Ebola virus entry requires the cholesterol transporter Niemann-Pick C1

Infections by the Ebola and Marburg filoviruses cause a rapidly fatal haemorrhagic fever in humans for which no approved antivirals are available. Filovirus entry is mediated by the viral spike glycoprotein (GP), which attaches viral particles to the cell surface, delivers them to endosomes and catalyses fusion between viral and endosomal membranes. Additional host factors in the endosomal compartment are probably required for viral membrane fusion; however, despite considerable efforts, these critical host factors have defied molecular identification. Here we describe a genome-wide haploid genetic screen in human cells to identify host factors required for Ebola virus entry. Our screen uncovered 67 mutations disrupting all six members of the homotypic fusion and vacuole protein-sorting (HOPS) multisubunit tethering complex, which is involved in the fusion of endosomes to lysosomes, and 39 independent mutations that disrupt the endo/lysosomal cholesterol transporter protein Niemann-Pick C1 (NPC1). Cells defective for the HOPS complex or NPC1 function, including primary fibroblasts derived from human Niemann-Pick type C1 disease patients, are resistant to infection by Ebola virus and Marburg virus, but remain fully susceptible to a suite of unrelated viruses. We show that membrane fusion mediated by filovirus glycoproteins and viral escape from the vesicular compartment require the NPC1 protein, independent of its known function in cholesterol transport. Our findings uncover unique features of the entry pathway used by filoviruses and indicate potential antiviral strategies to combat these deadly agents.     

Effects of cytochalasin H on the embryonic endodermal cells of Microhyla ornata

Summary Cytochalasin H (CH) like CB causes disaggregation of embryonic endodermal cells and reduces their adhesivity to the glass surface. These cells reaggregate on removal of the drug from the medium. Reversibility depends on the duration of drug treatment. The mechanism of drug action is explained.We thank the University Grants Commission India for financia assistance for the Research project and Mr J. C. Daniel the Curator of Bombay Natural History Museum for identification of the frog.     

Alleviation of the toxicity of actinomycin D by uridine and thymidine on the morphogenesis of chick embryos cultivated in vitro

Zusammenfassung Untersuchung über die Wirkung von Actinomycin D auf Primitivstreifen- und Entwicklungsstadien der Kopfregion bei Hühnerembryonen in vitro: Anormale Entwicklung des Zentralnervensystems, der Somiten und des Herzens; diese Effekter konnten durch Thymidin oder Uridin zum Teil aufgehoben werden.

---

---

One of us (S.M.K.) wishes to thank the UGC for financial assistance

---

We thank Dr.P. N. Joshi of biochemistry and Mr.S. Biswas of statistics for their valuable help in the discussion.     

Paper chromatographic study of the role of sulphur-containing amino acids in the process of induction in the chick embryo

Zusammenfassung Die Organisatorregion von Hühnchenembryonen wurde mit CAP behandelt und die Wirkung des CAP auf schwefelhaltige Aminosäuren papierchromatographisch untersucht. Die Analyse ergab, dass Glutathion stärker beeinflusst wurde als Methionin. Die Reduktion des Glutathiongehaltes könnte dem Abfall der Induktionskapazität des Hensenschen Knotens entsprechen, der durch die Behandlung mit CAP hervorgerufen wird.     

Further observations on the mode of action of chloramphenicol on the chick morphogenesis

Zusammenfassung Acetylsalicylsäure,p-Hydroxybenzoesäure, 2-Methyl-1,4-Naphthachinon und Vitamin E heben die in einem Hühnerembryo durch Chloramphenicol bewirkte Hemmung der Morphogenese auf, währendp-Aminobenzoesäure undp-Aminosalicylsäure keinen Einfluss auf diese Hemmung haben.     

A study of the mode of action of chloramphenicol on the chick morphogenesis

Zusammenfassung Hühnerembryonen, die in vitro mit Chloramphenicol behandelt wurden, zeigten verschiedene Missbildungen, wie Mikrocephalie, offene Neuralrinne, gerade bleibenden Herzschlauch, verkürzte Körperachse. Nachbehandlung solcher Chloramphenicol-Keime mit äquimolaren Lösungen von Phenylalanin, Tyrosin oderOrtho-Aminobenzoesäure ergibt weitgehend oder völlig normale Entwicklung. Durch Behandlung mit Alanin, Phenylmilchsäure oderPara-Aminobenzoesäure wird dagegen die Chloramphenicolwirkung nicht aufgehoben. Auf Grund dieser Ergebnisse wird der mögliche Mechanismus der Chloramphenicolwirkung diskutiert.

---

---

One of us (L.M.) wishes to thank the Atomic Energy Commission for financial assistance.     

Two independent alleles at 6q23 associated with risk of rheumatoid arthritis

To identify susceptibility alleles associated with rheumatoid arthritis, we genotyped 397 individuals with rheumatoid arthritis for 116,204 SNPs and carried out an association analysis in comparison to publicly available genotype data for 1,211 related individuals from the Framingham Heart Study. After evaluating and adjusting for technical and population biases, we identified a SNP at 6q23 (rs10499194, approximately 150 kb from TNFAIP3 and OLIG3) that was reproducibly associated with rheumatoid arthritis both in the genome-wide association (GWA) scan and in 5,541 additional case-control samples (P = 10(-3), GWA scan; P < 10(-6), replication; P = 10(-9), combined). In a concurrent study, the Wellcome Trust Case Control Consortium (WTCCC) has reported strong association of rheumatoid arthritis susceptibility to a different SNP located 3.8 kb from rs10499194 (rs6920220; P = 5 x 10(-6) in WTCCC). We show that these two SNP associations are statistically independent, are each reproducible in the comparison of our data and WTCCC data, and define risk and protective haplotypes for rheumatoid arthritis at 6q23.