© Mario Izquierdo

 Resumen de noticias: Nature

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Editorial

· Steps to help Turkey build a future on research. (15.02.2017) The Turkish government must stop university dismissals and commit itself to creating a welcoming research environment if its grand plans for science are to succeed. 271-271.

· US Republican idea for tax on carbon makes climate sense. (14.02.2017) A conservative solution to global warming. 271-272.

· The dark side of social media. (15.02.2017) Psychologists find that Internet trolls seem impervious to any efforts to change their behaviour. 272-272.

Column

· Shout about the European Union?s success. (14.02.2017) As people in other nations watch the UK prepare to sever ties, Herman Goossens urges more scientists to stress what the EU does for them. 273-273.

Research Highlights

· Microbiology: Gut bacteria boost bee immunity. (15.02.2017) Gut microbes are important for digestion and immunity in humans— and may also be beneficial to bees.Waldan Kwong at Yale University in New Haven, Connecticut, and his colleagues hand-reared larvae of the honeybee (Apis mellifera; pictured) in the laboratory. They allowed 274-274.

· Chemistry: Helium succumbs to pressure. (15.02.2017) Helium is a famously inert element, but researchers have made a stable compound from helium and sodium.Artem Oganov at Stony Brook University in New York and his colleagues used an algorithm to look for potentially stable helium compounds and predicted that Na2He 274-274.

· Materials: Hybrid film cools in the Sun. (15.02.2017) A material can cool surfaces by dissipating heat to outer space as infrared radiation, even when the Sun is at its peak. Similar materials developed previously worked only at night, or were not cost-effective enough to make on a large scale.Xiaobo Yin and Ronggui 274-274.

· Ecology: Toxic build-up in deep-sea life. (15.02.2017) High levels of industrial pollution have been found in animals living in the deepest reaches of the Pacific Ocean.The production of polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs)— toxic, non-biodegradable pollutants — was phased out in the 1970s. Alan Jamieson, now at 274-275.

· Conservation: Penguins caught in ecological trap. (15.02.2017) Endangered African penguins are at risk from overfishing and climate change, which have reduced stocks of prey fish in their juvenile feeding grounds.Richard Sherley and Stephen Votier at the University of Exeter, UK, and their colleagues used satellites to track 54 juvenile African penguins 275-275.

· Transportation: Superconductors drive trains. (15.02.2017) The first test of a commercial electric train using superconducting cables suggests that the technology could help a typical urban rail network to save an average of 5% in energy.Most electric railways in urban centres suffer from voltage drops because of power losses as 275-275.

· Infection: How malaria boosts its spread. (15.02.2017) The malaria parasite produces a molecule that affects red blood cells, luring mosquitoes to bite infected people, and may enhance the parasite's spread.Ingrid Faye at Stockholm University and her colleagues found that the parasite Plasmodium falciparum produces a metabolite called HMBPP. This stimulates 275-275.

· Climate change: The high cost of keeping cool. (15.02.2017) The potential increase in air-conditioning use in a warming climate could boost the cost of meeting peak demand for electricity in the United States by up to US$180 billion by the end of the century.Maximilian Auffhammer at the University of California, Berkeley, and his 275-275.

· Physiology: Cells remember high altitude. (15.02.2017) Mountain climbers tend to acclimatize to high altitudes faster during a second ascent than during the first. Red blood cells have a role in this, 'remembering' how they initially adapted to the low-oxygen conditions.Yang Xia at the University of Texas Health Science Center in 275-275.

Seven Days

· Human gene editing, a letter to President Trump and a no to homeopathy. (15.02.2017) The week in science: 10–16 February 2017. 276-277.

News

· Three sites where NASA might retrieve its first Mars rock. (11.02.2017) Agency narrows possible targets for the first-ever sample return from the red planet. 279-280.

· 'Riskiest ideas' win $50 million from Chan Zuckerberg Biohub. (08.02.2017) Initiative's first grants will fund a medley of wild ideas from top San Francisco Bay Area biologists, engineers and programmers. 280-281.

· Long-awaited mathematics proof could help scan Earth's innards. (10.02.2017) Proposed solution to geometry puzzle allows an object’s structure to be determined from limited information. 281-282.

· World?s largest wind-mapping project spins up in Portugal. (14.02.2017) International team seeks better picture of wind as it moves over rugged terrain. 282-283.

