Rh-catalyzed desymmetrization of α-quaternary centers by isomerization-hydroacylation

We describe a Rh-catalyzed desymmetrization of all-carbon quaternary centers from α,α-bis(allyl)aldehydes by a cascade featuring isomerization and hydroacylation. This desymmetrization competes with two other novel olefin functionalizations that are triggered by C–H bond activation, including carboacylation and bisacylation. A BIPHEP ligand promotes enantioselective formation of α-vinylcyclopentanones. Mechanistic studies support irreversible and enantioselective olefin-isomerization followed by olefin-hydroacylation.     

Direct interfacial Y731 oxidation in α2 by a photoβ2 subunit of E. coli class Ia ribonucleotide reductase

Proton-coupled electron transfer (PCET) is a fundamental mechanism important in a wide range of biological processes including the universal reaction catalysed by ribonucleotide reductases (RNRs) in making de novo, the building blocks required for DNA replication and repair. These enzymes catalyse the conversion of nucleoside diphosphates (NDPs) to deoxynucleoside diphosphates (dNDPs). In the class Ia RNRs, NDP reduction involves a tyrosyl radical mediated oxidation occurring over 35 Å across the interface of the two required subunits (β₂ and α₂) involving multiple PCET steps and the conserved tyrosine triad [Y₃₅₆(β₂)–Y₇₃₁(α₂)–Y₇₃₀(α₂)]. We report the synthesis of an active photochemical RNR (photoRNR) complex in which a Re(i)-tricarbonyl phenanthroline ([Re]) photooxidant is attached site-specifically to the Cys in the Y₃₅₆C-(β₂) subunit and an ionizable, 2,3,5-trifluorotyrosine (2,3,5-F₃Y) is incorporated in place of Y₇₃₁ in α₂. This intersubunit PCET pathway is investigated by ns laser spectroscopy on [Re₃₅₆]-β₂:2,3,5-F₃Y₇₃₁-α₂ in the presence of substrate, CDP, and effector, ATP. This experiment has allowed analysis of the photoinjection of a radical into α₂ from β₂ in the absence of the interfacial Y₃₅₆ residue. The system is competent for light-dependent substrate turnover. Time-resolved emission experiments reveal an intimate dependence of the rate of radical injection on the protonation state at position Y₇₃₁(α₂), which in turn highlights the importance of a well-coordinated proton exit channel involving the key residues, Y₃₅₆ and Y₇₃₁, at the subunit interface.     

The notion of motion: covariational reasoning and the limit concept

This paper investigates outcomes of building students’ intuitive understanding of a limit as a function's predicted value by examining introductory calculus students’ conceptions of limit both before and after instruction. Students’ responses suggest that while this approach is successful at reducing the common limit equals function value misconception of a limit, new misconceptions emerged in students’ responses. Analysis of students’ reasoning indicates a lack of covariational reasoning that coordinates changes in both x and y may be at the root of the emerging limit reached near x = c misconception. These results suggest that although dynamic interpretations of limit may be intuitive for many students, care must be taken to foster a dynamic conception that is both useful at the introductory calculus level and is in line with the formal notion of limit learned in advanced mathematics. In light of the findings, suggestions for adapting the pedagogical approach used in this study are provided.     

An interior-point trust-funnel algorithm for nonlinear optimization

We present an interior-point trust-funnel algorithm for solving large-scale nonlinear optimization problems. The method is based on an approach proposed by Gould and Toint (Math Prog 122(1):155–196, 2010) that focused on solving equality constrained problems. Our method is similar in that it achieves global convergence guarantees by combining a trust-region methodology with a funnel mechanism, but has the additional capability of being able to solve problems with both equality and inequality constraints. The prominent features of our algorithm are that (i) the subproblems that define each search direction may be solved with matrix-free methods so that derivative matrices need not be formed or factorized so long as matrix-vector products with them can be performed; (ii) the subproblems may be solved approximately in all iterations; (iii) in certain situations, the computed search directions represent inexact sequential quadratic optimization steps, which may be desirable for fast local convergence; (iv) criticality measures for feasibility and optimality aid in determining whether only a subset of computations need to be performed during a given iteration; and (v) no merit function or filter is needed to ensure global convergence.     

A Districtwide Study of Automaticity When Included in Concept‐Based Elementary School Mathematics Instruction

While conceptual understanding of properties, operations, and the base‐ten number system is certainly associated with the ability to access math facts fluently, the role of math fact memorization to promote conceptual understanding remains contested. In order to gain insight into this question, this study looks at the results when one of three elementary schools in a school district implements mandatory automaticity drills for 10 minutes each day while the remaining two elementary schools, with the same curriculum and very similar demographics, do not. This study looks at (a) the impact that schoolwide implementation of automaticity drills has on schoolwide computational math skills as measured by the ITBS and (b) the relationship between automaticity and conceptual understanding as measured by statewide standardized testing. The results suggest that while there may be an association between automaticity and higher performance on standardized tests, caution should be taken before assuming there are benefits to promoting automaticity drills. These results are consistent with those that support a process‐driven approach to automaticity based on familiarity with properties and strategies associated with the base‐ten number system; they are not consistent with those that support an answer‐driven approach to automaticity based on memorization of answers.     

