Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal-dominant central nervous system white-matter disease with variable clinical presentations, including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes. We combined genome-wide linkage analysis with exome sequencing and identified 14 different mutations affecting the tyrosine kinase domain of the colony stimulating factor 1 receptor (encoded by CSF1R) in 14 families with HDLS. In one kindred, we confirmed the de novo occurrence of the mutation. Follow-up sequencing identified an additional CSF1R mutation in an individual diagnosed with corticobasal syndrome. In vitro, CSF-1 stimulation resulted in rapid autophosphorylation of selected tyrosine residues in the kinase domain of wild-type but not mutant CSF1R, suggesting that HDLS may result from partial loss of CSF1R function. As CSF1R is a crucial mediator of microglial proliferation and differentiation in the brain, our findings suggest an important role for microglial dysfunction in HDLS pathogenesis.     

Chemical genetic discovery of targets and anti-targets for cancer polypharmacology

The complexity of cancer has led to recent interest in polypharmacological approaches for developing kinase-inhibitor drugs; however, optimal kinase-inhibition profiles remain difficult to predict. Using a Ret-kinase-driven Drosophila model of multiple endocrine neoplasia type 2 and kinome-wide drug profiling, here we identify that AD57 rescues oncogenic Ret-induced lethality, whereas related Ret inhibitors imparted reduced efficacy and enhanced toxicity. Drosophila genetics and compound profiling defined three pathways accounting for the mechanistic basis of efficacy and dose-limiting toxicity. Inhibition of Ret plus Raf, Src and S6K was required for optimal animal survival, whereas inhibition of the 'anti-target' Tor led to toxicity owing to release of negative feedback. Rational synthetic tailoring to eliminate Tor binding afforded AD80 and AD81, compounds featuring balanced pathway inhibition, improved efficacy and low toxicity in Drosophila and mammalian multiple endocrine neoplasia type 2 models. Combining kinase-focused chemistry, kinome-wide profiling and Drosophila genetics provides a powerful systems pharmacology approach towards developing compounds with a maximal therapeutic index.     

An assessment of the effect of hormone and neurotransmitters on adenine and guanine derivatives simultaneously in rat brain cortical slices.

A A 2-dimensional thin-layer method has been developed for the separation on cellulose of adenine and guanine derivatives. Using incubated rat cerebral cortex slices it was shown that noradrenaline and acetylcholine stimulated cAMP and cGMP production respectively but glutamate and gamma-aminobutyric acid stimulated production of both cyclic nucleotides.     

Neocortical transplants in the rat brain: an ultrastructural study

Summary Electron microscopic analysis of neocortical transplants in the cerebellum of the host animals showed that the nerve cells, glial cells, and neuropil of the transplants were normal. These transplants showed anatomical integration with the host brain through various regions of interface. Neuropil interfaces were found to have a high density of synaptic profiles, and medullary interfaces had a very small number of synaptic profiles.Acknowledgment. Research supported by Contract No. N00014-83 from the Office of Naval Research, Department of the Navy to E.N.A., and N.I.H. Research Grant No. NS-08817 to G.D. Das.     

Biochemical changes of muscle proteins in goldfish (Carassius auratus) during thermal acclimatization

Zusammenfassung Kälteadaptierte Goldfische (Carassius auratus) bauen mehr Leuzin in Muskelproteine ein, wobei die Steigerung in verschiedenen Muskeleiweissfraktionen gleich ist. Aus kälteadaptierten Goldfischmuskeln ist mehr Myosin und sarkoplasmisches Eiweiss extrahierbar.     

Neuroscience: rewiring the adult brain

Any analysis of plastic reorganization at a neuronal locus needs a veridical measure of changes in the functional output--that is, spiking responses of the neurons in question. In a study of the effect of retinal lesions on adult primary visual cortex (V1), Smirnakis et al. propose that there is no cortical reorganization. Their results are based, however, on BOLD (blood-oxygen-level-dependent) fMRI (functional magnetic resonance imaging), which provides an unreliable gauge of spiking activity. We therefore question their criterion for lack of plasticity, particularly in the light of the large body of earlier work that demonstrates cortical plasticity.     

In vitro demonstration of peroxidase activity in the fish kidney soluble supernatant and its physiological importance

Zusammenfassung In der Kopfniere des TeleostiersAnabes testudineus wurde eine besonders hohe Peroxidase-Aktivität nachgewiesen, insbesondere deren Iodid-Oxydation zu Tri-Iodid.     

Stereotaxic technique for transplantation of neural tissues in the brain of adult rats

Summary A technique of neural transplantation in the brains of adult animals, using stereotaxic apparatus, is described. It facilitates transplantation of neural tissues of small volumes in precisely defined structures of the host brain, and yields a high percentage of successful transplantations.Supported by N.I.H. Research grant No. NS-08817. Suggestions from Drs N. Mangini, M. M. Oblinger and J. Weibers on various aspects of this procedure are gratefully acknowledged.