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Universal resilience patterns in complex networks

Nature530, 307–312 (2016); doi:10.1038/nature16948In the last sentence of page 310 of this Letter, the parameter h should equal 2, rather than 1. In addition, after equation (4), the text should have stated ‘Aij

2016-08-16

Corrigendum: Dietary emulsifiers impact the mouse gut microbiota promoting colitis and metabolic syndrome

Nature519, 92–96 (2015); doi:10.1038/nature14232Some clarifications are provided to this Letter; these do not alter any of the central conclusions but, rather, are provided in the interests of transparency and reproducibility. Our Letter indicated that experiments were

2016-08-16

Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis

Nature526, 564–568 (2015); doi:10.1038/nature15695In the Methods of this Letter, ‘5,000’ should have read ‘15,000’ in the sentence: “Then, cells were again plated on a Matrigel-coated at 15,000 cells per cm2 in MEF-CM.” This error

2016-08-16

Reconstruction of bacterial transcription-coupled repair at single-molecule resolution

Escherichia coli Mfd translocase enables transcription-coupled repair by displacing RNA polymerase (RNAP) stalled on a DNA lesion and then coordinating assembly of the UvrAB(C) components at the damage site. Recent studies have shown that after binding to and dislodging stalled RNAP, Mfd remains on the DNA in the form of a stable, slowly translocating complex with evicted RNAP attached. Here we find, using a series of single-molecule assays, that recruitment of UvrA and UvrAB to Mfd–RNAP arrests the translocating complex and causes its dissolution. Correlative single-molecule nanomanipulation and fluorescence measurements show that dissolution of the complex leads to loss of both RNAP and Mfd. Subsequent DNA incision by UvrC is faster than when only UvrAB(C) are available, in part because UvrAB binds 20–200 times more strongly to Mfd–RNAP than to DNA damage. These observations provide a quantitative framework for comparing complementary DNA repair pathways in vivo.

2016-08-16

Mechanism of arginine sensing by CASTOR1 upstream of mTORC1

The mechanistic Target of Rapamycin Complex 1 (mTORC1) is a major regulator of eukaryotic growth that coordinates anabolic and catabolic cellular processes with inputs such as growth factors and nutrients, including amino acids. In mammals arginine is particularly important, promoting diverse physiological effects such as immune cell activation, insulin secretion, and muscle growth, largely mediated through activation of mTORC1 (refs 4, 5, 6, 7).Arginine activates mTORC1 upstream of the Rag family of GTPases, through either the lysosomal amino acid transporter SLC38A9 or the GATOR2-interacting Cellular Arginine Sensor for mTORC1 (CASTOR1). However, the mechanism by which the mTORC1 pathway detects and transmits this arginine signal has been elusive. Here, we present the 1.8 Å crystal structure of arginine-bound CASTOR1. Homodimeric CASTOR1 binds arginine at the interface of two Aspartate kinase, Chorismate mutase, TyrA (ACT) domains, enabling allosteric control of the adjacent GATOR2-binding site to trigger dissociation from GATOR2 and downstream activation of mTORC1. Our data reveal that CASTOR1 shares substantial structural homology with the lysine-binding regulatory domain of prokaryotic aspartate kinases, suggesting that the mTORC1 pathway exploited an ancient, amino-acid-dependent allosteric mechanism to acquire arginine sensitivity. Together, these results establish a structural basis for arginine sensing by the mTORC1 pathway and provide insights into the evolution of a mammalian nutrient sensor.

2016-08-16

Cotranslational signal-independent SRP preloading during membrane targeting

Ribosome-associated factors must properly decode the limited information available in nascent polypeptides to direct them to their correct cellular fate. It is unclear how the low complexity information exposed by the nascent chain suffices for accurate recognition by the many factors competing for the limited surface near the ribosomal exit site. Questions remain even for the well-studied cotranslational targeting cycle to the endoplasmic reticulum, involving recognition of linear hydrophobic signal sequences or transmembrane domains by the signal recognition particle (SRP). Notably, the SRP has low abundance relative to the large number of ribosome–nascent-chain complexes (RNCs), yet it accurately selects those destined for the endoplasmic reticulum. Despite their overlapping specificities, the SRP and the cotranslationally acting Hsp70 display precise mutually exclusive selectivity in vivo for their cognate RNCs. To understand cotranslational nascent chain recognition in vivo, here we investigate the cotranslational membrane-targeting cycle using ribosome profiling in yeast cells coupled with biochemical fractionation of ribosome populations. We show that the SRP preferentially binds secretory RNCs before their targeting signals are translated. Non-coding mRNA elements can promote this signal-independent pre-recruitment of SRP. Our study defines the complex kinetic interaction between elongation in the cytosol and determinants in the polypeptide and mRNA that modulate SRP–substrate selection and membrane targeting.

