Research articles

During replication, topological stress builds ahead of the polymerase. Current models propose that linear eukaryotic chromosomes are divided into topological domains, and that stress is relieved by the activity of a topoisomerase. Here, it is found that replication stress seems to be present throughout the chromosome, rather than in domains, and that the relief of stress in longer chromosomes is facilitated by the activity of the cohesin/condensin-like Smc5/6 complex as well as by topoisomerase. They propose that the Smc5/6 complex prevent formation of topological tension ahead of the replication fork by promoting fork rotation, leading to the formation of sister chromatin intertwinings behind.

According to the Milankovitch theory, glacial to interglacial climate variability — as recorded in Antarctica ice cores — is governed by summer insolation at high northern latitudes. It is now shown that accumulation of Antarctic snow is biased towards austral winter and may be explained simply by variations in local insolation, with no recourse to northern influences. Although not constituting a complete negative proof, the results show that the Antarctic ice core records do not, in themselves, provide sufficient support for the Milankovitch theory.

Simulations of interacting particles in classical systems generally involve the Metropolis algorithm. A quantum version of this approach has been hindered by the lack of a means to simulate the equilibrium and static properties of quantum systems. This study overcomes this problem. Its quantum version of the Metropolis algorithm could find widespread application in many body quantum physics, such as computing the binding energies of complex molecules or determining hadron masses in gauge theories.

Double deficiency of FADD and RIPK1 is shown to rescue the defects in mouse embryonic development and lymphocyte proliferation that are characteristic for mice with single gene deficiencies. This work suggests that the activity of FADD (presumably in conjunction with caspase-8 and c-FLIP) is to keep necrosis in check by causing the cleavage of RIPK1.

Direct observations over the past four centuries show that the number of sunspots observed on the Sun's surface varies periodically. After sunspot cycle 23, the Sun went into a prolonged minimum characterized by a very weak polar magnetic field and an unusually large number of days without sunspots. This study reports kinematic dynamo simulations which demonstrate that a fast meridional flow in the early half of a cycle, followed by a slower flow in the latter half, reproduces both characteristics of the minimum of sunspot cycle 23.

The presence of DNA lesions is a clear signal that initiates the DNA damage response; however, the mechanisms that attenuate this response when repair has occurred are less clear. Here, deacetylation of Sae2 by Rpd3 and Hda1 is shown to be required for it to act on Mre11. When the role of Sae2 in resection is completed, it is acetylated by Gcn5 and degraded through an autophagic pathway. This work highlights links between DNA damage signalling, acetylation of repair factors, and autophagy mediated degradation of these factors.

Using whole-transcriptome sequencing, this paper identifies recurrent gene translocations in B-cell lymphomas that involve the MHC class II transactivator CIITA. These translocations lead to downregulation of cell surface HLA class II expression and, in the case of some fusion partners, overexpression of CD274/CD273 ligands, which have the potential to reduce the antitumour response against these lymphomas.

The annelids, or ringed worms, comprise one of the largest and most diverse animal phyla, and are found everywhere from garden soil to the deep sea. Their precise phylogeny has always been sketchy, but now, a new phylogenomic analysis unravels annelid evolution. Notable features include a division of most annelids into the Errantia and Sedentaria — a restitution for two groups based on classical morphology — showing how many details of anatomy and life history bear on the evolution of this important animal group.

This study shows that a dynamic two-stage model can unify a wide range of apparently contradictory observations from both large plutonic bodies and volcanic systems by a mechanism of rapid remobilization, or 'unzipping', of highly viscous crystal-rich mushes. This remobilization can lead to rapid overturn and produce the observed juxtaposition of magmatic materials with very disparate ages and complex chemical zoning. The agreement between calculated and observed unzipping rates for historical eruptions at Pinatubo and Montserrat demonstrates the potentially wide applicability of the model.

Regulated proteolysis by ATP-dependent proteases have a crucial role in protein quality control in cells. The Clp/Hsp100 proteins of the AAA+ superfamily of ATP-dependent chaperones unfold and translocate proteins into the proteolytic chamber of protease complexes. ClpC requires the adaptor protein MecA for activation and substrate targetting to the ClpCP protease complex. Here, a structural and biochemical analysis is presented of the MecA–ClpC complex revealing organizational principles and providing mechanistic insights into this complex molecular machine.

