Volume 525 Number 7569

Editorials

Too close for comfort? p.289

Relationships between industry and researchers can be hard to define, but universities and other institutions must do more to scrutinize the work of their scientists for conflicts of interest.

doi: 10.1038/525289a

Mind meld p.289

Interdisciplinary science must break down barriers between fields to build common ground.

doi: 10.1038/525289b

Protection priority p.290

All involved in animal research must ensure that rules for ethical experiments are observed.

doi: 10.1038/525290a

News

NIH disclosure rules falter p.300

Regulations that require researchers to disclose conflicts of interest yield questionable data and cost universities millions.

doi: 10.1038/525300a

News Features

How to solve the world's biggest problems p.308

Interdisciplinarity has become all the rage as scientists tackle climate change and other intractable issues. But there is still strong resistance to crossing borders.

doi: 10.1038/525308a

News & Views

Forgetfulness illuminated p.324

Memories are stored in the complex network of neurons in the brain. With the help of innovative tools to manipulate the connections between neurons, memories in mice can now be erased with a beam of light. See Article p.333

doi: 10.1038/nature15211

Tens of thousands of atoms replaced by one p.325

Many catalysts comprise metal nanoparticles on solid supports. The discovery that single atoms of palladium anchored to a solid support also exhibit high catalytic activity might help to conserve the supply of this and related rare metals.

doi: 10.1038/525325a

Perplexing effects of phenotypic plasticity p.326

Research on guppies provides evidence that phenotypic plasticity — an organism's ability to alter its characteristics in response to changes in the environment — can both constrain and facilitate adaptive evolution. See Letter p.372

doi: 10.1038/nature15214

Repositioned to kill stem cells p.328

Chemotherapy-resistant cancer stem cells make it hard to cure many forms of the disease. Repositioning an existing drug to tackle this problem could significantly improve treatment for one form of leukaemia. See Letter p.380

doi: 10.1038/nature15213

Charge topology in superconductors p.329

X-ray images of cuprate superconductors reveal the fractured, defect-riddled backbone on which superconductivity develops. The results take us a step closer to understanding how supercurrent flows on small spatial scales. See Letter p.359

doi: 10.1038/525329a

The death toll from air-pollution sources p.330

Estimates of worldwide deaths associated with exposure to fine particles in atmospheric pollution provide some surprising results. The findings will guide future research and act as a wake-up call for policymakers. See Letter p.367

doi: 10.1038/525330a

Articles

Labelling and optical erasure of synaptic memory traces in the motor cortex p.333

A new light-activated probe that targets recently active neuronal spines for manipulation induces shrinkage of recently potentiated spines following a motor learning task; spine shrinkage disrupted learning, suggesting a causal relationship between the specific subset of targeted spines and the learned behaviour.

doi: 10.1038/nature15257

Panorama of ancient metazoan macromolecular complexes p.339

Using biochemical fractionation and mass spectrometry, animal protein complexes are identified from nine species in parallel, and, along with genome sequence information, complex conservation is investigated and over one million protein–protein interactions are predicted in 122 eukaryotes.

doi: 10.1038/nature14877

Letters

Spawning rings of exceptional points out of Dirac cones p.354

Exceptional points are singularities in non-Hermitian systems that can produce unusual effects, and it is shown that a Dirac cone in a photonic crystal can generate a continuous ring of exceptional points through flattening the tip of the cone.

doi: 10.1038/nature14889

Erosion of the chronic myeloid leukaemia stem cell pool by PPARγ agonists p.380

Whether cancer is maintained by a small number of stem cells or is composed of proliferating cells with approximate phenotypic equivalency is a central question in cancer biology. In the stem cell hypothesis, relapse after treatment may occur by failure to eradicate cancer stem cells. Chronic myeloid leukaemia (CML) is quintessential to this hypothesis. CML is a myeloproliferative disorder that results from dysregulated tyrosine kinase activity of the fusion oncoprotein BCR–ABL. During the chronic phase, this sole genetic abnormality (chromosomal translocation Ph+: t(9;22)(q34;q11)) at the stem cell level causes increased proliferation of myeloid cells without loss of their capacity to differentiate. Without treatment, most patients progress to the blast phase when additional oncogenic mutations result in a fatal acute leukaemia made of proliferating immature cells. Imatinib mesylate and other tyrosine kinase inhibitors (TKIs) that target the kinase activity of BCR–ABL have improved patient survival markedly. However, fewer than 10% of patients reach the stage of complete molecular response (CMR), defined as the point when BCR-ABL transcripts become undetectable in blood cells. Failure to reach CMR results from the inability of TKIs to eradicate quiescent CML leukaemia stem cells (LSCs). Here we show that the residual CML LSC pool can be gradually purged by the glitazones, antidiabetic drugs that are agonists of peroxisome proliferator-activated receptor-γ (PPARγ). We found that activation of PPARγ by the glitazones decreases expression of STAT5 and its downstream targets HIF2α and CITED2, which are key guardians of the quiescence and stemness of CML LSCs. When pioglitazone was given temporarily to three CML patients in chronic residual disease in spite of continuous treatment with imatinib, all of them achieved sustained CMR, up to 4.7 years after withdrawal of pioglitazone. This suggests that clinically relevant cancer eradication may become a generally attainable goal by combination therapy that erodes the cancer stem cell pool.

doi: 10.1038/nature15248

The spliceosome is a therapeutic vulnerability in MYC-driven cancer p.384

Splicing factors such as BUD31 are identified in a synthetic-lethal screen with cells overexpressing the transcription factor MYC; oncogenic MYC leads to an increase in pre-mRNA synthesis, and spliceosome inhibition impairs the growth and tumorigenicity of MYC-dependent breast cancers, suggesting that spliceosome components may be potential therapeutic targets for MYC-driven cancers.

doi: 10.1038/nature14985

Replisome speed determines the efficiency of the Tus−Ter replication termination barrier p.394

In all domains of life, DNA synthesis occurs bidirectionally from replication origins. Despite variable rates of replication fork progression, fork convergence often occurs at specific sites. Escherichia coli sets a ‘replication fork trap’ that allows the first arriving fork to enter but not to leave the terminus region. The trap is set by oppositely oriented Tus-bound Ter sites that block forks on approach from only one direction. However, the efficiency of fork blockage by Tus–Ter does not exceed 50% in vivo despite its apparent ability to almost permanently arrest replication forks in vitro. Here we use data from single-molecule DNA replication assays and structural studies to show that both polarity and fork-arrest efficiency are determined by a competition between rates of Tus displacement and rearrangement of Tus–Ter interactions that leads to blockage of slower moving replisomes by two distinct mechanisms. To our knowledge this is the first example where intrinsic differences in rates of individual replisomes have different biological outcomes.

doi: 10.1038/nature14866

Integrator mediates the biogenesis of enhancer RNAs p.399

This study demonstrates a role for the Integrator complex in the stimulus-dependent induction of eRNAs and their 3′ processing; together with previously known roles of Integrator in transcription elongation and RNA processing, these results indicate that Integrator has broad functions in the regulation of eukaryotic gene expression.

doi: 10.1038/nature14906

Crystal structure of the dynamin tetramer p.404

The crystal structure of the large GTPase dynamin tetramer is presented, suggesting a mechanism by which oligomerization of dynamin is regulated, and revealing how mutations that interfere with tetramer formation and autoinhibition are of relevance to understanding the congenital muscle disorders Charcot–Marie–Tooth neuropathy and centronuclear myopathy.

doi: 10.1038/nature14880