· Heavyweight funders back central site for life-sciences preprints. (13.02.2017) Coalition of scientists and research agencies argue for a one-stop shop server. 283-284.

· Elusive triangulene created by moving atoms one at a time. (13.02.2017) Unstable molecule couldn’t be made through conventional synthesis, so IBM researchers carried out molecular surgery using a microscope tip. 284-285.

Feature

· The Turkish paradox: Can scientists thrive in a state of emergency?. (15.02.2017) Political upheaval threatens Turkey’s ambitious plans for research and development. 286-288.

Comment

· Winston Churchill?s essay on alien life found. (15.02.2017) A newly unearthed article by the great politician reveals that he reasoned like a scientist about the likelihood of extraterrestrials, writes Mario Livio. 289-291.

Books and Arts

· Physics: Six decades of science advising. (15.02.2017) Ann Finkbeiner scrutinizes a biography of supremely inventive particle physicist Richard Garwin. 292-293.

· Books in brief. (15.02.2017) Barbara Kiser reviews five of the week's best science picks. 293-293.

· Medicine: Discovery through doing. (15.02.2017) Roger Kneebone explores how lacemakers, glass artists and percussionists are sharing skills with researchers. 294-294.

Correspondence

· United States: Restore public files on animal welfare. (15.02.2017) The US Department of Agriculture's sudden removal of thousands of public records relating to animal welfare, supposedly based on a“commitment to being transparent” (see go.nature.com/2ktvzhp), undermines the very purposes of the Animal Welfare Act (see Naturedoi.org/bzg3; 2017). If the department 295-295.

· Trump: a confluence of tipping points?. (15.02.2017) Dramatic change can suddenly happen when there is a confluence of factors reaching a 'tipping point'— the fall of the Berlin Wall in 1989 is an example. As climate change and societal change both move towards tipping points, the crisis prompted by the election 295-295.

· Corporate culture: threat to researchers. (15.02.2017) Early-stage researchers in Denmark are particularly vulnerable to the 'creeping corporate culture' of universities (Nature540, 315;10.1038/540315a2016). Managers are tightening spending after government budget cuts last year ended individual postdoctoral grants from the Danish Council for Independent Research.Furthermore, 295-295.

· Corporate culture: research can benefit. (15.02.2017) We disagree that a 'creeping corporate culture' is harming the University of Copenhagen (Nature540, 315;10.1038/540315a2016). Its continuous rise in the international rankings argues against this suggestion. If the art of science is indeed under corporate pressure, we should 295-295.

· Brazil: Biodiversity at risk from austerity law. (15.02.2017) In December 2016, Brazil's government amended its constitution to freeze public spending on biodiversity protection for the next 20 years, along with funding for scientific research, education and health care. As conservation scientists in Brazil, we believe that the country's remarkable biodiversity is an important 295-295.

Obituary

· George Klein (1925?2016). (15.02.2017) A pioneering cancer biologist and Renaissance man. 296-296.

Naturejobs

· Culture: Cultivate the muse. (15.02.2017) Creative writing can enrich scientists' research. 381-383.

· Trade talk: Support system. (15.02.2017) A way to help. 383-383.

Futures

· In cygnus and in hell. (15.02.2017) A ticket to ride. 386-386.

Correction

· Correction. (15.02.2017) The Editorial‘Keep science on track’ (Nature542, 137; 2017) wrongly attributed to Till Sawala and then to Nadine El-Enany the opinion that the proposed boycott of US-based conferences is intended to demonstrate against a ban that hurts everyone. The article also 285-285.

· Correction. (15.02.2017) In the graphic in the Comment 'Journals invite too few women to referee' ( J.Lerback& B.HansonNature541, 455–457; 2017 ), the bar representing the acceptance rate for male first authors in their 70s was mislabelled. 291-291.

News& Views

· Palaeoclimate science: Pulsating ice sheet. (15.02.2017) During the last ice age, huge numbers of icebergs were episodically discharged from an ice sheet that covered North America. Numerical modelling suggests that these events resulted from a conceptually simple feedback cycle. See Letter p.332 298-299.

· Physiology: An atypical switch for metabolism and ageing. (08.02.2017) The enzyme S6K1 phosphorylates the enzyme glutamyl-prolyl tRNA synthetase to modulate metabolic activity and lifespan, revealing an atypical role for this synthetase as a target of a key metabolic signalling pathway. See Letter p.357 299-300.

