Macrophage Immunomodulation Through New Polymers that Recapitulate Functional Effects of Itaconate as a Power House of Innate Immunity

Itaconate (ITA) is an emerging powerhouse of innate immunity with therapeutic potential that is limited in its ability to be administered in a soluble form. A library of polyester materials that incorporate ITA into polymer backbones resulting in materials with inherent immunoregulatory behavior is developed. Harnessing hydrolytic degradation release from polyester backbones, ITA polymers result in the mechanism specific immunoregulatory properties on macrophage polarization in vitro. In a functional assay, the polymer-released ITA inhibits bacterial growth on acetate. Translation to an in vivo model of biomaterial associated inflammation, intraperitoneal injection of ITA polymers demonstrate a rapid resolution of inflammation in comparison to a control polymer silicone, demonstrating the value of sustained biomimetic presentation of ITA.     

Many-Body Terms in van der Waals Cohesion Energy of Nanotubes

We have developed a model for the calculation of van der Waals force for layered systems with axial symmetry. Our result can be applied to compute the cohesion of a carbon nanotube to a substrate, the cohesion between nanotubes, and between shells of multiwall nanotubes. We have obtained unusal power laws for the distance dependence of the many-body van der Waals potential.     

Instructional designs for the development of transferable knowledge and skills: A cognitive load perspective

This paper analyzes the main points and results of a set of the previous papers in this Special Issue from the point of view of developing characteristics of flexible—transferable—expertise. It focuses on cognitive load issues related to the acquisition of deep transferable knowledge structures and developing metacognitive and self-regulation skills. The contributions to this Special Issue demonstrate that appropriate instructional support and optimal levels of control over the learning processes, enhanced by self-explanation and self-visualization techniques, may enhance learners’ abilities to transfer their knowledge and skills. Better understanding of the role of germane cognitive load, as well as our abilities to measure different types of load and high-level cognitive processes are essential for further progress in this area.     

When less is more in cognitive diagnosis: A rapid online method for diagnosing learner task-specific expertise.

Rapid cognitive diagnosis allows measuring current levels of learner domain-specific knowledge in online learning environments. Such measures are required for individualizing instructional support in real time, as students progress through a learning session. This article describes 2 experiments designed to validate a rapid online diagnostic method that was inspired by experimental procedures applied in classical cognitive studies of chess expertise. With the described rapid verification method, learners are required to rapidly verify suggested steps at various stages of a problem solution procedure. In this study involving 33 university students, a high degree of correlation was found between rapid testing scores and results of in-depth cognitive diagnosis based on observations of problem-solving steps using video recordings and concurrent verbal reports in the domains of kinematics (vector addition motion problems) and mathematics (transforming graphs of linear and quadratic functions). The article discusses possible applications of the suggested method in adaptive learning environments. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Tetrahydroisoquinolines: New Inhibitors of Neutrophil Extracellular Trap (NET) Formation

Neutrophils are short‐lived leukocytes that migrate to sites of infection as part of the acute immune response, where they phagocytose, degranulate, and form neutrophil extracellular traps (NETs). During NET formation, the nuclear lobules of neutrophils disappear and the chromatin expands and, accessorized with neutrophilic granule proteins, is expelled. NETs can be pathogenic in, for example, sepsis, cancer, and autoimmune and cardiovascular diseases. Therefore, the identification of inhibitors of NET formation is of great interest. Screening of a focused library of natural‐product‐inspired compounds by using a previously validated phenotypic NET assay identified a group of tetrahydroisoquinolines as new NET formation inhibitors. This compound class opens up new avenues for the study of cellular death through NET formation (NETosis) at different stages, and might inspire new medicinal chemistry programs aimed at NET‐dependent diseases.     

Enantioselective Organocatalytic Synthesis of a Secoyohimbane‐Inspired Compound Collection with Neuritogenic Activity

Natural products provide evolutionary validated core structures to inspire the synthesis of new compound collections endowed with neurite growth‐promoting activity. Rhynchophylline is the major component of Uncaria species, and has been used to treat neurological diseases in Chinese traditional medicine. Based on the structure of this spirocyclic secoyohimbane alkaloid, we developed a highly enantioselective and efficient organocatalyzed synthesis method to provide a tetracyclic secoyohimbane scaffold incorporating a quaternary and three tertiary stereogenic centers, in a one‐pot multistep reaction sequence. A compound collection of derived secoyohimbanes was synthesized and expanded by decorating the periphery of the basic scaffold with additional substituents to increase the diversity. Evaluation of the different subcollections of secoyohimbanes for modulation of neurite outgrowth in the SH‐SY5Y human cell line led to the discovery of new compounds that promote neurite outgrowth.     

Small Molecules Inspired by the Natural Product Withanolides as Potent Inhibitors of Wnt Signaling

Wnt signaling is a fundamental pathway that drives embryonic development and is essential for stem cell maintenance and tissue homeostasis. Dysregulation of Wnt signaling is linked to various diseases, and a constitutively active Wnt pathway drives tumorigenesis. Thus, disruption of the Wnt response is deemed a promising strategy for cancer drug discovery. However, only few clinical drug candidates that target Wnt signaling are available so far, and new small‐molecule modulators of Wnt‐related processes are in high demand. Here we describe the synthesis of small molecules inspired by withanolide natural products by using a pregnenolone‐derived β‐lactone as the key intermediate that was transformed into a δ‐lactone appended to the D‐ring of the steroidal scaffold. This natural‐product‐inspired compound library contained potent inhibitors of Wnt signaling that act upstream of the destruction complex to stabilize Axin in a tankyrase‐independent manner.     

Large-Area Single-Crystal Graphene via Self-Organization at the Macroscale

In 1665 Christiaan Huygens first noticed how two pendulums, regardless of their initial state, would synchronize.  It is now known that the universe is full of complex self-organizing systems, from neural networks to correlated materials. Here, graphene flakes, nucleated over a polycrystalline graphene film, synchronize during growth so as to ultimately yield a common crystal orientation at the macroscale. Strain and diffusion gradients are argued as the probable causes for the long-range cross-talk between flakes and the formation of a single-grain graphene layer. The work demonstrates that graphene synthesis can be advanced to control the nucleated crystal shape, registry, and relative alignment between graphene crystals for large area, that is, a single-crystal bilayer, and (AB-stacked) few-layer graphene can been grown at the wafer scale.