네이처 컨텐츠

Editorials

Nuclear error p.5

Japan should bring in international help to study and mitigate the Fukushima crisis.

doi: 10.1038/501005b

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The power of treaties p.5

International weapons conventions may not be perfect, but they are a vital mechanism for making wars less barbaric and less frequent — a cause that should galvanize scientists and others.

doi: 10.1038/501005a

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The nitrogen fix p.6

A simple iron complex offers a chance to update how the global supply of ammonia is made.

doi: 10.1038/501006a

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News

News Features

Biology on the high seas p.20

How Eric Karsenti's quest to understand the cell launched a trip around the world.

Claire Ainsworth

doi: 10.1038/501020a

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News & Views

A long genetic explanation p.36

Topoisomerase enzymes facilitate gene transcription by resolving DNA tangles. Malfunction of these enzymes seems to compromise the expression of very long genes, potentially mediating neurodevelopmental disorders. See Article p.58

Robert N. Plasschaert & Marisa S. Bartolomei

doi: 10.1038/nature12553

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Sharing quantum secrets p.37

A cost-effective architecture for quantum cryptography has been demonstrated in which a single receiver positioned at a network-hub node is shared by many end users to exchange secret encryption keys. See Letter p.69

Rupert Ursin & Richard Hughes

doi: 10.1038/501037a

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Mimicry all the way down p.38

Morphological mimicry among organisms has long been recognized as an adaptive strategy, but mimicry also occurs at the molecular level. One emerging example is microbial pathogens' use of structural mimics that engage host-cell receptors.

Matthew F. Barber & Nels C. Elde

doi: 10.1038/501038a

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As different as night and day p.39

An analysis of northern ecosystems shows that the effects on plant growth of rising night-time temperatures are opposite to those of increasing daytime temperatures — a finding that has implications for carbon-cycle models. See Letter p.88

Christopher Still

doi: 10.1038/501039a

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Recycling in sight p.40

Vision requires the continuous recycling of photobleached pigments. An atypical form of a degradative pathway called autophagy seems to participate in this process in retinal pigment epithelial cells.

Patricia Boya & Patrice Codogno

doi: 10.1038/501040a

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B-cell development in the gut p.42

B cells arise in the bone marrow and go on to produce antibodies that protect against microbial infection. Surprisingly, it seems that B-cell development also occurs in the gut, where it is stimulated by resident microbes. See Letter p.112

Mark Schlissel

doi: 10.1038/nature12551

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Bacteria get on your nerves p.43

During infection, the inflammatory immune response can cause pain by activating nociceptor neurons. A bacterial pathogen also seems to stimulatepain directly, modulating the immune response in its favour. See Article p.52

Victor Nizet & Tony Yaksh

doi: 10.1038/nature12550

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Review

Self-propagation of pathogenic protein aggregates in neurodegenerative diseases p.45

For several decades scientists have speculated that the key to understanding age-related neurodegenerative disorders may be found in the unusual biology of the prion diseases. Recently, owing largely to the advent of new disease models, this hypothesis has gained experimental momentum. In a remarkable variety of diseases, specific proteins have been found to misfold and aggregate into seeds that structurally corrupt like proteins, causing them to aggregate and form pathogenic assemblies ranging from small oligomers to large masses of amyloid. Proteinaceous seeds can therefore serve as self-propagating agents for the instigation and progression of disease. Alzheimer’s disease and other cerebral proteopathies seem to arise from the de novo misfolding and sustained corruption of endogenous proteins, whereas prion diseases can also be infectious in origin. However, the outcome in all cases is the functional compromise of the nervous system, because the aggregated proteins gain a toxic function and/or lose their normal function. As a unifying pathogenic principle, the prion paradigm suggests broadly relevant therapeutic directions for a large class of currently intractable diseases.

Mathias Jucker & Lary C. Walker

doi: 10.1038/nature12481

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Articles

Bacteria activate sensory neurons that modulate pain and inflammation p.52

This study shows that most known mediators of immunity, such as TLR2, MyD88, T cells or B cells, and neutrophils and monocytes, are dispensable for pain produced by Staphylococcus aureus infection; instead, bacterial products, such as N-formylated peptides and α-haemolysin, induce pain by directly activating nociceptor neurons, which in turn modulate inflammation.

