Establishing a Robust and Reliable Response from a Potent Osmium-Based Photosensitizer Via Lipid Nanoformulation†

Osmium (Os) based photosensitizers (PSs) are a unique class of nontetrapyrrolic metal-containing PSs that absorb red light. We recently reported a highly potent Os(II) PS, rac-[Os(phen)₂(IP-4T)](Cl)₂, referred to as ML18J03 herein, with light EC₅₀ values as low as 20 pm . ML18J03 also exhibits low dark toxicity and submicromolar light EC₅₀ values in hypoxia in some cell lines. However, owing to its longer oligothiophene chain, ML18J03 is not completely water soluble and forms 1–2 μm sized aggregates in PBS containing 1% DMSO. This aggregation causes variability in PDT efficacy between assays and thus unreliable and irreproducible reports of in vitro activity. To that end, we utilized PEG-modified DPPC liposomes (138 nm diameter) and DSPE-mPEG₂₀₀₀ micelles (10.2 nm diameter) as lipid nanoformulation vehicles to mitigate aggregation of ML18J03 and found that the spectroscopic properties important to biological activity were maintained or improved. Importantly, the lipid formulations decreased the interassay variance between the EC₅₀ values by almost 20-fold, with respect to the unformulated ML18J03 when using broadband visible light excitation (P = 0.0276). Herein, lipid formulations are presented as reliable platforms for more accurate in vitro photocytotoxicity quantification for PSs prone to aggregation (such as ML18J03) and will be useful for assessing their in vivo PDT effects.     

Interactions of the complete cellobiohydrolase I from Trichodera reesei with microcrystalline cellulose Iβ

We describe the construction of a model complex of the cellobiohydrolase I (CBH I) cellulase from Trichoderma reesei bound to a cellulose microfibril in an aqueous environment for use in molecular dynamics (MD) simulations. Preliminary characterization from the initial phases of an MD simulation of this complex is also described. The linker sequence between the two globular domains was found to be quite flexible, and the oligosaccharides bound to this linker were found to prefer to be splayed like the spokes in a wheel due to their hydration requirements. The overall conformations of the two globular domains remained stable in the simulations, although both underwent changes in their orientations.     

Digital image correlation using Newton-Raphson method of partial differential correction

Digital image correlation is finding wider use in the field of mechanics. One area of weakness in the current technique is the lack of available displacement gradient terms. This technique, based on a coarse-fine search method, is capable of calculating the gradients. However the speed at which it does so has prevented widespread use. Presented in this paper is the development and limited experimental verification of a method which can determine displacements and gradients using the Newton-Raphson method of partial corrections. It will be shown that this method is accurate in determining displacements and certain gradients, while using significantly less CPU time than the current coarse-fine search method. Paper was presented at the 1988 SEM Spring Conference on Experimental Mechanics held in Portland, OR on June 5–10.     

Synthesis of new penicillin derivatives as drug-like molecules for biological screening

Chemical modification of penicillin β-lactam ring was made.Six thiazolidine amides were produced through N4-C7 β-lactam ring opening of penicillin V methyl ester with various aliphatic,aromatic,and heterocyclic primary amines.Five 8-hydroxypenillic acid derivatives with side chains of methyl,propyl,benzyl,and diethylaminoethyl groups were yielded via β-lactam ring rearrangement from6-aminopenicillanic acid(6-APA).Parallel synthetic methods were used for the alkylation of8-hydroxypenillic acid and β-lactam ring opening of penicillin V methyl ester.The biological activities of the compounds were evaluated.     

Styrene Aziridination by Iron(IV) Nitrides

Thermolysis of the iron(IV) nitride complex [PhB(tBuIm)₃Fe?N] with styrene leads to formation of the high‐spin iron(II) aziridino complex [PhB(tBuIm)₃Fe‐N(CH₂CHPh)]. Similar aziridination occurs with both electron‐rich and electron‐poor styrenes, while bulky styrenes hinder the reaction. The aziridino complex [PhB(tBuIm)₃Fe‐N(CH₂CHPh)] acts as a nitride synthon, reacting with electron‐poor styrenes to generate their corresponding aziridino complexes, that is, aziridine cross‐metathesis. Reaction of [PhB(tBuIm)₃Fe‐N(CH₂CHPh)] with Me₃SiCl releases the N‐functionalized aziridine Me₃SiN(CH₂CHPh) while simultaneously generating [PhB(tBuIm)₃FeCl]. This closes a synthetic cycle for styrene azirdination by a nitride complex. While the less hindered iron(IV) nitride complex [PhB(MesIm)₃Fe?N] reacts with styrenes below room temperature, only bulky styrenes lead to tractable aziridino products.     

