Predetermined Breaking Points Research Articles

On-The-Fly Path Reduction

Path reduction is a well-known technique to alleviate the state-explosion problem incurred by explicit-state model checking, its key idea being to store states only at predetermined breaking points. This paper presents an adaptation of this technique which detects breaking points on-the-fly during state-space generation. This method is especially suitable for the detection of breaking points in systems where static analyses yield coarse over-approximations. We evaluate the effectiveness of this technique by applying it to binary code verification.

Abstract 4436: Biological evaluation of folate prodrugs with a highly toxic derivative of doxorubicin

Abstract Folic acid is itself not biologically active but it is essential for the proliferation of cells. Cellular uptake of folate in the body is primarily mediated by the folate receptor (FR), a membrane-bound protein for which three isomers have been identified. The isomer FR-α is highly over-expressed in many human tumors. Since FR-α has a high affinity for binding and transporting physiologic levels of folic acid into cells, coupling a drug through a cleavable linker to folic acid can yield a prodrug that can be delivered inside tumor cells. Many studies have focused on reducible or acid-sensitive based linkers that are cleaved in the endosomes and/or cytoplasm. For the development of new folate receptor-targeted prodrugs, the highly active doxorubicin derivative N-(5,5-diacetoxybut-1-yl)doxorubicin was chosen to avoid potential saturation of the folate receptor. This acyclic doxorubicin diacetate undergoes an ester-mediated hydrolysis producing 2-pyrrolinodoxorubicin that is 500-1000 times more active than doxorubicin. Two prodrugs were designed to contain an acid-sensitive hydrazone bond (1) or in addition a disulfide bond (2) in order to elucidate the importance of the pre-determined breaking point for their in vitro and in vivo activity. In a 24h MTT assay, 1 was 5-fold more active than 2 in folate-positive KB cells in the nanomolar range whereas no activity was observed in the folate-negative A549 lung cancer cells, an observation that correlated well with the uptake of 1 and 2 in fluorescence microscopy studies. In subsequent in vivo studies in the folate-positive KB model, 1 was as active as the free drug but significantly less toxic when dosed at twice the dose of the free drug whereas 2 showed no anticancer efficacy. As an explanation, we could show by HPLC that prodrug 2 that additionally contains a disulfide bond undergoes rapid disulfide exchange in murine and human plasma in the order of 40% after 5 h at 37°C in contrast to 1 which was essentially stable after a 5 h incubation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4436. doi:10.1158/1538-7445.AM2011-4436

Photoinhibition: molecular mechanisms and physiological significance

Photoinhibition: molecular mechanisms and physiological significance

Biomechanical properties of aquatic plants and their effects on plant–flow interactions in streams and rivers

We analysed the biomechanical properties of aquatic plant stems of four common submerged river macrophyte species with bending, tension and cyclic loading/unloading tests and related these properties to the hydraulic habitats of the plants. The studied species included Glyceria fluitans, Ranunculus penicillatus, Myriophyllum alterniflorum and Fontinalis antipyretica. Habitat assessment shows that these species occur in a range from low to high flow velocities, respectively. G. fluitans is a semi-aquatic species with stems of a high flexural rigidity and high breaking force and breaking stress that enable them to carry their own weight and balance gravity when growing upright in slow flowing rivers. G. fluitans may also grow horizontally often producing emerged terrestrial stems. In contrast, F. antipyretica grows in fierce water flow. Its stems have the highest flexibility, a significantly higher ‘tension’ Young’s modulus, breaking stress and work of fracture and a lower plastic deformation compared to M. alterniflorum and R. penicillatus. These traits enable F. antipyretica to survive even in swift flowing streams and constrict the growth of M. alterniflorum and R. penicillatus to the river reaches with moderate flow velocities. R. penicillatus has a weak bottom part with a low breaking force and breaking stress acting as a predetermined breaking point and enabling seasonal regrowth from root parts.

