A “four-ferrocene” modified stem-loop structure as a probe for sensitive detection and single-base mismatch discrimination of DNA

We report the use of a four-ferrocene modified oligonucleotide as a probe for DNA detection with a gold electrode microsystem. This oligonucleotide is synthesized by automated solid-phase synthesis with four successive ferrocene moieties at the 5′-end and a C6-thiol modifier group at the 3′-end. The grafting of this 4Fc-DNA probe on a gold electrode microsystem results in the appearance of the ferrocene redox couple in cyclic voltammetry. The probe sequence is a stem-loop structure that folds efficiently on the electrode, thus optimizing electron transfer. Such architecture serves as sensor for DNA detection which is based on hybridization. The resulting disposable voltammetric sensor allowed direct, reagentless DNA detection in a small volume (20 μL). Electrochemical response upon hybridization with complementary short sequence (30-base length) and long sequence (50-base length) strands was observed by differential pulse voltammetry. Current variations were compared. The longer the sequence, the greater the decrease in current. The system's detection limit was estimated at 3.5 pM (0.07 fmol in 20 μL) with the 50-base length target and provided a dynamic detection range between 3.5 pM and 5 nM. Single mismatch detection showed a good level of sensitivity. The system was regenerated twice with no significant loss of Fc signal. Finally, 1 pM sensitivity was reached with a long chain analog of DNA PCR products of Influenza virus.     

Shock-Wave Attenuation and Energy-Dissipation Potential of Granular Materials

The propagation of uniaxial-stress planar shocks in granular materials is analyzed using a conventional shock-physics approach. Within this approach, both compression shocks and decompression waves are treated as (stress, specific volume, particle velocity, mass-based internal energy density, temperature, and mass-based entropy density) propagating discontinuities. In addition, the granular material is considered as being a continuum (i.e., no mesoscale features like grains, voids, and their agglomerates are considered). However, while the granular material is treated as a (smeared-out) continuum, it is recognized that it contains a solid constituent (parent matter), and that the structurodynamic properties (i.e., Equations of State (EOS) and Hugoniot relations) of the granular material are related to its parent matter. Three characteristic shock loading regimes of granular material are considered and, in each case, an analysis is carried out to elucidate shock attenuation and energy dissipation processes. In addition, an attempt is made to identify a metric (a combination of the material parameters) which quantifies the intrinsic ability of a granular material to attenuate a shock and dissipate the energy carried by the shock. Toward that end, the response of a typical granular material to a flat-topped compressive stress pulse is analyzed in each of the three shock loading regimes.     

Role of orlistat in the treatment of obese patients with type 2 diabetes. A 1-year randomized double-blind study

OBJECTIVE: Obesity is an important risk factor for type 2 diabetes. Weight loss in patients with type 2 diabetes is associated with improved glycemic control and reduced cardiovascular disease risk factors, but weight loss is notably difficult to achieve and sustain with caloric restriction and exercise. The purpose of this study was to assess the impact of treatment with orlistat, a pancreatic lipase inhibitor, on weight loss, glycemic control, and serum lipid levels in obese patients with type 2 diabetes on sulfonylurea medications. RESEARCH DESIGN AND METHODS: In a multicenter 57-week randomized double-blind placebo-controlled study, 120 mg orlistat or placebo was administered orally three times a day with a mildly hypocaloric diet to 391 obese men and women with type 2 diabetes who were aged > 18 years, had a BMI of 28-40 kg/m2, and were clinically stable on oral sulfonylureas. Changes in body weight, glycemic control, lipid levels, and drug tolerability were measured. RESULTS: After 1 year of treatment, the orlistat group lost 6.2 +/- 0.45% (mean +/- SEM) of initial body weight vs. 4.3 +/- 0.49% in the placebo group (P < 0.001). Twice as many patients receiving orlistat (49 vs. 23%) lost > or = 5% of initial body weight (P < 0.001). Orlistat treatment plus diet compared with placebo plus diet was associated with significant improvement in glycemic control, as reflected in decreases in HbA1c (P < 0.001) and fasting plasma glucose (P < 0.001) and in dosage reductions of oral sulfonylurea medication (P < 0.01). Orlistat therapy also resulted in significantly greater improvements than placebo in several lipid parameters, namely, greater reductions in total cholesterol, (P < 0.001), LDL cholesterol (P < 0.001), triglycerides (P < 0.05), apolipoprotein B (P < 0.001), and the LDL-to-HDL cholesterol ratio (P < 0.001). Mild to moderate and transient gastrointestinal events were reported with orlistat therapy, although their association with study withdrawal was low. Fat-soluble vitamin levels generally remained within the reference range, and vitamin supplementation was required in only a few patients. CONCLUSIONS: Orlistat is an effective treatment modality in obese patients with type 2 diabetes with respect to clinically meaningful weight loss and maintenance of weight loss, improved glycemic control, and improved lipid profile.     

Meso-scale Computational Investigation of Shock-Wave Attenuation by Trailing Release Wave in Different Grades of Polyurea

Over the past several years, considerable research efforts have been made toward investigating polyurea, a segmented thermoplastic elastomer, and particularly its shock-mitigation capacity, i.e., an ability to attenuate and disperse shock-waves. These research efforts have clearly established that the shock-mitigation capacity of polyurea is closely related to its chemistry, processing route, and the resulting microstructure. Polyurea typically possesses a nano-segregated microstructure consisting of (high glass transition temperature, T _g) hydrogen-bonded discrete hard domains and a (low T _g) contiguous soft matrix. While the effect of polyurea microstructure on its shock-mitigation capacity is well-established, it is not presently clear what microstructure-dependent phenomena and processes control its shock-mitigation capacity. To help identify these phenomena and processes, meso-scale simulations of the formation of nano-segregated microstructure and its interaction with a leading shock-wave and a trailing release-wave is analyzed in the present work. The results obtained revealed that shock-induced hard-domain densification makes an important contribution to the superior shock-mitigation capacity of polyurea, and that the extent of densification is a sensitive function of the polyurea soft-segment molecular weight. In particular, the ability of release-waves to capture and neutralize shock-waves has been found to depend strongly on the extent of shock-induced hard-domain densification and, thus, on the polyurea soft-segment molecular weight.     

