Notes: Summary: Major histocompatibihty complex (MHC)-encoded glycoproteins bind peptide antigens through non-covalent interactions to generate complexes that are displayed on tbe surface of antigen-presenting cells (APC) for recognition by T ceils, Peptide-binding site occupancy is necessary for stable assembly of newly synthesized MHC proteins and export from the endoplasmic reticulum (ER), The MHC class II antigen-processing pathway provides a mechanism for presentation of peptides generated in the endosomal pathway of APC, The chaperone protein, invariant chain, includes a surrogate peptide that stahilizes newly synthesized class II molecules during transport to endosomal compartments. The invariant chain-derived peptide must be replaced through a peptide exchange reaction that is promoted by acidic pH and the MHC-encoded co-factor HLA-DM, Peptide exchange reactions are not required for presentation of antigens by MHC class I molecules because they bind antigens during initial assembly in the ER, However, exchange reactions may play an important role in editing the repertoire of peptides presented by both class II and class I molecules, thus influencing the specificity of immunity and tolerance.

Notes: We present a general theory of equilibrium polymerization in a binary mixture by applying the n-vector model for magnetism in a weak field. Results are given for the temperature dependence of the order parameters, polymer length, and phase diagrams in the concentration–temperature plane. In addition to phase separations between two monomer phases and between a monomer and a polymer phase, the phase diagrams show the possibility of coexistence between two polymer phases with a critical point. It is shown that our theory becomes identical to the earlier theory for equilibrium copolymerization of Tobolsky and Owen when the molecular field approximation and some additional approximations are used.

Notes: ATP/ADP ratios were varied in different ways and the degree of negative supercoiling was determined in Escherichia coli. Independent of whether the ATP/ADP ratio was reduced by a shift to anaerobic conditions, by addition of a protonophore (dinitrophenol) or by potassium cyanide addition, DNA supercoiling decreased similarly with the ATP/ADP ratio. The experiments were performed under well-defined conditions, where oxidative phosphorylation was the dominant route for ATP synthesis, i.e. using a minimal salts medium with succinate as the sole free-energy and carbon source, and in the presence or absence of ammonia as the nitrogen source. The results of the different experiments were consistent with a single linear relationship between the log(ATP/ADP) and the change in linking number. The dependence of DNA supercoiling on the ATP/ADP ratio was not influenced by inhibitors of transcription or translation. Because the ATP/ADP ratio was modulated in different ways, the unique relationship suggests coupling between the phosphorylation potential and DNA supercoiling. This was most probably mediated by the DNA gyrase, independent of topoisomerase I or transcription.

Notes: Abstract The mechanisms that determine chromosome structure and chromosome partitioning in bacteria are largely unknown. Here we discuss two hypotheses: (i) the structure of the Escherichia coli nucleoid is determined by DNA binding proteins and DNA supercoiling, representing a compaction force on the one hand, and by the coupled transcription/translation/ translocation of plasma membrane and cell wall proteins, representing an expansion force on the other hand; (ii) the two forces are important for the partitioning process of chromosomes.

