Toxicity of an antitumor ribonuclease to Purkinje neurons

Purkinje cell toxicity is one of the characteristic features of the Gordon phenomenon, a syndrome manifested by ataxia, muscular rigidity, paralysis, and tremor that may lead to death (Gordon, 1933). Two members of the RNase superfamily found in humans, EDN (eosinophil-derived neurotoxin) and ECP (eosinophil cationic protein), cause the Gordon phenomenon when injected intraventricularly into guinea pigs or rabbits. We have found that another member of the RNase superfamily, an antitumor protein called onconase, isolated from Rana pipiens oocytes and early embryos, will also cause the Gordon phenomenon when injected into the cerebrospinal fluid of guinea pigs at a dose similar to that of EDN (LD50, 3-4 micrograms). Neurologic abnormalities of onconase-treated animals were indistinguishable from those of EDN-treated animals, and histology showed dramatic Purkinje cell loss in the brains of onconase-treated animals. The neurotoxic activity of onconase correlates with ribonuclease activity. Onconase modified by iodoacetic acid to eliminate 70% and 98% of the ribonuclease activity of the native enzyme displays a similar decrease in ability to cause the Gordon phenomenon. In contrast, the homologous bovine pancreatic RNase A injected intraventricularly at a dose 5000 times greater than the LD50 dose of EDN or onconase is not toxic and does not cause the Gordon phenomenon. A comparison of the RNase activities of EDN, onconase, and bovine pancreatic RNase A using three pancreatic RNA substrates demonstrates that onconase is orders of magnitude less active enzymatically than EDN and RNase A. Thus, another member of the RNase superfamily in addition to EDN and ECP can cause the Gordon phenomenon.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adenosine Receptor Agonist HE-NECA Enhances Antithrombotic Activities of Cangrelor and Prasugrel in vivo by Decreasing of Fibrinogen Density in Thrombus

Blood platelets’ adenosine receptors (AR) are considered to be a new target for the anti-platelet therapy. This idea is based on in vitro studies which show that signaling mediated by these receptors leads to a decreased platelet response to activating stimuli. In vivo evidence for the antithrombotic activity of AR agonists published to date were limited, however, to the usage of relatively high doses given in bolus. The present study was aimed at verifying if these substances used in lower doses in combination with inhibitors of P2Y₁₂ could serve as components of dual anti-platelet therapy. We have found that a selective A_2A agonist 2-hexynyl-5’-N-ethylcarboxamidoadenosine (HE-NECA) improved the anti-thrombotic properties of either cangrelor or prasugrel in the model of ferric chloride-induced experimental thrombosis in mice. Importantly, HE-NECA was effective not only when applied in bolus as other AR agonists in the up-to-date published studies, but also when given chronically. In vitro thrombus formation under flow conditions revealed that HE-NECA enhanced the ability of P2Y₁₂ inhibitors to decrease fibrinogen content in thrombi, possibly resulting in their lower stability. Adenosine receptor agonists possess a certain hypotensive effect and an ability to increase the blood–brain barrier permeability. Therefore, the effects of anti-thrombotic doses of HE-NECA on blood pressure and the blood–brain barrier permeability in mice were tested. HE-NECA applied in bolus caused a significant hypotension in mice, but the effect was much lower when the substance was given in doses corresponding to that obtained by chronic administration. At the same time, no significant effect of HE-NECA was observed on the blood–brain barrier. We conclude that chronic administration of the A_2A agonist can be considered a potential component of a dual antithrombotic therapy. However, due to the hypotensive effect of the substances, dosage and administration must be elaborated to minimize the side-effects. The total number of animals used in the experiments was 146.     

Synthesis and crosslinking properties of phenolphtalein dimethacrylate

Summary By reacting esterification of phenolphtalein with methacrylate chloride, phenolphtalein dimethacrylate was obtained. Based on the results of elemental analysis, FTIR, ¹H-NMR and ¹³C-NMR spectra, the structure of the product was proposed. The dimethacrylate was used as new crosslinker to crosslink poly(methyl methacrylate) (PMMA). The influence of the amount dimethacrylate on the crosslink density and some properties of the crosslinked polymers networks such as swelling, mechanical properties (tensile strength and elongation at break) and thermal stability were examined.     