Using Thin Film Stress for Nanoscaled Sensors

Thin film stress is often seen as an unwanted effect in micro- and nanostructures. Since recent years, we could employ thin film stress as a useful tool to create nanowires. By creating stress at predetermined breaking points, e.g., in microstructured photo resist thin films, cracks occur on the nanoscale in a well defined and reproducible manner [ ]. By using those as a simple mask for thin film deposition, nanowires can be created. More recently this fabrication scheme could be improved by utilizing delamination of the thin film, in order to obtain suitable shadow masks for thin film deposition in vacuum [ ]. Now, these stress based nanowires can be integrated in microelectronic devices and used as field effect transistors or as hydrogen sensors [ ]. For the functional part of the sensor, it was proposed that thin film stress created by hydrogen adsorption in the nanowire is the driving force. In terms of function, thin films can be also applied on free standing nanoscale whiskers or wires to modify their mechanical features or adding additional functionality. As a second example for the utilization of thin film stress, recent experiments on a piezoelectric and magnetostrictive material combination will be presented. These piezoelectric-magnetostrictive nano-composites are potential candidates for novel magnetic field sensors [ ]. In these composites the magnetostriction will be transferred to the piezoelectric component, resulting in a polarization of the piezoelectric material, that can be used as the sensor signal. The results of two different composite layouts will be presented and discussed with a special focus on the comparison between classical macroscopic composites and the novel nanocomposites.

Primäre Alloarthroplastik des frakturierten Ellenbogens beim hochbetagten Patienten

Inadequate treatment of distal intra-articular fractures of the humerus results in painful restriction of movement or malarticulation. Especially in geriatric patients with osteoporosis, stable osteosynthesis can be difficult. Primary total endoprosthetic replacement of the cubital joint could offer an alternative. In 12 patients with a distal intra-articular fracture of the humerus a cemented semi-constrained Coonrad-Morrey prosthesis was implanted. Patient were followed-up after an average of 13 months and assessed according to the Mayo score. In 6 patients additional computerized tomography was carried out. Minimally invasive Kirschner wire osteosynthesis resulted in immediate postoperative loss of correction due to osteoporosis. As with the external distraction-compression apparatus the ulnar pinholes can form a predetermined breaking point and fixation in a long-arm cast is recommended. The mean Mayo score was 90.5 points and mean range of motion in extension/flexion was 84.5 degrees. In elderly patients primary endoprosthetic treatment of a distal intra-articular fracture of the humerus with a semi-constrained cemented prosthesis may offer an alternative to osteosynthesis thus enabling creation of a mobile, painless and stable cubital joint.

Palladium-, Platin- und Dieisenkomplexe mit Isocyanacetat: Ringschluß, säureinduzierte Ringöffnung, Diprotonierung

Palladium, Platinum, and Diiron Complexes with Isocyanoacetate: Ring Closure, Acid-Induced Ring Opening, Diprotonation Substitution by isocyanoacetate (CNCH2CO2−) of one chloro ligand in trans-[MCl2(PPh3)2] (M = Pd, Pt) results in the Δ2-oxazolin-5-on-2-ato complexes 4a, b, i.e. immediate cyclization occurs in contact with these metal(II) species. In contrast, the open-chain form of the functional isocyanide is retained in [K(18-crown-6][Fe2Cp2(CNCH2CO2)(CO)3] (16) in which it occupies a terminal position. Protonation (alkylation) of the platinum complex 4b proceeds with ring cleavage and formation of isocyano acetic acid 11 (ethyl isocyanoacetate 12) stabilized by metal ion coordination. Protonation of 16 requires two equivalents of acid to yield the aminocarbyne-bridged complex [{μ-C=N(H)CH2CO2H}Fe2Cp2(CO)3](BF4) (17) as the only isolable product. Here isocyanoacetate displays a third kind of reactivity pattern in addition to that at PdII/PtII and that at Cr0/W0 where the primary species [M(CO)5CNCH2CO2]− and [M(CO)5CNCH2CO2H] proved to be the most stable. All of the proposed structures are substantiated by analytical and the usual spectroscopic (IR, NMR{1H, 13C, 31P}, FAB-MS) data, that of 4b also by an X-ray structure determination which reveals a practically perpendicular arrangement of the coordination and the ring plane, and a long C2-O bond as the predetermined breaking point of the heterocycle.

Copulatory mechanism in a sexually cannibalistic spider with genital mutilation (Araneae: Araneidae: Argiope bruennichi)

Genitalia are among the fastest evolving morphological traits as evidenced by their common function as diagnostic traits in species identification. Even though the main function of genitalia is the successful transfer of spermatozoa, the presence of diverse structures that are obviously not necessary for this suggests that genitalia are a target of sexual selection. The male genitalia of many spider species are extremely complex and equipped with numerous sclerites, plates and spines whose functions are largely unknown. Selection on male genitalia may be particularly strong in sexually cannibalistic spiders, where mating success of males is restricted to a single female. We investigated the copulatory mechanism of the sexually cannibalistic orb weaving spider Argiope bruennichi by shock freezing mating pairs and revealed a complicated interaction between the appendices and sclerites that make up the male gonopods (paired pedipalps). The plate that covers the female genital opening (scape) is secured between two appendices of the male genital bulb, while three sclerites that bear the sperm duct are unfolded and extended into the female copulatory opening. During copulation, females attack and cannibalise the male and males mutilate their genitalia in about 80% of cases. Our study demonstrates that (i) genital coupling is largely accomplished on the external part of the female genitalia, (ii) that the mechanism requires an interaction between several non-sperm-transferring structures and (iii) that there are two predetermined breaking points in the male genitalia. Further comparative work on the genus Argiope will test if the copulatory mechanism with genital mutilation indeed is an adaptation to sexual cannibalism or if cannibalism is a female counter adaptation to male monopolisation through genital plugging.

