CENP-B preserves genome integrity at replication forks paused by retrotransposon LTR

Centromere-binding protein B (CENP-B) is a widely conserved DNA binding factor associated with heterochromatin and centromeric satellite repeats. In fission yeast, CENP-B homologues have been shown to silence long terminal repeat (LTR) retrotransposons by recruiting histone deacetylases. However, CENP-B factors also have unexplained roles in DNA replication. Here we show that a molecular function of CENP-B is to promote replication-fork progression through the LTR. Mutants have increased genomic instability caused by replication-fork blockage that depends on the DNA binding factor switch-activating protein 1 (Sap1), which is directly recruited by the LTR. The loss of Sap1-dependent barrier activity allows the unhindered progression of the replication fork, but results in rearrangements deleterious to the retrotransposon. We conclude that retrotransposons influence replication polarity through recruitment of Sap1 and transposition near replication-fork blocks, whereas CENP-B counteracts this activity and promotes fork stability. Our results may account for the role of LTR in fragile sites, and for the association of CENP-B with pericentromeric heterochromatin and tandem satellite repeats.     

Geochemical evidence for widespread euxinia in the later Cambrian ocean

Widespread anoxia in the ocean is frequently invoked as a primary driver of mass extinction as well as a long-term inhibitor of evolutionary radiation on early Earth. In recent biogeochemical studies it has been hypothesized that oxygen deficiency was widespread in subsurface water masses of later Cambrian oceans, possibly influencing evolutionary events during this time. Physical evidence of widespread anoxia in Cambrian oceans has remained elusive and thus its potential relationship to the palaeontological record remains largely unexplored. Here we present sulphur isotope records from six globally distributed stratigraphic sections of later Cambrian marine rocks (about 499 million years old). We find a positive sulphur isotope excursion in phase with the Steptoean Positive Carbon Isotope Excursion (SPICE), a large and rapid excursion in the marine carbon isotope record, which is thought to be indicative of a global carbon cycle perturbation. Numerical box modelling of the paired carbon sulphur isotope data indicates that these isotope shifts reflect transient increases in the burial of organic carbon and pyrite sulphur in sediments deposited under large-scale anoxic and sulphidic (euxinic) conditions. Independently, molybdenum abundances in a coeval black shale point convincingly to the transient spread of anoxia. These results identify the SPICE interval as the best characterized ocean anoxic event in the pre-Mesozoic ocean and an extreme example of oxygen deficiency in the later Cambrian ocean. Thus, a redox structure similar to those in Proterozoic oceans may have persisted or returned in the oceans of the early Phanerozoic eon. Indeed, the environmental challenges presented by widespread anoxia may have been a prevalent if not dominant influence on animal evolution in Cambrian oceans.     

Lunar activity from recent gas release

Samples of material returned from the Moon have established that widespread lunar volcanism ceased about 3.2 Gyr ago. Crater statistics and degradation models indicate that last-gasp eruptions of thin basalt flows continued until less than 1.0 Gyr ago, but the Moon is now considered to be unaffected by internal processes today, other than weak tidally driven moonquakes and young fault systems. It is therefore widely assumed that only impact craters have reshaped the lunar landscape over the past billion years. Here we report that patches of the lunar regolith in the Ina structure were recently removed. The preservation state of relief, the number of superimposed small craters, and the 'freshness' (spectral maturity) of the regolith together indicate that features within this structure must be as young as 10 Myr, and perhaps are still forming today. We propose that these features result from recent, episodic out-gassing from deep within the Moon. Such out-gassing probably contributed to the radiogenic gases detected during past lunar missions. Future monitoring (including Earth-based observations) should reveal the composition of the gas, yielding important clues to volatiles archived at great depth over the past 4-4.5 Gyr.     

RNAi-mediated gene silencing in non-human primates

The opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines. Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs), there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA, and there are no reports of systemic efficacy in non-rodent species. Here we show that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B (ApoB) in non-human primates. APOB-specific siRNAs were encapsulated in stable nucleic acid lipid particles (SNALP) and administered by intravenous injection to cynomolgus monkeys at doses of 1 or 2.5 mg kg(-1). A single siRNA injection resulted in dose-dependent silencing of APOB messenger RNA expression in the liver 48 h after administration, with maximal silencing of >90%. This silencing effect occurred as a result of APOB mRNA cleavage at precisely the site predicted for the RNAi mechanism. Significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels were observed as early as 24 h after treatment and lasted for 11 days at the highest siRNA dose, thus demonstrating an immediate, potent and lasting biological effect of siRNA treatment. Our findings show clinically relevant RNAi-mediated gene silencing in non-human primates, supporting RNAi therapeutics as a potential new class of drugs.     

