Rfx6 Maintains the Functional Identity of Adult Pancreatic β Cells.

SummaryIncreasing evidence suggests that loss of β cell characteristics may cause insulin secretory deficiency in diabetes, but the underlying mechanisms remain unclear. Here, we show that Rfx6, whose mutation leads to neonatal diabetes in humans, is essential to maintain key features of functionally mature β cells in mice. Rfx6 loss in adult β cells leads to glucose intolerance, impaired β cell glucose sensing, and defective insulin secretion. This is associated with reduced expression of core components of the insulin secretion pathway, including glucokinase, the Abcc8/SUR1 subunit of KATP channels and voltage-gated Ca2+ channels, which are direct targets of Rfx6. Moreover, Rfx6 contributes to the silencing of the vast majority of “disallowed” genes, a group usually specifically repressed in adult β cells, and thus to the maintenance of β cell maturity. These findings raise the possibility that changes in Rfx6 expression or activity may contribute to β cell failure in humans

Rapid liposomal formulation for nucleolin targeting to rhabdomyosarcoma cells.

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. More effective and less toxic therapies are urgently needed for high-risk patients. Peptide-guided targeted drug delivery can increase the therapeutic index of encapsulated drugs and improve patients' well-being. To apply this strategy to RMS, we identified the peptide F3 in a screening for peptides binding to RMS cells surface. F3 binds to nucleolin, which is present on the surface of RMS cells and is abundantly expressed at the mRNA level in RMS patients' biopsies compared to healthy tissues. We developed a rapid microfluidic formulation of F3-decorated PEGylated liposomes and remote loading of the chemotherapeutic drug vincristine. Size, surface charge, drug loading and retention of targeted and control liposomes were studied. Enhanced cellular binding and uptake were observed in three different nucleolin-positive RMS cell lines. Importantly, F3-functionalized liposomes loaded with vincristine were up to 11 times more cytotoxic than non-targeted liposomes for RMS cell lines. These results demonstrate that F3-functionalized liposomes are promising for targeted drug delivery to RMS and warrant further in vivo investigations

Projekt "Weidekuh-Genetik": Problemstellung und Beschreibung des Versuchs

Die Schweiz ist ein Grasland. Die effiziente Nutzung der Ressource Gras ist für die Schweizer Milchindustrie zentral, weshalb effiziente Milchproduktionssysteme und dafür geeignete Kühe nötig sind. Die heutigen Schweizer Rassen sind stark von nordamerikanischer Genetik, die an die Stallhaltung mit Totalmischration adaptiert ist, mitgeprägt. Aufgrund der belegten Interaktion zwischen Genotyp und Umwelt für stark kontrastierende Produktionsbedingungen stellt sich die Frage nach der Eignung unserer Rassen für die Low-Input-Systeme mit saisonaler Abkalbung. In Neuseeland, wo dieser Systemtyp seit Jahrzehnten vorherrscht, wurden fruchtbare und für die Produktion von Milchinhaltsstoffen effiziente Kühe gezüchtet. Im hier beschriebenen Versuch wurde die Gesamtleistung der drei Schweizer Hauptrassen (Fleckvieh, Brown Swiss und Holstein) mit derjenigen neuseeländischer Holstein-Friesian auf Vollweidebetrieben mit saisonaler Abkalbung Ende Winter verglichen

Projet "Quelle vache pour la pâture?": problématique et description de l'essai

La Suisse est un pays d'herbages, dont la bonne valorisation est essentielle pour la filière laitière suisse. Celle-ci nécessite des systèmes efficaces de production laitière et des vaches adaptées à ces systèmes. L'existence d'interactions entre le génotype et l'environnement, lorsque l'on compare des conditions de production contrastées, pose la question de l'adaptation de nos races suisses à des systèmes à bas intrants et vêlages saisonniers, alors qu'elles sont largement influencées par la génétique nord-américaine particulièrement adaptée aux environnements confinés et rations complètes. La Nouvelle-Zélande, où le système pâturant saisonnier domine depuis des décennies, a sélectionné des vaches fertiles et efficaces en production de lait riche en matières utiles à partir d'herbe pâturée. Dans cet essai, il s'agissait de comparer les performances globales des trois principales races laitières suisses (Tachetée rouge, Brown Swiss et Holstein) aux performances des Holstein-Friesian néo-zélandaises, sur des exploitations pratiquant la pâture intégrale avec vêlages saisonniers de fin d'hiver

Efficiency of Swiss and New Zealand dairy breeds under grazing conditions on commercial dairy farms