2016-08-16

Global profiling of SRP interaction with nascent polypeptides

Signal recognition particle (SRP) is a universally conserved protein–RNA complex that mediates co-translational protein translocation and membrane insertion by targeting translating ribosomes to membrane translocons. The existence of parallel co- and post-translational transport pathways, however, raises the question of the cellular substrate pool of SRP and the molecular basis of substrate selection. Here we determine the binding sites of bacterial SRP within the nascent proteome of Escherichia coli at amino acid resolution, by sequencing messenger RNA footprints of ribosome–nascent-chain complexes associated with SRP. SRP, on the basis of its strong preference for hydrophobic transmembrane domains (TMDs), constitutes a compartment-specific targeting factor for nascent inner membrane proteins (IMPs) that efficiently excludes signal-sequence-containing precursors of periplasmic and outer membrane proteins. SRP associates with hydrophobic TMDs enriched in consecutive stretches of hydrophobic and bulky aromatic amino acids immediately on their emergence from the ribosomal exit tunnel. By contrast with current models, N-terminal TMDs are frequently skipped and TMDs internal to the polypeptide sequence are selectively recognized. Furthermore, SRP binds several TMDs in many multi-spanning membrane proteins, suggesting cycles of SRP-mediated membrane targeting. SRP-mediated targeting is not accompanied by a transient slowdown of translation and is not influenced by the ribosome-associated chaperone trigger factor (TF), which has a distinct substrate pool and acts at different stages during translation. Overall, our proteome-wide data set of SRP-binding sites reveals the underlying principles of pathway decisions for nascent chains in bacteria, with SRP acting as the dominant triaging factor, sufficient to separate IMPs from substrates of the SecA–SecB post-translational translocation and TF-assisted cytosolic protein folding pathways.

2016-08-16

Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis

Metastasis is the leading cause of cancer-related death in humans. It is a complex multistep process during which individual tumour cells spread primarily through the circulatory system to colonize distant organs. Once in the circulation, tumour cells remain vulnerable, and their metastatic potential largely depends on a rapid and efficient way to escape from the blood stream by passing the endothelial barrier. Evidence has been provided that tumour cell extravasation resembles leukocyte transendothelial migration. However, it remains unclear how tumour cells interact with endothelial cells during extravasation and how these processes are regulated on a molecular level. Here we show that human and murine tumour cells induce programmed necrosis (necroptosis) of endothelial cells, which promotes tumour cell extravasation and metastasis. Treatment of mice with the receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-inhibitor necrostatin-1 or endothelial-cell-specific deletion of RIPK3 reduced tumour-cell-induced endothelial necroptosis, tumour cell extravasation and metastasis. In contrast, pharmacological caspase inhibition or endothelial-cell-specific loss of caspase-8 promoted these processes. We furthermore show in vitro and in vivo that tumour-cell-induced endothelial necroptosis leading to extravasation and metastasis requires amyloid precursor protein expressed by tumour cells and its receptor, death receptor 6 (DR6), on endothelial cells as the primary mediators of these effects. Our data identify a new mechanism underlying tumour cell extravasation and metastasis, and suggest endothelial DR6-mediated necroptotic signalling pathways as targets for anti-metastatic therapies.

2016-08-16

A trans-synaptic nanocolumn aligns neurotransmitter release to receptors

Synaptic transmission is maintained by a delicate, sub-synaptic molecular architecture, and even mild alterations in synapse structure drive functional changes during experience-dependent plasticity and pathological disorders. Key to this architecture is how the distribution of presynaptic vesicle fusion sites corresponds to the position of receptors in the postsynaptic density. However, while it has long been recognized that this spatial relationship modulates synaptic strength, it has not been precisely described, owing in part to the limited resolution of light microscopy. Using localization microscopy, here we show that key proteins mediating vesicle priming and fusion are mutually co-enriched within nanometre-scale subregions of the presynaptic active zone. Through development of a new method to map vesicle fusion positions within single synapses in cultured rat hippocampal neurons, we find that action-potential-evoked fusion is guided by this protein gradient and occurs preferentially in confined areas with higher local density of Rab3-interacting molecule (RIM) within the active zones. These presynaptic RIM nanoclusters closely align with concentrated postsynaptic receptors and scaffolding proteins, suggesting the existence of a trans-synaptic molecular ‘nanocolumn’. Thus, we propose that the nanoarchitecture of the active zone directs action-potential-evoked vesicle fusion to occur preferentially at sites directly opposing postsynaptic receptor–scaffold ensembles. Remarkably, NMDA receptor activation triggered distinct phases of plasticity in which postsynaptic reorganization was followed by trans-synaptic nanoscale realignment. This architecture suggests a simple organizational principle of central nervous system synapses to maintain and modulate synaptic efficiency.

