Dynamics of the p53-Mdm2 feedback loop in individual cells

The tumor suppressor p53, one of the most intensely investigated proteins, is usually studied by experiments that are averaged over cell populations, potentially masking the dynamic behavior in individual cells. We present a system for following, in individual living cells, the dynamics of p53 and its negative regulator Mdm2 (refs. 1,4-7): this system uses functional p53-CFP and Mdm2-YFP fusion proteins and time-lapse fluorescence microscopy. We found that p53 was expressed in a series of discrete pulses after DNA damage. Genetically identical cells had different numbers of pulses: zero, one, two or more. The mean height and duration of each pulse were fixed and did not depend on the amount of DNA damage. The mean number of pulses, however, increased with DNA damage. This approach can be used to study other signaling systems and suggests that the p53-Mdm2 feedback loop generates a 'digital' clock that releases well-timed quanta of p53 until damage is repaired or the cell dies.     

A dynamic upper atmosphere of Venus as revealed by VIRTIS on Venus Express

The upper atmosphere of a planet is a transition region in which energy is transferred between the deeper atmosphere and outer space. Molecular emissions from the upper atmosphere (90-120 km altitude) of Venus can be used to investigate the energetics and to trace the circulation of this hitherto little-studied region. Previous spacecraft and ground-based observations of infrared emission from CO2, O2 and NO have established that photochemical and dynamic activity controls the structure of the upper atmosphere of Venus. These data, however, have left unresolved the precise altitude of the emission owing to a lack of data and of an adequate observing geometry. Here we report measurements of day-side CO2 non-local thermodynamic equilibrium emission at 4.3 microm, extending from 90 to 120 km altitude, and of night-side O2 emission extending from 95 to 100 km. The CO2 emission peak occurs at approximately 115 km and varies with solar zenith angle over a range of approximately 10 km. This confirms previous modelling, and permits the beginning of a systematic study of the variability of the emission. The O2 peak emission happens at 96 km +/- 1 km, which is consistent with three-body recombination of oxygen atoms transported from the day side by a global thermospheric sub-solar to anti-solar circulation, as previously predicted.     

Genetic variation near IRS1 associates with reduced adiposity and an impaired metabolic profile

Genome-wide association studies have identified 32 loci influencing body mass index, but this measure does not distinguish lean from fat mass. To identify adiposity loci, we meta-analyzed associations between ～2.5 million SNPs and body fat percentage from 36,626 individuals and followed up the 14 most significant (P < 10(-6)) independent loci in 39,576 individuals. We confirmed a previously established adiposity locus in FTO (P = 3 × 10(-26)) and identified two new loci associated with body fat percentage, one near IRS1 (P = 4 × 10(-11)) and one near SPRY2 (P = 3 × 10(-8)). Both loci contain genes with potential links to adipocyte physiology. Notably, the body-fat-decreasing allele near IRS1 is associated with decreased IRS1 expression and with an impaired metabolic profile, including an increased visceral to subcutaneous fat ratio, insulin resistance, dyslipidemia, risk of diabetes and coronary artery disease and decreased adiponectin levels. Our findings provide new insights into adiposity and insulin resistance.     

ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTS-like proteins in TGF-beta bioavailability regulation

Geleophysic dysplasia is an autosomal recessive disorder characterized by short stature, brachydactyly, thick skin and cardiac valvular anomalies often responsible for an early death. Studying six geleophysic dysplasia families, we first mapped the underlying gene to chromosome 9q34.2 and identified five distinct nonsense and missense mutations in ADAMTSL2 (a disintegrin and metalloproteinase with thrombospondin repeats-like 2), which encodes a secreted glycoprotein of unknown function. Functional studies in HEK293 cells showed that ADAMTSL2 mutations lead to reduced secretion of the mutated proteins, possibly owing to the misfolding of ADAMTSL2. A yeast two-hybrid screen showed that ADAMTSL2 interacts with latent TGF-beta-binding protein 1. In addition, we observed a significant increase in total and active TGF-beta in the culture medium as well as nuclear localization of phosphorylated SMAD2 in fibroblasts from individuals with geleophysic dysplasia. These data suggest that ADAMTSL2 mutations may lead to a dysregulation of TGF-beta signaling and may be the underlying mechanism of geleophysic dysplasia.     

A guest-free germanium clathrate

The challenges associated with synthesizing expanded semiconductor frameworks with cage-like crystal structures continue to be of interest. Filled low-density germanium and silicon framework structures have distinct properties that address important issues in thermoelectric phonon glass-electron crystals, superconductivity and the possibility of Kondo insulators. Interest in empty framework structures of silicon and germanium is motivated by their predicted wide optical bandgaps of the same magnitude as quantum dots and porous silicon, making them and their alloys promising materials for silicon-based optoelectronic devices. Although almost-empty Na(1-x)Si136 has already been reported, the synthesis of guest-free germanium clathrate has so far been unsuccessful. Here we report the high-yield synthesis and characteristics of germanium with the empty clathrate-II structure through the oxidation of Zintl anions in ionic liquids under ambient conditions. The approach demonstrates the potential of ionic liquids as media for the reactions of polar intermetallic phases.