structure of the resulting network, and the dynamics and mechanics of the final material. The purpose is not to serve as a detailed manual for conducting these measurements but rather to unify the underlying principles, point out remaining challenges, and provide a concise overview by which chemists can plan characterization strategies that suit their research objectives. Because polymer networks cannot often be sufficiently characterized with a single method, strategic combinations of multiple techniques are typically required for their molecular characterization.

Direct evidence that hyperglycemia, rather than concomitant increases in known risk factors, induces atherosclerosis is lacking. Most diabetic mice do not exhibit a higher degree of atherosclerosis unless the development of diabetes is associated with more severe hyperlipidemia. We hypothesized that normal mice were deficient in a gene that accelerated atherosclerosis with diabetes. The gene encoding aldose reductase (AR), an enzyme that mediates the generation of toxic products from glucose, is expressed at low levels in murine compared with human tissues. Mice in which diabetes was induced through streptozotocin (STZ) treatment, but not nondiabetic mice, expressing human AR (hAR) crossed with LDL receptor-deficient (Ldlr -/-) C57BL/6 male mice had increased aortic atherosclerosis. Diabetic hAR-expressing heterozygous LDL receptor-knockout mice (Ldlr +/-) fed a cholesterol/cholic acid-containing diet also had increased aortic lesion size. Lesion area at the aortic root was increased by STZ treatment alone but was further increased by hAR expression. Macrophages from hARtransgenic mice expressed more scavenger receptors and had greater accumulation of modified lipoproteins than macrophages from nontransgenic mice. Expression of genes that regulate regeneration of glutathione was reduced in the hAR-expressing aortas. Thus, hAR increases atherosclerosis in diabetic mice. Inhibitors of AR or other enzymes that mediate glucose toxicity could be useful in the treatment of diabetic atherosclerosis. IntroductionAlthough people with both type 1 and type 2 diabetes develop increased atherosclerosis, which leads to more heart attacks and strokes, direct evidence that this is mediated by hyperglycemia is lacking. In part, this is because additional atherogenic factors such as lipid abnormalities and hypertension accompany the diabetes (1, 2). Efforts to demonstrate the presumed toxic effects of hyperglycemia in experimental animals have been similarly hindered (3). Diabetes has been superimposed onto wild-type and atherosclerosis-prone mice in an attempt to reproduce the relationship between diabetes and macrovascular disease. However, a clear model of diabetes-induced accelerated atherosclerosis is lacking. In several situations, genetic insulin resistance and streptozotocin-mediated (STZ-mediated) destruction of islet cells produced greater hyperlipidemia and, not surprisingly, more atherosclerosis (4). This was noted in both LDL receptorknockout (Ldlr -/-) (5, 6) and apoE-knockout mice (7). In a recent study, chow-fed Ldlr -/-diabetic mice had more atherosclerosis at the aortic root, but when these mice were fed cholesterol-containing diet, the atherosclerosis correlated with plasma cholesterol and not glucose (8). Thus, as in many previous reports, the more advanced vascular lesions in these mice were attributable to greater hyperlipidemia and not hyperglycemia or defective insulin actions.

5.0% 2.6% 1.2% 0.6% 0.4% 0.2% 9.6% 6.8% 4.8% 3.7% 2.7% 1.5% 54.5% 26.9% 8.1% 1.9% 0.5% 0.1% 8.7% 2.1% 0.6% 0.2% 0.1% >1m >2m >4m >8m >16m >32m 0% 10% 20% 30% 40% 50% TetGen CGAL TetWild Ours CGAL #T = 1 362 980 444s TetGen #T = 8 221 130 1705s TetWild #T = 459 626 1588s Ours #T = 278 997 291s Input #F = 392 040 Fig. 1. A mouse skull model (from micro-CT) tetrahedralized by fTetWild (right) compared with other popular tetrahedral meshing algorithms. The plot shows the percentage of models requiring more than a certain time for the different approaches over 4540 inputs (the subset of Thingi10k where all 4 algorithms succeed). Our algorithm successfully meshes 99.4% of the input models in less than 2 minutes, and processes all models within 32 minutes. The comparison has been done using the experimental setup of TetWild ] and selecting a similar target resolution for all methods. The CGAL surface approximation parameter has been selected to be comparable to the envelope size used for TetWild and for our method.We propose a new tetrahedral meshing technique, fTetWild, to convert triangle soups into high-quality tetrahedral meshes. Our method builds upon the TetWild algorithm, inheriting its unconditional robustness, but dramatically reducing its computation cost and guaranteeing the generation of a valid tetrahedral mesh with floating point coordinates. This is achieved by introducing a new problem formulation, which is well suited for a pure floating point implementation and naturally leads to a parallel implementation. Our algorithm produces results qualitatively and quantitatively similar to TetWild, but at a fraction of the computational cost, with a running time comparable to Delaunay-based tetrahedralization algorithms. ACM Reference format:

Increasing the loading of active materials by thickening the battery electrode coating can enhance the energy density of a Li-ion cell, but the trade-off is the much reduced Li transport kinetics. To reach the optimum energy and power density for thick electrodes, the effective chemical diffusion coefficient of Li ( D) must be maximized. However, the diffusion of Li inside an electrode is a complex process involving both microscopic and macroscopic processes. Fundamental understandings are needed on the rate-limiting process that governs the diffusion kinetics of Li to minimize the negative impact of the large electrode thickness on their electrochemical performance. In this work, lithium Ni-Mn-Co oxide (NMC) cathodes of various thicknesses ranging from 100 to 300 μm were used as a model system to study the rate-limiting diffusion process during charge/discharge. The rate-limiting diffusion coefficient of Li was investigated and quantified, which was correlated to the electrochemical performance degradation of thick electrodes. It is revealed here that the under-utilization of the active material was caused by the limited diffusion of Li inside the porous electrode, leading to a critical electrode thickness, beyond which the specific capacity was significantly reduced.

The study of voice behavior examines the inclination of staff and team members to speak up and contribute ideas to the team. In this article, we investigate how factors such as leader-member exchange (LMX), psychological safety and psychological empowerment influence such behavior. Our findings, which are based on a sample of 308 employees working for a state-owned telecommunications company in China, indicate that ethical leadership promotes employees’ voice behavior through enhanced LMX, which also leads to greater feelings of psychological safety and psychological empowerment. The theoretical and practical implications of these results are discussed.