2016-08-16

Emergence of a Homo sapiens-specific gene family and chromosome 16p11.2 CNV susceptibility

Genetic differences that specify unique aspects of human evolution have typically been identified by comparative analyses between the genomes of humans and closely related primates, including more recently the genomes of archaic hominins. Not all regions of the genome, however, are equally amenable to such study. Recurrent copy number variation (CNV) at chromosome 16p11.2 accounts for approximately 1% of cases of autism and is mediated by a complex set of segmental duplications, many of which arose recently during human evolution. Here we reconstruct the evolutionary history of the locus and identify bolA family member 2 (BOLA2) as a gene duplicated exclusively in Homo sapiens. We estimate that a 95-kilobase-pair segment containing BOLA2 duplicated across the critical region approximately 282 thousand years ago (ka), one of the latest among a series of genomic changes that dramatically restructured the locus during hominid evolution. All humans examined carried one or more copies of the duplication, which nearly fixed early in the human lineage—a pattern unlikely to have arisen so rapidly in the absence of selection (P < 0.0097). We show that the duplication of BOLA2 led to a novel, human-specific in-frame fusion transcript and that BOLA2 copy number correlates with both RNA expression (r = 0.36) and protein level (r = 0.65), with the greatest expression difference between human and chimpanzee in experimentally derived stem cells. Analyses of 152 patients carrying a chromosome 16p11.2 rearrangement show that more than 96% of breakpoints occur within the H. sapiens-specific duplication. In summary, the duplicative transposition of BOLA2 at the root of the H. sapiens lineage about 282 ka simultaneously increased copy number of a gene associated with iron homeostasis and predisposed our species to recurrent rearrangements associated with disease.

2016-08-16

Abrupt plate accelerations shape rifted continental margins

Rifted margins are formed by persistent stretching of continental lithosphere until breakup is achieved. It is well known that strain-rate-dependent processes control rift evolution, yet quantified extension histories of Earth’s major passive margins have become available only recently. Here we investigate rift kinematics globally by applying a new geotectonic analysis technique to revised global plate reconstructions. We find that rifted margins feature an initial, slow rift phase (less than ten millimetres per year, full rate) and that an abrupt increase of plate divergence introduces a fast rift phase. Plate acceleration takes place before continental rupture and considerable margin area is created during each phase. We reproduce the rapid transition from slow to fast extension using analytical and numerical modelling with constant force boundary conditions. The extension models suggest that the two-phase velocity behaviour is caused by a rift-intrinsic strength–velocity feedback, which can be robustly inferred for diverse lithosphere configurations and rheologies. Our results explain differences between proximal and distal margin areas and demonstrate that abrupt plate acceleration during continental rifting is controlled by the nonlinear decay of the resistive rift strength force. This mechanism provides an explanation for several previously unexplained rapid absolute plate motion changes, offering new insights into the balance of plate driving forces through time.

2016-08-16

Single-layer MoS2 nanopores as nanopower generators

Making use of the osmotic pressure difference between fresh water and seawater is an attractive, renewable and clean way to generate power and is known as ‘blue energy’. Another electrokinetic phenomenon, called the streaming potential, occurs when an electrolyte is driven through narrow pores either by a pressure gradient or by an osmotic potential resulting from a salt concentration gradient. For this task, membranes made of two-dimensional materials are expected to be the most efficient, because water transport through a membrane scales inversely with membrane thickness. Here we demonstrate the use of single-layer molybdenum disulfide (MoS2) nanopores as osmotic nanopower generators. We observe a large, osmotically induced current produced from a salt gradient with an estimated power density of up to 106 watts per square metre—a current that can be attributed mainly to the atomically thin membrane of MoS2. Low power requirements for nanoelectronic and optoelectric devices can be provided by a neighbouring nanogenerator that harvests energy from the local environment—for example, a piezoelectric zinc oxide nanowire array or single-layer MoS2 (ref. 12). We use our MoS2 nanopore generator to power a MoS2 transistor, thus demonstrating a self-powered nanosystem.