Isaac M. Chiu, Balthasar A. Heesters, Nader Ghasemlou, Christian A. Von Hehn, Fan Zhao, Johnathan Tran, Brian Wainger, Amanda Strominger, Sriya Muralidharan, Alexander R. Horswill + et al.

doi: 10.1038/nature12479

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Topoisomerases facilitate transcription of long genes linked to autism p.58

Reducing topoisomerase activity in mouse and human neurons is found to reduce the expression of long genes by impairing transcription elongation: among genes affected are numerous high-confidence candidates for autism spectrum disorder.

Ian F. King, Chandri N. Yandava, Angela M. Mabb, Jack S. Hsiao, Hsien-Sung Huang, Brandon L. Pearson, J. Mauro Calabrese, Joshua Starmer, Joel S. Parker, Terry Magnuson + et al.

doi: 10.1038/nature12504

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Key tissue targets responsible for anthrax-toxin-induced lethality p.63

Cell-type-specific anthrax toxin receptor CMG2-null mice are generated and used to show that the Bacillus anthracis toxins lethal toxin (LT) and oedema toxin (ET) target distinct cell types; in contrast to previous suggestions, it is shown that endothelial cells are not key targets for either toxin and instead LT targets cardiomyocytes and vascular smooth muscle cells whereas ET targets hepatocytes.

Shihui Liu, Yi Zhang, Mahtab Moayeri, Jie Liu, Devorah Crown, Rasem J. Fattah, Alexander N. Wein, Zu-Xi Yu, Toren Finkel & Stephen H. Leppla

doi: 10.1038/nature12510

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Letters

A quantum access network p.69

The theoretically proven security of quantum key distribution (QKD) could revolutionize the way in which information exchange is protected in the future. Several field tests of QKD have proven it to be a reliable technology for cryptographic key exchange and have demonstrated nodal networks of point-to-point links. However, until now no convincing answer has been given to the question of how to extend the scope of QKD beyond niche applications in dedicated high security networks. Here we introduce and experimentally demonstrate the concept of a ‘quantum access network’: based on simple and cost-effective telecommunication technologies, the scheme can greatly expand the number of users in quantum networks and therefore vastly broaden their appeal. We show that a high-speed single-photon detector positioned at a network node can be shared between up to 64 users for exchanging secret keys with the node, thereby significantly reducing the hardware requirements for each user added to the network. This point-to-multipoint architecture removes one of the main obstacles restricting the widespread application of QKD. It presents a viable method for realizing multi-user QKD networks with efficient use of resources, and brings QKD closer to becoming a widespread technology.

Bernd Fröhlich, James F. Dynes, Marco Lucamarini, Andrew W. Sharpe, Zhiliang Yuan & Andrew J. Shields

doi: 10.1038/nature12493

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Microscopic origin of the ‘0.7-anomaly’ in quantum point contacts p.73

Quantum point contacts are narrow, one-dimensional constrictions usually patterned in a two-dimensional electron system, for example by applying voltages to local gates. The linear conductance of a point contact, when measured as function of its channel width, is quantized in units of GQ = 2e2/h, where e is the electron charge and h is Planck’s constant. However, the conductance also has an unexpected shoulder at ∼0.7GQ, known as the ‘0.7-anomaly’, whose origin is still subject to debate. Proposed theoretical explanations have invoked spontaneous spin polarization, ferromagnetic spin coupling, the formation of a quasi-bound state leading to the Kondo effect, Wigner crystallization and various treatments of inelastic scattering. However, explicit calculations that fully reproduce the various experimental observations in the regime of the 0.7-anomaly, including the zero-bias peak that typically accompanies it, are still lacking. Here we offer a detailed microscopic explanation for both the 0.7-anomaly and the zero-bias peak: their common origin is a smeared van Hove singularity in the local density of states at the bottom of the lowest one-dimensional subband of the point contact, which causes an anomalous enhancement in the Hartree potential barrier, the magnetic spin susceptibility and the inelastic scattering rate. We find good qualitative agreement between theoretical calculations and experimental results on the dependence of the conductance on gate voltage, magnetic field, temperature, source–drain voltage (including the zero-bias peak) and interaction strength. We also clarify how the low-energy scale governing the 0.7-anomaly depends on gate voltage and interactions. For low energies, we predict and observe Fermi-liquid behaviour similar to that associated with the Kondo effect in quantum dots. At high energies, however, the similarities between the 0.7-anomaly and the Kondo effect end.

