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.     

Surveillance after colorectal cancer surgery

Early diagnosis of local and distant recurrences of colorectal cancer remains difficult and there is no agreement on the effectiveness of follow-up in these patients. The aim of this study is to assess the value of our method of follow-up. We consider 239 patients with colorectal cancer and at least 2 years follow-up following radical resection. A local recurrence appeared in 26 patients (10.9%), a distant metastasis in 41 (17.1%), while in seven (2.9%) local and distant recurrences appeared simultaneously. Local recurrence was detected because of an increase in carcinoembryonic antigen (CEA) level in 15 patients (57.7%), during a scheduled endoscopy in four (15.4%) and because of symptoms in seven (26.9%). In seven patients (26.9%) a radical resection was possible. Distant metastases were detected by CEA levels in 20 patients (48.8%), by ultrasonography (U.S.) in 12 (29.3%) and by chest X-ray in five (12.2%). In 13 of 26 patients with liver metastases a resection was performed. This study shows that few patients benefit from follow-up and only CEA levels and liver U.S. performed intensively between 15 and 36 months after surgery are useful in early detection of recurrences. A modification of the follow-up to the single patient, according to the stage, location and grading of cancer, could improve the results, so lowering the costs of this expensive practice.     

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.     

Selective interactions among the multiple connexin proteins expressed in the vertebrate lens: the second extracellular domain is a determinant of compatibility between connexins

Gap junctions are collections of intercellular channels composed of structural proteins called connexins (Cx). We have examined the functional interactions of the three rodent connexins present in the lens, Cx43, Cx46, and Cx50, by expressing them in paired Xenopus oocytes. Homotypic channels containing Cx43, Cx46, or Cx50 all developed high conductance. heterotypic channels composed of Cx46 paired with either Cx43 or Cx50 were also well coupled, whereas Cx50 did not form functional channels with Cx43. We also examined the functional response of homotypic and heterotypic channels to transjunctional voltage and cytoplasmic acidification. We show that all lens connexins exhibited sensitivity to cytoplasmic acidification as well as to voltage, and that voltage-dependent closure of heterotypic channels for a given connexin was dramatically influenced by its partner connexins in the adjacent cell. Based on the observation that Cx43 can discriminate between Cx46 and Cx50, we investigated the molecular determinants that specify compatibility by constructing chimeric connexins from portions of Cx46 and Cx50 and testing them for their ability to form channels with Cx43. When the second extracellular (E2) domain in Cx46 was replaced with the E2 of Cx50, the resulting chimera could no longer form heterotypic channels with Cx43. A reciprocal chimera, where the E2 of Cx46 was inserted into Cx50, acquired the ability to functionally interact with Cx43. Together, these results demonstrate that formation of intercellular channels is a selective process dependent on the identity of the connexins expressed in adjacent cells, and that the second extracellular domain is a determinant of heterotypic compatibility between connexins.     

Fast, large-scale model predictive control by partial enumeration

Partial enumeration (PE) is presented as a method for treating large, linear model predictive control applications that are out of reach with available MPC methods. PE uses both a table storage method and online optimization to achieve this goal. Versions of PE are shown to be closed-loop stable. PE is applied to an industrial example with more than 250 states, 32 inputs, and a 25-sample control horizon. The performance is less than 0.01% suboptimal, with average speedup factors in the range of 80-220, and worst-case speedups in the range of 4.9-39.2, compared to an existing MPC method. Small tables with only 25-200 entries were used to obtain this performance, while full enumeration is intractable for this example.     

Semantical investigations into nonmonotonic and probabilistic logics

Different forms of semantics have been proposed for conditionals of the form “Usually, if A then B”, ranging from quantitative probability distributions to qualitative approaches using plausibility orderings, possibility distributions, or conditional objects. Atomic-bound systems, also called big-stepped probabilities, allow qualitative reasoning with probabilities, aiming at bridging the gap between qualitative and quantitative argumentation and providing a model for the nonmonotonic reasoning system P. By using Goguen and Burstall’s notion of institutions for the formalization of logical systems, we elaborate precisely which formal connections exist among big-stepped probabilities, standard probabilities, and qualitative logics. Based on our investigations, we also develop two variants of conditional objects, one of them having a simpler semantics while still providing a model for system P.     

Ionic conductivity of synthetic analcime,sodalite and offretite

The ionic conductivity of pressed pellets of dehydrated synthetic analcime, sodalite and offretite was determined by a.c. measurements within the range 10 Hz to 10 MHz. The ionic conductivity values of those zeolites exchanged with various monovalent cations were determined by the complex impedance plane method. The conduction activation energies range between 63 and 101 kJ mol^–1. Sodium analcime shows the best ionic conductivity, namely 1.8×10^–4–1 cm^–1 at 400° C. A comparison with the conductivity of other ion-conducting solids was made.     

Diffusion of the hydroxide-ion in liquid CaO-Al2O3-slags by application of Fourier-Transform-lnfrared-Spectroscopy

Water vapour is soluted in liquid CaO-Al₂O₃-slags as OH^?-ion. To determine the diffusion coefficient a capillary technique is used. Roughly 5 cm long platinum capillaries filled with liquid slag are equilibrated at 1500 and 1600 °C and bar different times and then are quenched in liquid D₂O. By dividing these capillaries into roughly 3 mm long segments enough sample substance is won to obtain FT-IR spectra of the OH-band. From measurement of the integral extinction of the OH-band and OH^?-concentration profile through the capillary is obtained. FT-IR-spectroscopy is very suitable for this capillary technique because it needs only very little sample substance.