Rapid screening of phenylketonuria using a CD microfluidic device

We herein present a compact disc (CD) microfluidic chip based hybridization assay for phenylketonuria (PKU) screening. This CD chip is composed of a polydimethylsiloxane (PDMS) top layer containing 12 DNA hybridization microchannels, and a glass bottom layer with hydrogel pad conjugated DNA oligonucleotides. Reciprocating flow was generated on the CD chip through a simple rotation-pause operation to facilitate rapid DNA hybridization. When rotated the CD chip, the sample solution was driven into the hybridization channel by centrifugal force. When stopped the CD chip, the sample plug was pulled backward through the channel by capillary force. The hybridization assay was firstly validated with control samples and was then used to analyze 30 clinical samples from pregnant women with suspected PKU fetus. The on-chip DNA hybridization was completed in 15 min with a sample consumption as low as 1.5μL, and the limit-of-detection (LOD) of DNA template was 0.7ng/μL. Among the 30 samples tested, V245V mutation was identified in 4 cases while R243Q mutation was detected in one case. Results of the hybridization assay were confirmed by DNA sequencing. This CD-chip based hybridization assay features short analysis time, simple operation and low cost, thus has the potential to serve as the tool for PKU screening.     

Hydrogen-bonding interactions in ferrocene-peptide conjugates containing valine

The synthesis and characterization of a series of ferrocene (Fc) peptide conjugates containing the amino acid valine is reported, where the peptide substituents are part of the hydrophobic sequence of the amyloid β-peptide. The hydrogen-bonding (H-bonding) interaction in these compounds is studied by variable temperature ¹H NMR spectroscopy. The solid-state structures, determined by single crystal X-ray crystallography, of two of the conjugates (Fc[CO-Leu-Val-OMe]₂1 and Fc[CO-Gly-Val-OH]₂6) are reported. Both structures are stabilized by intramolecular H-bonds exhibiting the familiar “Herrick motif” involving the proximal amide NH and the amide CO of the adjacent amino acid. This motif is sufficiently rigid and is maintained in solution as suggested by CD studies. However, the intermolecular H-bonding patterns observed on conjugates 1 and 6 are significantly different resulting in very different supramolecular architectures. For conjugate 1, a more conventional set of head-to-tail stacking interactions which is stabilized by β-sheet-like H-bonding interactions between the individual molecules is observed. However, for conjugate 6, the presence of the C-terminal acid group and presumably the flexibility of the Gly linker enables the formation of a more open structure that contains hydrophobic channels occupied by solvent molecules.     

One target, different effects: a comparison of distinct therapeutic antibodies against the same targets

To date, more than 30 antibodies have been approved worldwide for therapeutic use. While the monoclonal antibody market is rapidly growing, the clinical use of therapeutic antibodies is mostly limited to treatment of cancers and immunological disorders. Moreover, antibodies against only five targets (TNF-α, HER2, CD20, EGFR, and VEGF) account for more than 80 percent of the worldwide market of therapeutic antibodies. The shortage of novel, clinically proven targets has resulted in the development of many distinct therapeutic antibodies against a small number of proven targets, based on the premise that different antibody molecules against the same target antigen have distinct biological and clinical effects from one another. For example, four antibodies against TNF-α have been approved by the FDA -- infliximab, adalimumab, golimumab, and certolizumab pegol -- with many more in clinical and preclinical development. The situation is similar for HER2, CD20, EGFR, and VEGF, each having one or more approved antibodies and many more under development. This review discusses the different binding characteristics, mechanisms of action, and biological and clinical activities of multiple monoclonal antibodies against TNF-α, HER-2, CD20, and EGFR and provides insights into the development of therapeutic antibodies.     

Optimal estimates of the field enhancement in presence of a bow-tie structure of perfectly conducting inclusions in two dimensions

This paper deals with the field enhancement due to insertion of a bow-tie structure of perfectly conducting inclusions into the two-dimensional space with a given field. The field enhancement is represented by the gradient blow-up of a solution to the conductivity problem. The bow-tie structure consists of two disjoint bounded domains which have corners with possibly different aperture angles. The domains are parts of cones near the vertices which are nearly touching to each other. We construct functions explicitly which characterize the field enhancement. As consequences, we derive optimal estimates of the gradient in terms of the distance between two inclusions and aperture angles of the corners. The estimates show in quantitatively precise way that the field is enhanced beyond the corner singularities due to the interaction between two inclusions, and the blow-up rate is much higher than the one for the case of inclusions with smooth boundaries.     

