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Nature is the international weekly journal of science: a magazine style journal that publishes full-length research papers in all disciplines of science, as well as News and Views, reviews, news, features, commentaries, web focuses and more, covering all



 



Fantasy politics over fetal-tissue research

2017-01-11

A US congressional investigation has distorted the truth about research that uses human fetal tissue — and sets a troubling precedent.



‘Nature-based solutions’ is the latest green jargon that means more than you might think

2017-01-11

It may sound vague, but the term represents real and vital concepts.



Announcement: Nature launches five new journals for 2017

2017-01-11

Since Nature Genetics was launched in 1992, the stable of Nature research and review journals has grown significantly. This year they’ll be joined by five more — a launch rate that is unprecedented and unlikely to be repeated. These new online-only subscription journals are responding to positive



Where science and nonsense collide

2017-01-10

After a decade of progress, Argentina’s scientists are battling a government bent on twisting public conceptions of their role, writes Alberto Kornblihtt.



Microbiology: Bacterial explorers move fast

2017-01-11

Bacteria that were long thought to be stationary are capable of rapid movement across surfaces when grown alongside yeast.Streptomyces bacteria are common in soil and generate many antibiotics. Marie Elliot at McMaster University in Hamilton, Canada, and her colleagues cultured Streptomyces venezuelae



Physiology: How alcohol ramps up hunger signals

2017-01-11

Brain cells that regulate appetite and feeding are activated by alcohol, offering a possible explanation for why drinking can lead to overeating.Sarah Cains at the Francis Crick Institute in London and her colleagues exposed mice to alcohol for three days and found that the



Ecology: Invasive wild pigs spread across US

2017-01-11

Eurasian wild pigs transmit disease and destroy crops in the United States, and are expected to spread throughout the country in the coming decades.The invasive wild pigs (Sus scrofa; pictured) compete with the country's native wildlife and cost the agricultural industry



Neuroscience: Age sees boost in facial recognition

2017-01-11

The brain is thought to trim back neural connections as it develops, but scientists report that the region we rely on to recognize faces continues to increase in size into adulthood.Kalanit Grill-Spector at Stanford University in California and her colleagues measured the brains of



Cancer: 'Old' cells linked to drug side effects

2017-01-11

Cancer chemotherapy causes a host of side effects, and a particular group of cells that have stopped dividing could be at the root of this problem.Chemotherapy drugs cause some healthy cells to stop dividing and become senescent, and such cells are thought to promote



Biomaterials: Silk gland mimic spins strong fibres

2017-01-11

A device that recreates the conditions in spiders' silk-spinning apparatus has produced 1,000 metres of material that is tougher than other spun artificial spider silks.Anna Rising and Jan Johansson at the Swedish University of Agricultural Sciences in Uppsala and their colleagues used the bacterium



Medical devices: Mini machines deliver drugs

2017-01-11

A small device with moving parts can release drugs and be wirelessly controlled after being placed in the body.Sau Yin Chin and Samuel Sia at Columbia University in New York and their colleagues used biocompatible hydrogels to build the device, which is just over



Conservation: Effects of wildlife trade mapped

2017-01-11

Global maps that show where the impact of consumer demand for wildlife is felt most strongly could help to guide conservation spending and priorities.Daniel Moran at the Norwegian University of Science and Technology in Trondheim and Keiichiro Kanemoto at Shinshu University in Matsumoto, Japan,



Planetary science: Many collisions made the Moon

2017-01-11

The Moon may have been formed not from one big cosmic smash, as the leading theory holds, but from multiple smaller collisions.Billions of years ago in the early Solar System, space debris would have collided with the young Earth. Using computer simulations, a team



SEVEN DAYS
The week in science: 6–12 January 2017



Chinese AI company plans to mine health data faster than rivals

2017-01-10

iCarbonX believes its cutting-edge partners and generous funding give it the upper hand.



Google reveals secret test of AI bot to beat top Go players

2017-01-04

Updated version of DeepMind's AlphaGo program behind mystery online competitor.



Legendary radio telescope hangs in the balance

2017-01-10

US National Science Foundation looks to slash funding for Puerto Rico’s Arecibo Observatory.



Deceptive curcumin offers cautionary tale for chemists

2017-01-11

Spice extract dupes assays and leads some drug hunters astray.



Brexit offers rare chance to make Britain greener

2017-01-11

Environmental scientists plan to push for policy changes but are nervous about losing current protections.



Gene-edited cows, rogue clinics, speedier drug approvals: the challenges facing Trump's FDA chief

2017-01-06

The agency's next leader will have an opportunity to reshape its approach to regulation.



Behind New Zealand’s wild plan to purge all pests

2017-01-11

The country is gearing up to get rid of rats, possums, stoats and other invasive predators by 2050. Is it a pipe dream?