Florian Bauer, Jan Heyder, Enrico Schubert, David Borowsky, Daniela Taubert, Benedikt Bruognolo, Dieter Schuh, Werner Wegscheider, Jan von Delft & Stefan Ludwig

doi: 10.1038/nature12421

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Odd and even Kondo effects from emergent localization in quantum point contacts p.79

A quantum point contact (QPC) is a basic nanometre-scale electronic device: a short and narrow transport channel between two electron reservoirs. In clean channels, electron transport is ballistic and the conductance is then quantized as a function of channel width with plateaux at integer multiples of 2e2/h (where e is the electron charge and h is Planck’s constant). This can be understood in a picture where the electron states are propagating waves, without the need to account for electron–electron interactions. Quantized conductance could thus be the signature of ultimate control over nanoscale electron transport. However, even studies with the cleanest QPCs generically show significant anomalies in the quantized conductance traces, and there is consensus that these result from electron many-body effects. Despite extensive experimental and theoretical studies, understanding these anomalies is an open problem. Here we report that the many-body effects have their origin in one or more spontaneously localized states that emerge from Friedel oscillations in the electron charge density within the QPC channel. These localized states will have electron spins associated with them, and the Kondo effect—related to electron transport through such localized electron spins—contributes to the formation of the many-body state. We present evidence for such localization, with Kondo effects of odd or even character, directly reflecting the parity of the number of localized states; the evidence is obtained from experiments with length-tunable QPCs that show a periodic modulation of the many-body properties with Kondo signatures that alternate between odd and even Kondo effects. Our results are of importance for assessing the role of QPCs in more complex hybrid devices and for proposals for spintronic and quantum information applications. In addition, our results show that tunable QPCs offer a versatile platform for investigating many-body effects in nanoscale systems, with the ability to probe such physics at the level of a single site.

M. J. Iqbal, Roi Levy, E. J. Koop, J. B. Dekker, J. P. de Jong, J. H. M. van der Velde, D. Reuter, A. D. Wieck, Ramón Aguado, Yigal Meir + et al.

doi: 10.1038/nature12491

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Catalytic conversion of nitrogen to ammonia by an iron model complex p.84

The reduction of nitrogen (N2) to ammonia (NH3) is a requisite transformation for life. Although it is widely appreciated that the iron-rich cofactors of nitrogenase enzymes facilitate this transformation, how they do so remains poorly understood. A central element of debate has been the exact site or sites of N2 coordination and reduction. In synthetic inorganic chemistry, an early emphasis was placed on molybdenum because it was thought to be an essential element of nitrogenases and because it had been established that well-defined molybdenum model complexes could mediate the stoichiometric conversion of N2 to NH3 (ref. 9). This chemical transformation can be performed in a catalytic fashion by two well-defined molecular systems that feature molybdenum centres. However, it is now thought that iron is the only transition metal essential to all nitrogenases, and recent biochemical and spectroscopic data have implicated iron instead of molybdenum as the site of N2 binding in the FeMo-cofactor. Here we describe a tris(phosphine)borane-supported iron complex that catalyses the reduction of N2 to NH3 under mild conditions, and in which more than 40 per cent of the proton and reducing equivalents are delivered to N2. Our results indicate that a single iron site may be capable of stabilizing the various NxHy intermediates generated during catalytic NH3 formation. Geometric tunability at iron imparted by a flexible iron–boron interaction in our model system seems to be important for efficient catalysis. We propose that the interstitial carbon atom recently assigned in the nitrogenase cofactor may have a similar role, perhaps by enabling a single iron site to mediate the enzymatic catalysis through a flexible iron–carbon interaction.

John S. Anderson, Jonathan Rittle & Jonas C. Peters

doi: 10.1038/nature12435

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Asymmetric effects of daytime and night-time warming on Northern Hemisphere vegetation p.88

