The michaelis constants of catheptic activity in xenopus tail tissue afterin vivo treatment with two leucine analogues

Zusammenfassung Die Michaelis-KonstanteKm der katheptischen Aktivität im Schwanzgewebe von Xenopuslarven wird durch das stark regenerationshemmende leucinanaloge Aminoketon E 9 nicht beeinflusst, obwohl nach 5 Tagenin vivo-Behandlung der Larven mit 3 · 10^–3 M E 9 ein starker Anstieg der spezifischen Kathepsinaktivität im Schwanzgewebe zu beobachten ist. Das leucinanaloge-Bromallylglycin (BAG) hemmt die Regeneration wenig, erhöht jedoch dieKm deutlich. Es wird postuliert, dass E 9 eine Zunahme der Kathepsine im Schwanzgewebe bewirkt, ohne die kinetischen Eigenschaften dieser Enzyme zu beeinflussen, während BAG an den aktiven Zentren der Kathepsine wirkt und die Affinität zum Substrat herabsetzt.

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With the aid of a grant from the Schweizerischer Nationalfonds zur Förderung der wissenschaftlichen Forschung. — Author's present address: Institut für experimentelle Gerontologie, Nonnenweg 7, Basel (Switzerland).     

Mutations in Rab3a alter circadian period and homeostatic response to sleep loss in the mouse

Rab3a is the most abundant Rab (ras-associated binding) protein in the brain and has a regulatory role in synaptic vesicle trafficking. Mice with a targeted loss-of-function mutation in Rab3a have defects in Ca(2+)-dependent synaptic transmission: the number of vesicles released in response to an action potential is greater than in wildtype mice, resulting in greater synaptic depression and the abolishment of CA3 mossy-fiber long term potentiation. The effect of these changes on behavior is unknown. In a screen for mouse mutants with abnormal rest-activity and sleep patterns, we identified a semidominant mutation, called earlybird, that shortens the circadian period of locomotor activity. Sequence analysis of Rab3a identified a point mutation in the conserved amino acid (Asp77Gly) within the GTP-binding domain of this protein in earlybird mutants, resulting in significantly reduced levels of Rab3a protein. Phenotypic assessment of earlybird mice and a null allele of Rab3a revealed anomalies in circadian period and sleep homeostasis, providing evidence that Rab3a-mediated synaptic transmission is involved in these behaviors.     

Antibody neutralization and escape by HIV-1

Neutralizing antibodies (Nab) are a principal component of an effective human immune response to many pathogens, yet their role in HIV-1 infection is unclear. To gain a better understanding of this role, we examined plasma from patients with acute HIV infection. Here we report the detection of autologous Nab as early as 52 days after detection of HIV-specific antibodies. The viral inhibitory activity of Nab resulted in complete replacement of neutralization-sensitive virus by successive populations of resistant virus. Escape virus contained mutations in the env gene that were unexpectedly sparse, did not map generally to known neutralization epitopes, and involved primarily changes in N-linked glycosylation. This pattern of escape, and the exceptional density of HIV-1 envelope glycosylation generally, led us to postulate an evolving 'glycan shield' mechanism of neutralization escape whereby selected changes in glycan packing prevent Nab binding but not receptor binding. Direct support for this model was obtained by mutational substitution showing that Nab-selected alterations in glycosylation conferred escape from both autologous antibody and epitope-specific monoclonal antibodies. The evolving glycan shield thus represents a new mechanism contributing to HIV-1 persistence in the face of an evolving antibody repertoire.     

CD43, a molecule defective in Wiskott-Aldrich syndrome, binds ICAM-1.

THE protein CD43 (also known as sialophorin, leukosialin, large sialoglycoprotein or gp115) is expressed on the surface of T lymphocytes, monocytes, neutrophils, platelets and some B lymphocytes. Expression of CD43 is deficient and/or defective in the X-chromosome-linked immunodeficiency disorder Wiscott-Aldrich syndrome, suggesting that CD43 might have a role in T-cell activation. We have shown that expression of human CD43 in an HLA-DR-specific murine T-cell hybridoma enhances the antigen-specific response to stimulation by the human lymphoblastoid cell line Daudi, and that Daudi cells bind specifically to purified immobilized CD43. These data indicate that the specific interaction of CD43 with a ligand on the surface of Daudi cells might contribute to T-cell activation. Here we report evidence that intercellular adhesion molecule-1 (ICAM-1, or CD54), is a ligand for CD43.     

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