Keys for unlocking photolabile metal-containing cages

Photolabile metal-containing cages are metal complexes that undergo a change in coordination environment upon exposure to light of an appropriate wavelength. The light-responsive functionality can either be a component of the encapsulating ligand or a property of the metal complex itself. The altered coordination properties of light-responsive complexes can result in release of the coordinated metal ion into its surroundings, a differential reactivity of the metal center, or the liberation of a reactive molecule that had been passivated by binding to the metal center. These triggerable agents can be useful tools for manipulating the bioavailability of metals or their coordinating ligands in order to study biological pathways or for potential therapeutic purposes.     

Small Fluorogenic Amino Acids for Peptide-Guided Background-Free Imaging

The multiple applications of super-resolution microscopy have prompted the need for minimally invasive labeling strategies for peptide-guided fluorescence imaging. Many fluorescent reporters display limitations (e.g., large and charged scaffolds, non-specific binding) as building blocks for the construction of fluorogenic peptides. Herein we have built a library of benzodiazole amino acids and systematically examined them as reporters for background-free fluorescence microscopy. We have identified amine-derivatized benzoselenadiazoles as scalable and photostable amino acids for the straightforward solid-phase synthesis of fluorescent peptides. Benzodiazole amino acids retain the binding capabilities of bioactive peptides and display excellent signal-to-background ratios. Furthermore, we have demonstrated their application in peptide-PAINT imaging of postsynaptic density protein-95 nanoclusters in the synaptosomes from mouse brain tissues.     

Synthesis, structure, and magnetism of an f element nitrosyl complex, (C5Me4H)3UNO

(C(5)Me(4)H)(3)U, 1, reacts with 1 equiv of NO to form the first f element nitrosyl complex (C(5)Me(4)H)(3)UNO, 2. X-ray crystallography revealed a 180° U-N-O bond angle, typical for (NO)(1+) complexes. However, 2 has a 1.231(5) ? N═O distance in the range for (NO)(1-) complexes and a short 2.013(4) ? U-N bond like the U═N bond of uranium imido complexes. Structural, spectroscopic, and magnetic data as well as DFT calculations suggest that reduction of NO by U(3+) has occurred to form a U(4+) complex of (NO)(1-) that has π interactions between uranium 5f orbitals and NO π* orbitals. These bonding interactions account for the linear geometry and short U-N bond. The complex displays temperature-independent paramagnetism with a magnetic moment of 1.36 μ(B) at room temperature. Complex 2 reacts with Al(2)Me(6) to form the adduct (C(5)Me(4)H)(3)UNO(AlMe(3)), 3.     

Exploring structure-activity relationships of tricyclic farnesyltransferase inhibitors using ECLiPS libraries

The development of structure-activity relationships (SARs) relating to the function of a biological protein is often a long and protracted undertaking when using an iterative medicinal chemistry approach. High throughput screening of ECLiPS (Encoded Combinatorial Libraries on Polymeric Support) libraries can be used to simplify this process. In this paper, we illustrate how a large ECLiPS library of 26,908 compounds, based on a tricyclic core structure, was used to define a multitude of SARs for the oncogenic target, farnesyltransferase (FTase). This library, FT-2, was prepared using a split-and-pool approach in which small molecules are constructed on resin that contains tag/linker constructs to track the synthetic process [1-5] Highly defined SARs were produced from this screen that enhanced our understanding of FTase binding site interactions. The pivotal compounds culled from this library were potent in both cell-free and cell-based FTase assays, selective over the closely related enzyme, geranylgeranyltransferase I (GGTase I), and inhibited the adherent-independent growth of a transformed cell line.     

Use of a carbon nanocage as a catalyst support in polymer electrolyte membrane fuel cells

The corrosion-resistance of a carbon nanocage used as a catalyst support in a polymer electrolyte membrane fuel cell was investigated by measuring CO₂ generation using on-line mass spectrometry at a constant potential of 1.4 V for 30 min. Polarization curves of membrane electrode assemblies containing Pt/carbon nanocage were obtained and used to evaluate performance degradation. The carbon nanocage was found to possess significant resistance to electrochemical corrosion, exhibiting low performance degradation of only about 2.3% after the corrosion test. This high corrosion resistance is attributed both to the strong hydrophobic nature of the surface and the graphitic structure of the carbon nanocage.     

Neural mechanisms underlying the facilitation of naming in aphasia using a semantic task: an fMRI study

ABSTRACT: BACKGROUND: Previous attempts to investigate the effects of semantic tasks on picture naming in both healthy controls and people with aphasia have typically been confounded by inclusion of the phonological word form of the target item. As a result, it is difficult to isolate any facilitatory effects of a semantically-focused task to either lexical-semantic or phonological processing. This functional magnetic resonance imaging (fMRI) study examined the neurological mechanisms underlying short-term (within minutes) and long-term (within days) facilitation of naming from a semantic task that did not include the phonological word form, in both participants with aphasia and age-matched controls. RESULTS: Behavioral results showed that a semantic task that did not include the phonological word form can successfully facilitate subsequent picture naming in both healthy controls and individuals with aphasia. The whole brain neuroimaging results for control participants identified a repetition enhancement effect in the short-term, with modulation of activity found in regions that have not traditionally been associated with semantic processing, such as the right lingual gyrus (extending to the precuneus) and the left inferior occipital gyrus (extending to the fusiform gyrus). In contrast, the participants with aphasia showed significant differences in activation over both the short- and the long-term for facilitated items, predominantly within either left hemisphere regions linked to semantic processing or their right hemisphere homologues. CONCLUSIONS: For control participants in this study, the short-lived facilitation effects of a prior semantic task that did not include the phonological word form were primarily driven by object priming and episodic memory mechanisms. However, facilitation effects appeared to engage a predominantly semantic network in participants with aphasia over both the short- and the long-term. The findings of the present study also suggest that right hemisphere involvement may be supportive rather than maladaptive, and that a large distributed perisylvian network in both cerebral hemispheres supports the facilitation of naming in individuals with aphasia.     

