Evolutionary genetics. Clonal inheritance of avian mitochondrial DNA.

We have taken a new approach to test the commonly accepted, but recently questioned, principle of clonal inheritance of vertebrate mitochondrial DNA (mtDNA) by relating its inheritance to a female-specific marker of nuclear DNA. Whereas this is impossible in organisms with male heterogamy (such as mammals), we show here that genealogies of mtDNA and the female-specific W chromosome of a bird species are completely concordant. Our results indicate that inheritance of mtDNA is free of detectable recombination effects over an evolutionary timescale.     

Superconductivity in CaCuO2 as a result of field-effect doping.

Understanding the doping mechanisms in the simplest superconducting copper oxide-the infinite-layer compound ACuO2 (where A is an alkaline earth metal)-is an excellent way of investigating the pairing mechanism in high-transition-temperature (high-Tc) superconductors more generally. Gate-induced modulation of the carrier concentration to obtain superconductivity is a powerful means of achieving such understanding: it minimizes the effects of potential scattering by impurities, and of structural modifications arising from chemical dopants. Here we report the transport properties of thin films of the infinite-layer compound CaCuO2 using field-effect doping. At high hole- and electron-doping levels, superconductivity is induced in the nominally insulating material. Maximum values of Tc of 89 K and 34 K are observed respectively for hole- and electron-type doping of around 0.15 charge carriers per CuO2. We can explore the whole doping diagram of the CuO2 plane while changing only a single electric parameter, the gate voltage.     

Novel neurotrophic factor CDNF protects and rescues midbrain dopamine neurons in vivo

In Parkinson's disease, brain dopamine neurons degenerate most prominently in the substantia nigra. Neurotrophic factors promote survival, differentiation and maintenance of neurons in developing and adult vertebrate nervous system. The most potent neurotrophic factor for dopamine neurons described so far is the glial-cell-line-derived neurotrophic factor (GDNF). Here we have identified a conserved dopamine neurotrophic factor (CDNF) as a trophic factor for dopamine neurons. CDNF, together with its previously described vertebrate and invertebrate homologue the mesencephalic-astrocyte-derived neurotrophic factor, is a secreted protein with eight conserved cysteine residues, predicting a unique protein fold and defining a new, evolutionarily conserved protein family. CDNF (Armetl1) is expressed in several tissues of mouse and human, including the mouse embryonic and postnatal brain. In vivo, CDNF prevented the 6-hydroxydopamine (6-OHDA)-induced degeneration of dopaminergic neurons in a rat experimental model of Parkinson's disease. A single injection of CDNF before 6-OHDA delivery into the striatum significantly reduced amphetamine-induced ipsilateral turning behaviour and almost completely rescued dopaminergic tyrosine-hydroxylase-positive cells in the substantia nigra. When administered four weeks after 6-OHDA, intrastriatal injection of CDNF was able to restore the dopaminergic function and prevent the degeneration of dopaminergic neurons in substantia nigra. Thus, CDNF was at least as efficient as GDNF in both experimental settings. Our results suggest that CDNF might be beneficial for the treatment of Parkinson's disease.     

Expanding the diversity of chemical protein modification allows post-translational mimicry

One of the most important current scientific paradoxes is the economy with which nature uses genes. In all higher animals studied, we have found many fewer genes than we would have previously expected. The functional outputs of the eventual products of genes seem to be far more complex than the more restricted blueprint. In higher organisms, the functions of many proteins are modulated by post-translational modifications (PTMs). These alterations of amino-acid side chains lead to higher structural and functional protein diversity and are, therefore, a leading contender for an explanation for this seeming incongruity. Natural protein production methods typically produce PTM mixtures within which function is difficult to dissect or control. Until now it has not been possible to access pure mimics of complex PTMs. Here we report a chemical tagging approach that enables the attachment of multiple modifications to bacterially expressed (bare) protein scaffolds: this approach allows reconstitution of functionally effective mimics of higher organism PTMs. By attaching appropriate modifications at suitable distances in the widely-used LacZ reporter enzyme scaffold, we created protein probes that included sensitive systems for detection of mammalian brain inflammation and disease. Through target synthesis of the desired modification, chemistry provides a structural precision and an ability to retool with a chosen PTM in a manner not available to other approaches. In this way, combining chemical control of PTM with readily available protein scaffolds provides a systematic platform for creating probes of protein-PTM interactions. We therefore anticipate that this ability to build model systems will allow some of this gene product complexity to be dissected, with the aim of eventually being able to completely duplicate the patterns of a particular protein's PTMs from an in vivo assay into an in vitro system.     

