Ein weiterer Versuch, die Orientierung von Brieftauben durch jahreszeitliche ?nderung der Sonnenh?he zu beeinflussen. Gleichzeitig eine Kritik der Theorie des Versuchs

Zusammenfassung Der Versuch, bei Brieftauben durch zeitweisen Entzug der Sonnensicht eine Orientierungstäuschung hervorzurufen, verlief auch im Herbst 1954 erfolglos. (Negativer Ausfall des ersten Wilhelmshavener Versuchs: K. undA. Rawson, diese Ztschr., dieses Heft, S. 168.)Dieser Ausfall spricht zunächst gegen dieMatthewssche Hypothese der Sonnennavigation, ohne jedoch unbedingt tödlich für sie zu sein (s. Diskussion, S. 176).Unabhängig von der Verschiedenheit der Versuchsergebnisse bedarf die Theorie des Warteversuchs einer Klärung. Durch Sonnenabschluß während der Warteperiode wird zwar eine Abnahme der Sonnenmittagshöhe bewirkt, die, für sich allein wahrgenommen, von den Tauben im Sinne einer Nordversetzung gedeutet werden könnte. Die Bahn aber, welche zum Scheitelpunkt führt, weicht ab von der Sonnenbahn, die am vorgetäuschten Heimatort unmittelbar vor der Warteperiode zu beobachten gewesen wäre. Soll also die Versuchserwartung (südwärts gerichtete Abflüge der Wartetauben unabhängig von der Tageszeit) aufrechterhalten werden, so muß die Navigationshypothese ergänzend präzisiert werden: Die Taube müßte ihre Position nicht nach beobachteten Bahnstückchen, sondern ausschließlich nach den aus ihnen erschlossenen Sonnenmittagspunkten errechnen, und zwar auch dann, wenn sie nie Gelegenheit hatte, die Mittagshöhe selber zu beobachten. Nur durch das Wieder-Vergessen der Bahnbeobachtungen könnte verständlich gemacht werden, daß z. B. frühmorgens am Versuchsort aufgelassene Wartetauben nicht ostwärts, sondern südwärts fliegen. (Hierzu Abb. 4.)Wenn beobachtete Abschnitte der Sonnenbahn ohne Vergleich mit vorher gesehenen Abschnitten zur Gewinnung der Scheitelhöhe taugen sollen, so muß die Taube die Fähigkeit der Kurvenextrapolation a priori besitzen. Da jede Sonnenbahn eine mathematische Individualität ist, kann der Taube dies grundsätzlich zugestanden werden, aber nur innerhalb der Wendepunkte (d. h. im konvexen Bereich der Sonnenbahn). Außerhalb derselben müßte die Taube versagen. Damit sind Anhaltspunkte für die weitere experimentelle Analyse aufgezeigt: Erstens muß in Cambridge geprüft werden, ob eine Korrelation zwischen Tageszeit und Abflugsrichtung (morgens: Ost; mittags: Süd; nachmittags: West) besteht, wie sie nach der Methode des empirischen Bahnvergleichs zu fordern ist. Zweitens kann überall geprüft werden, ob Tauben während des konkaven Verlaufs der Sonnenbahn unorientiert sind, wie nach der rein mathematischen Extrapolationsmethode zu fordern wäre.

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Summary The sun occlusion experiment as proposed byMatthews was again repeated with a negative result. (First repeat in Wilhelmshaven, also with a negative result: K. andA. Rawson, this volume p. 168.)This does not conform to the sun navigation hypothesis. Some possibilities how to interpret the conflict of results obtained by the two research groups (Cambridge and Wilhelmshaven) are suggested (see p. 176).Apart from the diverging facts, the sun occlusion experiment needs further theoretical clarification. By the experimental procedure a fall of the midday sun altitude is observable and could in fact be interpreted as caused by a north displacement. Yet the curves traced by the sun at the release position (after the occlusion period) and at the false home (before the occlusion period) are very different, except for their common vertex. If the pigeon is supposed to compare a fragment of the seen sun path with a homologous fragment of the remembered sun path, the positional interpretation will diverge the more fromMatthews' solstice home spot, the more the release time differs from noon. E. g., in the early morning time, the observed sun path is parallel to the remembered home sun path with a deviation in azimuth which must be interpreted as caused by a considerable longitudinal (westward) displacement. No difference in midday altitude is detectable to the bird.There is one way to save the expectation of southward departures regardless of time of day: If the pigeon has the gift to extrapolate seen fragments of any sun curve independently of previous experience, it might be argued that only the midday point is furtherly used (even if it was not observed but determined by extrapolation). It also might be assumed that the observed part of the sun curve is promptly erased from the memory of the bird after having led to the completion of the arc. Yet this procedure of determining the midday point, involving pure mathematics without any help of remembered parts of the sun curve, would be conceivable only within the convex-upwards part of the sun path (from 6. a. m. to 6 p. m. local time). So the question is left to further investigation whether pigeons are unorientatet before 6 and after 18 h in the summer half year. On the other hand, it should be ascertained in the Cambridge region if, in the departure of sun-occluded pigions, there is a correlation between initial directions and time of day as would be expected if the pigeon compares sun path fragments. In this case, experimentally treated pigeons released in the early morning hours should steer east; those released about midday, south; those released near sun-set, west.