Learned kin recognition cues in a social bird

In many cooperatively breeding birds, kin selection has an important role in the evolution and maintenance of social behaviour, and 'helpers' can maximize indirect fitness gains by preferentially allocating care to close relatives. Although there is evidence for kin-biased helping behaviour in several species, the mechanism of kin recognition underlying this behaviour is poorly understood. Vocalizations are the most commonly used cues in avian recognition systems, but the effectiveness of vocal signals as reliable recognition cues must depend on how they are acquired. However, there have been no experimental studies of the development of vocal recognition cues in cooperative birds; indeed, the ontogeny of all bird vocalizations other than song is poorly known in any species. Here, we show that cooperatively breeding long-tailed tits (Aegithalos caudatus) can discriminate between kin and non-kin according to the individual-specific characteristics of contact calls, and show experimentally that individuals learn these calls from provisioning adults during the nestling period. Finally, we show that the pattern of cooperative behaviour in this species is consistent with the use of recognition cues learned through association.     

An integrated semiconductor device enabling non-optical genome sequencing

The seminal importance of DNA sequencing to the life sciences, biotechnology and medicine has driven the search for more scalable and lower-cost solutions. Here we describe a DNA sequencing technology in which scalable, low-cost semiconductor manufacturing techniques are used to make an integrated circuit able to directly perform non-optical DNA sequencing of genomes. Sequence data are obtained by directly sensing the ions produced by template-directed DNA polymerase synthesis using all-natural nucleotides on this massively parallel semiconductor-sensing device or ion chip. The ion chip contains ion-sensitive, field-effect transistor-based sensors in perfect register with 1.2 million wells, which provide confinement and allow parallel, simultaneous detection of independent sequencing reactions. Use of the most widely used technology for constructing integrated circuits, the complementary metal-oxide semiconductor (CMOS) process, allows for low-cost, large-scale production and scaling of the device to higher densities and larger array sizes. We show the performance of the system by sequencing three bacterial genomes, its robustness and scalability by producing ion chips with up to 10 times as many sensors and sequencing a human genome.     

Recovery of learning and memory is associated with chromatin remodelling

Neurodegenerative diseases of the central nervous system are often associated with impaired learning and memory, eventually leading to dementia. An important aspect in pre-clinical research is the exploration of strategies to re-establish learning ability and access to long-term memories. By using a mouse model that allows temporally and spatially restricted induction of neuronal loss, we show here that environmental enrichment reinstated learning behaviour and re-established access to long-term memories after significant brain atrophy and neuronal loss had already occurred. Environmental enrichment correlated with chromatin modifications (increased histone-tail acetylation). Moreover, increased histone acetylation by inhibitors of histone deacetylases induced sprouting of dendrites, an increased number of synapses, and reinstated learning behaviour and access to long-term memories. These data suggest that inhibition of histone deacetylases might be a suitable therapeutic avenue for neurodegenerative diseases associated with learning and memory impairment, and raises the possibility of recovery of long-term memories in patients with dementia.     

The genome sequence of the filamentous fungus Neurospora crassa

Neurospora crassa is a central organism in the history of twentieth-century genetics, biochemistry and molecular biology. Here, we report a high-quality draft sequence of the N. crassa genome. The approximately 40-megabase genome encodes about 10,000 protein-coding genes--more than twice as many as in the fission yeast Schizosaccharomyces pombe and only about 25% fewer than in the fruitfly Drosophila melanogaster. Analysis of the gene set yields insights into unexpected aspects of Neurospora biology including the identification of genes potentially associated with red light photobiology, genes implicated in secondary metabolism, and important differences in Ca2+ signalling as compared with plants and animals. Neurospora possesses the widest array of genome defence mechanisms known for any eukaryotic organism, including a process unique to fungi called repeat-induced point mutation (RIP). Genome analysis suggests that RIP has had a profound impact on genome evolution, greatly slowing the creation of new genes through genomic duplication and resulting in a genome with an unusually low proportion of closely related genes.