Temperature data over the past five decades show faster warming of the global land surface during the night than during the day. This asymmetric warming is expected to affect carbon assimilation and consumption in plants, because photosynthesis in most plants occurs during daytime and is more sensitive to the maximum daily temperature, Tmax, whereas plant respiration occurs throughout the day and is therefore influenced by both Tmax and the minimum daily temperature, Tmin. Most studies of the response of terrestrial ecosystems to climate warming, however, ignore this asymmetric forcing effect on vegetation growth and carbon dioxide (CO2) fluxes. Here we analyse the interannual covariations of the satellite-derived normalized difference vegetation index (NDVI, an indicator of vegetation greenness) with Tmax and Tmin over the Northern Hemisphere. After removing the correlation between Tmax and Tmin, we find that the partial correlation between Tmax and NDVI is positive in most wet and cool ecosystems over boreal regions, but negative in dry temperate regions. In contrast, the partial correlation between Tmin and NDVI is negative in boreal regions, and exhibits a more complex behaviour in dry temperate regions. We detect similar patterns in terrestrial net CO2 exchange maps obtained from a global atmospheric inversion model. Additional analysis of the long-term atmospheric CO2 concentration record of the station Point Barrow in Alaska suggests that the peak-to-peak amplitude of CO2 increased by 23 ± 11% for a +1 °C anomaly in Tmax from May to September over lands north of 51° N, but decreased by 28 ± 14% for a +1 °C anomaly in Tmin. These lines of evidence suggest that asymmetric diurnal warming, a process that is currently not taken into account in many global carbon cycle models, leads to a divergent response of Northern Hemisphere vegetation growth and carbon sequestration to rising temperatures.

Shushi Peng, Shilong Piao, Philippe Ciais, Ranga B. Myneni, Anping Chen, Frédéric Chevallier, Albertus J. Dolman, Ivan A. Janssens, Josep Peñuelas, Gengxin Zhang + et al.

doi: 10.1038/nature12434

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Evolutionary origins of the avian brain p.93

Features that were once considered exclusive to modern birds, such as feathers and a furcula, are now known to have first appeared in non-avian dinosaurs. However, relatively little is known of the early evolutionary history of the hyperinflated brain that distinguishes birds from other living reptiles and provides the important neurological capablities required by flight. Here we use high-resolution computed tomography to estimate and compare cranial volumes of extant birds, the early avialan Archaeopteryx lithographica, and a number of non-avian maniraptoran dinosaurs that are phylogenetically close to the origins of both Avialae and avian flight. Previous work established that avian cerebral expansion began early in theropod history and that the cranial cavity of Archaeopteryx was volumetrically intermediate between these early forms and modern birds. Our new data indicate that the relative size of the cranial cavity of Archaeopteryx is reflective of a more generalized maniraptoran volumetric signature and in several instances is actually smaller than that of other non-avian dinosaurs. Thus, bird-like encephalization indices evolved multiple times, supporting the conclusion that if Archaeopteryx had the neurological capabilities required of flight, so did at least some other non-avian maniraptorans. This is congruent with recent findings that avialans were not unique among maniraptorans in their ability to fly in some form.

Amy M. Balanoff, Gabe S. Bever, Timothy B. Rowe & Mark A. Norell

doi: 10.1038/nature12424

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Video game training enhances cognitive control in older adults p.97

Cognitive control is defined by a set of neural processes that allow us to interact with our complex environment in a goal-directed manner. Humans regularly challenge these control processes when attempting to simultaneously accomplish multiple goals (multitasking), generating interference as the result of fundamental information processing limitations. It is clear that multitasking behaviour has become ubiquitous in today’s technologically dense world, and substantial evidence has accrued regarding multitasking difficulties and cognitive control deficits in our ageing population. Here we show that multitasking performance, as assessed with a custom-designed three-dimensional video game (NeuroRacer), exhibits a linear age-related decline from 20 to 79 years of age. By playing an adaptive version of NeuroRacer in multitasking training mode, older adults (60 to 85 years old) reduced multitasking costs compared to both an active control group and a no-contact control group, attaining levels beyond those achieved by untrained 20-year-old participants, with gains persisting for 6 months. Furthermore, age-related deficits in neural signatures of cognitive control, as measured with electroencephalography, were remediated by multitasking training (enhanced midline frontal theta power and frontal–posterior theta coherence). Critically, this training resulted in performance benefits that extended to untrained cognitive control abilities (enhanced sustained attention and working memory), with an increase in midline frontal theta power predicting the training-induced boost in sustained attention and preservation of multitasking improvement 6 months later. These findings highlight the robust plasticity of the prefrontal cognitive control system in the ageing brain, and provide the first evidence, to our knowledge, of how a custom-designed video game can be used to assess cognitive abilities across the lifespan, evaluate underlying neural mechanisms, and serve as a powerful tool for cognitive enhancement.

