The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS) are neurodegenerative conditions that affect large motor neurons of the central nervous system. We have identified a familial juvenile PLS (JPLS) locus overlapping the previously identified ALS2 locus on chromosome 2q33. We report two deletion mutations in a new gene that are found both in individuals with ALS2 and those with JPLS, indicating that these conditions have a common genetic origin. The predicted sequence of the protein (alsin) may indicate a mechanism for motor-neuron degeneration, as it may include several cell-signaling motifs with known functions, including three associated with guanine-nucleotide exchange factors for GTPases (GEFs).     

AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1

The Wnt signaling pathway is essential for development and organogenesis. Wnt signaling stabilizes beta-catenin, which accumulates in the cytoplasm, binds to 1-cell factor (TCF; also known as lymphocyte enhancer-binding factor, LEF) and then upregulates downstream genes. Mutations in CTNNB1 (encoding beta-catenin) or APC (adenomatous polyposis coli) have been reported in human neoplasms including colon cancers and hepatocellular carcinomas (HCCs). Because HCC5 tend to show accumulation of beta-catenin more often than mutations in CTNNB1, we looked for mutations in AXIN1, encoding a key factor for Wnt signaling, in 6 HCC cell lines and 100 primary HCC5. Among the 4 cell lines and 87 HCC5 in which we did not detect CTNNB1 mutations, we identified AXIN1 mutations in 3 cell lines and 6 mutations in 5 of the primary HCCs. In cell lines containing mutations in either gene, we observed increased DNA binding of TCF associated with beta-catenin in nuclei. Adenovirus mediated gene transfer of wild-type AXINI induced apoptosis in hepatocellular and colorectal cancer cells that had accumulated beta-catenin as a consequence of either APC, CTNNB1 or AXIN1 mutation, suggesting that axin may be an effective therapeutic molecule for suppressing growth of hepatocellular and colorectal cancers.     

Superconductivity in two-dimensional CoO2 layers

Since the discovery of high-transition-temperature (high-T(c)) superconductivity in layered copper oxides, many researchers have searched for similar behaviour in other layered metal oxides involving 3d-transition metals, such as cobalt and nickel. Such attempts have so far failed, with the result that the copper oxide layer is thought to be essential for superconductivity. Here we report that Na(x)CoO2*yH2O (x approximately 0.35, y approximately 1.3) is a superconductor with a T(c) of about 5 K. This compound consists of two-dimensional CoO2 layers separated by a thick insulating layer of Na+ ions and H2O molecules. There is a marked resemblance in superconducting properties between the present material and high-T(c) copper oxides, suggesting that the two systems have similar underlying physics.     

A single GTP-binding protein regulates K+-channels coupled with dopamine, histamine and acetylcholine receptors

Recently, a GTP-binding protein sensitive to islet activating protein (IAP) has been suggested to be important in producing K+-currents when the muscarinic receptor of the atrial muscle is activated by acetylcholine (ACh). Here we confirm the blocking effects of IAP and GTP gamma S (a nonhydrolysable analogue of GTP) on the ACh-induced K+-current recorded from the ganglion cells of the sea slug Aplysia and compare their effects on histamine (HA)-induced and dopamine (DA)-induced K+-currents. Intracellular injections of IAP irreversibly and selectively block the openings of K+-channels activated by either ACh, HA, or DA without affecting the resting potential or conductance states of the membranes. Intracellular application of GTP gamma S alone caused extremely slow, irreversible opening of K+-channels; however, repetitive receptor activations significantly increase the rate of the GTP gamma S effect. These results strongly suggest that a GTP-binding protein such as Gi regulates the opening of K+-channels coupled with these receptors.     

Plakorin,a potent Ca2+-ATPase activator from the Okinawan marine spongePlakortis sp.

Summary A new cyclic peroxide, plakorin, which is a potent sarcoplasmic reticulum (SR) Ca^a+-ATPase activator has been isolated from the Okinawan marine spongePlakortis sp., its structure was elucidated on the basis of spectral data.Acknowledgments. We thank Ms M. Hamashima and Ms A. Muroyama for their technical assistance.     

Symbioramide, a novel Ca2+-ATPase activator from the cultured dinoflagellate Symbiodinium sp

A novel sphingosine derivative, symbioramide, has been isolated from the laboratory-cultured dinoflagellate Symbiodinium sp. as a sarcoplasmic reticulum (SR)Ca2+-ATPase activator, and its structure elucidated to be 1 on the basis of spectral and chemical means.     

Preferential mutation of paternally derived RB gene as the initial event in sporadic osteosarcoma

Successive loss of function of both alleles of the retinoblastoma susceptibility gene (RB) on human chromosome 13 seems to be critical in the development of retinoblastoma and osteosarcoma. In cases where the tumour is familial and susceptibility is inherited, a mutation in one of the alleles is carried in the germline. We have recently shown that cytogenetically visible germline mutations are usually in the paternally derived gene. Such a bias would not be expected for sporadic (non-familial) tumours, where both mutations occur in somatic tissue, but there has been some indication of a bias towards initial somatic mutation in the paternally derived gene on chromosome 11 in sporadic Wilms tumour. We have now examined 13 sporadic osteosarcomas and find evidence which indicates that in 12 cases the initial mutation was in the paternal gene, suggesting the involvement of germinal imprinting in producing the differential susceptibility of the two genes to mutation.     

Ultrastructural localization of microfibrillar fibulin-1 and fibulin-2 during heart development indicates a switch in molecular associations

The microfibrillar proteins fibulin-1 and fibulin-2 were previously identified as prominent components of the endocardial cushion tissue (ECT) during heart development and shown to persist in adult valves and septa. Immunogold staining has now been used to compare their localization in embryonic (days 9–11) and adult mouse heart with that of fibronectin and the chondroitin sulphate proteoglycan versican. All four proteins were deposited in the ECT, which consists of a hyaluronan-rich, mainly unstructured matrix, but were barely detectable in myocardial basement membranes or within endocardial cells. Digestion with hyaluronate lyase selectively released the fibulins and versican but not fibronectin from the ECT. Yet neither of the two fibulins bound to hyluronan in solid-phase assays, in contrast to versican. In the adult heart valve, all four proteins could be detected close to cross-striated collagen fibrils or microfibrils, but only versican was lost upon exposure to hyaluronate lyase. The data indicate that fibulins are associated with the hyaluronan-matrix of ECT through a bridge of versican, but that this association changes upon valve development to another supramolecular, presumably microfibrillar organization based on fibronectin and/or fibrillins. Received 3 April 1998; accepted 8 April 1998