The Mercury (II) Catalyzed,One-Pot Oxidation of Terminal Alkynes by Sodium Perborate in Acetic Acid

A series of terminal alkynes has been reacted with sodium perborate and mercuric acetate catalyst in acetic acid to produce 1-acetoxyalkan-2-ones in good yield. The reaction constitutes a mild and convenient method for the oxidation of terminal triple bonds.     

Reactivity of Diarylnitrenium Ions

Hydride abstraction from diarylamines with the trityl ion is explored in an attempt to generate a stable diarylnitrenium ion, Ar₂N⁺. Sequential H-atom abstraction reactions ensue. The first H-atom abstraction leads to intensely colored aminium radical cations, Ar₂NH^.+, some of which are quite stable. However, most undergo a second H-atom abstraction leading to ammonium ions, Ar₂NH₂⁺. In the absence of a ready source of H-atoms, a unique self-abstraction reaction occurs when Ar=Me₅C₆, leading to a novel iminium radical cation, Ar=N^.+Ar, which decays via a second self H-atom abstraction reaction to give a stable iminium ion, Ar=N⁺HAr. These products differ substantially from those derived via photochemically produced diarylnitrenium ions.     

Allostatic load as a complex clinical construct: A case‐based computational modeling approach

Allostatic load (AL) is a complex clinical construct, providing a unique window into the cumulative impact of stress. However, due to its inherent complexity, AL presents two major measurement challenges to conventional statistical modeling (the field's dominant methodology): it is comprised of a complex causal network of bioallostatic systems, represented by an even larger set of dynamic biomarkers; and, it is situated within a web of antecedent socioecological systems, linking AL to differences in health outcomes and disparities. To address these challenges, we employed case‐based computational modeling (CBM), which allowed us to make four advances: (1) we developed a multisystem, 7‐factor (20 biomarker) model of AL's network of allostatic systems; (2) used it to create a catalog of nine different clinical AL profiles (causal pathways); (3) linked each clinical profile to a typology of 23 health outcomes; and (4) explored our results (post hoc) as a function of gender, a key socioecological factor. In terms of highlights, (a) the Healthy clinical profile had few health risks; (b) the pro‐inflammatory profile linked to high blood pressure and diabetes; (c) Low Stress Hormones linked to heart disease, TIA/Stroke, diabetes, and circulation problems; and (d) high stress hormones linked to heart disease and high blood pressure. Post hoc analyses also found that males were overrepresented on the High Blood Pressure (61.2%), Metabolic Syndrome (63.2%), High Stress Hormones (66.4%), and High Blood Sugar (57.1%); while females were overrepresented on the Healthy (81.9%), Low Stress Hormones (66.3%), and Low Stress Antagonists (stress buffers) (95.4%) profiles. © 2015 Wiley Periodicals, Inc. Complexity 21: 291–306, 2016     

Engineering strategy to improve peptide analogs: from structure-based computational design to tumor homing

We present a chemical strategy to engineer analogs of the tumor-homing peptide CREKA (Cys-Arg-Glu-Lys-Ala), which binds to fibrin and fibrin-associated clotted plasma proteins in tumor vessels (Simberg et al. in Proc Natl Acad Sci USA 104:932–936, 2007) with improved ability to inhibit tumor growth. Computer modeling using a combination of simulated annealing and molecular dynamics were carried out to design targeted replacements aimed at enhancing the stability of the bioactive conformation of CREKA. Because this conformation presents a pocket-like shape with the charged groups of Arg, Glu and Lys pointing outward, non-proteinogenic amino acids α-methyl and N-methyl derivatives of Arg, Glu and Lys were selected, rationally designed and incorporated into CREKA analogs. The stabilization of the bioactive conformation predicted by the modeling for the different CREKA analogs matched the tumor fluorescence results, with tumor accumulation increasing with stabilization. Here we report the modeling, synthetic procedures, and new biological assays used to test the efficacy and utility of the analogs. Combined, our results show how studies based on multi-disciplinary collaboration can converge and lead to useful biomedical advances.     

