Mutations in TTC19 cause mitochondrial complex III deficiency and neurological impairment in humans and flies

Although mutations in CYTB (cytochrome b) or BCS1L have been reported in isolated defects of mitochondrial respiratory chain complex III (cIII), most cIII-defective individuals remain genetically undefined. We identified a homozygous nonsense mutation in the gene encoding tetratricopeptide 19 (TTC19) in individuals from two families affected by progressive encephalopathy associated with profound cIII deficiency and accumulation of cIII-specific assembly intermediates. We later found a second homozygous nonsense mutation in a fourth affected individual. We demonstrated that TTC19 is embedded in the inner mitochondrial membrane as part of two high-molecular-weight complexes, one of which coincides with cIII. We then showed a physical interaction between TTC19 and cIII by coimmunoprecipitation. We also investigated a Drosophila melanogaster knockout model for TTC19 that showed low fertility, adult-onset locomotor impairment and bang sensitivity, associated with cIII deficiency. TTC19 is a putative cIII assembly factor whose disruption is associated with severe neurological abnormalities in humans and flies.     

Spatial distribution of ichthyofauna in the northern Alboran Sea (western Mediterranean)

This study describes the four main demersal fish assemblages identified along the continental shelf and slope (30–800 m depth) of the northern Alboran Sea (western Mediterranean), based on the analysis of the MEDITS (International bottom trawl survey in the Mediterranean) 12-year data series. We collected 186 fish species belonging to three classes, 24 orders and 69 families. Taxonomically, the order Perciformes was the most diverse, represented by 18 families and 58 species. Each assemblage had particular characteristics of abundance, biomass, mean fish weight and species richness. The geographical differences associated with the distribution of some species occurred within shelf assemblages. The middle slope was characterised by the highest similarity between samples, probably due to its lower environmental variability compared to that of the other assemblages.     

Effects of antithymic reticuloepithelial cells serum on the levels of circulating thymic factor and on the sensitivity to azathioprine of spleen spontaneous rosette-forming cells

Summary Swiss mice treated with an antithymic reticuloepithelial cells serum (ATRES) showed a drastic and prolonged depression of the serum thymic factor. A similar but less pronounced effect was also observed following the administration of the antithymocyte (ATS) and the antilymphocyte (ALS) sera. Conversely, the azathioprine sensitivity of spleen spontaneous rosette-forming cells was highly modified by the ATRES but not by the ATS or the ALS. The probable mechanisms of such effects are discussed.     

Translocation of lipid-linked oligosaccharides across the ER membrane requires Rft1 protein.

N-linked glycosylation of proteins in eukaryotic cells follows a highly conserved pathway. The tetradecasaccharide substrate (Glc3Man9GlcNAc2) is first assembled at the membrane of the endoplasmic reticulum (ER) as a dolichylpyrophosphate (Dol-PP)-linked intermediate, and then transferred to nascent polypeptide chains in the lumen of the ER. The assembly of the oligosaccharide starts on the cytoplasmic side of the ER membrane with the synthesis of a Man5GlcNAc2-PP-Dol intermediate. This lipid-linked intermediate is then translocated across the membrane so that the oligosaccharides face the lumen of the ER, where the biosynthesis of Glc3Man9GlcNAc2-PP-Dol continues to completion. The fully assembled oligosaccharide is transferred to selected asparagine residues of target proteins. The transmembrane movement of lipid-linked Man5GlcNAc2 oligosaccharide is of fundamental importance in this biosynthetic pathway, and similar processes involving phospholipids and glycolipids are essential in all types of cells. The process is predicted to be catalysed by proteins, termed flippases, which to date have remained elusive. Here we provide evidence that yeast RFT1 encodes an evolutionarily conserved protein required for the translocation of Man5GlcNAc2-PP-Dol from the cytoplasmic to the lumenal leaflet of the ER membrane.     

