The complete genome sequence of Francisella tularensis, the causative agent of tularemia

Francisella tularensis is one of the most infectious human pathogens known. In the past, both the former Soviet Union and the US had programs to develop weapons containing the bacterium. We report the complete genome sequence of a highly virulent isolate of F. tularensis (1,892,819 bp). The sequence uncovers previously uncharacterized genes encoding type IV pili, a surface polysaccharide and iron-acquisition systems. Several virulence-associated genes were located in a putative pathogenicity island, which was duplicated in the genome. More than 10% of the putative coding sequences contained insertion-deletion or substitution mutations and seemed to be deteriorating. The genome is rich in IS elements, including IS630 Tc-1 mariner family transposons, which are not expected in a prokaryote. We used a computational method for predicting metabolic pathways and found an unexpectedly high proportion of disrupted pathways, explaining the fastidious nutritional requirements of the bacterium. The loss of biosynthetic pathways indicates that F. tularensis is an obligate host-dependent bacterium in its natural life cycle. Our results have implications for our understanding of how highly virulent human pathogens evolve and will expedite strategies to combat them.     

Mutations in MERTK, the human orthologue of the RCS rat retinal dystrophy gene, cause retinitis pigmentosa

Mutation of a receptor tyrosine kinase gene, Mertk, in the Royal College of Surgeons (RCS) rat results in defective phagocytosis of photoreceptor outer segments by the retinal pigment epithelium (RPE) and retinal degeneration. We screened the human orthologue, MERTK, located at 2q14.1 (ref. 10), in 328 DNA samples from individuals with various retinal dystrophies and found three mutations in three individuals with retinitis pigmentosa (RP). Our findings are the first conclusive evidence implicating the RPE phagocytosis pathway in human retinal disease.     

Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome

ARC syndrome (OMIM 208085) is an autosomal recessive multisystem disorder characterized by neurogenic arthrogryposis multiplex congenita, renal tubular dysfunction and neonatal cholestasis with bile duct hypoplasia and low gamma glutamyl transpeptidase (gGT) activity. Platelet dysfunction is common. Affected infants do not thrive and usually die in the first year of life. To elucidate the molecular basis of ARC, we mapped the disease to a 7-cM interval on 15q26.1 and then identified germline mutations in the gene VPS33B in 14 kindreds with ARC. VPS33B encodes a homolog of the class C yeast vacuolar protein sorting gene, Vps33, that contains a Sec1-like domain important in the regulation of vesicle-to-target SNARE complex formation and subsequent membrane fusion.     

The influence of chlorothiazide and tolbutamide upon intestinal serotonin levels in the sprague-dawley rat

Zusammenfassung Der Serotoningehalt der Schleimhaut im obern Duodenumteil, im mittleren Jejunum, im Ileumendteil und im Appendix von Sprague-Dawley Charles River Rattenmännchen wurde ohne Vorbehandlung und mit Chlorothiazid- und Tolbutamidvorbehandlung spektrophotofluorimetrisch bestimmt. Die Serotoningehalte für die 3 Gruppen vergleichbarer Gewebe waren ähnlich, was zeigt, dass die früher beschriebene Erhöhung des Serotoningehaltes der Schleimhaut nach Sulfamerazinvorbehandlung wahrscheinlich nicht mit einer unspezifischen Wirkung des Sulfonamidteils verbunden ist.

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This study was supported in part by an award from the National Science Foundation toJ. H. Thompson, M.D., M.R.C.P.I., Department of Pharmacology, U.C.L.A. School of Medicine, Los Angeles, California 90024.     

A rapid method for the fractionation of avian blood cell nuclei

Summary Red blood cell nuclei from avian anaemic blood have been fractionated by rate sedimentation on discontinous sucrose gradients into fractions which can be distinguished both by their RNA synthesizing ability and by their morphology as revealed by electron microscopy.Acknowledgment. We wish to thank H. Gitay for the electron micrographs. This work was supported by grants from the University of Cape Town Research Committee and the Council for Scientific and Industrial Research.     

A new N-glucuronide metabolite of carbamazepine

Summary An N-glucuronide metabolite of carbamazepine was identified in the bile of the isolated perfused rat liver by means of permethylation, gas chromatography and mass spectrometry.This research was supported by grants from the National Institutes of Health (Nos. N01-NS-5-2328, AM-17665) and the James Whitcomb Riley Memorial Association (No. 74-15) and a grant from the Epilepsy, Foundation of America.