Design and characterization of superpotent bivalent ligands targeting oxytocin receptor dimers via a channel-like structure

Dimeric/oligomeric states of G-protein coupled receptors have been difficult to target. We report here bivalent ligands consisting of two identical oxytocin-mimetics that induce a three order magnitude boost in G-protein signaling of oxytocin receptors (OTRs) in vitro and a 100- and 40-fold gain in potency in vivo in the social behavior of mice and zebrafish. Through receptor mutagenesis and interference experiments with synthetic peptides mimicking transmembrane helices (TMH), we show that such superpotent behavior follows from the binding of the bivalent ligands to dimeric receptors based on a TMH1-TMH2 interface. Moreover, in this arrangement, only the analogues with a well-defined spacer length (∼25 Å) precisely fit inside a channel-like passage between the two protomers of the dimer. The newly discovered oxytocin bivalent ligands represent a powerful tool for targeting dimeric OTR in neurodevelopmental and psychiatric disorders and, in general, provide a framework to untangle specific arrangements of G-protein coupled receptor dimers

Istraživanje nekih antidota i laboratorijskih pokazatelja pri pokusnom otrovanju pilića ohratoksinom A i penicilinskom kiselinom.

The objects of this study were the main haematological and biochemical changes in experimental ochratoxicosis in 85 broiler chicks fed on a diet containing: 130, 300 and 800 ppb ochratoxin A (OTA) and 1000-2000 ppb penicillic acid (PA), corresponding to those in the field. Biochemical and haematological changes were characteristic in increased serum levels of uric acid and glucose, decreased serum levels of cholesterol and total protein, and slight normocyte anaemia. These changes were induced by several times lower contamination levels of OTA in feed than the levels described in literature of pure OTA, due to the probable synergism between OTA and PA. A positive protective effect of 5% total water extract of Artichoke and Rosallsat against the toxic effect of OTA was established.Istraživane su glavne hematoloske i biokemijske promjene u pokusnoj ohratoksikozi u 85 pilića koji su u hrani primali 130, 300 i 800 ppb ohratoksina A (OTA) i 1000-2000 ppb penicilinske kiseline (PA) te su uspoređeni s nalazima u 20 pilića koji nisu primali OTA i PA. Primijenjeni otrovi su izazvali povišenje razine mokraćne kiseline i krvnog sećera, te smanjenje razine kolesterola i ukupnih bjelančevina u krvnom serumu kao i laganu normocitnu anemiju. Ove promjene su bile izazvane s nekoliko puta manjim koncentracijama OTA u hrani, nego što su opisane u literaturi s čistim OTA, što je vjerojatno posljedica sinergističkog djelovanja OTA i PA. Utvrđeno je pozitivno zaštitno djelovanje 5% vodenog iscrpka artičoke i Rosallsata protiv otrovnog djelovanja ohratoksina A