Compare voting systems to improve them

2017-01-10

Research is needed on how groups make choices in real situations, write Guruprasad Madhavan, Charles Phelps and Rino Rappuoli.



Chemistry: The hidden war

2017-01-11

Paul A. Lombardo applauds a shocking study detailing the Allies' Second World War experimentation with chemical weapons on their own troops.



Books in brief

2017-01-11

Barbara Kiser reviews five of the week's best science picks.



Neuroscience: The risks of reading the brain

2017-01-11

Russell Poldrack assesses a primer on the implications of advances in brain imaging.



African elephants: Scale up elephant anti-poaching funds

2017-01-11

Many populations of Asian elephants (Elephas maximus) have enjoyed 15 years of protection against poachers. We suggest that increasing investment in anti-poaching measures and law enforcement in Africa could help to stem the escalating crisis for African elephants (Loxodonta africana).Since



Emissions: Step on the natural gas for German cars

2017-01-11

The decision by Germany's Federal Council to phase out petrol and diesel vehicles by 2030 is at odds with the government's investment in renewable energy, which is not enough to produce the extra power that electric cars will need. We show how natural gas could



Horizon 2020: Funds to help Eastern Europe close the gap

2017-01-11

The incentive for investigators in Eastern Europe to apply for Horizon 2020 funding from the European Union is undermined by the grant model defining how researchers should be paid (go.nature.com/2hqxgxi). It requires that research stipends conform to national basic salaries, which are much



Endangered species: Illegal lemur trade grows in Madagascar

2017-01-11

We call for urgent action to increase government effectiveness in fighting Madagascar's illegal trade in live lemurs (see go.nature.com/2i6hvor). More funding is needed to investigate the issue, its extent and the factors behind it. Facilities to rehabilitate confiscated lemurs must be improved, and more



Climate change: Save last cloud forests in western Andes

2017-01-11

Wildfires in November 2016 consumed much of the last relic cloud forests on the western slopes of the Andes in northern Peru, a well-known biodiversity hotspot. Normally protected against fire by mist throughout the year, these forests were suffering from severe drought. Climate change and



Health and safety: Danger zone

2017-01-11

Fieldwork often involves significant threats to safety.



Turning point: Uncertain future

2017-01-11

How Brexit could affect cancer research.



Playing for keeps

2017-01-11

It's no game.



Corrections

2017-01-10

The News story ‘Major rethink for outbreak response’ (Nature 540, 494–495; 2016) stated that a funding shortfall pertained to EDCARN. But it is the overarching WHO health-emergencies programme that is currently underfunded. The News Feature ‘What’s killing the world’s shorebirds?’ (Nature 541,



Biological techniques: Stomach growth in a dish

2017-01-04

A protocol has been developed to grow structures that resemble the main part of the stomach in vitro from human embryonic stem cells — an advance that provides insights into stomach development. See Article p.182



Fluid dynamics: Water flows out of touch

2017-01-11

Superhydrophobic surfaces reduce the frictional drag between water and solid materials, but this effect is often temporary. The realization of sustained drag reduction has applications for water vehicles and pipeline flows.



Cancer genomics: Spot the difference

2017-01-04

A molecular analysis of human oesophageal cancers reveals abnormalities that might be targetable by existing drugs, and indicates that the current stratification of these tumours into subtypes is incomplete. See Article p.169



Optical physics: Supercavity lasing

2017-01-11

Light in a laser is confined in the form of standing waves. By engineering such waves, scientists have designed an optical system that enhances this confinement, producing a compact laser that emits a high-quality beam. See Letter p.196



Physiology: Mechanosensor of lung inflation identified

2016-12-21

The Piezo2 protein senses changes in lung volume, acting in different neurons to convey this information to the brain. This finding adds to the list of roles for Piezo2 in mechanosensation. See Article p.176



Stem cells: Valine starvation leads to a hungry niche

2016-12-14

The haematopoietic stem cells that rejuvenate blood depend on a dietary source of the amino acid valine — a finding that has been exploited to reduce the toxicity of bone-marrow transplantation in mice.



