Immunogenicity of a highly attenuated MVA smallpox vaccine and protection against monkeypox

The potential use of smallpox as a biological weapon has led to the production and stockpiling of smallpox vaccine and the immunization of some healthcare workers. Another public health goal is the licensing of a safer vaccine that could benefit the millions of people advised not to take the current one because they or their contacts have increased susceptibility to severe vaccine side effects. As vaccines can no longer be tested for their ability to prevent smallpox, licensing will necessarily include comparative immunogenicity and protection studies in non-human primates. Here we compare the highly attenuated modified vaccinia virus Ankara (MVA) with the licensed Dryvax vaccine in a monkey model. After two doses of MVA or one dose of MVA followed by Dryvax, antibody binding and neutralizing titres and T-cell responses were equivalent or higher than those induced by Dryvax alone. After challenge with monkeypox virus, unimmunized animals developed more than 500 pustular skin lesions and became gravely ill or died, whereas vaccinated animals were healthy and asymptomatic, except for a small number of transient skin lesions in animals immunized only with MVA.     

Mutations in SEC63 cause autosomal dominant polycystic liver disease

Mutations in PRKCSH, encoding the beta-subunit of glucosidase II, an N-linked glycan-processing enzyme in the endoplasmic reticulum (ER), cause autosomal dominant polycystic liver disease. We found that mutations in SEC63, encoding a component of the protein translocation machinery in the ER, also cause this disease. These findings are suggestive of a role for cotranslational protein-processing pathways in maintaining epithelial luminal structure and implicate noncilial ER proteins in human polycystic disease.     

The molecular nature of the zebrafish tail organizer

Based on grafting experiments, Mangold and Spemann showed the dorsal blastopore lip of an amphibian gastrula to be able to induce a secondary body axis. The equivalent of this organizer region has been identified in different vertebrates including teleosts. However, whereas the graft can induce ectopic head and trunk, endogenous and ectopic axes fuse in the posterior part of the body, raising the question of whether a distinct organizer region is necessary for tail development. Here we reveal, by isochronic and heterochronic transplantation, the existence of a tail organizer deriving from the ventral margin of the zebrafish embryo, which is independent of the dorsal Spemann organizer. Loss-of-function experiments reveal that bone morphogenetic protein (BMP), Nodal and Wnt8 signalling pathways are required for tail development. Moreover, stimulation of naive cells by a combination of BMP, Nodal and Wnt8 mimics the tail-organizing activity of the ventral margin and induces surrounding tissues to become tail. In contrast to induction of the vertebrate head, known to result from the triple inhibition of BMP, Nodal and Wnt, here we show that induction of the tail results from the triple stimulation of BMP, Nodal and Wnt8 signalling pathways.     

146Sm-142Nd evidence from Isua metamorphosed sediments for early differentiation of the Earth's mantle

Application of the 147Sm-143Nd chronometer (half-life of 106 Gyr) suggests that large-scale differentiation of the Earth's mantle may have occurred during the first few hundred million years of its history. However, the signature of mantle depletion found in early Archaean rocks is often obscured by uncertainties resulting from open-system behaviour of the rocks during later high-grade metamorphic events. Hence, although strong hints exist regarding the presence of differentiated silicate reservoirs before 4.0 Gyr ago, both the nature and age of early mantle differentiation processes remain largely speculative. Here we apply short-lived 146Sm-142Nd chronometry (half-life of 103 Myr) to early Archaean rocks using ultraprecise measurement of Nd isotope ratios. The analysed samples are well-preserved metamorphosed sedimentary rocks from the 3.7-3.8-Gyr Isua greenstone belt of West Greenland. Our coupled isotopic calculations, combined with an initial epsilon 143Nd value from ref. 6, constrain the mean age of mantle differentiation to 4,460 +/- 115 Myr. This early Sm/Nd fractionation probably reflects differentiation of the Earth's mantle during the final stage of terrestrial accretion.     

A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease

Mice that overexpress the human mutant amyloid precursor protein (hAPP) show learning deficits, but the apparent lack of a relationship between these deficits and the progressive beta-amyloid plaque formation that the hAPP mice display is puzzling. In the water maze, hAPP mice are impaired before and after amyloid plaque deposition. Here we show, using a new water-maze training protocol, that PDAPP mice also exhibit a separate age-related deficit in learning a series of spatial locations. This impairment correlates with beta-amyloid plaque burden and is shown in both cross-sectional and longitudinal experimental designs. Cued navigation and object-recognition memory are normal. These findings indicate that A beta overexpression and/or A beta plaques are associated with disturbed cognitive function and, importantly, suggest that some but not all forms of learning and memory are suitable behavioural assays of the progressive cognitive deficits associated with Alzheimer's-disease-type pathologies.     