· Genomics: Keen insights from quinoa. (08.02.2017) Technological advances have allowed scientists to sequence the complex quinoa genome. This highlights the ongoing expansion of genomics beyond major crops to other plants that have relevance for global food security. See Article p.307 300-302.

· Physiology: Gut feeling for food choice. (08.02.2017) One effect of weight-loss surgery is a change in food preferences. An analysis in rats shows that this is caused by altered nutrient signals in the intestine. These activate the vagus nerve to increase signalling in the brain by the neurotransmitter dopamine. 302-303.

· Environmental science: Oceans lose oxygen. (15.02.2017) Oxygen is essential to most life in the ocean. An analysis shows that oxygen levels have declined by 2% in the global ocean over the past five decades, probably causing habitat loss for many fish and invertebrate species. See Letter p.335 303-304.

· Evolution: Catastrophe triggers diversification. (01.02.2017) An analysis of more than 2,000 species of bird provides insight into how the animals' diverse beak shapes evolved, and points to a single rare event as a trigger for the rapid initial divergence of avian lineages. See Letter p.344 304-305.

Article

· The genome of Chenopodium quinoa. (08.02.2017) Chenopodium quinoa (quinoa) is a highly nutritious grain identified as an important crop to improve world food security. Unfortunately, few resources are available to facilitate its genetic improvement. Here we report the assembly of a high-quality, chromosome-scale reference genome sequence for quinoa, which was 307-312.

· Identity and dynamics of mammary stem cells during branching morphogenesis. (30.01.2017) During puberty, the mouse mammary gland develops into a highly branched epithelial network. Owing to the absence of exclusive stem cell markers, the location, multiplicity, dynamics and fate of mammary stem cells (MaSCs), which drive branching morphogenesis, are unknown. Here we show that morphogenesis is 313-317.

· Cryo-EM structure of a human spliceosome activated for step 2 of splicing. (11.01.2017) Spliceosome rearrangements facilitated by RNA helicase PRP16 before catalytic step two of splicing are poorly understood. Here we report a 3D cryo-electron microscopy structure of the human spliceosomal C complex stalled directly after PRP16 action (C*). The architecture of the catalytic U2–U6 ribonucleoprotein (RNP) core 318-323.

Letter

· Photovoltage field-effect transistors. (08.02.2017) The detection of infrared radiation enables night vision, health monitoring, optical communications and three-dimensional object recognition. Silicon is widely used in modern electronics, but its electronic bandgap prevents the detection of light at wavelengths longer than about 1,100 nanometres. It is therefore of interest to extend the performance of silicon photodetectors into the infrared spectrum, beyond the bandgap of silicon. Here we demonstrate a photovoltage field-effect transistor that uses silicon for charge transport, but is also sensitive to infrared light owing to the use of a quantum dot light absorber. The photovoltage generated at the interface between the silicon and the quantum dot, combined with the high transconductance provided by the silicon device, leads to high gain (more than 104 electrons per photon at 1,500 nanometres), fast time response (less than 10 microseconds) and a widely tunable spectral response. Our photovoltage field-effect transistor has a responsivity that is five orders of magnitude higher at a wavelength of 1,500 nanometres than that of previous infrared-sensitized silicon detectors. The sensitization is achieved using a room-temperature solution process and does not rely on traditional high-temperature epitaxial growth of semiconductors (such as is used for germanium and III–V semiconductors). Our results show that colloidal quantum dots can be used as an efficient platform for silicon-based infrared detection, competitive with state-of-the-art epitaxial semiconductors. 324-327.

· Stable colloids in molten inorganic salts. (15.02.2017) A colloidal solution is a homogeneous dispersion of particles or droplets of one phase (solute) in a second, typically liquid, phase (solvent). Colloids are ubiquitous in biological, chemical and technological processes, homogenizing highly dissimilar constituents. To stabilize a colloidal system against coalescence and aggregation, the surface of each solute particle is engineered to impose repulsive forces strong enough to overpower van der Waals attraction and keep the particles separated from each other. Electrostatic stabilization of charged solutes works well in solvents with high dielectric constants, such as water (dielectric constant of 80). In contrast, colloidal stabilization in solvents with low polarity, such as hexane (dielectric constant of about 2), can be achieved by decorating the surface of each particle of the solute with molecules (surfactants) containing flexible, brush-like chains. Here we report a class of colloidal systems in which solute particles (including metals, semiconductors and magnetic materials) form stable colloids in various molten inorganic salts. The stability of such colloids cannot be explained by traditional electrostatic and steric mechanisms. Screening of many solute–solvent combinations shows that colloidal stability can be traced to the strength of chemical bonding at the solute–solvent interface. Theoretical analysis and molecular dynamics modelling suggest that a layer of surface-bound solvent ions produces long-ranged charge-density oscillations in the molten salt around solute particles, preventing their aggregation. Colloids composed of inorganic particles in inorganic melts offer opportunities for introducing colloidal techniques to solid-state science and engineering applications. 328-331.

