Perinatal changes in plasma carnitine levels in 4 species of mammal

Summary Plasma levels of carnitine, acetylcarnitine, and -hydroxybutyrate rise perinatally in rats, guinea-pigs and sheep but not in rabbits. In the fetus, carnitine levels are high in rabbits and guinea-pigs but not in rats and sheep.     

Mutation of Vps54 causes motor neuron disease and defective spermiogenesis in the wobbler mouse

Vacuolar-vesicular protein sorting (Vps) factors are involved in vesicular trafficking in eukaryotic cells. We identified the missense mutation L967Q in Vps54 in the wobbler mouse, an animal model of amyotrophic lateral sclerosis, and also characterized a lethal allele, Vps54(beta-geo). Motoneuron survival and spermiogenesis are severely compromised in the wobbler mouse, indicating that Vps54 has an essential role in these processes.     

Mutations in the human retinal degeneration slow gene in autosomal dominant retinitis pigmentosa.

The murine retinal degeneration slow (rds) gene is a semidominant mutation with a phenotype having rod and cone photoreceptors that develop abnormally and then slowly degenerate. The phenotype is a possible model for retinitis pigmentosa, one of the scores of hereditary human retinal degenerations, which is also characterized by photoreceptor degeneration. We report here three mutations of the human homologue of the rds gene (RDS) that cosegregate with autosomal dominant retinitis pigmentosa in separate families. Our results indicate that some cases of autosomal dominant retinitis pigmentosa are due to mutations at the RDS locus.     

COT drives resistance to RAF inhibition through MAP kinase pathway reactivation

Oncogenic mutations in the serine/threonine kinase B-RAF (also known as BRAF) are found in 50-70% of malignant melanomas. Pre-clinical studies have demonstrated that the B-RAF(V600E) mutation predicts a dependency on the mitogen-activated protein kinase (MAPK) signalling cascade in melanoma-an observation that has been validated by the success of RAF and MEK inhibitors in clinical trials. However, clinical responses to targeted anticancer therapeutics are frequently confounded by de novo or acquired resistance. Identification of resistance mechanisms in a manner that elucidates alternative 'druggable' targets may inform effective long-term treatment strategies. Here we expressed ～600 kinase and kinase-related open reading frames (ORFs) in parallel to interrogate resistance to a selective RAF kinase inhibitor. We identified MAP3K8 (the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives resistance to RAF inhibition in B-RAF(V600E) cell lines. COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signalling. Moreover, COT expression is associated with de novo resistance in B-RAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. We further identify combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting. Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies.     

Ketamine-xylazine anaesthesia blocks consolidation of ocular dominance changes in kitten visual cortex

In the visual cortex of mammals, response properties of single neurons can be changed by restricted visual experience during early postnatal development. Covering one eye for four to eight hours when kittens are at the peak of the sensitive period is sufficient to weaken the influence of the occluded eye on cortical neurons resulting in a noticeable shift of ocular dominance towards the open eye. The underlying changes in synaptic connections do not occur so readily when a kitten is anaesthetized and paralysed. We report here that an ocular dominance shift is prevented in alert kittens that receive repeated brief monocular exposures when these are followed by ketamine-xylazine anaesthesia. This retrograde effect on cortical plasticity suggests that the process by which synaptic activity is converted into structural changes has been disturbed.     

Catalase activity in the regenerating tail tip of xenopus larvae and the effect of 3-amino-1,2,4-triazole

Zusammenfassung In der regenerierenden Schwanzspitze der Xenopuslarve bleibt die Katalase-Aktivität (bezogen auf Totalstickstoff) bis zum Ende der Regenerationsperiode auf etwa 50% des normalen Niveaus, während sie im anschliessenden Schwanzstumpf unverändert ist. 3-Amino-1,2,4-triazol erniedrigt die Katalase-Aktivität in den Regeneraten, den Stümpfen und dem Kontrollgewebe nicht-amputierter Larven auf etwa 20–40% des normalen Niveaus. Es bewirkt eine kurzfristige Regenerationshemmung in den ersten Tagen nach Amputation, die im weiteren Verlauf wieder vollständig ausgeglichen wird.

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This work was supported by a grant of theEidgenössische Kommission zur Förderung der wissenschaftlichen Forschung aus Arbeitsbeschaffungsmitteln des Bundes. I would like to express my gratitude to Prof.F. E. Lehmann for his constant interest and his valuable advice. I am also indebted to Mrs.J. Weber and to MissM. Pieren for technical assistance.     

The non-histone protein pattern of rat brain during ontogenesis

Zusammenfassung Die «non-histone»-Proteine (NHP) aus Hirn- und Leberzellkernen der Ratte wurden bei 5, 10 und 20 Tage alten und adulten Tieren extrahiert und das NHP/DNA-Verhältnis bestimmt. Die NHP aus den Gehirnzellkernen wurden disk-elektrophoretisch aufgetrennt. Leber- und Gehirnkerne zeigten eine geringe Zunahme des NHP/DNA-Quotienten während der ersten 20 postnatalen Tage. Es konnten jedoch für diese Altersstadien keine Veränderungen im Proteinmuster des Hirns gefunden werden.

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This investigation was supported by grant No 89 of the Fritz Hoffmann-La Roche Foundation.