The nature of aquatic landscapes in the Miocene of western Amazonia: An integrated palaeontological and geochemical approach

The Miocene Pebas Formation from the section Santa Rosa de Pichana (Loreto, Peru) was investigated using a combination of analyses of sedimentary facies, molluscan communities and taphonomy, and stable isotopes of both entire shells and growth bands in bivalves. Three sequences, comprising a succession of transgressive, maximum flooding and regressive/prograding intervals, are documented. Molluscs are most common in the transgressive/highstand intervals and are almost absent in regressive/prograding intervals. The fauna is dominated by endemic Pebasian species, such as Pachydon and Dyris spp. The nature of the deposits as well as the availability of oxygen varied in a predictable way within each of the sequences and determined the nature of the assemblages. Highest diversity was reached in the late transgressive phase before the development of dysoxia that was widespread during the late highstand and early regressive/prograding phase. The mollusc and isotope data show no indications of elevated salinities, in contrast to ichnofossils found in the section. This discrepancy is interpreted to result either from temporal separation of the ichnofossils and the mollusc fossils or from evolution beyond usual ecological tolerances of taxa that produced these ichnofossils into freshwater settings

Dual action antifungal small molecule modulates multidrug efflux and TOR signaling.

There is an urgent need for new strategies to treat invasive fungal infections, which are a leading cause of human mortality. Here, we establish two activities of the natural product beauvericin, which potentiates the activity of the most widely deployed class of antifungal against the leading human fungal pathogens, blocks the emergence of drug resistance, and renders antifungal-resistant pathogens responsive to treatment in mammalian infection models. Harnessing genome sequencing of beauvericin-resistant mutants, affinity purification of a biotinylated beauvericin analog, and biochemical and genetic assays reveals that beauvericin blocks multidrug efflux and inhibits the global regulator TORC1 kinase, thereby activating the protein kinase CK2 and inhibiting the molecular chaperone Hsp90. Substitutions in the multidrug transporter Pdr5 that enable beauvericin efflux impair antifungal efflux, thereby impeding resistance to the drug combination. Thus, dual targeting of multidrug efflux and TOR signaling provides a powerful, broadly effective therapeutic strategy for treating fungal infectious disease that evades resistance

Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions

Rho GTPases are central regulators of the cytoskeleton and, in humans, are controlled by 145 multidomain guanine nucleotide exchange factors (RhoGEFs) and GTPase-activating proteins (RhoGAPs). How Rho signalling patterns are established in dynamic cell spaces to control cellular morphogenesis is unclear. Through a family-wide characterization of substrate specificities, interactomes and localization, we reveal at the systems level how RhoGEFs and RhoGAPs contextualize and spatiotemporally control Rho signalling. These proteins are widely autoinhibited to allow local regulation, form complexes to jointly coordinate their networks and provide positional information for signalling. RhoGAPs are more promiscuous than RhoGEFs to confine Rho activity gradients. Our resource enabled us to uncover a multi-RhoGEF complex downstream of G-protein-coupled receptors controlling CDC42-RHOA crosstalk. Moreover, we show that integrin adhesions spatially segregate GEFs and GAPs to shape RAC1 activity zones in response to mechanical cues. This mechanism controls the protrusion and contraction dynamics fundamental to cell motility. Our systems analysis of Rho regulators is key to revealing emergent organization principles of Rho signalling