Research articles

Intrinsically photosensitive retinal ganglion cells sense and transmit light information to brain centres that control non-image-forming visual functions, such as the pupillary light reflex and circadian photoentrainment. This paper describes the biophysical properties of these melanopsin-containing cells. It is found that single-photons of light are sufficient to elicit large and prolonged responses.

This paper generates an iPS cell line from patients with spinal muscular atrophy, an autosomal recessive genetic disorder that is one of the most common inherited forms of neurological disease in children.

When damaged DNA is replicated, gaps can be left behind in the replicated DNA. Two processes, recombinational repair or post-replication repair (PRR), were thought to act independently in gap filling. This study defines how the error-free branch of PRR is involved in lesion bypass and finds that when the replicative clamp PCNA is SUMO modified, Rad18 and Rad5 are able to promote polyubiquitination of PCNA.

A proteomics study unveils a large collection of proteins that get reversibly palmitoylated in response to neuronal activity — the neuronal palmitoyl-proteome. In particular, this study focuses on the discovery of a brain-specific isoform of the small GTPase Cdc42, whose unexpected palmitoylation specifically affects dendritic spine morphogenesis in response to neuronal activity. These findings identify palmitoylation as a key modifiable signal on many synapse-enriched proteins that contribute to activity-driven changes in synapse morphology and function.

Geometric frustration arises when lattice structure prevents energetic interactions between neighbouring particles to be minimized, leading to complex phases of matter. This paper reports a simple geometrically frustrated system composed of closely packed colloidal spheres confined between parallel walls. Because the diameter of the spheres is tunable, the system provides a unique means to directly visualize the dynamics of frustration, thermal excitations and defects.

The structure of a thermophilic Ago protein bound to a duplex nucleic acid that mimics the interaction of the single-strand of the small RNA and the target mRNA has been solved. This structure reveals the conformational changes that are necessary to accommodate the target, and the changes that occur in the vicinity of the site of cleavage.

The DNA and RNA polymerases encode proofreading activities that help to ensure the fidelity of the readout. The ribosome, which synthesizes protein, was believed to lack a similar activity that would recognize errors after a peptide bond had been formed. This study provides evidence that the ribosome does have such a quality control mechanism. It is shown that after an incorrect amino acid has been incorporated into the growing polypeptide chain, there is a general loss of specificity in the ribosome's active site, leading to an accumulation of errors that triggers premature termination of peptide synthesis.

An early cellular response to the occurrence of DNA double-strand breaks in mammals is the phosphorylation of the specialized histone variant H2A.X at Ser 139. The chromatin remodelling factor WSTF is found to phosphorylate H2A.X at another site, Tyr 142. Tyrosine phosphorylation has not been observed previously on histones.

Accumulation of misfolded proteins results in the activation of the unfolded protein response (UPR) in the endoplasmic reticulum. Ire1 is important in this pathway and functions as a kinase and endoribonuclease. This paper solves the crystal structure of Ire1 kinase and shows that it undergoes spontaneous assembly into a rod-shaped oligomer. This arrangement positions the kinase domains for trans-autophosphorylation, orders the RNase domains and creates an interaction site for mRNA substrate binding.

Antigenic variation is a process by which pathogens switch surface antigen expression during infection to escape immune recognition. Giardia lamblia, a major cause of parasitic diarrhoea, is now shown to regulate antigenic variation by RNA interference.

In the Saccharomyces cerevisiae pheromone response pathway, the MAP kinase Fus3 mediates the rapid negative feedback that adjusts the dose–response of the downstream system response to match that of receptor-ligand binding. This 'dose–response alignment' improves the fidelity of information transmission. Negative feedback could be used as a general mechanism in signalling systems to align dose–responses.

This work identifies the spliceosome, which normally excises introns from mRNAs, as being responsible for generating the 3′ end of TER. It does so by performing a site-specific cleavage reaction that previously had not been observed for the spliceosome.

Asymmetric division of adult stem cells generates one self-renewing stem cell and one differentiating cell, thereby maintaining tissue homeostasis. This paper shows that changes in stem cell orientation within the niche during ageing contribute to the decline in spermatogenesis in Drosophila male germ line.

Cancer stem cells in human tumours have been defined as cells that are tumourigenic and self-renew when transplanted into immunocompromised mice. It has been shown in a number of tumour types that such cancer stem cells exist at relatively low frequencies. This paper now shows that in human melanomas at least, there is a high proportion of tumourigenic cells when the conditions for such transplanation experiments are modified, casting doubt on the generality of the cancer stem cell model.

It is shown that a mitochondrial protein, mitofusin 2, is enriched at the mitochondrial–endoplasmic reticulum interface and mediates tethering of both organelles. Ablation of mitofusin 2 results in disruption of endoplasmic reticulum morphology and loss of calcium transfer between the two organelles. Thus, mitofusin-2 mediates tethering mitochondria to the endoplasmic reticulum.

This paper identifies a gene, kintoun (ktu), which is important for dynein arm formation resulting in the formation of motile cilia. It is conserved from ciliated unicellular organisms to higher mammals. Mutations in the homologous gene of two human primary ciliary dyskinesia families are also identified.

This paper reports on an intensive bioinformatic analysis of human alternative splicing in various tissues and cancers. The analysis offers insight into tissue specificity, coordinated regulation and sequence conservation of alternative splicing. Evidence is also obtained that alternative splicing is mechanistically linked to a modification of mRNAs known as polyadenylation.

Gibberellin is an important plant hormone that regulates several development processes. This paper presents a ternary complex of gibberellin bound to its receptor and a fragment of a DELLA protein. The structures reveal the mechanistic basis of gibberellin recognition, which is distinct from auxin perception.

It is shown that mice lacking the renal Rhcg factor have impaired ammonium excretion, thereby refuting the long-standing notion that rapid transepithelial transport of non-ionic ammonia occurs solely by lipid phase diffusion. In addition, it is shown that Rhcg is required for epididymal fluid homeostasis with clear consequences for male fertility.

A four-stranded DNA intermediate, known as a Holliday junction, is formed during meiosis and DNA repair. This structure covalently links two DNA molecules. The product of the RuvC gene in Escherichia coli was shown to be the bacterial Holliday junction resolvase. The mammalian enzyme has remained refractory to identification until now, where GEN1 is identified as the human resolvase.