Climate science: The resilience of Amazonian forests

2017-01-11

Isotope evidence suggests that, during dry periods associated with the most recent ice age, the Amazonian forest survived in a region that is sensitive to rainfall changes — settling a debate about Amazonian aridity. See Letter p.204



Integrated genomic characterization of oesophageal carcinoma

2017-01-04

Oesophageal cancers are prominent worldwide; however, there are few targeted therapies and survival rates for these cancers remain dismal. Here we performed a comprehensive molecular analysis of 164 carcinomas of the oesophagus derived from Western and Eastern populations. Beyond known histopathological and epidemiologic distinctions, molecular



Piezo2 senses airway stretch and mediates lung inflation-induced apnoea

2016-12-21

Respiratory dysfunction is a notorious cause of perinatal mortality in infants and sleep apnoea in adults, but the mechanisms of respiratory control are not clearly understood. Mechanical signals transduced by airway-innervating sensory neurons control respiration; however, the physiological significance and molecular mechanisms of these signals



Wnt/β-catenin promotes gastric fundus specification in mice and humans

2017-01-04

Despite the global prevalence of gastric disease, there are few adequate models in which to study the fundus epithelium of the human stomach. We differentiated human pluripotent stem cells (hPSCs) into gastric organoids containing fundic epithelium by first identifying and then recapitulating key events in



Penitentes as the origin of the bladed terrain of Tartarus Dorsa on Pluto

2017-01-04

Penitentes are snow and ice features formed by erosion that, on Earth, are characterized by bowl-shaped depressions several tens of centimetres across, whose edges grade into spires up to several metres tall. Penitentes have been suggested as an explanation for anomalous radar data on Europa, but until now no penitentes have been identified conclusively on planetary bodies other than Earth. Regular ridges with spacings of 3,000 to 5,000 metres and depths of about 500 metres with morphologies that resemble penitentes have been observed by the New Horizons spacecraft in the Tartarus Dorsa region of Pluto (220°–250° E, 0°–20° N). Here we report simulations, based upon a recent model representing conditions on Pluto, in which deepening penitentes reproduce both the tri-modal (north–south, east–west and northeast–southwest) orientation and the spacing of the ridges of this bladed terrain. At present, these penitentes deepen by approximately one centimetre per orbital cycle and grow only during periods of relatively high atmospheric pressure, suggesting a formation timescale of several tens of millions of years, consistent with crater ages. This timescale implies that the penitentes formed from initial topographic variations of no more than a few tens of metres, consistent with Pluto’s youngest terrains.



Sideband cooling beyond the quantum backaction limit with squeezed light

2017-01-11

Quantum fluctuations of the electromagnetic vacuum produce measurable physical effects such as Casimir forces and the Lamb shift. They also impose an observable limit—known as the quantum backaction limit—on the lowest temperatures that can be reached using conventional laser cooling techniques. As laser cooling experiments continue to bring massive mechanical systems to unprecedentedly low temperatures, this seemingly fundamental limit is increasingly important in the laboratory. Fortunately, vacuum fluctuations are not immutable and can be ‘squeezed’, reducing amplitude fluctuations at the expense of phase fluctuations. Here we propose and experimentally demonstrate that squeezed light can be used to cool the motion of a macroscopic mechanical object below the quantum backaction limit. We first cool a microwave cavity optomechanical system using a coherent state of light to within 15 per cent of this limit. We then cool the system to more than two decibels below the quantum backaction limit using a squeezed microwave field generated by a Josephson parametric amplifier. From heterodyne spectroscopy of the mechanical sidebands, we measure a minimum thermal occupancy of 0.19 ± 0.01 phonons. With our technique, even low-frequency mechanical oscillators can in principle be cooled arbitrarily close to the motional ground state, enabling the exploration of quantum physics in larger, more massive systems.



Lasing action from photonic bound states in continuum

2017-01-11

In 1929, only three years after the advent of quantum mechanics, von Neumann and Wigner showed that Schrödinger’s equation can have bound states above the continuum threshold. These peculiar states, called bound states in the continuum (BICs), manifest themselves as resonances that do not decay. For several decades afterwards the idea lay dormant, regarded primarily as a mathematical curiosity. In 1977, Herrick and Stillinger revived interest in BICs when they suggested that BICs could be observed in semiconductor superlattices. BICs arise naturally from Feshbach’s quantum mechanical theory of resonances, as explained by Friedrich and Wintgen, and are thus more physical than initially realized. Recently, it was realized that BICs are intrinsically a wave phenomenon and are thus not restricted to the realm of quantum mechanics. They have since been shown to occur in many different fields of wave physics including acoustics, microwaves and nanophotonics. However, experimental observations of BICs have been limited to passive systems and the realization of BIC lasers has remained elusive. Here we report, at room temperature, lasing action from an optically pumped BIC cavity. Our results show that the lasing wavelength of the fabricated BIC cavities, each made of an array of cylindrical nanoresonators suspended in air, scales with the radii of the nanoresonators according to the theoretical prediction for the BIC mode. Moreover, lasing action from the designed BIC cavity persists even after scaling down the array to as few as 8-by-8 nanoresonators. BIC lasers open up new avenues in the study of light–matter interaction because they are intrinsically connected to topological charges and represent natural vector beam sources (that is, there are several possible beam shapes), which are highly sought after in the fields of optical trapping, biological sensing and quantum information.