CD47 in the Brain and Neurodegeneration: An Update on the Role in Neuroinflammatory Pathways

CD47 is a receptor belonging to the immunoglobulin (Ig) superfamily and broadly expressed on cell membranes. Through interactions with ligands such as SIRPα, TSP-1, integrins, and SH2-domain bearing protein tyrosine phosphatase substrate-1 (SHPS-1), CD47 regulates numerous functions like cell adhesion, proliferation, apoptosis, migration, homeostasis, and the immune system. In this aspect, previous research has shown that CD47 modulates phagocytosis via macrophages, the transmigration of neutrophils, and the activation of T-cells, dendritic cells, and B-cells. Moreover, several studies have reported the increased expression of the CD47 receptor in a variety of diseases, including acute lymphoblastic leukemia (ALL), chronic myeloid leukemia, non-Hodgkin’s lymphoma (NHL), multiple myeloma (MM), bladder cancer, acute myeloid leukemia (AML), Gaucher disease, Multiple Sclerosis and stroke among others. The ubiquitous expression of the CD47 cell receptor on most resident cells of the CNS has previously been established through different methodologies. However, there is little information concerning its precise functions in the development of different neurodegenerative pathologies in the CNS. Consequently, further research pertaining to the specific functions and roles of CD47 and SIRP is required prior to its exploitation as a druggable approach for the targeting of various neurodegenerative diseases that affect the human population. The present review attempts to summarize the role of both CD47 and SIRP and their therapeutic potential in neurodegenerative disorders.     

Monotone strain-stress models for shape memory alloys hysteresis loop and pseudoelastic behaviorx

To describe the behavior of Shape Memory Alloy we use a thermomechanical model, founded on a free energy which is a convex function with respect to the strain and to the martensitic volume fraction, and a concave one with respect to the temperature. The material parameters of the model are experimentally determined.Received: November 26, 2001; revised: March 20, 2002     

4Cr5MoVSi(H11)钢内氧化型渗碳后性能的研究

4Cr5MoVSi(AISI H11)钢在 0.90～1.36％ 碳势下渗碳后,渗碳层组织由马氏体基体及均匀分布着的大量细小的粒状M_7C_3 型碳化物组成,致使H11钢表面硬度高达 HV1200左右,其耐磨性也明显优于 Cr12MoV钢。将 H11钢制成的 M16螺母冷冲头,经 CD渗碳处理后,其使用寿命为 Cr12MoV 钢的 2倍,且失效方式为均匀磨损。H11钢CD 渗碳的动力学受碳在奥氏体中的体积扩散控制。     

Some Primitive Concepts in Continuum Mechanics Regarded in Terms of Objective Space-Time Molecular Averaging: The Key Rôle Played by Inertial Observers

In Continuum Mechanics the notions of body, material point, and motion, are primitive. Here these concepts are derived for any (possibly time-dependent) material system via mass and momentum densities whose values are local spacetime averages of molecular quantities. The averaging procedure necessary to ensure molecular-based densities can be agreed upon by all observers (that is, are objective) has implications for constitutive relations. Specifically, such relations should first be expressed in terms of Galilean-invariant functions of the motion relative to an inertial frame. Thereafter such relations can be re-phrased for general observers, thereby yielding general-frame constitutive relations compatible with material frame-indifference. Two postulates concerning observer agreement (which together constitute a statement of material frame-indifference) are shown to imply that any stress response function which is assumed to depend upon the motion in an inertial (general) frame must be Galilean-invariant (invariant under superposed rigid body motions). Accordingly, invariance under superposed rigid body motions is not a fundamental tenet of continuum physics, but rather a consequence of material frame-indifference whenever constitutive dependence upon motion in a general observer frame is postulated.     

A bifurcation-based decohesion model for simulating the transition from localization to decohesion with the MPM

Based on recent experimental observations on the formation of localization before delamination, a bifurcation-based decohesion approach is proposed in this paper to simulate the transition from localization to decohesion involved in the delamination process of compressed films. The onset and orientation of discontinuous failure are identified from the discontinuous bifurcation analysis. A discrete constitutive model is then formulated based on the bifurcation analysis to predict the evolution of material failure as decohesion or separation of continuum. The Material Point Method, that does not employ fixed mesh-connectivity, is developed as a robust spatial discretization method to accommodate the multi-scale discontinuities involved in the film delamination. To demonstrate the potential of the proposed approach, a parametric study is conducted to explore the effects of aspect ratio and failure mode on the evolution of failure patterns under different boundary conditions, which provides a better understanding on the physics behind the film delamination process.Received: January 16, 2003; revised: August 11, 2003     

Effective elastic moduli and stress concentrator factors in random structure aligned fiber composites

We consider a linearly elastic composite medium, which consists of a homogeneous matrix containing a statistically uniform random set of aligned fibers. Effective elastic moduli as well as the stress concentrator factors in the components are estimated. The micromechanical approach is based on the Green’s function technique as well as on the generalization of the “multiparticle effective field method” (MEFM, see for references, Buryachenko [1]). The refined version of the MEFM takes into account the variation of the effective fields acting on each pair of fibers. The dependence of effective elastic moduli and stress concentrator factors on the radial distribution function of the fiber locations is analyzed. Received: October 20, 2004