2016-08-16

A photon–photon quantum gate based on a single atom in an optical resonator

That two photons pass each other undisturbed in free space is ideal for the faithful transmission of information, but prohibits an interaction between the photons. Such an interaction is, however, required for a plethora of applications in optical quantum information processing. The long-standing challenge here is to realize a deterministic photon–photon gate, that is, a mutually controlled logic operation on the quantum states of the photons. This requires an interaction so strong that each of the two photons can shift the other’s phase by π radians. For polarization qubits, this amounts to the conditional flipping of one photon’s polarization to an orthogonal state. So far, only probabilistic gates based on linear optics and photon detectors have been realized, because “no known or foreseen material has an optical nonlinearity strong enough to implement this conditional phase shift”. Meanwhile, tremendous progress in the development of quantum-nonlinear systems has opened up new possibilities for single-photon experiments. Platforms range from Rydberg blockade in atomic ensembles to single-atom cavity quantum electrodynamics. Applications such as single-photon switches and transistors, two-photon gateways, nondestructive photon detectors, photon routers and nonlinear phase shifters have been demonstrated, but none of them with the ideal information carriers: optical qubits in discriminable modes. Here we use the strong light–matter coupling provided by a single atom in a high-finesse optical resonator to realize the Duan–Kimble protocol of a universal controlled phase flip (π phase shift) photon–photon quantum gate. We achieve an average gate fidelity of (76.2 ± 3.6) per cent and specifically demonstrate the capability of conditional polarization flipping as well as entanglement generation between independent input photons. This photon–photon quantum gate is a universal quantum logic element, and therefore could perform most existing two-photon operations. The demonstrated feasibility of deterministic protocols for the optical processing of quantum information could lead to new applications in which photons are essential, especially long-distance quantum communication and scalable quantum computing.

2016-08-16

Heating of Jupiter’s upper atmosphere above the Great Red Spot

The temperatures of giant-planet upper atmospheres at mid- to low latitudes are measured to be hundreds of degrees warmer than simulations based on solar heating alone can explain. Modelling studies that focus on additional sources of heating have been unable to resolve this major discrepancy. Equatorward transport of energy from the hot auroral regions was expected to heat the low latitudes, but models have demonstrated that auroral energy is trapped at high latitudes, a consequence of the strong Coriolis forces on rapidly rotating planets. Wave heating, driven from below, represents another potential source of upper-atmospheric heating, though initial calculations have proven inconclusive for Jupiter, largely owing to a lack of observational constraints on wave parameters. Here we report that the upper atmosphere above Jupiter’s Great Red Spot—the largest storm in the Solar System—is hundreds of degrees hotter than anywhere else on the planet. This hotspot, by process of elimination, must be heated from below, and this detection is therefore strong evidence for coupling between Jupiter’s lower and upper atmospheres, probably the result of upwardly propagating acoustic or gravity waves.

2016-08-16

An evolutionarily conserved pathway controls proteasome homeostasis

The proteasome is essential for the selective degradation of most cellular proteins, but how cells maintain adequate amounts of proteasome is unclear. Here we show that there is an evolutionarily conserved signalling pathway controlling proteasome homeostasis. Central to this pathway is TORC1, the inhibition of which induced all known yeast 19S regulatory particle assembly-chaperones (RACs), as well as proteasome subunits. Downstream of TORC1 inhibition, the yeast mitogen-activated protein kinase, Mpk1, acts to increase the supply of RACs and proteasome subunits under challenging conditions in order to maintain proteasomal degradation and cell viability. This adaptive pathway was evolutionarily conserved, with mTOR and ERK5 controlling the levels of the four mammalian RACs and proteasome abundance. Thus, the central growth and stress controllers, TORC1 and Mpk1/ERK5, endow cells with a rapid and vital adaptive response to adjust proteasome abundance in response to the rising needs of cells. Enhancing this pathway may be a useful therapeutic approach for diseases resulting from impaired proteasomal degradation.

2016-08-16

SAR11 bacteria linked to ocean anoxia and nitrogen loss

Bacteria of the SAR11 clade constitute up to one half of all microbial cells in the oxygen-rich surface ocean. SAR11 bacteria are also abundant in oxygen minimum zones (OMZs), where oxygen falls below detection and anaerobic microbes have vital roles in converting bioavailable nitrogen to

2016-08-16

A multi-modal parcellation of human cerebral cortex

Understanding the amazingly complex human cerebral cortex requires a map (or parcellation) of its major subdivisions, known as cortical areas. Making an accurate areal map has been a century-old objective in neuroscience. Using multi-modal magnetic resonance images from the Human Connectome Project (HCP) and an

2016-08-16

Tempo and mode of genome evolution in a 50,000-generation experiment

Adaptation by natural selection depends on the rates, effects and interactions of many mutations, making it difficult to determine what proportion of mutations in an evolving lineage are beneficial. Here we analysed 264 complete genomes from 12 Escherichia coli populations to characterize their dynamics

2016-08-16

Synergistic, ultrafast mass storage and removal in artificial mixed conductors

Mixed conductors—single phases that conduct electronically and ionically—enable stoichiometric variations in a material and, therefore, mass storage and redistribution, for example, in battery electrodes. We have considered how such properties may be achieved synergistically in solid two-phase systems, forming artificial mixed conductors. Previously investigated composites

2016-08-16

Cancer: Fat and the fate of pancreatic tumours

In obese people with pancreatic cancer, the many interactions between fat cells and the inflammatory microenvironment surrounding the tumour leads to below-average prognosis and chemotherapy outcome.

2016-08-16
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