An Impermeant Ganetespib Analog Inhibits Extracellular Hsp90-Mediated Cancer Cell Migration that Involves Lysyl Oxidase 2-like Protein

Extracellular Hsp90 (eHsp90) activates a number of client proteins outside of cancer cells required for migration and invasion. Therefore, eHsp90 may serve as a novel target for anti-metastatic drugs as its inhibition using impermeant Hsp90 inhibitors would not affect the numerous vital intracellular Hsp90 functions in normal cells. While some eHsp90 clients are known, it is important to establish other proteins that act outside the cell to validate eHsp90 as a drug target to limit cancer spread. Using mass spectrometry we identified two precursor proteins Galectin 3 binding protein (G3BP) and Lysyl oxidase 2-like protein (LOXL2) that associate with eHsp90 in MDA-MB231 breast cancer cell conditioned media and confirmed that LOXL2 binds to eHsp90 in immunoprecipitates. We introduce a novel impermeant Hsp90 inhibitor STA-12-7191 derived from ganetespib and show that it is markedly less toxic to cells and can inhibit cancer cell migration in a dose dependent manner. We used STA-12-7191 to test if LOXL2 and G3BP are potential eHsp90 clients. We showed that while LOXL2 can increase wound healing and compensate for STA-12-7191-mediated inhibition of wound closure, addition of G3BP had no affect on this assay. These findings support of role for LOXL2 in eHsp90 stimulated cancer cell migration and provide preliminary evidence for the use of STA-12-7191 to inhibit eHsp90 to limit cancer invasion

Indicators of scientific value: An under-recognised ecosystem service of coastal and marine habitats

Coastal ecosystems provide a broad range of ecosystem services, which can be used to justify habitat conservation. The cultural ecosystem services of coastal ecosystems are generally underappreciated, and this is particularly the case when quantifying their scientific value. We created a tiered set of indicators to quantify scientific value spatially, and tested them using the case study of the island nation of Singapore. We conducted a systematic review of research papers, book chapters, conference reports and academic theses produced across 10 coastal ecosystems in Singapore, including mangroves, seagrasses, coral reefs, beaches and artificial coastal structures. At least 656 articles have been produced on Singapore’s coastal zone, with 2201 unique observations, showing that scientific value is spatially variable along Singapore’s coastline. Novel indicators such as the Site Impact Factor are able to differentiate scientific value between sites. This method has shed light on an under-recognised, but important cultural ecosystem service, and is applicable to other spatially-bounded coastal, marine and terrestrial landscapes

Aged-Related Neural Changes During Memory Conjunction Errors

Human behavioral studies demonstrate that healthy aging is often accompanied by increases in memory distortions or errors. Here we used event-related functional MRI to examine the neural basis of age-related memory distortions. We used the memory conjunction error paradigm, a laboratory procedure known to elicit high levels of memory errors. For older adults, right parahippocampal gyrus showed significantly greater activity during false than during accurate retrieval. We observed no regions in which activity was greater during false than during accurate retrieval for young adults. Young adults, however, showed significantly greater activity than old adults during accurate retrieval in right hippocampus. By contrast, older adults demonstrated greater activity than young adults during accurate retrieval in right inferior and middle prefrontal cortex. These data are consistent with the notion that age-related memory conjunction errors arise from dysfunction of hippocampal system mechanisms, rather than impairments in frontally-mediated monitoring processes.Psycholog

Model-driven analysis of experimentally determined growth phenotypes for 465 yeast gene deletion mutants under 16 different conditions

An iterative approach that integrates high-throughput measurements of yeast deletion mutants and flux balance model predictions improves understanding of both experimental and computational results

Blood Oxygen Level-Dependent (BOLD) MRI in Glomerular Disease

Renal hypoxia has recently been implicated as a key contributor and indicator of various glomerular diseases. As such, monitoring changes in renal oxygenation in these disorders may provide an early diagnostic advantage that could prevent potential adverse outcomes. Blood oxygen level-dependent magnetic resonance imaging (BOLD MRI) is an emerging noninvasive technique for assessing renal oxygenation in glomerular disease. Although BOLD MRI has produced promising initial results for the use in certain renal pathologies, the use of BOLD imaging in glomerular diseases, including primary and secondary nephrotic and nephritic syndromes, is relatively unexplored. Early BOLD studies on primary nephrotic syndrome, nephrotic syndrome secondary to diabetes mellitus, and nephritic syndrome secondary to systemic lupus erythematosus have shown promising results to support its future clinical utility. In this review, we outline the advancements made in understanding the use of BOLD MRI for the assessment, diagnosis, and screening of these pathologies