Notes: Abstract  The catalytic cycle of topoisomerase II is the target of some of the most successful antitumor agents used today, e.g., etoposide (VP-16), in the treatment of testicular cancer and small-cell lung cancer. The cell kill mediated by topoisomerase II poisons can be antagonized by distinct drug types. Thus, we have demonstrated etoposide antagonism with the type-II anthracycline aclarubicin, the antimalarial drug chloroquine, and the cardioprotective agent ICRF-187. In other setups, combinations of agonist and antagonists have led to high-dose regimens for counteracting drug resistance. Thus, the exploitation of folinic acid rescue for methotrexate toxicity and the use of mesna to protect against cyclophosphamide toxicity have enabled the use of high-dose methotrexate and cyclophosphamide protocols. Using a similar approach, we have studied possible ways to apply antagonists to topoisomerase II poisons. NDF1-hybrid female mice were treated with the various drugs and drug combinations. Lethality (LD10 and LD50 values) was computed by use of the maximum-likelihood method, and the antitumor effect of the drugs was compared in mice inoculated i.p. with either L1210 cells or Ehrlich ascites tumor cells. In addition, the compounds were tested on L1210 cells inoculated intracranially. The toxicity of the various drugs was evaluated by weight and leukocyte counts. ICRF-187 rescues healthy mice from lethal doses of topoisomerase II poisons. In mice the ICRF-187 LD10 was 500 mg/kg. Within a wide nontoxic dose range (50–250 mg/kg) of ICRF-187 we found protection against m-AMSA and etoposide lethality. Thus, the LD10 of etoposide increased from 34 mg/kg for the single agent to 122 mg/kg for its combination with ICRF-187, corresponding to a 3.6-fold etoposide dose escalation. In contrast, ICRF-187 did not protect against lethal doses of the non-topoisomerase II-directed drug paclitaxel. We further investigated the antitumor effect of equitoxic schedules in mice inoculated i.p. with L1210 or Ehrlich ascites tumor cells. The L1210-bearing mice appeared to obtain a larger increase in life span from the etoposide and ICRF-187 combination as compared with etoposide alone, whereas this was not the case in mice inoculated with Ehrlich ascites tumor cells. As the hydrophilic ICRF-187 is not expected to cross the blood-brain barrier, in contrast to the lipophilic etoposide, we investigated the effect of the drug combination in mice inoculated intracranially with L1210 cells. We obtained a significant increase in life span in mice treated with ICRF-187 + etoposide as compared with mice treated with an equitoxic dose of etoposide alone. Thus, there appear to be potential routes by which one can benefit from this antagonism. ICRF-187 is a powerful nontoxic protector against the lethality of the topoisomerase II-directed drugs etoposide and m-AMSA in vivo. A brain tumor model demonstrates the superiority of high-dose etoposide treatment with ICRF-187 protection as compared with etoposide treatment alone. This implies that tumors in the brain can be reached by cytotoxic drug doses and that normal tissues can be protected due to differences in drug transport across the blood-brain barrier. ICRF-187 is therefore a promising lead compound for the development of schedules using high-dose topoisomerase II poisons in the treatment of brain tumors and metastases.

Notes: [Auszug] The neural cell adhesion molecule (NCAM) plays a key role in neural development, regeneration, and learning. In this study, we identified a synthetic peptide-ligand of the NCAM Ig1 module by combinatorial chemistry and showed it could modulate NCAM-mediated cell adhesion and signal transduction ...

Notes: [Auszug] The structure in solution of the second Ig-module fragment of residues 117–208 of NCAM has been determined. Like the first Ig-module of residues 20–116, it belongs to the I set of the immunogloblin superfamily. Module 1 and module 2 interact weakly, and the binding sites of this ...

Notes: [Auszug] Sir—The neural cell adhesion molecule (NCAM) is a cell surface gly-coprotein1–3, which plays a key role in development of the nervous system and in learning4,5. NCAM contains five immunoglobulin (Ig) and two fibronectin type III (Fill) homology domains. It is known to mediate cell-cell ...

Notes: Abstract  In vitro both acetate and hyperosmolarity cause vasodilation, which could be physiologically important during food ingestion and during peritoneal dialysis. The purpose of this study was to investigate the role of the intracellular calcium concentration ([Ca2+]i, measured with fura-2), membrane potential (measured with glass microelectrodes) and intracellular pH [pHi, measured with bis-carboxyethylcarboxyfluorescein (BCECF)] in the vasodilation. Hyperosmolar sodium acetate (30 mM) concentration dependently relaxed noradrenaline-precontracted arteries. This response was associated with hyperpolarization and a fall in [Ca2+]i. In arteries precontracted with 50 mM K+ the relaxation was associated with a decrease of [Ca2+]i but no change in membrane potential. Isoosmolar sodium acetate neither relaxed or affect [Ca2+]i of K+-precontracted arteries, but induced a small relaxation with no reduction in [Ca2+]i in noradrenaline-precontracted arteries. Hyperosmolar acetate caused a transient reduction of pHi that was unrelated to relaxation. It is concluded that the mechanisms responsible for the relaxation to hyperosmolar acetate involve a decrease of [Ca2+]i, which is only partly explained by hyperpolarization and probably a decrease in the sensitivity of the contractile proteins to [Ca2+]i. pHi seems not to play a role in these effects.