South-polar features on Venus similar to those near the north pole

Venus has no seasons, slow rotation and a very massive atmosphere, which is mainly carbon dioxide with clouds primarily of sulphuric acid droplets. Infrared observations by previous missions to Venus revealed a bright 'dipole' feature surrounded by a cold 'collar' at its north pole. The polar dipole is a 'double-eye' feature at the centre of a vast vortex that rotates around the pole, and is possibly associated with rapid downwelling. The polar cold collar is a wide, shallow river of cold air that circulates around the polar vortex. One outstanding question has been whether the global circulation was symmetric, such that a dipole feature existed at the south pole. Here we report observations of Venus' south-polar region, where we have seen clouds with morphology much like those around the north pole, but rotating somewhat faster than the northern dipole. The vortex may extend down to the lower cloud layers that lie at about 50 km height and perhaps deeper. The spectroscopic properties of the clouds around the south pole are compatible with a sulphuric acid composition.     

Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.     

Female mate-choice drives the evolution of male-biased dispersal in a social mammal

Dispersal has a significant impact on lifetime reproductive success, and is often more prevalent in one sex than the other. In group-living mammals, dispersal is normally male-biased and in theory this sexual bias could be a response by males to female mate preferences, competition for access to females or resources, or the result of males avoiding inbreeding. There is a lack of studies on social mammals that simultaneously assess these factors and measure the fitness consequences of male dispersal decisions. Here we show that male-biased dispersal in the spotted hyaena (Crocuta crocuta) most probably results from an adaptive response by males to simple female mate-choice rules that have evolved to avoid inbreeding. Microsatellite profiling revealed that females preferred sires that were born into or immigrated into the female's group after the female was born. Furthermore, young females preferred short-tenured sires and older females preferred longer-tenured sires. Males responded to these female mate preferences by initiating their reproductive careers in groups containing the highest number of young females. As a consequence, 11% of males started their reproductive career in their natal group and 89% of males dispersed. Males that started reproduction in groups containing the highest number of young females had a higher long-term reproductive success than males that did not. The female mate-choice rules ensured that females effectively avoided inbreeding without the need to discriminate directly against close kin or males born in their own group, or to favour immigrant males. The extent of male dispersal as a response to such female mate preferences depends on the demographic structure of breeding groups, rather than the genetic relatedness between females and males.     

Identification of stem cells in small intestine and colon by marker gene Lgr5

The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. It is currently believed that four to six crypt stem cells reside at the +4 position immediately above the Paneth cells in the small intestine; colon stem cells remain undefined. Lgr5 (leucine-rich-repeat-containing G-protein-coupled receptor 5, also known as Gpr49) was selected from a panel of intestinal Wnt target genes for its restricted crypt expression. Here, using two knock-in alleles, we reveal exclusive expression of Lgr5 in cycling columnar cells at the crypt base. In addition, Lgr5 was expressed in rare cells in several other tissues. Using an inducible Cre knock-in allele and the Rosa26-lacZ reporter strain, lineage-tracing experiments were performed in adult mice. The Lgr5-positive crypt base columnar cell generated all epithelial lineages over a 60-day period, suggesting that it represents the stem cell of the small intestine and colon. The expression pattern of Lgr5 suggests that it marks stem cells in multiple adult tissues and cancers.