· Heinrich events triggered by ocean forcing and modulated by isostatic adjustment. (15.02.2017) During the last glacial period, the Laurentide Ice Sheet sporadically discharged huge numbers of icebergs through the Hudson Strait into the North Atlantic Ocean, leaving behind distinct layers of ice-rafted debris in the ocean sediments. Perplexingly, these massive discharge events—Heinrich events—occurred during the cold portion of millennial-scale climate oscillations called Dansgaard–Oeschger cycles. This is in contrast to the expectation that ice sheets expand in colder climates and shrink in warmer climates. Here we use an ice sheet model to show that the magnitude and timing of Heinrich events can be explained by the same processes that drive the retreat of modern marine-terminating glaciers. In our model, subsurface ocean warming associated with variations in the overturning circulation increases underwater melt along the calving face, triggering rapid margin retreat and increased iceberg discharge. On millennial timescales, isostatic adjustment causes the bed to uplift, isolating the terminus from subsurface warming and allowing the ice sheet to advance again until, at its most advanced position, it is poised for another Heinrich event. This mechanism not only explains the timing and magnitude of observed Heinrich events, but also suggests that ice sheets in contact with warming oceans may be vulnerable to catastrophic collapse even with little atmospheric warming. 332-334.

· Decline in global oceanic oxygen content during the past five decades. (15.02.2017) Ocean models predict a decline in the dissolved oxygen inventory of the global ocean of one to seven per cent by the year 2100, caused by a combination of a warming-induced decline in oxygen solubility and reduced ventilation of the deep ocean. It is thought that such a decline in the oceanic oxygen content could affect ocean nutrient cycles and the marine habitat, with potentially detrimental consequences for fisheries and coastal economies. Regional observational data indicate a continuous decrease in oceanic dissolved oxygen concentrations in most regions of the global ocean, with an increase reported in a few limited areas, varying by study. Prior work attempting to resolve variations in dissolved oxygen concentrations at the global scale reported a global oxygen loss of 550 ± 130 teramoles (1012 mol) per decade between 100 and 1,000 metres depth based on a comparison of data from the 1970s and 1990s. Here we provide a quantitative assessment of the entire ocean oxygen inventory by analysing dissolved oxygen and supporting data for the complete oceanic water column over the past 50 years. We find that the global oceanic oxygen content of 227.4 ± 1.1 petamoles (1015 mol) has decreased by more than two per cent (4.8 ± 2.1 petamoles) since 1960, with large variations in oxygen loss in different ocean basins and at different depths. We suggest that changes in the upper water column are mostly due to a warming-induced decrease in solubility and biological consumption. Changes in the deeper ocean may have their origin in basin-scale multi-decadal variability, oceanic overturning slow-down and a potential increase in biological consumption. 335-339.

