A Potent Mimetic of the Siglec-8 Ligand 6’-Sulfo-Sialyl Lewisx

Siglecs are members of the immunoglobulin gene family containing sialic acid binding N-terminal domains. Among them, Siglec-8 is expressed on various cell types of the immune system such as eosinophils, mast cells and weakly on basophils. Cross-linking of Siglec-8 with monoclonal antibodies triggers apoptosis in eosinophils and inhibits degranulation of mast cells, making Siglec-8 a promising target for the treatment of eosinophil- and mast cell-associated diseases such as asthma. The tetrasaccharide 6’-sulfo-sialyl Lewis^x has been identified as a specific Siglec-8 ligand in glycan array screening. Here, we describe an extended study enlightening the pharmacophores of 6’-sulfo-sialyl Lewis^x and the successful development of a high-affinity mimetic. Retaining the neuraminic acid core, the introduction of a carbocyclic mimetic of the Gal moiety and a sulfonamide substituent in the 9-position gave a 20-fold improved binding affinity. Finally, the residence time, which usually is the Achilles tendon of carbohydrate/lectin interactions, could be improved.     

Massively parallel algorithms for trace-driven cache simulations

Considers the use of massively parallel architectures to execute a trace-driven simulation of a single cache set. A method is presented for the least-recently-used (LRU) policy, which, regardless of the set size C, runs in time O(log N) using N processors on the EREW (exclusive read, exclusive write) parallel model. A simpler LRU simulation algorithm is given that runs in O(C log N) time using N/log N processors. We present timings of this algorithm's implementation on the MasPar MP-1, a machine with 16384 processors. A broad class of reference-based line replacement policies are considered, which includes LRU as well as the least-frequently-used (LFU) and random replacement policies. A simulation method is presented for any such policy that, on any trace of length N directed to a C line set, runs in O(C log N) time with high probability using N processors on the EREW model. The algorithms are simple, have very little space overhead, and are well suited for SIMD implementation     

Cardiorespiratory effects of conventional and high frequency ventilation in rabbits with bilateral pneumothoraces and surfactant depleted lungs

We compared high frequency ventilation (HFV) to conventional mechanical ventilation (CMV) under normoxic and normocapnic condition in surfactant depleted rabbits with bilateral pneumothoraces. We hypothesized that lower airway pressures would be required with HFV under these conditions. We applied CMV and HFV in 8 anaesthetized rabbits with a prototype ventilator at frequencies of 30, 100, 200, and 300 cycles/min. A positive end-expiratory pressure (PEEP) just below the pressure sufficient to open the air leak from the pneumothoraces was applied at all frequencies. Airway pressures, gas exchange, heart rate, and mean arterial pressure were recorded. Peak airway pressure decreased significantly from 2.50 to 2.10 kPa when the frequency of ventilation was increased from 30 to 300 cycles/min. There were no significant changes in mean airway pressure, PaO2, arterial pH, heart rate, and mean arterial pressure when HFV was compared to CMV. In conclusion, during HFV peak airway pressures measured at the mouth were decreased. Our ability to maintain adequate gas exchange in the face of ongoing pulmonary air leaks may reflect lower alveolar pressures.     

Automated Parallelization of Discrete State-Space Generation

We consider the problem of generating a large state-space in a distributed fashion. Unlike previously proposed solutions that partition the set of reachable states according to a hashing function provided by the user, we explore heuristic methods that completely automate the process. The first step is an initial random walk through the state space to initialize a search tree, duplicated in each processor. Then, the reachability graph is built in a distributed way, using the search tree to assign each newly found state to classes assigned to the available processors. Furthermore, we explore two remapping criteria that attempt to balance memory usage or future workload, respectively. We show how the cost of computing the global snapshot required for remapping will scale up for system sizes in the foreseeable future. An extensive set of results is presented to support our conclusions that remapping is extremely beneficial.     