Gordon Pask's Conversation Theory: A Domain Independent Constructivist Model of Human Knowing

Although it is conceded (as argued by many)that distinct knowledge domains do presentparticular problems of coming to know, in thispaper it is argued that it is possible (anduseful) to construct a domain independent modelof the processes of coming to know, one inwhich observers share understandings and do soin agreed ways. The model in question is partof the conversation theory (CT) of Gordon Pask. CT, as a theory of theory construction andcommunication, has particular relevance forfoundational issues in science and scienceeducation. CT explicitly propounds a ``radicalconstructivist' (RC) epistemology. A briefaccount is given of the main tenets of RC andCT's place in that tradition and the traditionsof cybernetics. The paper presents a briefnon-technical account of the main concepts ofCT including elaborations by Laurillard andHarri-Augstein and Thomas. As part of CT, Pask also elaborated a methodology – knowledgeand task analysis – for analysing the structureof different knowledge domains; thismethodology is sketched in outline.     

Gene silencing in cancer by histone H3 lysine 27 trimethylation independent of promoter DNA methylation

Epigenetic silencing in cancer cells is mediated by at least two distinct histone modifications, polycomb-based histone H3 lysine 27 trimethylation (H3K27triM) and H3K9 dimethylation. The relationship between DNA hypermethylation and these histone modifications is not completely understood. Using chromatin immunoprecipitation microarrays (ChIP-chip) in prostate cancer cells compared to normal prostate, we found that up to 5% of promoters (16% CpG islands and 84% non-CpG islands) were enriched with H3K27triM. These genes were silenced specifically in prostate cancer, and those CpG islands affected showed low levels of DNA methylation. Downregulation of the EZH2 histone methyltransferase restored expression of the H3K27triM target genes alone or in synergy with histone deacetylase inhibition, without affecting promoter DNA methylation, and with no effect on the expression of genes silenced by DNA hypermethylation. These data establish EZH2-mediated H3K27triM as a mechanism of tumor-suppressor gene silencing in cancer that is potentially independent of promoter DNA methylation.     

IgG purification to measure the level of an iodinated thyroglobulin peptide, the 3,5,3',5' tetraiodo-l-tyrosyl-l-tyrosine in human serum

Antibodies reacting with 3,5,3',5' tetraiodo-l-tyrosyl-l-tyrosine (I2Tyr-I2Tyr) were elicited in rabbits by immunization with an oxidized yeast conjugate coupled with I2Tyr-I2Tyr. Ion-exchange chromatography was used to purify immunoglobulins, in order to improve the specificity in measurement of I2Tyr-I2Tyr level in patient serum. IgG binding capacity versus I2Tyr-I2Tyr was considerably increased after immunoglobulin purification.     

AN EXPONENTIAL INEQUALITY FOR AUTOREGRESSIVE PROCESSES IN ADAPTIVE TRACKING

A wide range of literature concerning classical asymptotic properties for linear models with adaptive control is available, such as strong laws of large numbers or central limit theorems. Unfortunately, in contrast with the situation without control, it appears to be impossible to find sharp asymptotic or nonasymptotic properties such as large deviation principles or exponential inequalities. Our purpose is to provide a first step towards that direction by proving a very simple exponential inequality for the standard least squares estimator of the unknown parameter of Gaussian autoregressive process in adaptive tracking.     

Characterization of 64-, 123- and 182-base-pair exons in the mouse alpha 2(IV) collagen gene

Genes encoding types I, II and III collagens (fibrillar collagens) contain many discrete-size exons, most of them 54 base pairs (bp) long, in addition to the 45-, 99-, 108- and 162-bp exons. It has been suggested that these collagen genes evolved from an ancestral coding unit of 54 bp. Type IV collagen is a specific component of basement membranes and contains two genetically distinct polypeptides, the alpha 1(IV) and alpha 2(IV) chains. It differs from the types I-III collagens in that it contains interruptions in the Gly-X-Y repeat sequence and does not form ordered fibrillar structures. We have isolated complementary DNA and genomic clones for the mouse alpha 2(IV) collagen chain and here characterize 64-, 123- and 182-bp exons in the Gly-X-Y coding domain of the gene. The data suggest that the alpha 2(IV) collagen gene may have evolved differently from those encoding the fibrillar collagens.