Dimerization of FIR upon FUSE DNA binding suggests a mechanism of c-myc inhibition.

c-myc is essential for cell homeostasis and growth but lethal if improperly regulated. Transcription of this oncogene is governed by the counterbalancing forces of two proteins on TFIIH--the FUSE binding protein (FBP) and the FBP-interacting repressor (FIR). FBP and FIR recognize single-stranded DNA upstream of the P1 promoter, known as FUSE, and influence transcription by oppositely regulating TFIIH at the promoter site. Size exclusion chromatography coupled with light scattering reveals that an FIR dimer binds one molecule of single-stranded DNA. The crystal structure confirms that FIR binds FUSE as a dimer, and only the N-terminal RRM domain participates in nucleic acid recognition. Site-directed mutations of conserved residues in the first RRM domain reduce FIR's affinity for FUSE, while analogous mutations in the second RRM domain either destabilize the protein or have no effect on DNA binding. Oppositely oriented DNA on parallel binding sites of the FIR dimer results in spooling of a single strand of bound DNA, and suggests a mechanism for c-myc transcriptional control.

Structure-based discovery of a family of synthetic cyclophilin inhibitors showing a cyclosporin-A phenotype in Caenorhabditis elegans.

Cyclophilins, which are found in all cellular compartments and with diverse biological roles, are now drug targets for a number of diseases including HIV infection, malaria and ischaemia. We used the database-mining program LIDAEUS and in silico screening to discover the dimedone family of inhibitors which show a conserved 'ball and socket' binding mode with a dimethyl group in the hydrophobic binding pocket of human cyclophilin A (CypA) mimicking a key interaction of the natural inhibitor cyclosporin A (CsA). The most potent derivative binds CypA with a K(d) of 11.2+/-9.2 microM and an IC50 for activity against Caenorhabditis elegans (C. elegans) of 190 microM compared to 28 microM for CsA. These dimedone analogues provide a new scaffold for the synthesis of families of peptidomimetic molecules with potential activity against HIV, malaria, and helminth parasite infections.

Time-varying land subsidence detected by radar altimetry: California, Taiwan and north China.

Contemporary applications of radar altimetry include sea-level rise, ocean circulation, marine gravity, and icesheet elevation change. Unlike InSAR and GNSS, which are widely used to map surface deformation, altimetry is neither reliant on highly temporally-correlated ground features nor as limited by the available spatial coverage, and can provide long-term temporal subsidence monitoring capability. Here we use multi-mission radar altimetry with an approximately 23 year data-span to quantify land subsidence in cropland areas. Subsidence rates from TOPEX/POSEIDON, JASON-1, ENVISAT, and JASON-2 during 1992-2015 show time-varying trends with respect to displacement over time in California's San Joaquin Valley and central Taiwan, possibly related to changes in land use, climatic conditions (drought) and regulatory measures affecting groundwater use. Near Hanford, California, subsidence rates reach 18 cm yr(-1) with a cumulative subsidence of 206 cm, which potentially could adversely affect operations of the planned California High-Speed Rail. The maximum subsidence rate in central Taiwan is 8 cm yr(-1). Radar altimetry also reveals time-varying subsidence in the North China Plain consistent with the declines of groundwater storage and existing water infrastructure detected by the Gravity Recovery And Climate Experiment (GRACE) satellites, with rates reaching 20 cm yr(-1) and cumulative subsidence as much as 155 cm.