Caspase-8 mediates apoptosis induced by death receptors. At the same time, this protease is able to prevent RIP-dependent necrosis. Without caspase-8 mice die during their embryonic development. Two papers now show that lethality is not caused by the absence of apoptosis, but by RIP3-dependent necrosis that is unleashed without caspase-8. Mice that lack both caspase-8 and RIP3 develop into viable, immunocompetent, fertile adult mice, but suffer from a progressive lymphoaccumulative disease similar to mice that lack the death receptor CD95.

Misrepair of DNA double strand breaks produced by the V(D)J recombinase (the RAG1/RAG2 proteins) at immunoglobulin and T-cell receptor loci has been implicated in the pathogenesis of lymphoid malignancies. Here, the RAG2 carboxy terminus is shown to be critical for maintaining genomic stability. Rag2^c/c p53^−/− mice, unlike Rag1^c/c p53^−/− and p53^−/− mice, rapidly develop thymic lymphomas bearing complex chromosomal translocations, amplifications and deletions involving the Tcrα/δ and Igh loci. These results reveal a new 'genome guardian' role for RAG2 and suggest that similar 'end release/end persistence' mechanisms underlie genomic instability and lymphomagenesis in Rag2^c/c p53^−/− and Atm^−/− mice.

Different organisms use a variety of mechanisms to compensate for X chromosome dosage imbalance between the sexes. In Drosophila, the MSL complex increases transcription on the single X chromosome of males and is thought to regulate transcription elongation, although mechanistic details have been unclear. Here, a global run-on sequencing technique is used to reveal that the MSL complex seems to enhance transcription by facilitating the progression of RNA polymerase II across the bodies of active X linked genes. In this way, MSL can impose dosage compensation on diverse genes with a wide range of transcription levels along the X chromosome.

Reprogramming of somatic cells to induced pluripotent stem (iPS) cells that can be differentiated into many cell types has great potential for personalized therapy. By comparing copy number variations of early- and intermediate-passage human iPS cells to their respective parental fibroblast cells and human embryonic stem (ES) cells, this study finds that a high mutation rate is associated with the reprogramming process. However, during moderate length culture, human iPS cells undergo a selection process leading to decreased mutation load of cells equivalent to that observed in human ES cells.

This study describes a mechanotransduction pathway that links the body wall with the epidermis in Caenorhabditis elegans. The pathway involves the p21 activated kinase PAK 1, an adaptor GIT 1 and its partner PIX 1. Tension exerted by muscles or external pressure keeps GIT 1 on station at hemidesmosomes — the small rivet like bodies that attach epidermal cells to the underlying musculature — and stimulates PAK 1 through PIX 1 and Rac GTPase. The C. elegans hemidesmosome is more than a passive attachment structure, therefore, but a sensor that responds to tension by triggering signalling processes.

This is one of two papers demonstrating that in several cancer types including ovarian cancer and T-cell leukaemias, the apoptosis regulator MCL1 is targeted for degradation by the FBW7 tumour suppressor. This study finds that this mechanism can determine the response to drugs targeting BCL2 family apoptosis factors. Deletion or mutation of FBW7 found in cancer patients therefore can render tumours resistant to these therapies.

Reprogramming of somatic cells to induced pluripotent stem (iPS) cells that can be differentiated into many cell types has great potential for personalized therapy. This study finds that 22 human iPS cell lines that were reprogrammed using five different methods contain protein coding point mutations. Some mutations were pre existing in the somatic cells, others were new mutations that occurred during and after reprogramming. Therefore, it will be important to ensure iPS cell safety before clinical use.

Caspase-8 mediates apoptosis induced by death receptors. At the same time, this protease is able to prevent RIP-dependent necrosis. Without caspase-8 mice die during their embryonic development. Two papers now show that lethality is not caused by the absence of apoptosis, but by RIP3-dependent necrosis that is unleashed without caspase-8. Mice that lack both caspase-8 and RIP3 develop into viable, immunocompetent, fertile adult mice, but suffer from a progressive lymphoaccumulative disease similar to mice that lack the death receptor CD95. This paper further shows that caspase-8 forms a proteolytically active complex with FLIP_L, and that this complex is required for protection against RIP3-dependent necrosis.

Spin–orbit coupling describes the interaction between a quantum particle's spin and its momentum, and is important for many areas of physics such as spintronics and topological insulators. However, in systems of ultracold neutral atoms, there is no coupling between the spin and the centre of mass motion of the atom. This study uses lasers to engineer such spin–orbit coupling in a neutral atomic Bose–Einstein condensate, the first time this has been achieved for any bosonic system. This should lead to the realization of topological insulators in fermionic neutral atom systems.