Halogenated Phenazines that Potently Eradicate Biofilms,MRSA Persister Cells in Non‐Biofilm Cultures,and Mycobacterium tuberculosis

Conventional antibiotics are ineffective against non‐replicating bacteria (for example, bacteria within biofilms). We report a series of halogenated phenazines (HP), inspired by marine antibiotic 1 , that targets persistent bacteria. HP 14 demonstrated the most potent biofilm eradication activities to date against MRSA, MRSE, and VRE biofilms (MBEC=0.2–12.5 μM), as well as the effective killing of MRSA persister cells in non‐biofilm cultures. Frontline MRSA treatments, vancomycin and daptomycin, were unable to eradicate MRSA biofilms or non‐biofilm persisters alongside 14 . HP 13 displayed potent antibacterial activity against slow‐growing M. tuberculosis (MIC=3.13 μM), the leading cause of death by bacterial infection around the world. HP analogues effectively target persistent bacteria through a mechanism that is non‐toxic to mammalian cells and could have a significant impact on treatments for chronic bacterial infections.     

On the toughening of brittle materials by grain bridging: Promoting intergranular fracture through grain angle, strength, and toughness

The structural reliability of many brittle materials such as structural ceramics relies on the occurrence of intergranular, as opposed to transgranular, fracture in order to induce toughening by grain bridging. For a constant grain boundary strength and grain boundary toughness, the current work examines the role of grain strength, grain toughness, and grain angle in promoting intergranular fracture in order to maintain such toughening. Previous studies have illustrated that an intergranular path and the consequent grain bridging process can be partitioned into five distinct regimes, namely: propagate, kink, arrest, stall, and bridge. To determine the validity of the assumed intergranular path, the classical penetration/deflection problem of a crack impinging on an interface is re-examined within a cohesive zone framework for intergranular and transgranular fracture. Results considering both modes of propagation, i.e., a transgranular and intergranular path, reveal that crack-tip shielding is a natural outcome of the cohesive zone approach to fracture. Cohesive zone growth in one mode shields the opposing mode from the stresses required for cohesive zone initiation. Although stable propagation occurs when the required driving force is equivalent to the toughness for either transgranular or intergranular fracture, the mode of propagation depends on the normalized grain strength, normalized grain toughness, and grain angle. For each grain angle, the intersection of single path and multiple path solutions demarcates “strong” grains that increase the macroscopic toughness and “weak” grains that decrease it. The unstable transition to intergranular fracture reveals that an increasing grain toughness requires a growing region of the transgranular cohesive zone be near the cohesive strength. The inability of the body to provide the requisite stress field yields an overdriven and unstable configuration. The current results provide restrictions for the achievement of substantial toughening through intergranular fracture.     

Proton radiation effects of conjugated polymer thin films

Polymeric-thin-film-based electronic and optoelectronic materials and devices are attractive for potential space and certain radiation-related applications due to their inherent features such as lightweight, flexible, biocompatible, etc. Proton radiation is a major form of ionizing radiation in space, particularly in the so-called inner Van Allen belt region where most near-earth satellites are orbiting, yet very few literature and data are available on proton radiation effects on conjugated polymer systems. In this report, the proton radiation effects on potential electronic/optoelectronic properties of several conjugated polymers and their composites are briefly evaluated. Specifically, UV–VIS absorption spectra of several conjugated polymers and/or their composite thin films were measured and compared right before and after the proton radiations at different dosages. The results revealed that proton radiation has very little or insignificant impact up to 800?rad on the optoelectronic properties of poly-3-hexyl-thiophene (P3HT), P3HT:PC₆₀BM blend, a light harvesting donor-bridge-acceptor (DBA) and a novel donor-bridge-fluorinated-acceptor (DBfA)-type block copolymer thin films.