A Model for the Cobalamin-Dependent Methionine Synthase

The acid-catalyzed transfer of a Me group from N,N-dimethylaniline ( 6 ) to vitamin-B₁₂-derived Co^I complexes 2a , b was realized (Scheme 3). Hexane-1-thiol ( 8 ) was methylated by the methylcobalt complexes 4a , b in the presence of pyridine. Conditions for the complete cycle, i.e., Me transfer from 6 to 8 with Co^I complexes acting as a nucleophile and a nucleofuge have been established. The importance of Zn²⁺ as activating agent and of the basicity of tertiary amines for the Me transfer has been investigated.     

Halogen–Aromatic π Interactions Modulate Inhibitor Residence Times

Prolonged drug residence times may result in longer‐lasting drug efficacy, improved pharmacodynamic properties, and “kinetic selectivity” over off‐targets with high drug dissociation rates. However, few strategies have been elaborated to rationally modulate drug residence time and thereby to integrate this key property into the drug development process. Herein, we show that the interaction between a halogen moiety on an inhibitor and an aromatic residue in the target protein can significantly increase inhibitor residence time. By using the interaction of the serine/threonine kinase haspin with 5‐iodotubercidin (5‐iTU) derivatives as a model for an archetypal active‐state (type I) kinase–inhibitor binding mode, we demonstrate that inhibitor residence times markedly increase with the size and polarizability of the halogen atom. The halogen–aromatic π interactions in the haspin–inhibitor complexes were characterized by means of kinetic, thermodynamic, and structural measurements along with binding‐energy calculations.     

Multipronged Biomimetic Approach To Create Optically Tunable Nanoparticles

Current biomimetics for medical applications use a single biomimetic approach to imitate natural structures, which can be insufficient for reconstructing structurally complex natural systems. Multipronged efforts may resolve these complexities. To achieve interesting nanostructure‐driven optical properties, a dual‐biomimetic system contained within a single nanoagent was engineered to recapitulate chlorosomes, efficient light‐harvesting organelles that have unique dye assemblies and tunable photonic properties. A series of chlorin dyes was synthesized, and these hydrophobic assemblies were stabilized inside a high‐density lipoprotein, a second biomimetic that enabled in vivo utility. This system resulted in tunable tumor imaging of intact (photoacoustic) and disrupted (activatable fluorescence) nanostructures. The successful demonstration of this multipronged biomimetic approach opens the door for reconstruction of complex natural systems for biomedical applications.     

ROS‐Responsive N‐Alkylaminoferrocenes for Cancer‐Cell‐Specific Targeting of Mitochondria

Mitochondrial membrane potential is more negative in cancer cells than in normal cells, allowing cancer targeting by delocalized lipophilic cations (DLCs). However, as the difference is rather small, these drugs affect also normal cells. Now a concept of pro‐DLCs is proposed based on an N‐alkylaminoferrocene structure. These prodrugs are activated by the reaction with reactive oxygen species (ROS) forming ferrocenium‐based DLCs. Since ROS are overproduced in cancer, the high‐efficiency cancer‐cell‐specific targeting of mitochondria could be achieved as demonstrated by fluorescence microscopy in combination with two fluorogenic pro‐DLCs in vitro and in vivo. We prepared a conjugate of another pro‐DLC with a clinically approved drug carboplatin and confirmed that its accumulation in mitochondria was higher than that of the free drug. This was reflected in the substantially higher anticancer effect of the conjugate.     

Bismuth Oxyiodide Nanoflakes Showed Toxicity Against the Malaria Vector <Emphasis Type="Italic">Anopheles stephensi</Emphasis> and In Vivo Antiplasmodial Activity