Effect of grain size on the observed pseudoelastic behavior of a Cu-Zn-Al shape memory alloy

The shape of stress-strain curves for a pseudoelastic copper-based shape memory alloy (SMA) has been found to depend strongly on the grain size-to-sample thickness ratio (gs/t). Previous investigators have attributed this effect to reduced grain constraint in coarse-grain samples. The present investigation further analyzes the grain constraint effect by modeling shape memory alloy stress-strain curves. The model results reveal that varying grain constraint can explain the observed grain size effect on stress-strain curves. Furthermore, detailed consideration of the Taylor factor equivalent for Cu-Zn-Al and NiTi shape memory alloys can explain the opposite curvature of polycrystal stress-strain curves for these two materials. Finally, several indices of grain constraint are analyzed for the Cu-Zn-Al alloy examined in the present investigation and for similar alloys used in previous studies. This evaluation reveals that both transformation modulus and transformation stress correlate with gs/t, and each can be used as an index of grain constraint.     

Hole expansion in a variety of sheet steels

Expanding pierced holes is a common forming practice and problems during these operations are not unusual. A damczyk and Michal have previously developed an equation for maximum hole expansion of HSLA steels, for holes in the sheared then deburred condition. This paper expands the work of the above authors. Nineteen ferritic, ferritic stainless, and austenitic stainless steels were evaluated for hole expansion using various hole-edge conditions. It was found that the behavior of steels having finished holes is very different than those tested in the as-sheared condition. Relationships between hole expansion and tensile-mechanical properties were developed for both conditions.     

Deformation-induced phase transformation and strain hardening in type 304 austenitic stainless steel

Deformation-induced phase transformation in a type 304 austenitic stainless steel has been studied in tension at room temperature and −50 °C. The evolution of transformation products was monitored using X-ray diffraction (XRD) line profile analysis of diffraction peaks from a single XRD scan employing the direct comparison method. Crystallographic texture transitions due to deformation strain have been evaluated using (111) _γ pole figures. The tensile stress-strain data have been analyzed to explain the influence of underlying deformation-induced microstructural changes and associated texture changes in the steel. It is found that the initial stage of rapidly decreasing strain hardening rate in type 304 steel is primarily influenced by hcp ɛ-martensite formation, and the second stage of increasing strain hardening rate is associated with an increase in the α′-martensite formation. The formation of ɛ-martensite is associated with a gradual strengthening of the copper-type texture components up to 15 pct strain and decreasing with further strain at −50 °C. Texture changes during low-temperature deformation not only change the mechanism of ɛ-martensite formation but also influence the strain rate sensitivity of the present steel.     

Synthesis and biological evaluation of potent, selective, hexapeptide CCK-A agonist anorectic agents

Cholecystokinin (CCK) is a 33-amino acid peptide with multiple functions in both the central nervous system (via CCK-B receptors) and the periphery (via CCK-A receptors). CCK mediation of satiety via the A-receptor subtype suggest a role for CCK in the management of obesity. The carboxy terminal octapeptide (CCK-8) is fully active in this regard, but is lacking in receptor selectivity, metabolic stability, and oral bioavailability. Inversion of the chirality of Asp7 in conjunction with N-methylation of Phe8 produces compound 5 which exhibits high affinity and 2100-fold selectivity for CCK-A receptors. Compound 6 (Hpa(SO3H)-Nle-Gly-Trp-Nle-MeAsp-Phe-NH2), derived from moving the N-methyl group from Phe to Asp, decreased CCK-B affinity substantially without affecting CCK-A affinity, giving a compound with 6600-fold selectivity for CCK-A receptors. These compounds inhibit food intake with nanomolar potency following intraperitoneal administration in fasted rats. In addition to greater potency, compound 6 produces weight loss in rats when administered over nine consecutive days. Intranasal administration of 6 potently inhibits feeding in beagle dogs. Compound 6 produces potent anorectic activity via the CCK-A receptor system.     

Cytomegalovirus infection, lipoprotein(a), and hypercoagulability: an atherogenic link?

A link between cytomegalovirus (CMV) infection and atherosclerosis has been suggested by experimental, clinical, and epidemiologic studies. We investigated the association between CMV antibody titers in serum collected in 1974 in 300 adult residents in Washington County, Md, and hemostatic parameters in plasma collected in 1987 through 1989, when these individuals participated in the baseline examination of the Atherosclerosis Risk in Communities Study. The cross-sectional association of CMV serum antibodies and hemostatic parameters was also explored in another set of Atherosclerosis Risk in Communities cases and controls. In the longitudinal analyses, CMV titers in 1974 were directly associated with 1987 through 1989 plasma levels of von Willebrand factor, factor VIII, and protein C and negatively associated with activated partial thromboplastin time. In the cross-sectional analyses, CMV titers were directly related to antithrombin III and fibrinogen levels. When the association between CMV antibodies and atherosclerosis was examined in stratified analyses, a significant association was restricted to individuals with high levels of lipoprotein(a) and fibrinogen. These results are compatible with previous evidence suggesting that CMV virus might have procoagulant properties. The possible synergism of CMV infection and resulting hypercoagulability with reduced fibrinolysis due to increased lipoprotein(a) levels deserves further investigation.