Gone fishing p.5

doi: 10.1038/519005a

Fatal fallout p.5

doi: 10.1038/519005b

Hues and cry p.6

doi: 10.1038/519006a

Ebola’s mental-health wounds linger in Africa p.13

doi: 10.1038/519013a

Robo-rescuers battle it out in disaster challenge p.14

doi: 10.1038/519014a

UN climate panel charts next steps p.15

doi: 10.1038/519015a

World's deadliest volcanoes identified p.16

doi: 10.1038/519016a

Therapeutic cancer vaccine survives biotech bust p.17

doi: 10.1038/519017a

Slick idea proposed to stretch water supplies p.18

doi: 10.1038/519018a

The minority minority p.20

doi: 10.1038/519020a

Ebola’s lasting legacy p.24

doi: 10.1038/519024a

Tied down by its own receptor p.36

doi: 10.1038/nature14205

Nanoscale locomotion without fuel p.37

doi: 10.1038/519037a

A cellular basis for the munchies p.38

doi: 10.1038/nature14206

Signals across domains of life p.40

doi: 10.1038/nature14202

Gating mechanism under pressure p.41

doi: 10.1038/519041a

Dual catalysis at the flick of a switch p.42

doi: 10.1038/519042a

Hypothalamic POMC neurons promote cannabinoid-induced feeding p.45

doi: 10.1038/nature14260

A motor cortex circuit for motor planning and movement p.51

doi: 10.1038/nature14178

A gp130–Src–YAP module links inflammation to epithelial regeneration p.57

doi: 10.1038/nature14228

The double-degenerate, super-Chandrasekhar nucleus of the planetary nebula Henize 2-428 p.63

doi: 10.1038/nature14124

State preservation by repetitive error detection in a superconducting quantum circuit p.66

doi: 10.1038/nature14270

Liquid-based gating mechanism with tunable multiphase selectivity and antifouling behaviour p.70

doi: 10.1038/nature14253

The direct arylation of allylic sp³ C–H bonds via organic and photoredox catalysis p.74

The direct functionalization of unactivated sp3 C–H bonds is still one of the most challenging problems facing synthetic organic chemists. The appeal of such transformations derives from their capacity to facilitate the construction of complex organic molecules via the coupling of simple and otherwise inert building blocks, without introducing extraneous functional groups. Despite notable recent efforts, the establishment of general and mild strategies for the engagement of sp3 C–H bonds in C–C bond forming reactions has proved difficult. Within this context, the discovery of chemical transformations that are able to directly functionalize allylic methyl, methylene and methine carbons in a catalytic manner is a priority. Although protocols for direct oxidation and amination of allylic C–H bonds (that is, C–H bonds where an adjacent carbon is involved in a C = C bond) have become widely established, the engagement of allylic substrates in C–C bond forming reactions has thus far required the use of pre-functionalized coupling partners. In particular, the direct arylation of non-functionalized allylic systems would enable access to a series of known pharmacophores (molecular features responsible for a drug’s action), though a general solution to this long-standing challenge remains elusive. Here we report the use of both photoredox and organic catalysis to accomplish a mild, broadly effective direct allylic C–H arylation. This C–C bond forming reaction readily accommodates a broad range of alkene and electron-deficient arene reactants, and has been used in the direct arylation of benzylic C–H bonds.

doi: 10.1038/nature14255

Drought impact on forest carbon dynamics and fluxes in Amazonia p.78

doi: 10.1038/nature14213

Reconstructed Homo habilis type OH 7 suggests deep-rooted species diversity in early Homo p.83

doi: 10.1038/nature14224

AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges p.87

doi: 10.1038/nature14264

Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome p.92

doi: 10.1038/nature14232

Dauer-independent insulin/IGF-1-signalling implicates collagen remodelling in longevity p.97

doi: 10.1038/nature14021

Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation p.102

The BCR-ABL1 fusion gene is a driver oncogene in chronic myeloid leukaemia and 30–50% of cases of adult acute lymphoblastic leukaemia. Introduction of ABL1 kinase inhibitors (for example, imatinib) has markedly improved patient survival, but acquired drug resistance remains a challenge. Point mutations in the ABL1 kinase domain weaken inhibitor binding and represent the most common clinical resistance mechanism. The BCR–ABL1 kinase domain gatekeeper mutation Thr315Ile (T315I) confers resistance to all approved ABL1 inhibitors except ponatinib, which has toxicity limitations. Here we combine comprehensive drug sensitivity and resistance profiling of patient cells ex vivo with structural analysis to establish the VEGFR tyrosine kinase inhibitor axitinib as a selective and effective inhibitor for T315I-mutant BCR–ABL1-driven leukaemia. Axitinib potently inhibited BCR–ABL1(T315I), at both biochemical and cellular levels, by binding to the active form of ABL1(T315I) in a mutation-selective binding mode. These findings suggest that the T315I mutation shifts the conformational equilibrium of the kinase in favour of an active (DFG-in) A-loop conformation, which has more optimal binding interactions with axitinib. Treatment of a T315I chronic myeloid leukaemia patient with axitinib resulted in a rapid reduction of T315I-positive cells from bone marrow. Taken together, our findings demonstrate an unexpected opportunity to repurpose axitinib, an anti-angiogenic drug approved for renal cancer, as an inhibitor for ABL1 gatekeeper mutant drug-resistant leukaemia patients. This study shows that wild-type proteins do not always sample the conformations available to disease-relevant mutant proteins and that comprehensive drug testing of patient-derived cells can identify unpredictable, clinically significant drug-repositioning opportunities.

doi: 10.1038/nature14119

Folding of an intrinsically disordered protein by phosphorylation as a regulatory switch p.106

doi: 10.1038/nature13999

Initiation of translation in bacteria by a structured eukaryotic IRES RNA p.110

doi: 10.1038/nature14219

Structure of the F-actin––tropomyosin complex p.114

Filamentous actin (F-actin) is the major protein of muscle thin filaments, and actin microfilaments are the main component of the eukaryotic cytoskeleton. Mutations in different actin isoforms lead to early-onset autosomal dominant non-syndromic hearing loss, familial thoracic aortic aneurysms and dissections, and multiple variations of myopathies. In striated muscle fibres, the binding of myosin motors to actin filaments is mainly regulated by tropomyosin and troponin. Tropomyosin also binds to F-actin in smooth muscle and in non-muscle cells and stabilizes and regulates the filaments there in the absence of troponin. Although crystal structures for monomeric actin (G-actin) are available, a high-resolution structure of F-actin is still missing, hampering our understanding of how disease-causing mutations affect the function of thin muscle filaments and microfilaments. Here we report the three-dimensional structure of F-actin at a resolution of 3.7 Å in complex with tropomyosin at a resolution of 6.5 Å, determined by electron cryomicroscopy. The structure reveals that the D-loop is ordered and acts as a central region for hydrophobic and electrostatic interactions that stabilize the F-actin filament. We clearly identify map density corresponding to ADP and Mg2+ and explain the possible effect of prominent disease-causing mutants. A comparison of F-actin with G-actin reveals the conformational changes during filament formation and identifies the D-loop as their key mediator. We also confirm that negatively charged tropomyosin interacts with a positively charged groove on F-actin. Comparison of the position of tropomyosin in F-actin–tropomyosin with its position in our previously determined F-actin–tropomyosin–myosin structure reveals a myosin-induced transition of tropomyosin. Our results allow us to understand the role of individual mutations in the genesis of actin- and tropomyosin-related diseases and will serve as a strong foundation for the targeted development of drugs.

doi: 10.1038/nature14033