J. A. Anguera, J. Boccanfuso, J. L. Rintoul, O. Al-Hashimi, F. Faraji, J. Janowich, E. Kong, Y. Larraburo, C. Rolle, E. Johnston + et al.

doi: 10.1038/nature12486

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The toxicity of antiprion antibodies is mediated by the flexible tail of the prion protein p.102

Prion infections cause lethal neurodegeneration. This process requires the cellular prion protein (PrPC; ref. 1), which contains a globular domain hinged to a long amino-proximal flexible tail. Here we describe rapid neurotoxicity in mice and cerebellar organotypic cultured slices exposed to ligands targeting the α1 and α3 helices of the PrPC globular domain. Ligands included seven distinct monoclonal antibodies, monovalent Fab1 fragments and recombinant single-chain variable fragment miniantibodies. Similar to prion infections, the toxicity of globular domain ligands required neuronal PrPC, was exacerbated by PrPC overexpression, was associated with calpain activation and was antagonized by calpain inhibitors. Neurodegeneration was accompanied by a burst of reactive oxygen species, and was suppressed by antioxidants. Furthermore, genetic ablation of the superoxide-producing enzyme NOX2 (also known as CYBB) protected mice from globular domain ligand toxicity. We also found that neurotoxicity was prevented by deletions of the octapeptide repeats within the flexible tail. These deletions did not appreciably compromise globular domain antibody binding, suggesting that the flexible tail is required to transmit toxic signals that originate from the globular domain and trigger oxidative stress and calpain activation. Supporting this view, various octapeptide ligands were not only innocuous to both cerebellar organotypic cultured slices and mice, but also prevented the toxicity of globular domain ligands while not interfering with their binding. We conclude that PrPC consists of two functionally distinct modules, with the globular domain and the flexible tail exerting regulatory and executive functions, respectively. Octapeptide ligands also prolonged the life of mice expressing the toxic PrPC mutant, PrP(Δ94–134), indicating that the flexible tail mediates toxicity in two distinct PrPC-related conditions. Flexible tail-mediated toxicity may conceivably play a role in further prion pathologies, such as familial Creutzfeldt-Jakob disease in humans bearing supernumerary octapeptides.

Tiziana Sonati, Regina R. Reimann, Jeppe Falsig, Pravas Kumar Baral, Tracy O’Connor, Simone Hornemann, Sine Yaganoglu, Bei Li, Uli S. Herrmann, Barbara Wieland + et al.

doi: 10.1038/nature12402

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Induction of intestinal stem cells by R-spondin 1 and Slit2 augments chemoradioprotection p.107

Cancer research has been rightly and successfully focused on prevention, early detection, and identification of specific molecular targets that distinguish the malignant cells from the neighbouring benign cells. However, reducing lethal tissue injury caused by intensive chemoradiotherapy during treatment of late-stage metastatic cancers remains a key clinical challenge. Here we tested whether the induction of adult stem cells could repair chemoradiation-induced tissue injury and prolong overall survival in mice. We found that intestinal stem cells (ISCs) expressed Slit2 and its single-span transmembrane cell-surface receptor roundabout 1 (Robo1). Partial genetic deletion of Robo1 decreased ISC numbers and caused villus hypotrophy, whereas a Slit2 transgene increased ISC numbers and triggered villus hypertrophy. During lethal dosages of chemoradiation, administering a short pulse of R-spondin 1 (Rspo1; a Wnt agonist) plus Slit2 reduced ISC loss, mitigated gut impairment and protected animals from death, without concomitantly decreasing tumour sensitivity to chemotherapy. Therefore Rspo1 and Slit2 may act as therapeutic adjuvants to enhance host tolerance to aggressive chemoradiotherapy for eradicating metastatic cancers.

Wei-Jie Zhou, Zhen H. Geng, Jason R. Spence & Jian-Guo Geng

doi: 10.1038/nature12416

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Microbial colonization influences early B-lineage development in the gut lamina propria p.112