Towards language-to-language transformation

This paper proposes a simplicity-oriented approach and framework for language-to-language transformation of, in particular, graphical languages. Key to simplicity is the decomposition of the transformation specification into sub-rule systems that separately specify purpose-specific aspects. We illustrate this approach by employing a variation of Plotkin’s Structural Operational Semantics (SOS) for pattern-based transformations of typed graphs in order to address the aspect ‘computation’ in a graph rewriting fashion. Key to our approach are two generalizations of Plotkin’s structural rules: the use of graph patterns as the matching concept in the rules, and the introduction of node and edge types. Types do not only allow one to easily distinguish between different kinds of dependencies, like control, data, and priority, but may also be used to define a hierarchical layering structure. The resulting Type-based Structural Operational Semantics (TSOS) supports a well-structured and intuitive specification and realization of semantically involved language-to-language transformations adequate for the generation of purpose-specific views or input formats for certain tools, like, e.g., model checkers. A comparison with the general-purpose transformation frameworks ATL and Groove, illustrates along the educational setting of our graphical WebStory language that TSOS provides quite a flexible format for the definition of a family of purpose-specific transformation languages that are easy to use and come with clear guarantees.

     

Properties of diagnostic data distributions

In applications of statistical methods to medical diagnosis, information on patients' diseases and symptoms is collected and the resulting data-base is used to diagnose new patients. The data-structure is complicated by a number of factors, two of which are examined here: selection bias and unstable population. Under reasonable conditions, no correction for selection bias is required when assessing probabilities for diseases based on symptom information, and it is suggested that these "diagnostic distributions" should form the principal object of study. Transformation of these distributions under changing population structure is considered and shown to take on a simple form in many situations. It is argued that the prevailing paradigm of diagnostic statistics, which concentrates on incidence of symptoms for given disease, is largely inappropriate and should be replaced by an emphasis on diagnostic distributions. The generalized logistic model is seen to fit naturally into the new framework.     

Neutron poison distribution in the central reflector to reduce the DLOFC temperature of a Th-LEU fueled OTTO PBMR DPP-400 core

In a previous study using a mixture of thorium and 20 a/o% LEU at 16 gram per fuel sphere heavy metal loading and adjusting the effective fuel enrichment to produce the same amount of cumulative energy per fuel sphere as with the 10 a/o% Low Enriched Uranium (LEU), the maximum Depressurized Loss Of Forced Cooling (DLOFC) temperature was reduced from 2273 to 1925 °C and 1811 °C for a symmetric and asymmetric core, respectively using an once-through-then-out (OTTO) fuelling scheme. This article presents an additional strategy for reducing the maximum DLOFC temperature by placing an optimized distribution of neutron poisons in the central reflector. This strategy produced maximum DLOFC temperatures of 1509 and 1448 °C for the symmetric and the asymmetric cores, respectively. These results are impressive as it means that the less complicated OTTO cycle with its lower capital cost achieved the same cumulative energy produced per fuel sphere than the standard six-pass refuelling scheme and that at substantially lower maximum DLOFC temperatures. Both the addition of the neutron poisons to the central reflector and the creation of a radially asymmetric core resulted in lower burn-ups that had to be reversed by increasing the enrichment of the fuel.     

Using thorium to reduce the maximum fuel temperatures during depressurized loss of coolant accidents in a once-through-then-out (OTTO) PBMR DPP-400 core

This article presents the results for the PBMR-DPP-400, but for a once-through-then-out (OTTO) refueling scheme. An optimization attempt of the axial and radial power profiles is reported. The main aim was to reduce the maximum depressurized loss of forced coolant (DLOFC) temperature by adding thorium to the fuel and making the fuel layout radially asymmetric by placing lower enriched fuel in the inner and higher enriched fuel in the outer fuel flow regions. These measures (1) flattened the peaks in the axial power profiles and thus suppressed the hotspots in the axial DLOFC temperature profiles and (2) ‘pushed’ the power radially outwards, so as to reduce the distance that the decay heat must be evacuated towards the outside of the fuel core. This resulted in a huge reduction in the maximum DLOFC temperature for the OTTO cycle from 2273 to 1811 °C, which is still above the 1600 °C limit but represents a remarkable result. Maximum DLOFC temperature below the 1600 °C limit was obtained by reducing the power output. The results obtained and the proposed strategies for further improvement are applicable to the Chinese HTR-PM and could produce even better results in Prismatic Block Reactors such as the Japanese HTTR.     

Formulation and technology research of new silver solder with flux covering

In their eutectic compositions, Au–Si alloys have a melting point of 369°C, and a colour similar to that of high-grade gold. Results of the manufacture of gold alloys with 2.5%, 2.8% and 3.0% silicon, by means of melting in a plasma furnace with an inert argon atmosphere, are presented in this study. Chemical composition characterisation was carried out by energy dispersion spectroscopy and wave dispersion spectrometry, and metallographic and microstructural analysis by optical microscopy, SEM and DRX, Vickers hardness and mircohardness testing, melting point evaluation by DSC and determination of the SCIELab colorimetric coordinates. The results of the hardness and micro-hardness testing gave values around 110HV, presenting an important increase in the mechanical properties with respect to the traditional high purity gold alloys. The melting temperature for the alloys was around 374°C as well as being a heat very close to the values of pure gold.