From information to probability: An axiomatic approach—Inference is information processing

We define the very rich language of composed conditionals on a three‐valued logic and use this language as the communication tool between man and machine. Communication takes place for three reasons: knowledge acquisition, query, and response. Learning, thinking, and answering questions are of a pure information theoretical nature. The pivot of this knowledge processing concept is the amount of information (bit) we receive if a conditional becomes true. We follow an axiomatic approach to information theory rather than the classical probabilistic approach of Shannon; information comes first, and then comes probability. In the light of this philosophy, query and response experience new interpretations. Both, acquisition and response are realized by maximizing entropy and minimizing relative entropy, respectively. The iterative solution of these mathematical optimization problems gives new insights into the adaptation of prior knowledge to new information. Our expert system shell SPIRIT supports this kind of knowledge processing, which will be established by suitable examples. © 2003 Wiley Periodicals, Inc.     

Some aspects of the electrochemistry of the flotation of pyrrhotite

The iron sulfide mineral, pyrrhotite (Fe_(1–x)S), has long been known to be more difficult to recover by flotation from alkaline slurries than many other base metal sulfide minerals. This paper summarizes the results of an electrochemical study of the surface reactions that occur during the flotation of nickeliferous pyrrhotite in the recovery of nickel and the platinum group metals. Mixed potential measurements conducted with natural pyrrhotite electrodes in various stages of an operating flotation plant showed that the mineral potential is positive to the equilibrium potential of the xanthate/dixanthogen couple. Similar results were obtained during batch flotation experiments and in synthetic solutions in the laboratory. Cyclic voltammetric and potentiostatic current/time transient experiments were used to investigate the oxidation of pyrrhotite under various conditions. In addition, the reduction of oxygen, the reaction of copper ions and the oxidation of xanthate ions at the mineral surface were investigated. The formation of dixanthogen on pyrrhotite surfaces is thermodynamically favourable in plant flotation slurries. However the interaction with xanthate at pH values above 7 is inhibited by a surface species formed during the conditioning prior to xanthate addition. In acidic solutions copper ions react readily with pyrrhotite to form a species, possibly CuS that can be oxidized at potentials above 0.4 V. At pH 9 this species does not form and there is no electrochemical reaction between pyrrhotite and copper ions. The beneficial effects of copper ions to flotation performance appear to be related to an enhancement of the oxidation of xanthate.     

Using artificial intelligence to model heavy plate mill rolling

This research summary discusses the application of neural networks, evolutionary strategies, and other artificial intelligence techniques in the modeling and optimization of the models used for temperature, rolling force, and torque calculation in heavy plate milling.     

Cathodic processes in the leaching and electrochemistry of covellite in mixed sulfate–chloride media

The cathodic processes that occur on a covellite (CuS) surface in mixed sulfate–chloride solutions in the absence and presence of copper(II) ions have been studied using potentiostatic transients and cyclic voltammetry at rotating disk electrodes in the potential range 0.3–0.7 V (versus SHE). This range is relevant to the oxidative leaching of this copper mineral in sulfate and chloride lixiviants. Variations in the concentrations of sulfate and chloride ions had a small effect on the cathodic reduction of covellite in the potential range of 0.5–0.3 V, although the presence of chloride ion resulted in a significant increase in the anodic current on the reverse sweep. On the other hand, addition of copper(II) ions resulted in enhanced cathodic currents and subsequent anodic currents in both sulfate and chloride solutions due to reduction of covellite to an undefined reduced copper sulfide species. Reduction of copper(II) to copper(I) ions becomes the preferred cathodic reaction as the concentration of chloride ions increases, becoming mass transport controlled at a rotating disc electrode at potentials below about 0.4 V. Potentiostatic measurements at potentials negative to the mixed potential in acidic chloride solutions have shown that reduction of copper(II) ions is reversible and have been used to estimate the rate of oxidative dissolution of the mineral which value agrees reasonably well with previously reported leaching rates under similar conditions. Reduction of dissolved oxygen has been found to be very much slower that that of copper(II) ions under ambient conditions.