The RAG1/RAG2 endonuclease (RAG) initiates the V(D)J recombination reaction that assembles immunoglobulin heavy (IgH) and light (IgL) chain variable region exons from germline gene segments to generate primary antibody repertoires. IgH V(D)J assembly occurs in progenitor (pro-) B cells followed by that of IgL in precursor (pre-) B cells. Expression of IgH μ and IgL (Igκ or Igλ) chains generates IgM, which is expressed on immature B cells as the B-cell antigen-binding receptor (BCR). Rag expression can continue in immature B cells, allowing continued Igκ V(D)J recombination that replaces the initial VκJκ exon with one that generates a new specificity. This ‘receptor editing’ process, which can also lead to Igλ V(D)J recombination and expression, provides a mechanism whereby antigen encounter at the Rag-expressing immature B-cell stage helps shape pre-immune BCR repertoires. As the major site of postnatal B-cell development, the bone marrow is the principal location of primary immunoglobulin repertoire diversification in mice. Here we report that early B-cell development also occurs within the mouse intestinal lamina propria (LP), where the associated V(D)J recombination/receptor editing processes modulate primary LP immunoglobulin repertoires. At weanling age in normally housed mice, the LP contains a population of Rag-expressing B-lineage cells that harbour intermediates indicative of ongoing V(D)J recombination and which contain cells with pro-B, pre-B and editing phenotypes. Consistent with LP-specific receptor editing, Rag-expressing LP B-lineage cells have similar VH repertoires, but significantly different repertoires, compared to those of Rag2-expressing bone marrow counterparts. Moreover, colonization of germ-free mice leads to an increased ratio of Igλ-expressing versus Igκ-expressing B cells specifically in the LP. We conclude that B-cell development occurs in the intestinal mucosa, where it is regulated by extracellular signals from commensal microbes that influence gut immunoglobulin repertoires.

Duane R. Wesemann, Andrew J. Portuguese, Robin M. Meyers, Michael P. Gallagher, Kendra Cluff-Jones, Jennifer M. Magee, Rohit A. Panchakshari, Scott J. Rodig, Thomas B. Kepler & Frederick W. Alt

doi: 10.1038/nature12496

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Vesicular and non-vesicular transport feed distinct glycosylation pathways in the Golgi p.116

Newly synthesized proteins and lipids are transported across the Golgi complex via different mechanisms whose respective roles are not completely clear. We previously identified a non-vesicular intra-Golgi transport pathway for glucosylceramide (GlcCer)—the common precursor of the different series of glycosphingolipids—that is operated by the cytosolic GlcCer-transfer protein FAPP2 (also known as PLEKHA8) (ref. 1). However, the molecular determinants of the FAPP2-mediated transfer of GlcCer from the cis-Golgi to the trans-Golgi network, as well as the physiological relevance of maintaining two parallel transport pathways of GlcCer—vesicular and non-vesicular—through the Golgi, remain poorly defined. Here, using mouse and cell models, we clarify the molecular mechanisms underlying the intra-Golgi vectorial transfer of GlcCer by FAPP2 and show that GlcCer is channelled by vesicular and non-vesicular transport to two topologically distinct glycosylation tracks in the Golgi cisternae and the trans-Golgi network, respectively. Our results indicate that the transport modality across the Golgi complex is a key determinant for the glycosylation pattern of a cargo and establish a new paradigm for the branching of the glycosphingolipid synthetic pathway.

Giovanni D’Angelo, Takefumi Uemura, Chia-Chen Chuang, Elena Polishchuk, Michele Santoro, Henna Ohvo-Rekilä, Takashi Sato, Giuseppe Di Tullio, Antonio Varriale, Sabato D’Auria + et al.

doi: 10.1038/nature12423

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Recovery from slow inactivation in K+ channels is controlled by water molecules p.121

Application of a specific stimulus opens the intracellular gate of a K+ channel (activation), yielding a transient period of ion conduction until the selectivity filter spontaneously undergoes a conformational change towards a non-conductive state (inactivation). Removal of the stimulus closes the gate and allows the selectivity filter to interconvert back to its conductive conformation (recovery). Given that the structural differences between the conductive and inactivated filter are very small, it is unclear why the recovery process can take up to several seconds. The bacterial K+ channel KcsA from Streptomyces lividans can be used to help elucidate questions about channel inactivation and recovery at the atomic level. Although KcsA contains only a pore domain, without voltage-sensing machinery, it has the structural elements necessary for ion conduction, activation and inactivation. Here we reveal, by means of a series of long molecular dynamics simulations, how the selectivity filter is sterically locked in the inactive conformation by buried water molecules bound behind the selectivity filter. Potential of mean force calculations show how the recovery process is affected by the buried water molecules and the rebinding of an external K+ ion. A kinetic model deduced from the simulations shows how releasing the buried water molecules can stretch the timescale of recovery to seconds. This leads to the prediction that reducing the occupancy of the buried water molecules by imposing a high osmotic stress should accelerate the rate of recovery, which was verified experimentally by measuring the recovery rate in the presence of a 2-molar sucrose concentration.

Jared Ostmeyer, Sudha Chakrapani, Albert C. Pan, Eduardo Perozo & Benoît Roux

doi: 10.1038/nature12395

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