     

pH-dependent conformational flexibility of the SARS-CoV main proteinase (M(pro)) dimer: molecular dynamics simulations and multiple X-ray structure analyses

The SARS coronavirus main proteinase (M(pro)) is a key enzyme in the processing of the viral polyproteins and thus an attractive target for the discovery of drugs directed against SARS. The enzyme has been shown by X-ray crystallography to undergo significant pH-dependent conformational changes. Here, we assess the conformational flexibility of the M(pro) by analysis of multiple crystal structures (including two new crystal forms) and by molecular dynamics (MD) calculations. The MD simulations take into account the different protonation states of two histidine residues in the substrate-binding site and explain the pH-activity profile of the enzyme. The low enzymatic activity of the M(pro) monomer and the need for dimerization are also discussed.     

Apoptosis of oligodendrocytes via Fas and TNF-R1 is a key event in the induction of experimental autoimmune encephalomyelitis

In experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, immunization with myelin Ags leads to demyelination and paralysis. To investigate which molecules are crucial for the pathogenesis of EAE, we specifically assessed the roles of the death receptors Fas and TNF-R1. Mice lacking Fas expression in oligodendrocytes (ODCs) were generated and crossed to TNF-R1-deficient mice. To achieve specific deletion of a loxP-flanked fas allele in ODCs, we generated a new insertion transgene, expressing the Cre recombinase specifically in ODCs. Fas inactivation alone as well as the complete absence of TNF-R1 protected mice partially from EAE induced by the immunization with myelin ODC glycoprotein. The double-deficient mice, however, showed almost no clinical signs of EAE after immunization. Histological analysis revealed that demyelination was suppressed in CNS tissue and that lymphocyte infiltration was notably reduced. We conclude that the death receptors Fas and TNF-R1 are major initiators of ODC apoptosis in EAE. Although only moderate reduction of lymphocyte infiltration into CNS tissue was observed, the absence of these receptors appears to confer protection from demyelination and development of clinical disease.     

Cyclohexenyl nucleic acids: conformationally flexible oligonucleotides

Cyclohexenyl nucleic acid (CeNA) is a nucleic acid mimic, where the (deoxy)ribose sugar has been replaced by cyclohexenyl moieties. In order to study the conformation of cyclohexenyl nucleosides by NMR, the HexRot program was developed to calculate conformations from scalar coupling constants of cyclohexenyl compounds, analogous to the methods applied for (deoxy)ribose nucleosides. The conformational equilibria and the values of the thermodynamic parameters are very similar between a cyclohexenyl nucleoside [energy difference between ₂H³ (N-type) and ²H₃ (S-type) is 1.8 kJ/mol and equilibrium occurs via the eastern hemisphere with a barrier of 10.9 kJ/mol] and a natural ribose nucleoside (energy difference between N-type and S-type is 2 kJ/mol and equilibrium occurs via the eastern hemisphere with a barrier of 4–20 kJ/mol). The flexibility of the cyclohexenyl nucleoside was demonstrated by the fast equilibrium between two conformational states that was observed in a CeNA-U monomer, combined with the ₂H³ conformation of the cyclohexene moiety when incorporated into a Dickerson dodecamer and the ²H₃ conformation when incorporated in a d(5′-GCGT*GCG-3′)/d(5′-CGCACGC-3′) duplex, as determined by the NMR spectroscopy. This represents the first example of a synthetic nucleoside that adopts different conformations when incorporated in different double-stranded DNA sequences.     