Simple chemical route for nanorod-like cobalt oxide films for electrochemical energy storage applications

We used a simple chemical synthesis route to deposit nanorod-like cobalt oxide thin films on different substrates such as stainless steel (ss), indium tin oxide (ITO), and microscopic glass slides. The morphology of the films show that the films were uniformly spread having a nanorod-like structure with the length of the nanorods shortened on ss substrates. The electrochemical properties of the films deposited at different time intervals were studied using cyclic voltammetry (CV), galvanostatic charge–discharge (GCD), and electrochemical impedance spectroscopy (EIS). The film deposited after 20 cycles on ss gave the highest specific capacity of 67.6 mAh g^?1 and volumetric capacity of 123 mAh cm^?3 at a scan rate 5 mV s^?1 in comparison to 62.0 mAh g^?1 and 113 mAh cm^?3 obtained, respectively, for its counterpart on ITO. The film electrode deposited after 20 cycles on ITO gave the best rate capability and excellent cyclability with no depreciation after 2000 charge–discharge cycles.     

Aprotic metal-oxygen batteries: recent findings and insights

During the last two decades, we have observed a dramatic increase in the electrification of many technologies. What has enabled this transition to take place was the commercialization of Li-ion batteries in the early nineties. Mobile technologies such as cellular phones, laptops, and medical devices make these batteries crucial for our contemporary lifestyle. Like any other electrochemical cell, the Li-ion batteries are restricted to the thermodynamic limitations of the materials. It might be that the energy density of the most advance Li-ion battery is still too low for demanding technologies such as a full electric vehicle. To really convince future customers to switch from the internal combustion engine, new batteries and chemistry need to be developed. Non-aqueous metal-oxygen batteries—such as lithium–oxygen, sodium–oxygen, magnesium–oxygen, and potassium–oxygen—offer high capacity and high operation voltages. Also, by using suitable polar aprotic solvents, the oxygen reduction process that occurs during discharge can be reversed by applying an external potential during the charge process. Thus, in theory, these batteries could be electrically recharged a number of times. However, there are many scientific and technical challenges that need to be addressed. The current review highlights recent scientific insights related to these promising batteries. Nevertheless, the reader will note that many conclusions are applicable in other kinds of batteries as well.     

Serendipitous discovery of light-induced (<Emphasis Type="Italic">In Situ</Emphasis>) formation of an Azo-bridged dimeric sulfonated naphthol as a potent PTP1B inhibitor

Background

Protein tyrosine phosphatases (PTPs) like dual specificity phosphatase 5 (DUSP5) and protein tyrosine phosphatase 1B (PTP1B) are drug targets for diseases that include cancer, diabetes, and vascular disorders such as hemangiomas. The PTPs are also known to be notoriously difficult targets for designing inihibitors that become viable drug leads. Therefore, the pipeline for approved drugs in this class is minimal. Furthermore, drug screening for targets like PTPs often produce false positive and false negative results.

Results

Studies presented herein provide important insights into: (a) how to detect such artifacts, (b) the importance of compound re-synthesis and verification, and (c) how in situ chemical reactivity of compounds, when diagnosed and characterized, can actually lead to serendipitous discovery of valuable new lead molecules. Initial docking of compounds from the National Cancer Institute (NCI), followed by experimental testing in enzyme inhibition assays, identified an inhibitor of DUSP5. Subsequent control experiments revealed that this compound demonstrated time-dependent inhibition, and also a time-dependent change in color of the inhibitor that correlated with potency of inhibition. In addition, the compound activity varied depending on vendor source. We hypothesized, and then confirmed by synthesis of the compound, that the actual inhibitor of DUSP5 was a dimeric form of the original inhibitor compound, formed upon exposure to light and oxygen. This compound has an IC₅₀ of 36 μM for DUSP5, and is a competitive inhibitor. Testing against PTP1B, for selectivity, demonstrated the dimeric compound was actually a more potent inhibitor of PTP1B, with an IC₅₀ of 2.1 μM. The compound, an azo-bridged dimer of sulfonated naphthol rings, resembles previously reported PTP inhibitors, but with 18-fold selectivity for PTP1B versus DUSP5.

Conclusion

We report the identification of a potent PTP1B inhibitor that was initially identified in a screen for DUSP5, implying common mechanism of inhibitory action for these scaffolds.