Prospects of anionic nanolipoplexes in nanotherapy: transmission electron microscopy and light scattering studies

Currently nanosystems composed of polynucleotides and lipid vesicles (nanolipoplexes) are considered to be promising tools for gene therapeutics. Successful in vivo application of these vectors depends on their physicochemical, technological and biological characteristics including morphology, size distribution, molecular interactions and stability. Anionic nanoliposomes (DPPC:DCP:CHOL) were prepared by two different techniques, namely the conventional thin-film hydration method followed by extrusion, and the heating method (HM), in which no volatile solvent or detergent is used. A non-viral and non-cationic gene transfer vector was constructed by incorporating plasmid DNA (pcDNA3.1/His B/lacZ) to the HM-nanoliposomes by the electrostatic mediation of Ca²⁺ ions. Transfection efficiency of the nanolipoplexes was evaluated using a human bronchial epithelial cell line (16HBE14o-) in the presence of serum. Particle characterisation, stability of the formulations and lipid–DNA interaction studies were performed using transmission electron microscopy (TEM) and light scattering. TEM pictures of nanolipoplexes showed presence of two to four closely packed vesicles with signs of fusion. Efficient delivery of plasmid DNA and subsequent β-galactosidase expression was achieved using the anionic nanolipoplexes. Transfection efficiency increased with lipid:DNA ratio up to 7:1 (w/w), where transfection efficiency was 12-fold higher than in untreated cells. Further increase in lipid ratio decreased transfection. These nanolipoplexes appear to be safe, stable and efficient in the protection and delivery of DNA to different cells and tissues.     

Spectroscopic and Computational Study of a Nonheme Iron Nitrosyl Center in a Biosynthetic Model of Nitric Oxide Reductase

A major barrier to understanding the mechanism of nitric oxide reductases (NORs) is the lack of a selective probe of NO binding to the nonheme Fe_B center. By replacing the heme in a biosynthetic model of NORs, which structurally and functionally mimics NORs, with isostructural ZnPP, the electronic structure and functional properties of the Fe_B nitrosyl complex was probed. This approach allowed observation of the first S=3/2 nonheme {FeNO}⁷ complex in a protein‐based model system of NOR. Detailed spectroscopic and computational studies show that the electronic state of the {FeNO}⁷ complex is best described as a high spin ferrous iron (S=2) antiferromagnetically coupled to an NO radical (S= 1/2) [Fe²⁺‐NO^.]. The radical nature of the Fe_B‐bound NO would facilitate N? N bond formation by radical coupling with the heme‐bound NO. This finding, therefore, supports the proposed trans mechanism of NO reduction by NORs.     

Activation and Retention: A Magnetic Resonance Probe for the Detection of Acute Thrombosis

Blood‐clot formation that results in the complete occlusion of a blood vessel (thrombosis) often leads to serious life‐threatening events, such as strokes and heart attacks. As the composition of a thrombus changes as it matures, new imaging methods that are capable of distinguishing new clots from old clots may yield important diagnostic and prognostic information. To address this need, an activatable magnetic resonance (MR) probe that is responsive to a key biochemical process associated with recently formed clots has been developed.     

MVF Sensor Enables Analysis of Nucleic Acids with Stable Secondary Structures

One major challenge in nucleic acids analysis by hybridization probes is a compromise between the probe's tight binding and sequence‐selective recognition of nucleic acid targets folded into stable secondary structures. We have been developing a four‐way junction (4WJ)‐based sensor that consists of a universal stem‐loop (USL) probe immobilized on an electrode surface and two adaptor strands (M and F). The sensor was shown to be highly selective towards single base mismatches at room temperature, able to detect multiple targets using the same USL probe, and have improved ability to detect folded nucleic acids. However, some nucleic acid targets, including natural RNA, are folded into very stable secondary and tertiary structures, which may represent a challenge even for the 4WJ sensors. This work describes a new sensor, named MVF since it uses three probe stands M, V and F, which further improves the performance of 4WJ sensors with folded targets. The MVF sensor interrogating a 16S rRNA NASBA amplicon with calculated folding energy of ?32.82 kcal/mol has demonstrated 2.5‐fold improvement in a signal‐to‐background ratio in comparison with a 4WJ sensor lacking strand V. The proposed design can be used as a general strategy in the analysis of folded nucleic acids including natural RNA.     

Gradient-index fiber-optic microprobes for minimally invasive in vivo low-coherence interferometry

We describe the design, construction, and application of what are believed to be the smallest fiber-optic probes used to date during imaging or diagnosis involving low-coherence interferometry (LCI). The probes use novel fiber-optic gradient-index (GRIN) lenses fabricated by a recently developed modified chemical-vapor-deposition (MCVD) process that avoids on-axis aberrations commonly marring MCVD-fabricated GRIN substrate. Fusing GRIN fiber lenses onto single-mode fiber yields automatically aligned all-fiber probes that insert into tissue through hypodermic needles as small as 31-gauge (inner diameter, 127 mum). We demonstrate the use of such probes with LCI by measuring microscopic brain motions in vivo.     

A Bound on the Total Chromatic Number

. The proof is probabilistic. Received: November 26, 1996