Synthesis, characterisation and degradability of polyamides derived from aldaric acids and chain end functionalised polydimethylsiloxanes

Activated glucaric and galactaric acid derivatives were reacted with two different α,ω-diaminoalkyl polydimethylsiloxanes to give novel carbohydrate-segmented silicone polyamides, which were characterised by spectroscopic methods. Their intrinsic viscosities, Huggins constants, molecular weights and thermal properties have been determined by viscosimetric analysis, size exclusion chromatography, differential scanning calorimetry and thermal gravimetric analysis, respectively. Due to the immiscibility of carbohydrates and silicones, some of the presented materials demonstrate strong microphase separation with T gs up to 144 °C. It could be shown, that galactaric acid segmented silicones display a higher T g than their glucaric acid analogues. By varying the contents of glucaric and galactaric acid in a homologous series, which was dominated by cyclic products, as could be shown by MALDI TOF MS, the observed DSC signals could be shifted between 28 and 54 °C. In a first test on biodegradability, employing Proteinase XIV from Streptomyces griseus, it could be shown that this class of materials can be at least partly degraded by enzymes, with the amide bond functioning as a predetermined breaking point.

Irradiation Sensitivity of Self-Assembled Monolayers with an Introduced “Weak Link”

The irradiation sensitivity of n-alkanethiolate SAMs can be enhanced by the incorporation of an irradiation-sensitive functionality as a predetermined breaking point into the alkyl chain. Following this general strategy, several different sulfur-derived functional entities with a variable position in the alkyl chain were tested. In some cases, the incorporation of these entities resulted in a noticeable enhancement of the irradiation-induced desorption (by about 30%), even though the chains were not exclusively cut at the position of the incorporated group, but the scission events related to the "weak links" were just added to those in the alkyl matrix. The position of the incorporated group along the alkyl chain was found to be most essential for its performance as a weak link; the enhancement of irradiation-induced desorption was observed only when the groups were placed close to the SAM-ambient interface.

In vitro and in vivo Efficacy of Acid-Sensitive Transferrin and Albumin Doxorubicin Conjugates in a Human Xenograft Panel and in the MDA-MB-435 Mamma Carcinoma Model

Acid-sensitive transferrin and albumin conjugates with doxorubicin have recently been developed with the aim of circumventing the systemic toxicity and improving the therapeutic efficacy of this anticancer agent. The in vitro activity of two acid-sensitive transferrin and albumin doxorubicin conjugates and free doxorubicin was evaluated in twelve human tumour xenografts using a clonogenic assay. The inhibitory effects and the activity profile of the conjugates was, in general, comparable to that of doxorubicin (mean IC70-value for doxorubicin ≈ 0.1 μM and 0.1 – 0.4 μM for the conjugates). Subsequently, the efficacy of an acid-sensitive transferrin and albumin doxorubicin conjugate, which both incorporated a phenylacetyl hydrazone bond as a predetermined breaking point, was evaluated in the xenograft mamma carcinoma model MDA-MB-435 in comparison to free doxorubicin (dose, i.v.: 2 × 4, 8 and 12 mg/kg). The conjugates showed significantly reduced toxicity (reduced lethality and body weight loss) with a concomitantly stable or slightly improved antitumour activity compared to free doxorubicin. At the dose of 12 mg/kg mortality was unacceptably high in the doxorubicin treated group (≈80%); in contrast, no mortality was observed with the conjugate treated animals with body weight loss < 10 %. In a further experiment, therapy with the acid-sensitive doxorubicin albumin conjugate at 3 × 12 mg/kg in the MDA-MB-435 model resulted in a significantly improved antitumour activity over free doxorubicin at its optimal dose of 2 × 8 mg/kg. In conclusion, acid-sensitive transferrin and albumin doxorubicin conjugates can be administered at higher doses than free doxorubicin in nude mice models with a concomitant improvement in antitumour activity. Interestingly, there is no pronounced difference between identically constructed transferrin and albumin doxorubicin conjugates with regard to in vitro or in vivo efficacy.