Caveolin-1-Enhanced Motility and Focal Adhesion Turnover Require Tyrosine-14 but Not Accumulation to the Rear in Metastatic Cancer Cells

Caveolin-1 is known to promote cell migration, and increased caveolin-1 expression is associated with tumor progression and metastasis. In fibroblasts, caveolin-1 polarization and phosphorylation of tyrosine-14 are essential to promote migration. However, the role of caveolin-1 in migration of metastatic cells remains poorly defined. Here, caveolin-1 participation in metastatic cell migration was evaluated by shRNA targeting of endogenous caveolin-1 in MDA-MB-231 human breast cancer cells and ectopic expression in B16-F10 mouse melanoma cells. Depletion of caveolin-1 in MDA-MB-231 cells reduced, while expression in B16-F10 cells promoted migration, polarization and focal adhesion turnover in a sequence of events that involved phosphorylation of tyrosine-14 and Rac-1 activation. In B16-F10 cells, expression of a non-phosphorylatable tyrosine-14 to phenylalanine mutant failed to recapitulate the effects observed with wild-type caveolin-1. Alternatively, treatment of MDA-MB-231 cells with the Src family kinase inhibitor PP2 reduced caveolin-1 phosphorylation on tyrosine-14 and cell migration. Surprisingly, unlike for fibroblasts, caveolin-1 polarization and re-localization to the trailing edge were not observed in migrating metastatic cells. Thus, expression and phosphorylation, but not polarization of caveolin-1 favor the highly mobile phenotype of metastatic cells

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

A 50,000-year record of lake-level variations and overflow from Owens Lake, eastern California, USA

A continuous lake-level curve was constructed for Owens Lake, eastern California by integrating lake-core data and shoreline geomorphology with new wind-wave and sediment entrainment modeling of lake-core sedimentology. This effort enabled refinement of the overflow history and development of a better understanding of the effects of regional and global climate variability on lake levels of the paleo-Owens River system during the last 50,000 years. The elevations of stratigraphic sites, plus lake bottom and spillway positions were corrected for vertical tectonic deformation using a differential fault-block model to estimate the absolute hydrologic change of the watershed-lake system. New results include 14C dating of mollusk shells in shoreline deposits, plus post-IR-IRSL dating of a suite of five beach ridges and OSL dating of spillway alluvial and deltaic deposits in deep boreholes. Geotechnical data show the overflow area is an entrenched channel that had erodible sills composed of unconsolidated fluvial-deltaic and alluvial sediment at elevations of ∼1113–1165 m above mean sea level. Owens Lake spilled most of the time at or near minimum sill levels, controlled by a bedrock sill at ∼1113 m. Nine major transgressions at ∼40.0, 38.7, 23.3, 19.3, 15.6, 13.8, 12.8, 11.6, and 10.6 ka reached levels ∼10–45 m above the bedrock sill. Several major regressions at or below the bedrock sill from 36.9 to 28.5 ka, and at ∼17.8, 12.9, and 10.4–8.8 ka indicate little to no overflow during these times. The latest period of overflow occurred ∼10–20 m above the bedrock sill from ∼8.4 to 6.4 ka that was followed by closed basin conditions after ∼6.4 ka. Previous lake core age-depth models were revised by accounting for sediment compaction and using no reservoir correction for open basin conditions, thereby reducing discrepancies between Owens Lake shoreline and lake-core proxy records. The integrated analysis provides a continuous 50 ka lake-level record of hydroclimate variability along the south-central Sierra Nevada that is consistent with other shoreline and speleothem records in the southwestern U.S