· Primordial helium entrained by the hottest mantle plumes. (06.02.2017) Helium isotopes provide an important tool for tracing early-Earth, primordial reservoirs that have survived in the planet’s interior. Volcanic hotspot lavas, like those erupted at Hawaii and Iceland, can host rare, high 3He/4He isotopic ratios (up to 50 times the present atmospheric ratio, Ra) compared to the lower 3He/4He ratios identified in mid-ocean-ridge basalts that form by melting the upper mantle (about 8Ra; ref. 5). A long-standing hypothesis maintains that the high-3He/4He domain resides in the deep mantle, beneath the upper mantle sampled by mid-ocean-ridge basalts, and that buoyantly upwelling plumes from the deep mantle transport high-3He/4He material to the shallow mantle beneath plume-fed hotspots. One problem with this hypothesis is that, while some hotspots have 3He/4He values ranging from low to high, other hotspots exhibit only low 3He/4He ratios. Here we show that, among hotspots suggested to overlie mantle plumes, those with the highest maximum 3He/4He ratios have high hotspot buoyancy fluxes and overlie regions with seismic low-velocity anomalies in the upper mantle, unlike plume-fed hotspots with only low maximum 3He/4He ratios. We interpret the relationships between 3He/4He values, hotspot buoyancy flux, and upper-mantle shear wave velocity to mean that hot plumes—which exhibit seismic low-velocity anomalies at depths of 200 kilometres—are more buoyant and entrain both high-3He/4He and low-3He/4He material. In contrast, cooler, less buoyant plumes do not entrain this high-3He/4He material. This can be explained if the high-3He/4He domain is denser than low-3He/4Hemantle components hosted in plumes, and if high-3He/4He material is entrained from the deep mantle only by the hottest, most buoyant plumes. Such a dense, deep-mantle high-3He/4He domain could remain isolated from the convecting mantle, which may help to explain the preservation of early Hadean (>4.5 billion years ago) geochemical anomalies in lavas sampling this reservoir. 340-343.

· Mega-evolutionary dynamics of the adaptive radiation of birds. (01.02.2017) The origin and expansion of biological diversity is regulated by both developmental trajectories and limits on available ecological niches. As lineages diversify, an early and often rapid phase of species and trait proliferation gives way to evolutionary slow-downs as new species pack into ever more densely occupied regions of ecological niche space. Small clades such as Darwin’s finches demonstrate that natural selection is the driving force of adaptive radiations, but how microevolutionary processes scale up to shape the expansion of phenotypic diversity over much longer evolutionary timescales is unclear. Here we address this problem on a global scale by analysing acrowdsourced dataset of three-dimensional scanned bill morphology from more than 2,000 species. We find that bill diversity expanded early in extant avian evolutionary history, before transitioning to a phase dominated by packing of morphological space. However, this early phenotypic diversification is decoupled from temporal variation in evolutionary rate: rates of bill evolution vary among lineages but are comparatively stable through time. We find that rare, but major, discontinuities in phenotype emerge from rapid increases in rate along single branches, sometimes leading to depauperate clades with unusual bill morphologies. Despite these jumps between groups, the major axes of within-group bill-shape evolution are remarkably consistent across birds. We reveal that macroevolutionary processes underlying global-scale adaptive radiations support Darwinian and Simpsonian ideas of microevolution within adaptive zones and accelerated evolution between distinct adaptive peaks. 344-347.

· Early brain development in infants at high risk for autism spectrum disorder. (15.02.2017) Brain enlargement has been observed in children with autism spectrum disorder (ASD), but the timing of this phenomenon, and the relationship between ASD and the appearance of behavioural symptoms, are unknown. Retrospective head circumference and longitudinal brain volume studies of two-year olds followed up at four years of age have provided evidence that increased brain volume may emerge early in development. Studies of infants at high familial risk of autism can provide insight into the early development of autism and have shown that characteristic social deficits in ASD emerge during the latter part of the first and in the second year of life. These observations suggest that prospective brain-imaging studies of infants at high familial risk of ASD might identify early postnatal changes in brain volume that occur before an ASD diagnosis. In this prospective neuroimaging study of 106 infants at high familial risk of ASD and 42 low-risk infants, we show that hyperexpansion of the cortical surface area between 6 and 12 months of age precedes brain volume overgrowth observed between 12 and 24 months in 15 high-risk infants who were diagnosed with autism at 24 months. Brain volume overgrowth was linked to the emergence and severity of autistic social deficits. A deep-learning algorithm that primarily uses surface area information from magnetic resonance imaging of the brain of 6–12-month-old individuals predicted the diagnosis of autism in individual high-risk children at 24 months (with a positive predictive value of 81% and a sensitivity of 88%). These findings demonstrate that early brain changes occur during the period in which autistic behaviours are first emerging. 348-351.