The objective of the study was to investigate over three years (2007 – 2009) the attributes of cows adapted to a pasture-based seasonal milk production system (New Zealand Holstein Friesian) under Swiss conditions and to compare them with Swiss breeds. For this purpose, pairs of Swiss (CH) and New Zealand (NZHF) cows were established (100 cows in total) with similar age and calving date on 15 commercial farms. Body weight (BW) in the first and second lactations were higher in CH cows than in NZHF cows (in 2007, 544 vs. 477 kg, P<0.001; in 2008, 578 vs. 517 kg, P<0.001). Milk yield was similar in CH and NZ cows for the initial two years but the milk of NZ cows had higher fat and protein content. The NZ cows produced more energy corrected milk (ECM) in the second lactation than the CH cows (6017 vs. 5470 kg, P< 0.001). As a consequence, the efficiency (ECM per metabolic BW, kg kg-1) was higher in NZ than in CH cows in both years (2007, 49.7 vs. 44.2, P<0.001; 2008, 55.6 vs. 46.6, P<0.001). It is therefore concluded that New Zealand Holstein Friesians are more efficient in a pasture-based milk production system than Swiss breeds

Design and in vitro characterization of highly sst2-selective somatostatin antagonists suitable for radiotargeting

Radiolabeled sst 2 and sst 3 antagonists are better candidates for tumor targeting than agonists with comparable binding characteristics (Ginj, M.; Zhang, H.; Waser, B.; Cescato, R.; Wild, D.; Erchegyi, J.; Rivier, J.; Mäcke, H. R.; Reubi, J. C. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 16436-16441.). Because most of the neuroendocrine tumors express sst 2, we used the known antagonists acetyl- pNO 2Phe (2)- c[ dCys (3)-Tyr (7)- dTrp (8)-Lys (9)-Thr (10)-Cys (14)]- dTyr (15)-NH 2 ( 1) (Bass, R. T.; Buckwalter, B. L.; Patel, B. P.; Pausch, M. H.; Price, L. A.; Strnad, J.; Hadcock, J. R. Mol. Pharmacol. 1996, 50, 709-715. Bass, R. T.; Buckwalter, B. L.; Patel, B. P.; Pausch, M. H.; Price, L. A.; Strnad, J.; Hadcock, J. R. Mol. Pharmacol. 1997, 51, 170; Erratum.) and H-Cpa (2)- c[ dCys (3)-Tyr (7)- dTrp (8)-Lys (9)-Thr (10)-Cys (14)]-2Nal (15)-NH 2 ( 7) (Hocart, S. J.; Jain, R.; Murphy, W. A.; Taylor, J. E.; Coy, D. H. J. Med. Chem. 1999, 42, 1863-1871.) as leads for analogues with increased sst 2 binding affinity and selectivity. Among the 32 analogues reported here, DOTA- pNO 2Phe (2)- c[ dCys (3)-Tyr (7)- dAph (8)(Cbm)-Lys (9)-Thr (10)-Cys (14)- dTyr (15)-NH 2 ( 3) and DOTA-Cpa (2)- c[ dCys (3)-Aph (7)(Hor)- dAph (8)(Cbm)-Lys (9)-Thr (10)-Cys (14)]- dTyr (15)-NH 2 ( 31) had the highest sst 2 binding affinity and selectivity. All of the analogues tested kept their sst 2 antagonistic properties (i.e., did not affect calcium release in vitro and competitively antagonized the agonistic effect of [Tyr (3)]octreotide). Moreover, in an immunofluorescence-based internalization assay, the new analogues prevented sst 2 internalization induced by the sst 2 agonist [Tyr (3)]octreotide without being active by themselves. In conclusion, several analogues (in particular 3, 31, and 32) have outstanding sst 2 binding and functional antagonistic properties and, because of their DOTA moiety, are excellent candidates for in vivo targeting of sst 2-expressing cancers

Novel sst5-selective somatostatin dicarba-analogs: Synthesis and conformation-affinity relationships

We describe synthesis, conformational studies, and binding to the five somatostatin receptors (sst 1-5) of a few analogues of the cyclic octapeptide octreotide, where the disulfide bridge was replaced by a dicarba group. Binding experiments showed that two analogues had good affinity and high selectivity for the sst5 receptor. Three-dimensional structures of the active analogues were determined by (1)H NMR spectroscopy. Helical propensities well correlates with the peptide sst5 affinity. Finally, a new pharmacophore model for the sst5 was developed