Time for the social sciences p.5

doi: 10.1038/517005a

Nicaragua defies canal protests p.7

doi: 10.1038/517007a

Planet hunters plot a course p.8

doi: 10.1038/517008a

Ebola raises profile of blood-based therapy p.9

doi: 10.1038/517009a

What to expect in 2015 p.10

doi: 10.1038/517010a

Science in 2015 p.12

doi: 10.1038/517012a

Entry signals control development p.24

doi: 10.1038/nature14069

Like cartilage, but simpler p.25

doi: 10.1038/517025a

Photosynthetic complex in close-up p.26

doi: 10.1038/nature14072

Diverted on the way to memory p.28

doi: 10.1038/nature14083

It takes three to find the exit p.29

doi: 10.1038/nature14080

Ocean circulation and rapid climate change p.30

doi: 10.1038/nature14084

RNA regulons in Hox 5′ UTRs confer ribosome specificity to gene regulation p.33

doi: 10.1038/nature14010

Architecture and conformational switch mechanism of the ryanodine receptor p.39

doi: 10.1038/nature13916

Structure of a mammalian ryanodine receptor p.44

doi: 10.1038/nature13950

Structure of the rabbit ryanodine receptor RyR1 at near-atomic resolution p.50

doi: 10.1038/nature14063

A higher-than-predicted measurement of iron opacity at solar interior temperatures p.56

doi: 10.1038/nature14048

Higher-than-predicted saltation threshold wind speeds on Titan p.60

doi: 10.1038/nature14088

Observation of quantized conductance in neutral matter p.64

doi: 10.1038/nature14049

An anisotropic hydrogel with electrostatic repulsion between cofacially aligned nanosheets p.68

doi: 10.1038/nature14060

Strong and deep Atlantic meridional overturning circulation during the last glacial cycle p.73

doi: 10.1038/nature14059

Origins of major archaeal clades correspond to gene acquisitions from bacteria p.77

doi: 10.1038/nature13805

Identification of multipotent mammary stem cells by protein C receptor expression p.81

doi: 10.1038/nature13851

Hepatitis A virus and the origins of picornaviruses p.85

doi: 10.1038/nature13806

Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation p.89

Intracellular ISG15 is an interferon (IFN)-α/β-inducible ubiquitin-like modifier which can covalently bind other proteins in a process called ISGylation; it is an effector of IFN-α/β-dependent antiviral immunity in mice. We previously published a study describing humans with inherited ISG15 deficiency but without unusually severe viral diseases. We showed that these patients were prone to mycobacterial disease and that human ISG15 was non-redundant as an extracellular IFN-γ-inducing molecule. We show here that ISG15-deficient patients also display unanticipated cellular, immunological and clinical signs of enhanced IFN-α/β immunity, reminiscent of the Mendelian autoinflammatory interferonopathies Aicardi–Goutières syndrome and spondyloenchondrodysplasia. We further show that an absence of intracellular ISG15 in the patients’ cells prevents the accumulation of USP18, a potent negative regulator of IFN-α/β signalling, resulting in the enhancement and amplification of IFN-α/β responses. Human ISG15, therefore, is not only redundant for antiviral immunity, but is a key negative regulator of IFN-α/β immunity. In humans, intracellular ISG15 is IFN-α/β-inducible not to serve as a substrate for ISGylation-dependent antiviral immunity, but to ensure USP18-dependent regulation of IFN-α/β and prevention of IFN-α/β-dependent autoinflammation.

doi: 10.1038/nature13801

A PP1–PP2A phosphatase relay controls mitotic progression p.94

doi: 10.1038/nature14019

Native structure of photosystem II at 1.95 Å resolution viewed by femtosecond X-ray pulses p.99

Photosynthesis converts light energy into biologically useful chemical energy vital to life on Earth. The initial reaction of photosynthesis takes place in photosystem II (PSII), a 700-kilodalton homodimeric membrane protein complex that catalyses photo-oxidation of water into dioxygen through an S-state cycle of the oxygen evolving complex (OEC). The structure of PSII has been solved by X-ray diffraction (XRD) at 1.9 ångström resolution, which revealed that the OEC is a Mn₄CaO₅-cluster coordinated by a well defined protein environment. However, extended X-ray absorption fine structure (EXAFS) studies showed that the manganese cations in the OEC are easily reduced by X-ray irradiation, and slight differences were found in the Mn–Mn distances determined by XRD, EXAFS and theoretical studies. Here we report a ‘radiation-damage-free’ structure of PSII from Thermosynechococcus vulcanus in the S₁ state at a resolution of 1.95 ångströms using femtosecond X-ray pulses of the SPring-8 ångström compact free-electron laser (SACLA) and hundreds of large, highly isomorphous PSII crystals. Compared with the structure from XRD, the OEC in the X-ray free electron laser structure has Mn–Mn distances that are shorter by 0.1–0.2 ångströms. The valences of each manganese atom were tentatively assigned as Mn1D(iii), Mn2C(iv), Mn3B(iv) and Mn4A(iii), based on the average Mn–ligand distances and analysis of the Jahn–Teller axis on Mn(iii). One of the oxo-bridged oxygens, O5, has significantly longer distances to Mn than do the other oxo-oxygen atoms, suggesting that O5 is a hydroxide ion instead of a normal oxygen dianion and therefore may serve as one of the substrate oxygen atoms. These findings provide a structural basis for the mechanism of oxygen evolution, and we expect that this structure will provide a blueprint for the design of artificial catalysts for water oxidation.

doi: 10.1038/nature13991

Structure of an integral membrane sterol reductase from Methylomicrobium alcaliphilum p.104

Sterols are essential biological molecules in the majority of life forms. Sterol reductases including Δ14-sterol reductase (C14SR, also known as TM7SF2), 7-dehydrocholesterol reductase (DHCR7) and 24-dehydrocholesterol reductase (DHCR24) reduce specific carbon–carbon double bonds of the sterol moiety using a reducing cofactor during sterol biosynthesis. Lamin B receptor (LBR), an integral inner nuclear membrane protein, also contains a functional C14SR domain. Here we report the crystal structure of a Δ14-sterol reductase (MaSR1) from the methanotrophic bacterium Methylomicrobium alcaliphilum 20Z (a homologue of human C14SR, LBR and DHCR7) with the cofactor NADPH. The enzyme contains ten transmembrane segments (TM1–10). Its catalytic domain comprises the carboxy-terminal half (containing TM6–10) and envelops two interconnected pockets, one of which faces the cytoplasm and houses NADPH, while the other one is accessible from the lipid bilayer. Comparison with a soluble steroid 5β-reductase structure suggests that the reducing end of NADPH meets the sterol substrate at the juncture of the two pockets. A sterol reductase activity assay proves that MaSR1 can reduce the double bond of a cholesterol biosynthetic intermediate, demonstrating functional conservation to human C14SR. Therefore, our structure as a prototype of integral membrane sterol reductases provides molecular insight into mutations in DHCR7 and LBR for inborn human diseases.

doi: 10.1038/nature13797