The Structures of Gd(III) Chelates Conjugated at the Periphery of 3-(1’-Hexyloxy)ethyl-3-devinylpyropheophorbide-a (HPPH) Have a Significant Impact on the Imaging and Therapy of Cancer

3-(1’-Hexyloxyethyl)-3-devinyl-pyropheophorbide-a (HPPH or Photochlor), a tumor-avid chlorophyll-a derivative currently undergoing human clinical trials, was conjugated at various peripheral positions (position-17 or 20) of HPPH with either Gd(III)-aminobenzyl-DTPA (Gd(III) DTPA) or Gd(III)-aminoethylamido-DOTA (Gd(III) DOTA). The corresponding conjugates were evaluated for in vitro PDT efficacy, T₁, T₂ relaxivities, in vivo fluorescence, and MR imaging under similar treatment parameters. Among these analogs, the water-soluble Gd(III)-aminoethylamido-DOTA linked at position-17 of HPPH, i. e., HPPH-17-Gd(III) DOTA, demonstrated strong potential for tumor imaging by both MR and fluorescence, while maintaining the PDT efficacy in BALB/c mice bearing Colon-26 tumors (7/10 mice were tumor free on day 60). In contrast to Gd(III) DTPA (Magnevist) and Gd(III) DOTA (Dotarem), the HPPH-Gd(III) DOTA retains in the tumor for a long period of time (24 to 48 h) and provides an option of fluorescence-guided cancer therapy. Thus, a single agent can be used for cancer-imaging and therapy. However, further detailed pharmacokinetic, pharmacodynamic, and toxicological studies of the conjugate are required before initiating Phase I human clinical trials.     

Processing and electromechanical properties of high-coercive field ZnO-doped PIN-PZN-PT ceramics

This study explores sintering and piezoelectricity of ZnO-doped perovskite Pb(In_1/2Nb_1/2)O₃-Pb(Zn_1/3Nb_2/3)O₃-PbTiO₃ (PIN-PZN-PT) ceramics. The enhanced densification of ZnO-doped PIN-PZN-PT is attributed to the formation of oxygen vacancies by the incorporation of Zn²⁺ into the perovskite B-site and increased rate of bulk diffusion relative to undoped PIN-PZN-PT. Incorporation of Zn²⁺ into the perovskite lattice increased the tetragonal character of PIN-PZN-PT as demonstrated by tetragonal peak splitting and increased Curie temperature. Sintering in flowing oxygen reduced the solubility of Zn²⁺ in the perovskite lattice and resulted in rhombohedral PIN-PZN-PT. Sintering in oxygen prevented secondary phase formation which resulted in a high-piezoelectric coefficient (d₃₃ – 550 pC/N), high-coercive field (E_c – 13 kV/cm), and high-rhombohedral to tetragonal phase transition temperature (T_r-t – 165°C). We conclude that ZnO-doped PIN-PZN-PT ceramics are excellent candidates for high-power transducer applications.     

Addressing amorphization and transgranular fracture of B4C through Si doping and TiB2 microparticle reinforcing

Over the last two decades, many studies have contributed to improving our understanding of the brittle failure mechanisms of boron carbide and provided a road map for inhibiting the underlying mechanisms and improving the mechanical response of boron carbide. This paper provides a review of the design and processing approaches utilized to address the amorphization and transgranular fracture of boron carbide, which are mainly based on what we have found through 9 years of work in the field of boron carbides as armor ceramics.     

Clearing the Air on EPA's New Chief

On November 8, 2016, the citizens of the United States elected not just a new government, but a very different government. With the election of Donald Trump as the 45th president of the United States and the results in the many contested congressional races, the pendulum of politics swung, perhaps harder than it has swung in at least several decades.     

Predicted Ligands for the Human Urotensin‐II G Protein‐Coupled Receptor with Some Experimental Validation

Human Urotensin‐II (U‐II) is the most potent mammalian vasoconstrictor known. 1 Thus, a U‐II antagonist would be of therapeutic value in a number of cardiovascular disorders. 2 Here, we describe our work on the prediction of the structure of the human U‐II receptor (hUT₂R) using GEnSeMBLE (GPCR Ensemble of Structures in Membrane BiLayer Environment) complete sampling Monte Carlo method. With the validation of our predicted structures, we designed a series of new potential antagonists predicted to bind more strongly than known ligands. Next, we carried out R‐group screening to suggest a new ligand predicted to bind with 7 kcal mol^?1 better energy than 1‐{2‐[4‐(2‐bromobenzyl)‐4‐hydroxypiperidin‐1‐yl]ethyl}‐3‐(thieno[3,2‐b]pyridin‐7‐yl)urea, the designed antagonist predicted to have the highest affinity for the receptor. Some of these predictions were tested experimentally, validating the computational results. Using the pharmacophore generated from the predicted structure for hUT₂R bound to ACT‐058362, we carried out virtual screening based on this binding site. The most potent hit compounds identified contained 2‐(phenoxymethyl)‐1,3,4‐thiadiazole core, with the best derivative exhibiting an IC₅₀ value of 0.581 μM against hUT₂R when tested in vitro. Our efforts identified a new scaffold as a potential new lead structure for the development of novel hUT₂R antagonists, and the computational methods used could find more general applicability to other GPCRs.     

Catalytic Molecular Logic Devices by DNAzyme Displacement

Chemical reactions catalyzed by DNAzymes offer a route to programmable modification of biomolecules for therapeutic purposes. To this end, we have developed a new type of catalytic DNA‐based logic gates in which DNAzyme catalysis is controlled via toehold‐mediated strand displacement reactions. We refer to these as DNAzyme displacement gates. The use of toeholds to guide input binding provides a favorable pathway for input recognition, and the innate catalytic activity of DNAzymes allows amplification of nanomolar input concentrations. We demonstrate detection of arbitrary input sequences by rational introduction of mismatched bases into inhibitor strands. Furthermore, we illustrate the applicability of DNAzyme displacement to compute logic functions involving multiple logic gates. This work will enable sophisticated logical control of a range of biochemical modifications, with applications in pathogen detection and autonomous theranostics.