· Single-cell spatial reconstruction reveals global division of labour in the mammalian liver. (06.02.2017) The mammalian liver consists of hexagon-shaped lobules that are radially polarized by blood flow and morphogens. Key liver genes have been shown to be differentially expressed along the lobule axis, a phenomenon termed zonation, but a detailed genome-wide reconstruction of this spatial division of labour has not been achieved. Here we measure the entire transcriptome of thousands of mouse liver cells and infer their lobule coordinates on the basis of a panel of zonated landmark genes, characterized with single-molecule fluorescence in situ hybridization. Using this approach, we obtain the zonation profiles of all liver genes with high spatial resolution. We find that around 50% of liver genes are significantly zonated and uncover abundant non-monotonic profiles that peak at the mid-lobule layers. These include a spatial order of bile acid biosynthesis enzymes that matches their position in the enzymatic cascade. Our approach can facilitate the reconstruction of similar spatial genomic blueprints for other mammalian organs. 352-356.

· EPRS is a critical mTORC1?S6K1 effector that influences adiposity in mice. (08.02.2017) Metabolic pathways that contribute to adiposity and ageing are activated by the mammalian target of rapamycin complex 1 (mTORC1) and p70 ribosomal protein S6 kinase 1 (S6K1) axis. However, known mTORC1–S6K1 targets do not account for observed loss-of-function phenotypes, suggesting that there are additional downstream effectors of this pathway. Here we identify glutamyl-prolyl-tRNA synthetase (EPRS) as an mTORC1–S6K1 target that contributes to adiposity and ageing. Phosphorylation of EPRS atSer999 by mTORC1–S6K1 induces its release from the aminoacyl tRNA multisynthetase complex, which is required for execution of noncanonical functions of EPRS beyond protein synthesis. To investigate the physiological function of EPRS phosphorylation, we generated Eprs knock-in mice bearing phospho-deficient Ser999-to-Ala (S999A) and phospho-mimetic (S999D) mutations. Homozygous S999A mice exhibited low body weight, reduced adipose tissue mass, and increased lifespan, similar to S6K1-deficient mice and mice with adipocyte-specific deficiency of raptor, an mTORC1 constituent. Substitution of the EprsS999D allele in S6K1-deficient mice normalized body mass and adiposity, indicating that EPRS phosphorylation mediates S6K1-dependent metabolic responses. In adipocytes, insulin stimulated S6K1-dependent EPRS phosphorylation and release from the multisynthetase complex. Interaction screening revealed that phospho-EPRS binds SLC27A1 (that is, fatty acid transport protein 1, FATP1), inducing its translocation to the plasma membrane and long-chain fatty acid uptake. Thus, EPRS and FATP1 are terminal mTORC1–S6K1 axis effectors that are critical for metabolic phenotypes. 357-361.

· Synthetic vulnerabilities of mesenchymal subpopulations in pancreatic cancer. (08.02.2017) Malignant neoplasms evolve in response to changes in oncogenic signalling. Cancer cell plasticity in response to evolutionary pressures is fundamental to tumour progression and the development of therapeutic resistance. Here we determine the molecular and cellular mechanisms of cancer cell plasticity in a conditional oncogenic Kras mouse model of pancreatic ductal adenocarcinoma (PDAC), a malignancy that displays considerable phenotypic diversity and morphological heterogeneity. In this model, stochastic extinction of oncogenic Kras signalling and emergence of Kras-independent escaper populations (cells that acquire oncogenic properties) are associated with de-differentiation and aggressive biological behaviour. Transcriptomic and functional analyses of Kras-independent escapers reveal the presence of Smarcb1–Myc-network-driven mesenchymal reprogramming and independence from MAPK signalling. A somatic mosaic model of PDAC, which allows time-restricted perturbation of cell fate, shows that depletion of Smarcb1 activates the Myc network, driving an anabolic switch that increases protein metabolism and adaptive activation of endoplasmic-reticulum-stress-induced survival pathways. Increased protein turnover renders mesenchymal sub-populations highly susceptible to pharmacological and genetic perturbation of the cellular proteostatic machinery and the IRE1-α–MKK4 arm of the endoplasmic-reticulum-stress-response pathway. Specifically, combination regimens that impair the unfolded protein responses block the emergence of aggressive mesenchymal subpopulations in mouse and patient-derived PDAC models. These molecular and biological insights inform a potential therapeutic strategy for targeting aggressive mesenchymal features of PDAC. 362-366.

