Synthesis,characterization and antineoplastic activity of bis-aziridinyl dimeric naphthoquinone – A novel class of compounds with potent activity against acute myeloid leukemia cells

The synthesis, characterization and antileukemic activity of rationally designed amino dimeric naphthoquinone (BiQ) possessing aziridine as alkylating moiety is described. Bis-aziridinyl BiQ decreased proliferation of acute myeloid leukemia (AML) cell lines and primary cells from patients, and exhibited potent (nanomolar) inhibition of colony formation and overall cell survival in AML cells. Effective production of reactive oxygen species (ROS) and double stranded DNA breaks (DSB) induced by bis-aziridinyl BiQ is reported. Bis-dimethylamine BiQ, as the isostere of bis-aziridinyl BiQ but without the alkylating moiety did not show as potent anti-AML activity. Systemic administration of bis-aziridinyl BiQ was well tolerated in NSG mice.     

Haemodynamic assessment of human coronary arteries is affected by degree of freedom of artery movement

Abnormal haemodynamic parameters are associated with atheroma plaque progression and instability in coronary arteries. Flow recirculation, shear stress and pressure gradient are understood to be important pathogenic mediators in coronary disease. The effect of freedom of coronary artery movement on these parameters is still unknown. Fluid–structure interaction (FSI) simulations were carried out in 25 coronary artery models derived from authentic human coronaries in order to investigate the effect of degree of freedom of movement of the coronary arteries on flow recirculation, wall shear stress (WSS) and wall pressure gradient (WPG). Each FSI model had distinctive supports placed upon it. The quantitative and qualitative differences in flow recirculation, maximum wall shear stress (MWSS), areas of low wall shear stress (ALWSS) and maximum wall pressure gradient (MWPG) for each model were determined. The results showed that greater freedom of movement was associated with lower MWSS, smaller ALWSS, smaller flow recirculation zones and lower MWPG. With increasing percentage diameter stenosis (%DS), the effect of degree of freedom on flow recirculation and WSS diminished. Freedom of movement is an important variable to be considered for computational modelling of human coronary arteries, especially in the setting of mild to moderate stenosis.

Abbreviations: 3D: Three-dimensional; 3DR: Three-dimensional Reconstruction; 3D-QCA: Three-dimensional quantitative coronary angiography; ALWSS: Areas of low wall shear stress; CAD: Coronary artery disease; CFD: Computational fluid dynamics; %DS: Diameter stenosis percentage; EPCS: End point of counter-rotating streamlines; FSI: Fluid–structure interaction; IVUS: Intravascular ultrasound; LAD: Left anterior descending; MWSS: Maximum wall shear stress; SST: Shear stress transport; TAWSS: Time-averaged wall shear stress; WSS: wall shear stress; WPG: Wall pressure gradient; MWPG: Maximum wall pressure gradient; FFR: Fractional flow reserve; iFR: Instantaneous wave-free ratio     

D-4F reduces EO6 immunoreactivity, SREBP-1c mRNA levels, and renal inflammation in LDL receptor-null mice fed a Western diet

LDL receptor-null (LDLR(-/-)) mice on a Western diet (WD) develop endothelial dysfunction and atherosclerosis, which are improved by the apolipoprotein A-I (apoA-I) mimetic peptide D-4F. Focusing on the kidney, LDLR(-/-)mice were fed a WD with D-4F or the inactive control peptide scrambled D-4F (ScD-4F) added to their drinking water. The control mice (ScD-4F) developed glomerular changes, increased immunostaining for MCP-1/CCL2 chemokine, increased macrophage CD68 and F4/80 antigens, and increased oxidized phospholipids recognized by the EO6 monoclonal antibody in both glomerular and tublo-interstitial areas. All of these parameters were significantly reduced by D-4F treatment, approaching levels found in wild-type C57BL/6J or LDLR(-/-) mice fed a chow diet. Sterol-regulatory element binding protein-1c (SREBP-1c) mRNA levels and triglyceride levels were elevated in the kidneys of the control mice (ScD-4F) fed the WD compared with C57BL/6J and LDLR(-/-) mice on chow (P < 0.001 and P < 0.001, respectively) and compared with D-4F-treated mice on the WD (P < 0.01). There was no significant difference in plasma lipids, lipoproteins, glucose, blood pressure, or renal apoB levels between D-4F- and ScD-4F-treated mice. We conclude that D-4F reduced renal oxidized phospholipids, resulting in lower expression of SREBP-1c, which, in turn, resulted in lower triglyceride content and reduced renal inflammation.     

Simple testing procedures for the Holling type II model

In this paper, we consider predator–prey data that can be viewed as solutions to a planar system of ordinary differential equations (ODE) observed with random error. The ODE system admits a limit cycle, while the random error is supposed to act additively in the log-scale. One of the oldest such systems is Holling’s type II model. In spite of its simplicity, it is still very popular in data analyses, although more sophisticated models have been introduced in the literature. We propose a simple way of deciding whether a set of predator–prey pairs is indicative or not of a departure from this basic model by exploiting the geometric properties of the solution in the phase plane. To illustrate our method, we use simulated and real data.     

