Research articles

New molecular research has pulled acoel flatworms from their basal position in animal evolution, uniting them with creatures such as echinoderms (starfish, sea urchins and allies) — indeed, very much closer to the chordates, the group that includes ourselves. The work follows previous revelations that Xenoturbella, a simple flatworm of mysterious evolutionary connections, also belonged to this group. The research implies that acoels are not primitively simple, as had been thought, but have lost features such as a body cavity, anus and gill slits.

A mutation in the gene CACNA1C, encoding the L-type calcium channel Ca_V1.2 in humans, causes Timothy syndrome, a disorder characterized by autism, syndactyly, immune deficiency and cardiac arrhythmias. This study generated induced pluripotent stem cells from the fibroblasts of two patients with Timothy syndrome and converted them into cardiac cells. The patient cells displayed abnormal electrical and calcium signalling properties, which were restored by a drug, roscovitine, known to increase the voltage-dependent inactivation of Ca_V1.2.

A non-coding region on chromosome 9p21 was previously shown to associate with coronary artery disease and type 2 diabetes, and the region has been implicated in regulating neighbouring genes. Here, 33 distinct enhancers within this region are identified, showing that SNPs in one of the enhancers affect STAT1 binding. Furthermore, it is shown that in human vascular endothelial cells the enhancer interval physically interacts with a number of specific loci and that IFN-γ activation strongly affects the chromatin structure and transcriptional regulation of the 9p21 locus, including STAT1 binding, long-range enhancer interactions and expression of neighbouring genes.

Staufen 1 (STAU1) protein binds regions of dsRNA in the 3′ UTR of mRNAs and promotes their degradation, a process known as SMD (Staufen-mediated mRNA decay). Although a specific stem-loop binding site had been defined for one SMD target, it was unclear how STAU1 was directed to other SMD targets that lack this structure. This paper reports that pairing of Alu element sequences in long non-coding RNAs (lncRNAs) and in the 3′ UTR of the SMD target generates a dsRNA structure that STAU1 recognizes. This result highlights a new function for lncRNAs.

Certain regions of the hypothalamus are important in aggression, but until recently, it has been difficult to specifically stimulate specific cell types within a mixed population of cells. Here, optogenetics is used to solve this specificity problem, finding that optogenetic stimulation of a subdivision within the ventromedial hypothalamus can elicit inappropriate attack behaviours in mice, but electrical stimulation does not produce the same result. Additional analysis of genetic and electrophysiological activity revealed overlapping neuronal subpopulations involved in fighting and mating, with potential competition between these behaviours, as neurons activated during aggression are inhibited during mating.

Prostate cancer is a common cause of male cancer-related deaths. Complete sequencing of prostate cancer genomes now reveals previously unknown balanced rearrangements. Single-nucleotide resolution afforded by sequencing indicates that complex rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms.

In geographic atrophy, a type of macular degeneration, retinal pigmented epithelium (RPE) cells die. This paper finds that DICER1, which processes miRNA precursors, is reduced in RPE from individuals with geographic atrophy. Cell death is not due to loss of miRNA processing, however; rather, the absence of DICER1 allows accumulation of pathological Alu repeat sequence RNAs. This work reveals a novel function of Dicer in degrading Alu RNAs.

Recruitment of 53BP1 to double-strand DNA breaks is an important step in the cellular response to DNA damage. Here, the histone methyltransferase MMSET is shown to be responsible for localized increases in a histone modification that is involved in recruiting 53BP1. The mechanism of MMSET recruitment to DNA damage sites is also investigated.

Alternative stable states are common in ecosystems, and pose problems for management, but most studied examples are of strongly stable states that switch only rarely after major perturbations. This study fits a model of weakly stable states to a billabong system in which biological control is applied to an invasive weed. Frequent changes in water availability cause shifts between states in which control either is or is not effective. Understanding these shifts could allow intervention to keep the system in the controlled state.

This study demonstrates how it is possible to extract full three-dimensional structural information at atomic resolution using a combination of electron tomography and electron microscopy, coupled with separately available knowledge of the crystallographic structure adopted by the target nanoparticle. Such information should ultimately lead to a better understanding of the desirable properties of these systems.

Jawless fish were recently shown to possess T- and B-like lymphocytes expressing diverse assembled antigen receptors. This study identifies and characterizes lympho-epithelial thymus-like structures at the tips of gill filaments of lamprey larvae, thus providing evidence that the similarities underlying the adaptive immune systems of both types of vertebrate appear to extend to primary lymphoid organs.