· C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress. (08.02.2017) The toxicity of misfolded proteins and mitochondrial dysfunction are pivotal factors that promote age-associated functional neuronal decline and neurodegenerative disease. Accordingly, neurons invest considerable cellular resources in chaperones, protein degradation, autophagy and mitophagy to maintain proteostasis and mitochondrial quality. Complicating the challenges of neuroprotection, misfolded human disease proteins and mitochondria can move into neighbouring cells via unknown mechanisms, which may promote pathological spread. Here we show that adult neurons from Caenorhabditis elegans extrude large (approximately 4 μm) membrane-surrounded vesicles called exophers that can contain protein aggregates and organelles. Inhibition of chaperone expression, autophagy or the proteasome, in addition to compromising mitochondrial quality, enhances the production of exophers. Proteotoxically stressed neurons that generate exophers subsequently function better than similarly stressed neurons that did not produce exophers. The extruded exopher transits through surrounding tissue in which some contents appear degraded, but some non-degradable materials can subsequently be found in more remote cells, suggesting secondary release. Our observations suggest that exopher-genesis is a potential response to rid cells of neurotoxic components when proteostasis and organelle function are challenged. We propose that exophers are components of a conserved mechanism that constitutes a fundamental, but formerly unrecognized, branch of neuronal proteostasis and mitochondrial quality control, which, when dysfunctional or diminished with age, might actively contribute to pathogenesis in human neurodegenerative disease and brain ageing. 367-371.

· MFN1 structures reveal nucleotide-triggered dimerization critical for mitochondrial fusion. (23.01.2017) Mitochondria are double-membraned organelles with variable shapes influenced by metabolic conditions, developmental stage, and environmental stimuli. Their dynamic morphology is a result of regulated and balanced fusion and fission processes. Fusion is crucial for the health and physiological functions of mitochondria, including complementation of damaged mitochondrial DNAs and the maintenance of membrane potential. Mitofusins are dynamin-related GTPases that are essential for mitochondrial fusion. They are embedded in the mitochondrial outer membrane and thought to fuse adjacent mitochondria via combined oligomerization and GTP hydrolysis. However, the molecular mechanisms of this process remain unknown. Here we present crystal structures of engineered human MFN1 containing the GTPase domain and a helical domain during different stages of GTP hydrolysis. The helical domain is composed of elements from widely dispersed sequence regions of MFN1 and resembles the‘neck’ of the bacterial dynamin-like protein. The structures reveal unique features of its catalytic machinery and explain how GTP binding induces conformational changes to promote GTPase domain dimerization in the transition state. Disruption of GTPase domain dimerization abolishes the fusogenic activity of MFN1. Moreover, a conserved aspartate residue trigger was found to affect mitochondrial elongation in MFN1, probably through a GTP-loading-dependent domain rearrangement. Thus, we propose a mechanistic model for MFN1-mediated mitochondrial tethering, and our results shed light on the molecular basis of mitochondrial fusion and mitofusin-related human neuromuscular disorders. 372-376.

· Structure of a spliceosome remodelled for exon ligation. (11.01.2017) The spliceosome excises introns from pre-mRNAs in two sequential transesterifications—branching and exon ligation—catalysed at a single catalytic metal site in U6 small nuclear RNA (snRNA). Recently reported structures of the spliceosomal C complex with the cleaved 5′ exon and lariat–3′-exon bound to the catalytic centre revealed that branching-specific factors such as Cwc25 lock the branch helix into position for nucleophilic attack of the branch adenosine at the 5′ splice site. Furthermore, the ATPase Prp16 is positioned to bind and translocate the intron downstream of the branch point to destabilize branching-specific factors and release the branch helix from the active site. Here we present, at 3.8 Å resolution, the cryo-electron microscopy structure of a Saccharomyces cerevisiae spliceosome stalled after Prp16-mediated remodelling but before exon ligation. While the U6 snRNA catalytic core remains firmly held in the active site cavity of Prp8 by proteins common to both steps, the branch helix has rotated by 75° compared to the C complex and is stabilized in a new position by Prp17, Cef1 and the reoriented Prp8 RNase H-like domain. This rotation of the branch helix removes the branch adenosine from the catalytic core, creates a space for 3′ exon docking, and restructures the pairing of the 5′ splice site with the U6 snRNA ACAGAGA region. Slu7 and Prp18, which promote exon ligation, bind together to the Prp8 RNase H-like domain. The ATPase Prp22, bound to Prp8 in place of Prp16, could interact with the 3′ exon, suggesting a possible basis for mRNA release after exon ligation. Together with the structure of the C complex, our structure of the C* complex reveals the two major conformations of the spliceosome during the catalytic stages of splicing. 377-380.

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