Anopheles stephensi is a mosquito vector of malaria, which is still considered a relevant public health problem due to increasing outdoor transmission, growing resistance to insecticides used to target vectors, and antiplasmodial drugs as well. Thus, there is a vital need to explore novel sources of effective compounds. In this study, the hydrothermal method was used for the synthesis of bismuth oxyiodide (BiOI) nanoflakes. Furthermore, the toxicity of BiOI nanoflakes was evaluated for the first time on A. stephensi, as well as in vivo against the malaria parasite Plasmodium berghei. The synthesis of BiOI nanoflakes was confirmed by various characterization techniques, including X-ray diffraction, Fourier transform-infrared spectroscopy, field emission scanning electron microscopy and transmission electron microscopy (HR-TEM). LC₅₀ of BiOI nanoflakes on A. stephensi were 2.263 ppm (larva I), 3.414 ppm (II), 4.956 ppm (III), 6.983 ppm (IV) and 8.605 ppm (pupae). In vivo antiplasmodial experiments conducted on P. berghei infecting albino mice showed 27.2% of chemosuppression after 4 days of treatment with 300 mg/kg/day of BiOI, a lower performance if compared to chloroquine. Overall, our results suggested that hydrothermal synthesis of BiOI nanoflakes may be considered to develop newer and safer tools for malaria vector control.     

Cultivating Computational Thinking Practices and Mathematical Habits of Mind in Lattice Land

There is a great deal of overlap between the set of practices collected under the term “computational thinking” and the mathematical habits of mind that are the focus of much mathematics instruction. Despite this overlap, the links between these two desirable educational outcomes are rarely made explicit, either in classrooms or in the literature. This paper presents Lattice Land, a computational learning environment and accompanying curriculum designed to support the development of mathematical habits of mind and promote computational thinking practices in high-school mathematics classrooms. Lattice Land is a mathematical microworld where learners explore geometrical concepts by manipulating polygons drawn with discrete points on a plane. Using data from an implementation in a low-income, urban public high school, we show how the design of Lattice Land provides an opportunity for learners to use computational thinking practices and develop mathematical habits of mind, including tinkering, experimentation, pattern recognition, and formalizing hypothesis in conventional mathematical notation. We present Lattice Land as a restructuration of geometry, showing how this new and novel representational approach facilitates learners in developing computational thinking and mathematical habits of mind. The paper concludes with a discussion of the interplay between computational thinking and mathematical habits of mind, and how the thoughtful design of computational learning environments can support meaningful learning at the intersection of these disciplines.     

Application of nonlinear continuum dislocation theory to antiplane shear

We apply the nonlinear dislocation theory to the problem of antiplane constrained shear in a single crystal with one slip system. By taking dissipation into account, the relaxed energy functional has to be minimized. We show that, up to a threshold strain, no dislocations are nucleated and therefore the plastic slip is zero. Since this threshold value depends on the width of the specimen, a size effect takes place. The stress strain curve turns out to be a hysteresis loop exhibiting the work hardening due to the dislocation pile-up. It is shown that the Bauschinger effect holds true. (© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)     

Uptake of silver nanoparticles by monocytic THP-1 cells depends on particle size and presence of serum proteins

Human health risks by silver nanoparticle (AgNP) exposure are likely to increase due to the increasing number of NP-containing products and demonstrated adverse effects in various cell lines. Unfortunately, results from (toxicity) studies are often based on exposure dose and are often measured only at a fixed time point. NP uptake kinetics and the time-dependent internal cellular concentration are often not considered. Macrophages are the first line of defense against invading foreign agents including NPs. How macrophages deal with the particles is essential for potential toxicity of the NPs. However, there is a considerable lack of uptake studies of particles in the nanometer range and macrophage-like cells. Therefore, uptake rates were determined over 24 h for three different AgNPs sizes (20, 50 and 75 nm) in medium with and without fetal calf serum. Non-toxic concentrations of 10 ng Ag/mL for monocytic THP-1 cells, representing realistic exposure concentration for short-term exposures, were chosen. The uptake of Ag was higher in medium without fetal calf serum and showed increasing uptake for decreasing NP sizes, both on NP mass and on number basis. Internal cellular concentrations reached roughly 32/10 %, 25/18 % and 21/15 % of the nominal concentration in the absence of fetal calf serum/with fetal calf serum for 20-, 50- and 75-nm NPs, respectively. Our research shows that uptake kinetics in macrophages differ for various NP sizes. To increase the understanding of the mechanism of NP toxicity in cells, the process of uptake (timing) should be considered.