Hierarchical tensile structures with ultralow mechanical dissipation.

Structural hierarchy is found in myriad biological systems and has improved man-made structures ranging from the Eiffel tower to optical cavities. In mechanical resonators whose rigidity is provided by static tension, structural hierarchy can reduce the dissipation of the fundamental mode to ultralow levels due to an unconventional form of soft clamping. Here, we apply hierarchical design to silicon nitride nanomechanical resonators and realize binary tree-shaped resonators with room temperature quality factors as high as 7.8 × 108 at 107 kHz frequency (1.1 × 109 at T = 6 K). The resonators' thermal-noise-limited force sensitivities reach 740 zN/Hz1/2 at room temperature and 90 zN/Hz1/2 at 6 K, surpassing state-of-the-art cantilevers currently used for force microscopy. Moreover, we demonstrate hierarchically structured, ultralow dissipation membranes suitable for interferometric position measurements in Fabry-Pérot cavities. Hierarchical nanomechanical resonators open new avenues in force sensing, signal transduction and quantum optomechanics, where low dissipation is paramount and operation with the fundamental mode is often advantageous.

Fractal-like Mechanical Resonators with a Soft-Clamped Fundamental Mode.

Self-similar structures occur naturally and have been employed to engineer exotic physical properties. We show that acoustic modes of a fractal-like system of tensioned strings can display increased mechanical quality factors due to the enhancement of dissipation dilution. We describe a realistic resonator design in which the quality factor of the fundamental mode is enhanced by as much as 2 orders of magnitude compared to a simple string with the same size and tension. Our findings can open new avenues in force sensing, cavity quantum optomechanics, and experiments with suspended test masses.

Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor.

BACKGROUND AND PURPOSE: DF 2156A is a new dual inhibitor of IL-8 receptors CXCR1 and CXCR2 with an optimal pharmacokinetic profile. We characterized its binding mode, molecular mechanism of action and selectivity, and evaluated its therapeutic potential. EXPERIMENTAL APPROACH: The binding mode, molecular mechanism of action and selectivity were investigated using chemotaxis of L1.2 transfectants and human leucocytes, in addition to radioligand and [(35) S]-GTPγS binding approaches. The therapeutic potential of DF 2156A was evaluated in acute (liver ischaemia and reperfusion) and chronic (sponge-induced angiogenesis) experimental models of inflammation. KEY RESULTS: A network of polar interactions stabilized by a direct ionic bond between DF 2156A and Lys(99) on CXCR1 and the non-conserved residue Asp(293) on CXCR2 are the key determinants of DF 2156A binding. DF 2156A acted as a non-competitive allosteric inhibitor blocking the signal transduction leading to chemotaxis without altering the binding affinity of natural ligands. DF 2156A effectively and selectively inhibited CXCR1/CXCR2-mediated chemotaxis of L1.2 transfectants and leucocytes. In a murine model of sponge-induced angiogenesis, DF 2156A reduced leucocyte influx, TNF-α production and neovessel formation. In vitro, DF 2156A prevented proliferation, migration and capillary-like organization of HUVECs in response to human IL-8. In a rat model of liver ischaemia and reperfusion (I/R) injury, DF 2156A decreased PMN and monocyte-macrophage infiltration and associated hepatocellular injury. CONCLUSION AND IMPLICATIONS: DF 2156A is a non-competitive allosteric inhibitor of both IL-8 receptors CXCR1 and CXCR2. It prevented experimental angiogenesis and hepatic I/R injury in vivo and, therefore, has therapeutic potential for acute and chronic inflammatory diseases.

Targeting C5a: recent advances in drug discovery.

Activation of complement via the innate and adaptive immune system is vital to the body's defences in fighting infections. Unregulated complement activation is likely to play a crucial role in the pathogenesis of several diseases including psoriasis, adult (acute) respiratory distress syndrome (ARDS), bullous pemphigoid (BP), rheumatoid arthritis (RA) and ischemia-reperfusion (I/R) injury. The 74 amino acid peptide C5a is released after complement activation at sites of inflammation and is a potent chemoattractant for neutrophils, basophils, eosinophils, leukocytes, monocytes and macrophages. Recombinant proteins and humanized anti-C5 antibodies have been recently developed for blocking specific proteins of the complement system bringing renewed attention towards complement inhibition. Pharmacological studies have been highlighting the complement fragment C5a as an interesting target for the management of complement mediated diseases. Specific inhibition of C5a biological activity could gain therapeutic benefit without affecting the protective immune response. In the last few years several peptide and non-peptide antagonists of C5a have been discovered and tested in relevant pharmacological models; the availability of orally active compounds is rapidly helping to delineate the precise role of C5a in immunoinflammatory disorders. Moreover, mutagenesis data for the C5a/C5a receptor (C5aR) couple make C5aR a valuable model for mechanistic studies of peptidergic G-protein coupled receptors (GPCRs). The aim of this review is to outline the recent advances in C5a inhibition, especially highlighting the value of a multidisciplinary integrated approach in drug discovery.

