Efficient total synthesis of pulchellalactam,a CD45 protein tyrosine phosphatase inhibitor

A new approach to a CD45 protein tyrosine phosphatase inhibitor, pulchellalactam, is described. The key step of the sequence involves addition and elimination of an enolic lactam in a single step and 70% yield, employing an organocuprate reagent. The resulting alpha,beta-unsaturated lactam could be condensed with isobutyraldehyde to produce Z-pulchellalactam or converted into siloxypyrrole, which was subjected to the BF(3) x Et(2)O-promoted coupling reaction with isobutyraldehyde to afford E-pulchellalactam after E1-cB elimination and TFA deprotection. This first total synthesis afforded Z-pulchellalactam in six steps and 32% overall yield from Boc-glycine. The same sequence of reactions could also be applied to the liquid- or solid-phase synthesis of trifunctionalized pulchellalactam derivatives.     

System-oriented dispersion models of general-shaped electrophoresis microchannels

This paper presents a system-oriented model for analyzing the dispersion of electrophoretic transport of charged analyte molecules in a general-shaped microchannel, which is represented as a system of serially connected elemental channels of simple geometry. Parameterized analytical models that hold for analyte bands of virtually arbitrary initial shape are derived to describe analyte dispersion, including both the skew and broadening of the band, in elemental channels. These models are then integrated to describe dispersion in the general-shaped channel using appropriate parameters to represent interfaces of adjacent elements. This lumped-parameter system model offers orders-of-magnitude improvement in computational efficiency over full numerical simulations, and is verified by results from experiments and numerical simulations. The model is used to perform a systematic parametric study of serpentine channels consisting of a pair of complementary turn microchannels, and the results indicate that dispersion in a particular turn can contribute to either an increase or decrease of the overall band broadening. The efficiency and accuracy of the system model is further demonstrated by its application to general-shaped channels that occur in practice, including a serpentine channel with multiple complementary turns and a multi-turn spiral-shaped channel. The results indicate that our model is an accurate and efficient simulation tool useful for designing optimal electrophoretic separation microchips.     

Silicon-assisted propargylic transfer to aldehydes

A new and efficient method of obtaining homopropargylic alcohols via homopropargylic transfer from the allenic alcohol to various aldehydes in the presence of Lewis acid catalysts is described; stereochemical studies have shown that this process is the first oxonium [3,3]-sigmatropic rearrangement of an allenic alcohol to a homopropargylic alcohol in the presence of aldehydes and Lewis acid.     

Duality and intersection theory in complex manifolds. I

We introduce the concept of a twisting cochain and a twisted complex associated to a coherent sheaf. For sheaves of submanifolds these twisted complexes are used to construct on cochain level the Grothendieck theory of dual class and Gysin map. These explicit constructions give, for instance, a local formula for dual class of higher codimensional submanifolds. We prove a refined version of the Hirzebruch Riemann Roch using such local formulas. We also prove a theorem on when global analytic intersection classes can be computed from first order geometric data. This theory will be used to prove the Holomorphic Lefschetz formula (in Part II) and the Hirzebruch Riemann Roch for analytic coherent sheaves.The first author is supported in part by NSF grants GP-36418X1 and MCS 76-08478. The second by MCS 75-07986 and Sonderforschungsbereich Theoretische Mathematik at Bonn University     

Single-molecule nanopore sensing of actin dynamics and drug binding

Actin is a key protein in the dynamic processes within the eukaryotic cell. To date, methods exploring the molecular state of actin are limited to insights gained from structural approaches, providing a snapshot of protein folding, or methods that require chemical modifications compromising actin monomer thermostability. Nanopore sensing permits label-free investigation of native proteins and is ideally suited to study proteins such as actin that require specialised buffers and cofactors. Using nanopores, we determined the state of actin at the macromolecular level (filamentous or globular) and in its monomeric form bound to inhibitors. We revealed urea-dependent and voltage-dependent transitional states and observed the unfolding process within which sub-populations of transient actin oligomers are visible. We detected, in real-time, filament-growth, and drug-binding at the single-molecule level demonstrating the promise of nanopore sensing for in-depth understanding of protein folding landscapes and for drug discovery.