Iterative synthesis and characterization of cross-conjugated iso-polydiacetylenes.

An iterative synthesis of cross-conjugated iso-polydiacetylenes (iso-PDAs) is reported based on three fundamental building blocks: vinyl triflates 8, 9, and 25. An efficient sequence of palladium-catalyzed cross-coupling reactions of vinyl triflates and terminal alkynes has been employed to extend the chain length of these oligomers. The longest member of the series, nonamer 19, spans 3.4 nm from Si to Si atom. The stability and solubility of the conjugated oligomers have been evaluated as a function of pendant substitution. Assessment of solid-state structural properties was achieved via X-ray crystallographic analyses of monomer 12 and trimer 14. The electronic characteristics of the monodisperse oligomers have been fully analyzed by UV-vis spectroscopy in solution and as thin films, and these studies suggest that pi-electron communication is present along the enyne framework, but quickly reaches saturation by the stage of nonamer 19.     

One‐Reactant Photografting of ATRP Initiators for Surface‐Initiated Polymerization

Self‐initiated photografting polymerization is used to couple the polymerizable initiator monomer 2‐(2‐chloropropanoyloxy)ethyl acrylate to a range of polymeric substrates. The technique requires only UV light to couple the initiator to surfaces. The initiator surface density can be varied by inclusion of a diluent monomer or via selection of initiator and irradiation parameters. The functionality of the initiator surface is demonstrated by subsequent surface‐initiated atom transfer radical polymerization. Surfaces are characterized by x‐ray photoelectron spectroscopy (XPS), ellipsometry, and atomic force microscopy (AFM), and UV‐induced changes to the initiator are assessed by ¹H NMR and gel permeation chromatography (GPC). This is the first time this one‐reactant one‐step technique has been demonstrated for creating an initiator surface of variable density.

     

Beta-Amyloid (Aβ1-42) Increases the Expression of NKCC1 in the Mouse Hippocampus

Alzheimer’s disease (AD) is a neurodegenerative disorder with an increasing need for developing disease-modifying treatments as current therapies only provide marginal symptomatic relief. Recent evidence suggests the γ-aminobutyric acid (GABA) neurotransmitter system undergoes remodeling in AD, disrupting the excitatory/inhibitory (E/I) balance in the brain. Altered expression levels of K-Cl-2 (KCC2) and N-K-Cl-1 (NKCC1), which are cation–chloride cotransporters (CCCs), have been implicated in disrupting GABAergic activity by regulating GABA_A receptor signaling polarity in several neurological disorders, but these have not yet been explored in AD. NKCC1 and KCC2 regulate intracellular chloride [Cl⁻]_i by accumulating and extruding Cl⁻, respectively. Increased NKCC1 expression in mature neurons has been reported in these disease conditions, and bumetanide, an NKCC1 inhibitor, is suggested to show potential therapeutic benefits. This study used primary mouse hippocampal neurons to explore if KCC2 and NKCC1 expression levels are altered following beta-amyloid (Aβ_1-42) treatment and the potential neuroprotective effects of bumetanide. KCC2 and NKCC1 expression levels were also examined in 18-months-old male C57BL/6 mice following bilateral hippocampal Aβ_1-42 stereotaxic injection. No change in KCC2 and NKCC1 expression levels were observed in mouse hippocampal neurons treated with 1 nM Aβ_1-42, but NKCC1 expression increased 30-days post-Aβ_1-42-injection in the CA1 region of the mouse hippocampus. Primary mouse hippocampal cultures were treated with 1 nM Aβ_1-42 alone or with various concentrations of bumetanide (1 µM, 10 µM, 100 µM, 1 mM) to investigate the effect of the drug on cell viability. Aβ_1-42 produced 53.1 ± 1.4% cell death after 5 days, and the addition of bumetanide did not reduce this. However, the drug at all concentrations significantly reduced cell viability, suggesting bumetanide is highly neurotoxic. In summary, these results suggest that chronic exposure to Aβ_1-42 alters the balance of KCC2 and NKCC1 expression in a region-and layer-specific manner in mouse hippocampal tissue; therefore, this process most likely contributes to altered hippocampal E/I balance in this model. Furthermore, bumetanide induces hippocampal neurotoxicity, thus questioning its suitability for AD therapy. Further investigations are required to examine the effects of Aβ_1-42 on KCC2 and NKCC1 expression and whether targeting CCCs might offer a therapeutic approach for AD.