Carotid artery lesions in patients with nondiabetic chronic renal failure.

Atherosclerotic complications are the leading cause of death in chronic renal failure (CRF) patients. Therefore, we wished to investigate the prevalence of carotid artery lesions (CALs) in these subjects. Two groups were evaluated by high-resolution echo Doppler: group 1 included 103 patients (68 males and 35 females) affected by nonnephrotic CRF and group 2 included 100 control subjects (60 males and 40 females). The prevalence of hypertension was 84% in both groups. The exclusion criteria included diabetes mellitus and symptoms of cerebrovascular disease. In the two groups we evaluated clinical history, physical examination, total cholesterol, triglycerides, fibrinogen, blood cell counts, blood urea nitrogen, creatinine, 24-hour proteinuria, and urine analysis. In group 1 patients the following lipid profile parameters were also evaluated: low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, lipoprotein(a), ApoAI, ApoAII, and ApoB. Group 1 had higher triglycerides and fibrinogen than group 2. A lower body mass index was found in group 1 than in group 2. The prevalence of CALs was significantly higher in the CRF patients than in the control subjects (62% v 47%; P = 0.04). The difference between the two groups was more striking among normotensive patients (62% v 19%; P = 0.03). All CRF patients affected by peripheral arterial disease and 86% of those having coronary artery disease had associated CALs. In CRF patients the severity of CALs was positively correlated to age, white blood cell count, triglycerides, and fibrinogen. Nondiabetic CRF patients have a higher prevalence of carotid artery lesions than control subjects. Several factors besides hypertension, including lipids, blood coagulation, and leukocytes, could contribute to the accelerated atherosclerosis of CRF patients.

Determination of residual aromatic amine hydrochlorides in process samples of di-isocyanate used in the manufacture of polyurethane A comparison of electroanalytical methods.

Aromatic diamine hydrochlorides have been determined in the presence of different amounts of hydrochloric acid by acid-base titration followed potentiometrically, by linear sweep voltammetry, by differential pulse voltammetry and also by direct DPV measurement. Tests on simulated and production samples have shown that the best results are obtained by using DPV at a mercury electrode, because of its good resolution, which makes it possible to achieve good accuracy (error < - 1 %) and good precision (rsd 1.5%) at 0.1M levels. Moreover, it has the advantage that neither preliminary treatment of the sample nor a trial titration is required.

Influence of spasmolytic treatment and amniotomy on delivery times: a factorial clinical trial.

In a double-blind factorial clinical trial in 300 patients (150 primiparae and 150 multiparae), the effects of amniotomy, rociverine, and butylscopolamine bromide administration on the course of labor were investigated. Rociverine significantly reduced the dilatation time and had no effect on the delivery time. Butylscopolamine bromide had no appreciable effect on the dilatation and expulsion times. Amniotomy resulted in a lengthening of the dilatation time and no significant change in the expulsion time.

[Establishment, characteristics and experience of an abortion clinic]. / Istituzione, caratteristiche ed esperienza di un servizio per l'interruzione volontaria di gravidanza.

PIP: Abortion became legal in Italy in May 1978; since then the abortion services at the Institute of Obstetrics and Gynecology of the University of Bologna, Italy were able to comply with over 90% of requests for abortion; waiting time between the presentation of the request and the intervention is usually 7 days. Abortion seekers are treated on an outpatient basis; only 1.7% of patients require hospitalization. Only 6 interventions a day are done by the same doctor, who performs abortions 20 days/month. The choice of anesthesia is left to the patient, and abortion is done by vacuum aspiration. The patients are checked prior to discharge, and contraception is discussed and the patient is invited to come back after 1 month. Between June 1978 and September 1979 there were 1852 interruptions of pregnancy. 52.7% of women receive their certificate for abortion at one of the public family health centers, and only 33.4% by a private doctor. The majority of interventions takes place before the 11th week of pregnancy; 33.6% first pregnancies, and only a very limited number of requests are for medical reasons. Most women are in the age group 21-30, 40% are unmarried, most belong to the low middle class, 17.3% are students, and most come from Bologna. 41.6% of women have no children, 27.4% have 1 child, 22.3% have 2 children, and only 8.7% have more than 2 children. Clearly, at least from this study, the choice of abortion is a very conscious one, and it shows that women choose to become mothers only when they so desire.^ieng