Nanopipettes were used for real-time investigation into actin dynamics and drug binding at single-molecule resolution, showing promise for a better understanding of the mechanism of protein–protein interactions and drug discovery.     

The first indium-organic two-dimensional layer network with rhombus grids

The indium(III)-organic compound [In(HBtc)₂(4,4′-bpy)](4,4′-Hbpy)(H₂O)_0.5 (Btc=1,3,5-benzenetricarboxylate, 4,4′-bpy=4,4′-bipyridine) has been synthesized under hydrothermal condition and characterized by IR, fluorescent spectroscopy, TGA and single-crystal X-ray diffraction analyses. The compound crystallizes in monoclinic, space group P2(1)/c, a=17.0884(2) Å, b=12.28390(10) Å, c=17.9456(4) Å, β=104.1920(10)°, V=3652.03(10) Å³, Z=4, R₁=0.0572 and wR₂=0.1116 [I>2σ(I)]. All the indium atoms in the compound are hepta-coordinated and link 1,3,5-benzenetricarboxylate forming a 2-D layer structure with rhombus grids.     

A method for correcting the contact angle from the θ/2 method

The θ/2 method, a widely used technique on measuring the contact angle of a sessile drop, assumes that the drop profile is part of a sphere. However, the shape profile of a sessile drop is governed by the Young–Laplace equation and is different from a sphere, especially for drops with a large bound number (e.g. large volume or small surface tension). The spherical assumption, therefore, causes errors on evaluating the contact angles. The deviation of contact angle from the θ/2 method is evaluated from a theoretical calculation in this work. A simple means is given for correcting the measurement error. The corrected angle results from the drop volume, surface tension, liquid density and the contact angle from θ/2 method. An algorithm for finding the correct contact angle without knowing the density and surface tension is also given. At the end, two examples of pendant drops are given for the illustration.     

A versatile microfabricated platform for electrophoresis of double- and single-stranded DNA

We demonstrate a versatile microfabricated electrophoresis platform, incorporating arrays of integrated on-chip electrodes, heaters, and temperature sensors. This design allows a range of different sieving gels to be used within the same device to perform separations involving both single- and double-stranded DNA over distances on the order of 1 cm. We use this device to compare linear and cross-linked polyacrylamide, agarose, and thermo-reversible Pluronic-F127 gels on the basis of gel casting ease, reusability, and overall separation performance using a 100 base pair double-stranded DNA ladder as a standard sample. While cross-linked polyacrylamide matrices provide consistently high-quality separations in our system over a wide range of DNA fragment sizes, Pluronic gels also offer compelling advantages in terms of the ability to remove and reload the gel. Agarose gels offer good separation performance, however, additional care must be exercised to ensure consistent gel properties as a consequence of the need for elevated gel loading temperatures. We also demonstrate the use of denaturing cross-linked polyacrylamide gels at concentrations up to 19% to separate single-stranded DNA fragments ranging in size from 18 to 400 bases in length. Primers differing by 4 bases at a read length of 30 bases can be separated with a resolution of 0.9-1.0 in under 20 min. This level of performance is sufficient to conduct a variety of genotyping assays including the rapid detection of single nucleotide polymorphisms (SNPs) in a microfabricated platform. The ability to use a single microelectrophoresis system to satisfy a wide range of separation applications offers molecular biologists an unprecedented level of flexibility in a portable and inexpensive format.     

Templateless assembly of molecularly aligned conductive polymer nanowires: a new approach for oriented nanostructures

Although oriented carbon nanotubes, oriented nanowires of metals, semiconductors and oxides have attracted wide attention, there have been few reports on oriented polymer nanostructures such as nanowires. In this paper we report the assembly of large arrays of oriented nanowires containing molecularly aligned conducting polymers (polyaniline) without using a porous membrane template to support the polymer. The uniform oriented nanowires were prepared through controlled nucleation and growth during a stepwise electrochemical deposition process in which a large number of nuclei were first deposited on the substrate using a large current density. After the initial nucleation, the current density was reduced stepwise in order to grow the oriented nanowires from the nucleation sites created in the first step. The usefulness of these new polymer structures is demonstrated with a chemical sensor device for H(2)O(2), the detection of which is widely investigated for biosensors. Finally, we demonstrated that controlled nucleation and growth is a general approach and has potential for growing oriented nanostructures of other materials.