Base-excision repair of oxidative DNA damage

Maintaining the chemical integrity of DNA in the face of assault by oxidizing agents is a constant challenge for living organisms. Base-excision repair has an important role in preventing mutations associated with a common product of oxidative damage to DNA, 8-oxoguanine. Recent structural studies have shown that 8-oxoguanine DNA glycosylases use an intricate series of steps to locate and excise 8-oxoguanine lesions efficiently against a high background of undamaged bases. The importance of preventing mutations associated with 8-oxoguanine is shown by a direct association between defects in the DNA glycosylase MUTYH and colorectal cancer. The properties of other guanine oxidation products and the associated DNA glycosylases that remove them are now also being revealed.     

First-passage times in complex scale-invariant media

How long does it take a random walker to reach a given target point? This quantity, known as a first-passage time (FPT), has led to a growing number of theoretical investigations over the past decade. The importance of FPTs originates from the crucial role played by first encounter properties in various real situations, including transport in disordered media, neuron firing dynamics, spreading of diseases or target search processes. Most methods of determining FPT properties in confining domains have been limited to effectively one-dimensional geometries, or to higher spatial dimensions only in homogeneous media. Here we develop a general theory that allows accurate evaluation of the mean FPT in complex media. Our analytical approach provides a universal scaling dependence of the mean FPT on both the volume of the confining domain and the source-target distance. The analysis is applicable to a broad range of stochastic processes characterized by length-scale-invariant properties. Our theoretical predictions are confirmed by numerical simulations for several representative models of disordered media, fractals, anomalous diffusion and scale-free networks.     

Drosophila TCTP is essential for growth and proliferation through regulation of dRheb GTPase

Cellular growth and proliferation are coordinated during organogenesis. Misregulation of these processes leads to pathological conditions such as cancer. Tuberous sclerosis (TSC) is a benign tumour syndrome caused by mutations in either TSC1 or TSC2 tumour suppressor genes. Studies in Drosophila and other organisms have identified TSC signalling as a conserved pathway for growth control. Activation of the TSC pathway is mediated by Rheb (Ras homologue enriched in brain), a Ras superfamily GTPase. Rheb is a direct target of TSC2 and is negatively regulated by its GTPase-activating protein activity. However, molecules required for positive regulation of Rheb have not been identified. Here we show that a conserved protein, translationally controlled tumour protein (TCTP), is an essential new component of the TSC-Rheb pathway. Reducing Drosophila TCTP (dTCTP) levels reduces cell size, cell number and organ size, which mimics Drosophila Rheb (dRheb) mutant phenotypes. dTCTP is genetically epistatic to Tsc1 and dRheb, but acts upstream of dS6k, a downstream target of dRheb. dTCTP directly associates with dRheb and displays guanine nucleotide exchange activity with it in vivo and in vitro. Human TCTP (hTCTP) shows similar biochemical properties compared to dTCTP and can rescue dTCTP mutant phenotypes, suggesting that the function of TCTP in the TSC pathway is evolutionarily conserved. Our studies identify TCTP as a direct regulator of Rheb and a potential therapeutic target for TSC disease.     

Ultralow-power organic complementary circuits

The prospect of using low-temperature processable organic semiconductors to implement transistors, circuits, displays and sensors on arbitrary substrates, such as glass or plastics, offers enormous potential for a wide range of electronic products. Of particular interest are portable devices that can be powered by small batteries or by near-field radio-frequency coupling. The main problem with existing approaches is the large power consumption of conventional organic circuits, which makes battery-powered applications problematic, if not impossible. Here we demonstrate an organic circuit with very low power consumption that uses a self-assembled monolayer gate dielectric and two different air-stable molecular semiconductors (pentacene and hexadecafluorocopperphthalocyanine, F16CuPc). The monolayer dielectric is grown on patterned metal gates at room temperature and is optimized to provide a large gate capacitance and low gate leakage currents. By combining low-voltage p-channel and n-channel organic thin-film transistors in a complementary circuit design, the static currents are reduced to below 100 pA per logic gate. We have fabricated complementary inverters, NAND gates, and ring oscillators that operate with supply voltages between 1.5 and 3 V and have a static power consumption of less than 1 nW per logic gate. These organic circuits are thus well suited for battery-powered systems such as portable display devices and large-surface sensor networks as well as for radio-frequency identification tags with extended operating range.     

Early gas stripping as the origin of the darkest galaxies in the Universe

The known galaxies most dominated by dark matter (Draco, Ursa Minor and Andromeda IX) are satellites of the Milky Way and the Andromeda galaxies. They are members of a class of faint galaxies, devoid of gas, known as dwarf spheroidals, and have by far the highest ratio of dark to luminous matter. None of the models proposed to unravel their origin can simultaneously explain their exceptional dark matter content and their proximity to a much larger galaxy. Here we report simulations showing that the progenitors of these galaxies were probably gas-dominated dwarf galaxies that became satellites of a larger galaxy earlier than the other dwarf spheroidals. We find that a combination of tidal shocks and ram pressure swept away the entire gas content of such progenitors about ten billion years ago because heating by the cosmic ultraviolet background kept the gas loosely bound: a tiny stellar component embedded in a relatively massive dark halo survived until today. All luminous galaxies should be surrounded by a few extremely dark-matter-dominated dwarf spheroidal satellites, and these should have the shortest orbital periods among dwarf spheroidals because they were accreted early.