Nonparametric inverse-probability-weighted estimators based on the highly adaptive lasso

Inverse-probability-weighted estimators are the oldest and potentially most commonly used class of procedures for the estimation of causal effects. By adjusting for selection biases via a weighting mechanism, these procedures estimate an effect of interest by constructing a pseudopopulation in which selection biases are eliminated. Despite their ease of use, these estimators require the correct specification of a model for the weighting mechanism, are known to be inefficient, and suffer from the curse of dimensionality. We propose a class of nonparametric inverse-probability-weighted estimators in which the weighting mechanism is estimated via undersmoothing of the highly adaptive lasso, a nonparametric regression function proven to converge at nearly $n^{-1/3}$-rate to the true weighting mechanism. We demonstrate that our estimators are asymptotically linear with variance converging to the nonparametric efficiency bound. Unlike doubly robust estimators, our procedures require neither derivation of the efficient influence function nor specification of the conditional outcome model. Our theoretical developments have broad implications for the construction of efficient inverse-probability-weighted estimators in large statistical models and a variety of problem settings. We assess the practical performance of our estimators in simulation studies and demonstrate use of our proposed methodology with data from a large-scale epidemiologic study.     

Flow visualisation study of spiral flow in the aorta–renal bifurcation

The aim of this study was to analyse the flow dynamics in an idealised model of the aorta–renal bifurcation using flow visualisation, with a particular focus on the effect of aorta-to-renal flow ratio and flow spirality. The recirculation length was longest when there was low flow in the renal artery and smaller in the presence of spiral flow. The results also indicate that patients without spiral flow or who have low flow in the renal artery due to the presence of stenosis may be susceptible to heightened development of atherosclerotic lesions.     

Modeling habitat connectivity in support of multiobjective species movement: An application to amphibian habitat systems

Reasoning about the factors underlying habitat connectivity and the inter-habitat movement of species is essential to many areas of biological inquiry. In order to better describe and understand the ways in which the landscape may support species movement, an increasing amount of research has focused on identification of paths or corridors that may be important in providing connectivity among habitat. The least-cost path problem has proven to be an instrumental analytical tool in this sense. A complicating aspect of such path identification methods is how to best reconcile and integrate the array of criteria or objectives that species may consider in traversal of a landscape. In cases where habitat connectivity is thought to be influenced or guided by multiple objectives, numerous solutions to least-cost path problems can exist, representing tradeoffs between the objectives. In practice though, identification of these solutions can be very challenging and as such, only a small proportion of them are typically examined leading to a weak characterization of habitat connectivity. To address this computational challenge, a multiobjective optimization framework is proposed. A generalizable multiobjective least-cost path model is first detailed. A non-inferior set estimation (MONISE) algorithm for identifying supported efficient solutions to the multiobjective least-cost path model is then described. However, it is well known that unsupported efficient solutions (which are equally important) can also exist, but are typically ignored given that they are more difficult to identify. Thus, to enable the identification of the full set of efficient solutions (supported and unsupported) to the multiobjective model, a multi-criteria labeling algorithm is then proposed. The developed framework is applied to assess different conceptualizations of habitat connectivity supporting amphibian movement in a wetland system. The results highlight the range of tradeoffs in characterizations of connectivity that can exist when multiple objectives are thought to contribute to movement decisions and that the number of unsupported efficient solutions (which are typically ignored) can vastly outweigh that of the supported efficient solutions.     

A high-fat, refined-carbohydrate diet induces endothelial dysfunction and oxidant/antioxidant imbalance and depresses NOS protein expression.

We tested whether consumption of a high-fat, high-sucrose (HFS) diet can affect endothelium-dependent relaxation, whether this precedes the development of diet-induced hypertension previously noted in this model, and whether it is mediated, in part, by changes in nitric oxide synthase (NOS) and/or NOS regulatory proteins. Female Fischer rats were fed either a HFS diet or standard low-fat, complex-carbohydrate chow starting at 2 mo of age for 7 mo. Vasoconstrictive response to KCl and phenylephrine was similar in both groups. Vasorelaxation to acetylcholine was significantly impaired in the HFS animals, and there were no differences in relaxation to sodium nitroprusside, suggesting that the endothelial dysfunction is due, at least in part, to nitric oxide deficiency. HFS consumption decreased protein expression of endothelial NOS in aorta, renal, and heart tissues, neuronal NOS in kidney, heart, aorta, and brain, and inducible NOS in heart and aorta. Caveolin-1 and soluble guanylate cyclase protein expression did not change, but AKT protein expression decreased in heart and aorta and increased in kidney tissue. Consumption of HFS diet raised brain carbonyl content and plasma hydrogen peroxide concentration and diminished plasma total antioxidant capacity. Because blood pressure, which is known to eventually rise in this model, was not as yet significantly elevated, the present data suggest that endothelial dysfunction precedes the onset of diet-induced hypertension. The lack of a quantitative change in caveolin-1 and soluble guanylate cyclase protein content indicates that alteration in these proteins is not responsible for the endothelial dysfunction. Thus nitric oxide deficiency combined with antioxidant/oxidant imbalance, appears to be a primary factor in the development of endothelial dysfunction in this model.     

Rejoinder to “Instrumented difference-in-differences”

We thank all the discussants for the careful reading and insightful comments. In our rejoinder, we extend the discussion of how the assumptions of instrumented difference-in-differences (iDID) compare to the assumptions of the standard instrumental variable method. We also make additional comments on how iDID is related to the fuzzy DID. We highlight future research directions to enhance the utility of iDID, including extensions to adjust for covariate shift in two-sample iDID design, and generalization of iDID to multiple time points and a multi-valued instrumental variable for DID.