Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry

Hepatitis C virus (HCV) is a leading cause of cirrhosis and liver cancer worldwide. A better understanding of the viral life cycle, including the mechanisms of entry into host cells, is needed to identify novel therapeutic targets. Although HCV entry requires the CD81 co-receptor, and other host molecules have been implicated, at least one factor critical to this process remains unknown (reviewed in refs 1-3). Using an iterative expression cloning approach we identified claudin-1 (CLDN1), a tight junction component that is highly expressed in the liver, as essential for HCV entry. CLDN1 is required for HCV infection of human hepatoma cell lines and is the first factor to confer susceptibility to HCV when ectopically expressed in non-hepatic cells. Discrete residues within the first extracellular loop (EL1) of CLDN1, but not protein interaction motifs in intracellular domains, are critical for HCV entry. Moreover, antibodies directed against an epitope inserted in the CLDN1 EL1 block HCV infection. The kinetics of this inhibition indicate that CLDN1 acts late in the entry process, after virus binding and interaction with the HCV co-receptor CD81. With CLDN1 we have identified a novel key factor for HCV entry and a new target for antiviral drug development.     

Soluble polysialylated NCAM: a novel player of the innate immune system in the lung

Posttranslational modification of the neural cell adhesion molecule (NCAM) by polysialic acid (polySia) is well studied in the nervous system and described as a dynamic modulator of plastic processes like precursor cell migration, axon fasciculation, and synaptic plasticity. Here, we describe a novel function of polysialylated NCAM (polySia-NCAM) in innate immunity of the lung. In mature lung tissue of healthy donors, polySia was exclusively attached to the transmembrane isoform NCAM-140 and located to intracellular compartments of epithelial cells. In patients with chronic obstructive pulmonary disease, however, increased polySia levels and processing of the NCAM carrier were observed. Processing of polysialylated NCAM was reproduced in a mouse model by bleomycin administration leading to an activation of the inflammasome and secretion of interleukin (IL)-1β. As shown in a cell culture model, polySia-NCAM-140 was kept in the late trans-Golgi apparatus of lung epithelial cells and stimulation by IL-1β or lipopolysaccharide induced metalloprotease-mediated ectodomain shedding, resulting in the secretion of soluble polySia-NCAM. Interestingly, polySia chains of secreted NCAM neutralized the cytotoxic activity of extracellular histones as well as DNA/histone-network-containing “neutrophil extracellular traps”, which are formed during invasion of microorganisms. Thus, shedding of polySia-NCAM by lung epithelial cells may provide a host-protective mechanism to reduce tissue damage during inflammatory processes.     

Henry More and the development of absolute time

This paper explores the nature, development and influence of the first English account of absolute time, put forward in the mid-seventeenth century by the ‘Cambridge Platonist’ Henry More. Against claims in the literature that More does not have an account of time, this paper sets out More's evolving account and shows that it reveals the lasting influence of Plotinus. Further, this paper argues that More developed his views on time in response to his adoption of Descartes' vortex cosmology and cosmogony, providing new evidence of More's wider project to absorb Cartesian natural philosophy into his Platonic metaphysics. Finally, this paper argues that More should be added to the list of sources that later English thinkers – including Newton and Samuel Clarke – drew on in constructing their absolute accounts of time.     

Distribution, foraging behaviour, and capture results of the spotted bat ( Euderma maculatum ) in central Oregon

The spotted bat ( Euderma maculatum ) has been virtually unknown in Oregon despite the existence of potential habitat in many areas of the state. In 2002 and 2003 we searched for spotted bats along the John Day, Deschutes, and Crooked Rivers and at a remote dry canyon southeast of the city of Bend in central Oregon. The species was documented through the use of mist-nets, a bat detector, and recognition of audible spotted bat calls. Spotted bats were found at 11 locations in 6 Oregon counties. Nightly activity patterns of spotted bats were unpredictable. Spotted bats were found in 78% of search areas but on only 48% of survey nights. We observed spotted bats foraging above fields and low upland slopes adjacent to rivers and creeks and along the rims of cliffs. Estimated flying heights of spotted bats ranged from 3 m to 50 m aboveground. The species was difficult to capture and was captured only after considerable experimentation with methods and materials. Three spotted bats were captured toward the end of the project in 2003 and accounted for only 0.5% of all bats captured during the study. Although we attached radio transmitters to 2 spotted bats, we found no roost locations. We believe additional spotted bat surveys in Oregon are warranted, especially in higher-elevation habitats, but recommend that to increase their effectiveness, surveys accommodate the unique foraging behavior of the species.     

Demographic characteristics of American marten populations in Jackson Hole, Wyoming

Some American marten population characteristics (numbers, density, body weights, sex and age ratios, natality, mortality-survivorship, immigration-emigration, home ranges) were studied at four sites in the southern part of the Greater Yellowstone Ecosystem, Teton County, Wyoming, in 1975-1979. Ninety-eight different martens were examined. Males (n = 25) weighed 1,111 g (± 110 SD, range 875-1,235), whereas females (n = 17) averaged 743 g (± 83 SD, range 600-900). Live-trapping showed sex ratios of 1.5M:1.0F, whereas carcasses showed 3.0M:1.0F. Of 27males that were aged, 12 (44%) were less than 1 year old and 2 were 9-10 years old. Of 10 females, 6 were less than 1 year old and 1 was 12-13 years old. The mean length of time a male was present on the major study area was 144 days (± 266 SD, range 1-1,364), and for females it was 145 days (± 45 SD, range 1-560). Home ranges for six males averaged 3.2 km 2 (± 20 SD, range 0.7-5.8) on the main study area. Some management implications are given.     

HDAC2 and TXNL1 distinguish aneuploid from diploid colorectal cancers

DNA aneuploidy has been identified as a prognostic factor for epithelial malignancies. Further understanding of the translation of DNA aneuploidy into protein expression will help to define novel biomarkers to improve therapies and prognosis. DNA ploidy was assessed by image cytometry. Comparison of gel-electrophoresis-based protein expression patterns of three diploid and four aneuploid colorectal cancer cell lines detected 64 ploidy-associated proteins. Proteins were identified by mass spectrometry and subjected to Ingenuity Pathway Analysis resulting in two overlapping high-ranked networks maintaining Cellular Assembly and Organization, Cell Cycle, and Cellular Growth and Proliferation. CAPZA1, TXNL1, and HDAC2 were significantly validated by Western blotting in cell lines and the latter two showed expression differences also in clinical samples using a tissue microarray of normal mucosa (n?=?19), diploid (n?=?31), and aneuploid (n?=?47) carcinomas. The results suggest that distinct protein expression patterns, affecting TXNL1 and HDAC2, distinguish aneuploid with poor prognosis from diploid colorectal cancers.     

Adapting Salt Creek pupfish ( Cyprinodon salinus ) to fresh water

The Salt Creek pupfish, Cyprinodon salinus , is adapted to fresh water in aquaria.     

Edward Milne's influence on modern cosmology

During the 1930 and 1940s, the small world of cosmologists was buzzing with philosophical and methodological questions. The debate was stirred by Edward Milne's cosmological model, which was deduced from general principles that had no link with observation. Milne's approach was to have an important impact on the development of modern cosmology. But this article shows that it is an exaggeration to intimate, as some authors have done recently, that Milne's rationalism went on to infiltrate the discipline.