Polymeric Nanoparticles with a Glutathione‐Sensitive Heterodimeric Multifunctional Prodrug for In Vivo Drug Monitoring and Synergistic Cancer Therapy

Polymeric micelle‐based drug delivery systems have dramatically improved the delivery of small molecular drugs, yet multiple challenges remain to be overcome. A polymeric nanomedicine has now been engineered that possesses an ultrahigh loading (59 %) of a glutathione (GSH)‐sensitive heterodimeric multifunctional prodrug (HDMP) to effectively co‐deliver two synergistic drugs to tumors. An HDMP comprising of chemotherapeutic camptothecin (CPT) and photosensitizer 2‐(1‐hexyloxyethyl)‐2‐devinyl pyropheophorbide‐α (HPPH) was conjugated via a GSH‐cleavable linkage. The intrinsic fluorogenicity and label‐free radio‐chelation (⁶⁴Cu) of HPPH enabled direct drug monitoring by fluorescence imaging and positron emission tomography (PET). Through quantitative PET imaging, HDMP significantly improves drug delivery to tumors. The high synergistic therapeutic efficacy of HDMP‐loaded NPs highlights the rational design of HDMP, and presents exciting opportunities for polymer NP‐based drug delivery.     

Real-Time Change-Point Detection Algorithm with an Application to Glycemic Control for Diabetic Pregnant Women

Methodology and Computing in Applied Probability - Glycemic control in pregnancies of diabetic women is still suboptimal; birth defects and late miscarriages (i.e., second trimester miscarriages)...     

Photoinduced electron transfer between C60 and N,N,N′,N′-tetramethylbenzidine (NTMB). Fourier transform electron paramagnetic resonance study

Fourier transform EPR spectroscopy was employed in studying the electron transfer (ET) reaction and the quenching mechanisms of the photoexcited triplet state of C₆₀ as electron acceptor and N,N,N′,N′-tetramethylbenzidine (NTMB) as electron donor in benzonitrile solution. The ET reaction product, the cation radical NTMB^*+, interacts with ^3*C₆₀, leading to photoinduced electron polarization of NTMB^*+ via triplet-doublet mixing mechanism combined with triplet mechanism. The quenching of ^3*C₆₀ and the polarization behavior of NTMB^*+ are discussed.     

Comparison of osmotic pressures from EMF measurements,obtained according to cell-model considerations and exact Gibbs-Duhem integrations

Osmotic pressures of aqueous solutions of poly(diethylaminoethyl methacrylate) hydrochloride, in equilibrium with a precipitate of the un-ionized polybase, at various concentrations of polymer and NaCl in solution and at different values of pH are derived from emf measurements and the “cell” theory for polyelectrolytes. Single-ion activities are evaluated according to two procedures. The first is based on measurements with ion-specific electrodes versus a calomel electrode. The second makes use of a salt bridge, but assumes that the co-ions have activity coefficients equal to the mean activity coefficient of the salt in a polyelectrolyte-free solution of the same concentration. The results show that the calculated values of the osmotic pressures are consistent with those obtained by the exact integration of the Gibbs-Duhem relationship, when the first procedure is employed. If, however, the single-ion activities are evaluated by the second procedure, the osmotic pressures obtained are consistently lower by about 10%. These differences arise because the two methods yield different values of the activity coefficients of the single ions.     

Real-time quantification of protein expression and translocation at individual cell resolution using imaging-dish-based live cell array

