Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling

The adult stem cell marker Lgr5 and its relative Lgr4 are often co-expressed in Wnt-driven proliferative compartments. We find that conditional deletion of both genes in the mouse gut impairs Wnt target gene expression and results in the rapid demise of intestinal crypts, thus phenocopying Wnt pathway inhibition. Mass spectrometry demonstrates that Lgr4 and Lgr5 associate with the Frizzled/Lrp Wnt receptor complex. Each of the four R-spondins, secreted Wnt pathway agonists, can bind to Lgr4, -5 and -6. In HEK293 cells, RSPO1 enhances canonical WNT signals initiated by WNT3A. Removal of LGR4 does not affect WNT3A signalling, but abrogates the RSPO1-mediated signal enhancement, a phenomenon rescued by re-expression of LGR4, -5 or -6. Genetic deletion of Lgr4/5 in mouse intestinal crypt cultures phenocopies withdrawal of Rspo1 and can be rescued by Wnt pathway activation. Lgr5 homologues are facultative Wnt receptor components that mediate Wnt signal enhancement by soluble R-spondin proteins. These results will guide future studies towards the application of R-spondins for regenerative purposes of tissues expressing Lgr5 homologues.     

Use of Data Mining to Support the Development of Knowledge Intensive CAD

In order to compete in the global manufacturing mar ke t, agility is the only possible solution to response to the fragmented market se gments and frequently changed customer requirements. However, manufacturing agil ity can only be attained through the deployment of knowledge. To embed knowledge into a CAD system to form a knowledge intensive CAD (KIC) system is one of way to enhance the design compatibility of a manufacturing company. The most difficu lt phase to develop a KIC system is to capitalize a ...     

Systematic identification of genomic markers of drug sensitivity in cancer cells

Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers for responses to targeted agents. Here, to uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines--which represent much of the tissue-type and genetic diversity of human cancers--with 130 drugs under clinical and preclinical investigation. In aggregate, we found that mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing's sarcoma cells harbouring the EWS (also known as EWSR1)-FLI1 gene translocation to poly(ADP-ribose) polymerase (PARP) inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.     

Subnanometre-resolution structure of the intact Thermus thermophilus H+-driven ATP synthase

Ion-translocating rotary ATPases serve either as ATP synthases, using energy from a transmembrane ion motive force to create the cell's supply of ATP, or as transmembrane ion pumps that are powered by ATP hydrolysis. The members of this family of enzymes each contain two rotary motors: one that couples ion translocation to rotation and one that couples rotation to ATP synthesis or hydrolysis. During ATP synthesis, ion translocation through the membrane-bound region of the complex causes rotation of a central rotor that drives conformational changes and ATP synthesis in the catalytic region of the complex. There are no structural models available for the intact membrane region of any ion-translocating rotary ATPase. Here we present a 9.7?? resolution map of the H(+)-driven ATP synthase from Thermus thermophilus obtained by electron cryomicroscopy of single particles in ice. The 600-kilodalton complex has an overall subunit composition of A(3)B(3)CDE(2)FG(2)IL(12). The membrane-bound motor consists of a ring of L subunits and the carboxy-terminal region of subunit I, which are equivalent to the c and a subunits of most other rotary ATPases, respectively. The map shows that the ring contains 12 L subunits and that the I subunit has eight transmembrane helices. The L(12) ring and I subunit have a surprisingly small contact area in the middle of the membrane, with helices from the I subunit making contacts with two different L subunits. The transmembrane helices of subunit I form bundles that could serve as half-channels across the membrane, with the first half-channel conducting protons from the periplasm to the L(12) ring and the second half-channel conducting protons from the L(12) ring to the cytoplasm. This structure therefore suggests the mechanism by which a transmembrane proton motive force is converted to rotation in rotary ATPases.     

Sister chromatid differential staining pattern in prematurely condensed chromosomes

Summary Application of sister chromatid differential (SCD) procedure on G₁, S and G₂ prematurely condensed chromosomes (PCC) of cells in the second and third cycle of DNA replication in medium containing BrdU reveals differential staining patterns characteristic of their respective stages in the cell cycle. These findings also suggest a structural similarity between PCC and metaphase chromosomes.Supported in part by grants from the National Foundation-March of Dimes (grant No. 1-327) and from the National Cancer Institute (grant No. CA-16480).     

A comparative study of the gastric ulcerogenic effects of stress and reserpine in rats with decreased stomach wall mast cell populations

Summary Stress-induced gastric glandular ulcers in rats appeared less severe than those evoked by reserpine, although glandular mucosal mast cell counts were equally decreased. Prior depletion of the glandular mucosal mast cell population confirmed the hypothesis that an additional mechanism contributes to reserpine ulceration.     

Acetaldehyde oxidation inDrosophila null-mutants for alcohol dehydrogenase

Summary Aldehyde dehydrogenase (ALDH) activity is demonstrated in four strains ofD. melanogaster lacking active alcohol dehydrogenase (ADH-null mutants). In the four strains, ALDH activities are similar to those found in a wild strain. It is concluded that ADH-null flies are able to detoxify acetaldehyde. This finding is discussed in relation with the dual function of ADH proposed recently.This work was supported by a grant from the Medical Research Council of Canada (MRC 6920) to Dr F. Garcin.     

Effect of cortisone or triiodothyronine administration to pregnant rats on lysosomal hydrolases in fetal forebrain and cerebellum

Summary Triiodothyronine injected daily to pregnant rats for the last week of gestation (50 g/100 g b.wt) increased the specific activities of 5 acid glycosidases in the fetal forebrain and cerebellum. Cortisone (50 mg/100 g b.wt) administered in the same period had no effect on cerebellum acid hydrolases, but decreased their activity in the forebrain.Supported by grant No. HD 08536 from the National Institutes of Health, Bethesda, Maryland.     

Pycnogenol enhances immune and haemopoietic functions in senescence-accelerated mice

Pycnogenol (procyanidin extracted from Pinus maritima) has been shown to be a potent free radical scavenger and an antioxidant phytochemical. The effects of pycnogenol on immune and haemopoietic dysfunction in senescence-accelerated mice (SAM), as a murine model of accelerated ageing, were determined. SAMP8, a strain of senile-prone mice, exhibit learning and memory deficits, immunodeficiency and dysfunction of the haemopoietic system. Oral feeding with pycnogenol for 2 months significantly improved their T- and B-cell function. Pycnogenol also augmented the proliferative capacity of haemopoietic progenitors of bone marrow in SAMP8. These data suggest that pycnogenol may be useful for either retardation or restoration of parameters associated with ageing. Received 3 July 1998; accepted 28 July 1998     

Utilizing Statistical Semantic Similarity Techniques for Ontology Mapping——with Applications to AEC Standard Models

The objective of this paper is to introduce three semi-automated approaches for ontology mapping using relatedness analysis techniques. In the architecture, engineering, and construction (AEC) industry, there exist a number of ontological standards to describe the semantics of building models. Although the standards share similar scopes of interest, the task of comparing and mapping concepts among standards is challenging due to their differences in terminologies and perspectives. Ontology mapping is therefore necessary to achieve information interoperability, which allows two or more information sources to exchange data and to re-use the data for further purposes. The attribute-based approach, corpus-based approach, and name-based approach presented in this paper adopt the statistical relatedness analysis techniques to discover related concepts from heterogeneous ontologies. A pilot study is conducted on IFC and CIS/2 ontologies to evaluate the approaches. Preliminary results show that the attribute-based approach outperforms the other two approaches in terms of precision and F-measure.