Differential effects of NF-{kappa}B and p38 MAPK inhibitors and combinations thereof on TNF-{alpha}- and IL-1{beta}-induced proinflammatory status of endothelial cells in vitro

Endothelial cells actively participate in inflammatory events by regulating leukocyte recruitment via the expression of inflammatory genes such as E-selectin, VCAM-1, ICAM-1, IL-6, IL-8, and cyclooxygenase (COX)-2. In this study we showed by real-time RT-PCR that activation of human umbilical vein endothelial cells (HUVEC) by TNF- and IL-1 differentially affected the expression of these inflammatory genes. Combined treatment with TNF- and IL-1 resulted in nonadditive, additive, and even synergistic induction of expression of VCAM-1, IL-8, and IL-6, respectively. Overexpression of dominant-negative inhibitor B protein blocking NF-B signaling confirmed a major role of this pathway in controlling both TNF-- and IL-1-induced expression of most of the genes studied. Although dexamethasone exerted limited effects at 1 µM, the thioredoxin inhibitor MOL-294, which regulates the redox state of NF-B, mainly inhibited adhesion molecule expression. Its most pronounced effect was seen on VCAM-1 mRNA levels, especially in IL-1-activated endothelium. One micromolar RWJ-67657, an inhibitor of p38 MAPK activity, diminished TNF-- and IL-1-induced expression of IL-6, IL-8, and E-selectin but had little effect on VCAM-1 and ICAM-1. Combined treatment of HUVEC with MOL-294 and RWJ-67657 resulted in significant blocking of the expression of E-selectin, IL-6, IL-8, and COX-2. The inhibitory effects were much stronger than those observed with single drug treatment. Application of combinations of drugs that affect multiple targets in activated endothelial cells may therefore be considered as a potential new therapeutic strategy to inhibit inflammatory disease activity. inflammatory gene expression; anti-inflammatory drugs; pharmacology; combination treatment     

Investigation into the interaction of the bacterial protease OmpT with outer membrane lipids and biological activity of OmpT:lipopolysaccharide complexes

Outer-membrane proteases T (OmpT) are important defence molecules of Gram-negative bacteria such as Escherichia coli found in particular in clinical isolates. We studied the interaction of OmpT with the membrane-forming lipids phosphatidylethanolamine (PE) and phosphatidylglycerol (PG) from the inner leaflet and lipopolysaccharide (LPS) from the outer leaflet of the outer membrane. These investigations comprise functional aspects of the protein–lipid interaction mimicking the outer-membrane system as well as the bioactivity of LPS:OmpT complexes in the infected host after release from the bacterial surface. The molecular interaction of the lipids PE, PG, and LPS with OmpT was investigated by analysing molecular groups in the lipids originating from the apolar region (methylene groups), the interface region (ester), and the polar region (phosphates), and by analysing the acyl-chain melting-phase behaviour of the lipids. The activity of OmpT and LPS:OmpT complexes was investigated in biological test systems (human mononuclear cells and Limulus amoebocyte lysate assay) and with phospholipid model membranes. The results show a strong influence of OmpT on the mobility of the lipids leading to a considerable fluidization of the acyl chains of the phospholipids as well as LPS, and a rigidification of the phospholipid, but not LPS head groups. From this, a dominant role of the protein on the function of the outer membrane can be deduced. OmpT released from the outer membrane still contains slight contaminations of LPS, but its strong cytokine-inducing ability in mononuclear cells, which does not depend on the Toll-like receptors 2 and 4, indicates an LPS-independent mechanism of cell activation. This might be of general importance for infections induced by Gram-negative bacteria.     

Parelectric spectroscopy of drug-carrier-systems--distribution of carrier masses or activation energies

The answer of a high-frequency electromagnetic wave to a sample as termination of an open-ended coaxial line gives the mobility and the density of permanent electric dipole moments in the substance under test. As long as these dipoles are attached to carrier molecules of well defined masses, both parameters can be extracted from the reflected wave in a quick manner giving unambiguous results. The corresponding algorithm has been applied to solid lipid nanoparticles with glucocorticoid molecules attached to or incorporated in the carrier molecules. The results from measurements in the frequency region (0.1-100) MHz have recently been published. As soon as we have to envisage a distribution in carrier masses and/or in activation energies of the attached molecules, we have to apply a more sophisticated evaluation algorithm. The need for a more generalised algorithm is clear as well, when we have to deal with more than one dipole-carrying constituent in the samples. All these evaluation algorithms shall be presented together with the mathematical basis in a short but exact form.