Cell populations represent intrinsically heterogeneous systems with a high level of spatiotemporal complexity. Monitoring and understanding cell-to-cell diversity is essential for the research and application of intra- and interpopulation variations. Optical analysis of live cells is challenging since both adherent and nonadherent cells change their spatial location. However, most currently available single-cell techniques do not facilitate treatment and monitoring of the same live cells over time throughout multistep experiments. An imaging-dish-based live cell array (ID-LCA) has been developed and produced for cell handling, culturing, and imaging of numerous live cells. The dish is composed of an array of pico scale cavities—pico wells (PWs) embossed on its glass bottom. Cells are seeded, cultured, treated, and spatiotemporally measured on the ID-LCA, while each cell or small group of cells are locally constrained in the PWs. Finally, predefined cells can be retrieved for further evaluation. Various types of ID-LCAs were used in this proof-of-principle work, to demonstrate on-ID-LCA transfection of fluorescently tagged chimeric proteins, as well as the detection and kinetic analysis of their induced translocation. High variability was evident within cell populations with regard to protein expression levels as well as the extent and dynamics of protein redistribution. The association of these parameters with cell morphology and functional parameters was examined. Both the new methodology and the device facilitate research of the translocation process at individual cell resolution within large populations and thus, can potentially be used in high-throughput fashion. Graphical Abstract

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Four (algorithms) in one (bag): an integrative framework of knowledge for teaching the standard algorithms of the basic arithmetic operations

In this article we present an integrative framework of knowledge for teaching the standard algorithms of the four basic arithmetic operations. The framework is based on a mathematical analysis of the algorithms, a connectionist perspective on teaching mathematics and an analogy with previous frameworks of knowledge for teaching arithmetic operations with rational numbers. In order to evaluate the potential applicability of the framework to task design, it was used for the design of mathematical learning tasks for teachers. The article includes examples of the tasks, their theoretical analysis, and empirical evidence of the sensitivity of the tasks to variations in teachers’ knowledge of the subject. This evidence is based on a study of 46 primary school teachers. The article concludes with remarks on the applicability of the framework to research and practice, highlighting its potential to encourage teaching the four algorithms with an emphasis on conceptual understanding.     

Ortho‐Stabilized 18F‐Azido Click Agents and their Application in PET Imaging with Single‐Stranded DNA Aptamers

Azido ¹⁸F‐arenes are important and versatile building blocks for the radiolabeling of biomolecules via Huisgen cycloaddition (“click chemistry”) for positron emission tomography (PET). However, routine access to such clickable agents is challenged by inefficient and/or poorly defined multistep radiochemical approaches. A high‐yielding direct radiofluorination for azido ¹⁸F‐arenes was achieved through the development of an ortho‐oxygen‐stabilized iodonium derivative (OID). This OID strategy addresses an unmet need for a reliable azido ¹⁸F‐arene clickable agent for bioconjugation reactions. A ssDNA aptamer was radiolabeled with this agent and visualized in a xenograft mouse model of human colon cancer by PET, which demonstrates that this OID approach is a convenient and highly efficient way of labeling and tracking biomolecules.     

MRI rotating frame relaxation measurements for articular cartilage assessment

In the present work we introduced two MRI rotating frame relaxation methods, namely adiabatic T_1ρ and Relaxation Along a Fictitious Field (RAFF), along with an inversion-prepared Magnetization Transfer (MT) protocol for assessment of articular cartilage. Given the inherent sensitivity of rotating frame relaxation methods to slow molecular motions that are relevant in cartilage, we hypothesized that adiabatic T_1ρ and RAFF would have higher sensitivity to articular cartilage degradation as compared to laboratory frame T₂ and MT. To test this hypothesis, a proteoglycan depletion model was used. Relaxation time measurements were performed at 0 and 48 h in 10 bovine patellar specimens, 5 of which were treated with trypsin and 5 untreated controls were stored under identical conditions in isotonic saline for 48 h. Relaxation times measured at 48 h were longer than those measured at 0 h in both groups. The changes in T₂ and MT relaxation times after 48 h were approximately 3 times larger in the trypsin treated specimens as compared to the untreated group, whereas increases of adiabatic T_1ρ and RAFF were 4 to 5 fold larger. Overall, these findings demonstrate a higher sensitivity of adiabatic T_1ρ and RAFF to the trypsin-induced changes in bovine patellar cartilage as compared to the commonly used T₂ and MT. Since adiabatic T_1ρ and RAFF are advantageous for human applications as compared to standard continuous-wave T_1ρ methods, adiabatic T_1ρ and RAFF are promising tools for assessing cartilage degradation in clinical settings.