Characterization of a common precursor population for dendritic cells

Dendritic cells (DCs) are essential for the establishment of immune responses against pathogens and tumour cells, and thus have great potential as tools for vaccination and cancer immunotherapy trials. Experimental evidence has led to a dual DC differentiation model, which involves the existence of both myeloid- and lymphoid-derived DCs. But this concept has been challenged by recent reports demonstrating that both CD8- and CD8+ DCs, considered in mice as archetypes of myeloid and lymphoid DCs respectively, can be generated from either lymphoid or myeloid progenitors. The issue of DC physiological derivation therefore remains an open question. Here we report the characterization of a DC-committed precursor population, which has the capacity to generate all the DC subpopulations present in mouse lymphoid organs---including CD8- and CD8+ DCs, as well as the B220+ DC subset---but which is devoid of myeloid or lymphoid differentiation potential. These data support an alternative model of DC development, in which there is an independent, common DC differentiation pathway.     

High-throughput synthesis and catalytic properties of a molecular sieve with 18- and 10-member rings

Crystalline molecular sieves with large pores and high adsorption capacities have many potential applications. Of these materials, zeolites are of particular interest owing to their stability in a wide range of experimental conditions. An aluminophosphate with very large circular channels(5) containing 18 oxygen atoms (18-ring channels) has been synthesized, but in the search for large-pore zeolites, most of the materials which have been synthesized up to now contain only 14-ring channels; the synthesis of zeolites with larger ring structures has been believed to be hindered by the low Si-O-Si bond angles available. A silicogaloaluminate (ECR-34) with unidirectional 18-ring channels was recently reported, but exhibited low micropore volume, thus rendering the material less attractive for catalytic applications. Here we report the structure and catalytic activity of the silicogermanate zeolite ITQ-33; this material exhibits straight large pore channels with circular openings of 18-rings along the c axis interconnected by a bidirectional system of 10-ring channels, yielding a structure with very large micropore volume. The conditions for synthesis are easily accessible, but are not typical, and were identified using high-throughput techniques.     

Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice

Mice of the C57BL/6 strain are resistant to the development of skin squamous carcinomas (SCCs) induced by an activated Ras oncogene, whereas FVB/N mice are highly susceptible. The genetic basis of this difference in phenotype is unknown. Here we show that susceptibility to SCC is under the control of a carboxy-terminal polymorphism in the mouse Ptch gene. F1 hybrids between C57BL/6 and FVB/N strains ((B6FVB)F1) are resistant to Ras-induced SCCs, but resistance can be overcome either by elimination of the C57BL/6 Ptch allele (Ptch(B6)) or by overexpression of the FVB/N Ptch allele (Ptch(FVB)) in the epidermis of K5Hras-transgenic (B6FVB)F1 hybrid mice. The human Patched (PTCH) gene is a classical tumour suppressor gene for basal cell carcinomas and medulloblastomas, the loss of which causes increased signalling through the Sonic Hedgehog (SHH) pathway. SCCs that develop in PtchB6+/- mice do not lose the wild-type Ptch gene or show evidence of increased SHH signalling. Although Ptch(FVB) overexpression can promote SCC formation, continued expression is not required for tumour maintenance, suggesting a role at an early stage of tumour cell lineage commitment. The Ptch polymorphism affects Hras-induced apoptosis, and binding to Tid1, the mouse homologue of the Drosophila l(2)tid tumour suppressor gene. We propose that Ptch occupies a critical niche in determining basal or squamous cell lineage, and that both tumour types can arise from the same target cell depending on carcinogen exposure and host genetic background.     

Effect of dihydroergocristine infusion on tolbutamide-induced insulin secretion in man.

The insulinemic response to 1 g of tolbutamide i.v. is greatly enhanced (+ 145%) after a 60-min infusion of the alpha-lytic dihydrogenated ergot alkaloid, dihydroergocristine (83.3 micrograms/min, corresponding to a total dose of 5 mg) in 7 healthy subjects. No differences are observed in the glycemic responses.