The start-up of the new femtosecond hard X-ray laser facility in Stanford, the Linac Coherent Light Source, has brought high expectations for a new era for biological imaging. The intense, ultrashort X-ray pulses allow diffraction imaging of small structures before radiation damage occurs. This new capability is tested for the problem of structure determination from nanocrystals of macromolecules that cannot be grown in large crystals. Over three million diffraction patterns were collected from a stream of nanocrystals of the membrane protein complex photosystem I, which allowed the assembly of a three-dimensional data set for this protein, and proves the concept of this imaging technique.

In a mouse model of prostate cancer it is found that that the TGF-β signalling pathway limits tumour progression and metastasis. Using markers of this pathway and other biologically relevant factors, a four-gene signature is identified that is associated with poorer clinical outcome and metastatic progression in several prostate cancer cohorts, especially in combination with other clinical parameters. This signature may prove useful for the development of a better prognostic test for those cases of prostate cancer in which deciding on the right treatment regime while avoiding over-treatment constitutes an important clinical challenge.

The start-up of the new femtosecond hard X-ray laser facility in Stanford, the Linac Coherent Light Source, has brought high expectations for a new era for biological imaging. The intense, ultrashort X-ray pulses allow diffraction imaging of small structures before radiation damage occurs. This new capability is tested for the problem of imaging a non-crystalline biological sample. Images of mimivirus are obtained, the largest known virus with a total diameter of about 0.75 micrometres, by injecting a beam of cooled mimivirus particles into the X-ray beam. The measurements indicate no damage during imaging and prove the concept of this imaging technique.

When an extrasolar planet passes in front of its star (transits), its radius can be measured from the decrease in starlight and its orbital period from the time between transits. This study reports Kepler spacecraft observations of a single Sun-like star that reveal six transiting planets, five with orbital periods between 10 and 47 days plus a sixth one with a longer period. The five inner planets are among the smallest for which mass and size have both been measured, and these measurements imply substantial envelopes of light gases.

Circadian rhythms regulate a wide variety of developmental and metabolic processes resulting in enhanced fitness. In this study, a link is made between plant immune responses and the circadian clock. Plant defence against a fungal pathogen which causes downy mildew disease in Arabidopsis is studied, and it is shown that a novel set of defence genes are regulated by the circadian regulator CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1). The mechanism allows plants to 'anticipate' infection at dawn when the pathogen normally disperses its spores. Such a cross-talk mechanism reveals an important strategy for plants to time immune responses against pathogens.

The source of what seems to be an anomalous increase in atmospheric methane concentrations about 5,000 years ago compared to methane levels during previous interglacial periods has puzzled researchers. Possible explanations for the rise in methane levels include very early agricultural activity. Climate and wetland simulations of global methane levels over the last glacial cycle now suggest that the increase in methane concentrations can be explained by natural changes in the Earth's orbital configuration, with enhanced emissions in the Southern Hemisphere tropics linked to precession-induced modification of seasonal precipitation

Harnessing information from whole genome sequencing in 185 individuals, this study generates a high-resolution map of copy number variants. Nucleotide resolution of the map facilitates analysis of structural variant distribution and identification of the mechanisms of their origin. The study provides a resource for sequence-based association studies.

Reprogramming of somatic cells to induce pluripotent cellular properties that closely resemble those of embryonic stem (ES) cells has important therapeutic potential. The first whole genome single-base resolution profiling of the DNA methylomes of several human ES cell, induced pluripotent stem cell (iPSC) and somatic progenitor lines shows that iPSCs are fundamentally distinct from ES cells, insofar as they manifest common, quantifiable epigenomic differences. These 'hotspots of aberrant reprogramming' might be potentially useful as diagnostic markers for incomplete iPSC reprogramming, for the characterization of the efficacy of different reprogramming techniques, and for screening the potential propagation of altered methylation states into derivative differentiated cells.

In humans, vulnerability to tobacco addiction has been linked to variations in the gene encoding the α5 nicotinic acetylcholine receptor subunit, but the functional mechanisms linking gene to behaviour are unknown. Using a combination of knockout mice, lentiviral rescue, and RNAi knockdown in rats, this study shows that manipulating the levels of this subunit alters the drive to obtain nicotine, particularly at high doses that are aversive to wild-type animals. Furthermore, these subunits are implicated in the projection between medial habenula and interpeduncular nucleus in integrating negative side effects of high doses of nicotine and reward signals. It is proposed that this projection provides a negative motivational signal that limits nicotine consumption.