Aromatic and antiaromatic ring currents in a molecular nanoring

2016-12-19

Aromatic and antiaromatic molecules—which have delocalized circuits of [4n + 2] or [4n] electrons, respectively—exhibit ring currents around their perimeters. The direction of the ring current in an aromatic molecule is such as to generate a magnetic field that opposes the external field inside the ring (a ‘diatropic’ current), while the ring current in an antiaromatic molecule flows in the reverse direction (‘paratropic’). Similar persistent currents occur in metal or semiconductor rings, when the phase coherence of the electronic wavefunction is preserved around the ring. Persistent currents in non-molecular rings switch direction as a function of the magnetic flux passing through the ring, so that they can be changed from diatropic (‘aromatic’) to paratropic (‘antiaromatic’) simply by changing the external magnetic field. As in molecular systems, the direction of the persistent current also depends on the number of electrons. The relationship between ring currents in molecular and non-molecular rings is poorly understood, partly because they are studied in different size regimes: the largest aromatic molecules have diameters of about one nanometre, whereas persistent currents are observed in microfabricated rings with diameters of 20–1,000 nanometres. Understanding the connection between aromaticity and quantum-coherence effects in mesoscopic rings provides a motivation for investigating ring currents in molecules of an intermediate size. Here we show, using nuclear magnetic resonance spectroscopy and density functional theory, that a six-porphyrin nanoring template complex, with a diameter of 2.4 nanometres, is antiaromatic in its 4+ oxidation state (80 π electrons) and aromatic in its 6+ oxidation state (78 π electrons). The antiaromatic state has a huge paramagnetic susceptibility, despite having no unpaired electrons. This work demonstrates that a global ring current can be promoted in a macrocycle by adjusting its oxidation state to suppress the local ring currents of its components.The discovery of ring currents around a molecule with a circumference of 7.5 nanometres, at room temperature, shows that quantum coherence can persist in surprisingly large molecular frameworks.



Hydroclimate changes across the Amazon lowlands over the past 45,000 years

2017-01-11

Reconstructing the history of tropical hydroclimates has been difficult, particularly for the Amazon basin—one of Earth’s major centres of deep atmospheric convection. For example, whether the Amazon basin was substantially drier or remained wet during glacial times has been controversial, largely because most study sites have been located on the periphery of the basin, and because interpretations can be complicated by sediment preservation, uncertainties in chronology, and topographical setting. Here we show that rainfall in the basin responds closely to changes in glacial boundary conditions in terms of temperature and atmospheric concentrations of carbon dioxide. Our results are based on a decadally resolved, uranium/thorium-dated, oxygen isotopic record for much of the past 45,000 years, obtained using speleothems from Paraíso Cave in eastern Amazonia; we interpret the record as being broadly related to precipitation. Relative to modern levels, precipitation in the region was about 58% during the Last Glacial Maximum (around 21,000 years ago) and 142% during the mid-Holocene epoch (about 6,000 years ago). We find that, as compared with cave records from the western edge of the lowlands, the Amazon was widely drier during the last glacial period, with much less recycling of water and probably reduced plant transpiration, although the rainforest persisted throughout this time.



A symmoriiform chondrichthyan braincase and the origin of chimaeroid fishes

2017-01-04

Chimaeroid fishes (Holocephali) are one of the four principal divisions of modern gnathostomes (jawed vertebrates). Despite only 47 described living species, chimaeroids are the focus of resurgent interest as potential archives of genomic data and for the unique perspective they provide on chondrichthyan and gnathostome ancestral conditions. Chimaeroids are also noteworthy for their highly derived body plan. However, like other living groups with distinctive anatomies, fossils have been of limited use in unravelling their evolutionary origin, as the earliest recognized examples already exhibit many of the specializations present in modern forms. Here we report the results of a computed tomography analysis of Dwykaselachus, an enigmatic chondrichthyan braincase from the ~280 million year old Karoo sediments of South Africa. Externally, the braincase is that of a symmoriid shark and is by far the most complete uncrushed example yet discovered. Internally, the morphology exhibits otherwise characteristically chimaeroid specializations, including the otic labyrinth arrangement and the brain space configuration relative to exceptionally large orbits. These results have important implications for our view of modern chondrichthyan origins, add robust structure to the phylogeny of early crown group gnathostomes, reveal preconditions that suggest an initial morpho-functional basis for the derived chimaeroid cranium, and shed new light on the chondrichthyan response to the extinction at the end of the Devonian period.



Genome sequence and genetic diversity of European ash trees

2016-12-26

Ash trees (genus Fraxinus, family Oleaceae) are widespread throughout the Northern Hemisphere, but are being devastated in Europe by the fungus Hymenoscyphus fraxineus, causing ash dieback, and in North America by the herbivorous beetle Agrilus planipennis. Here we sequence the genome of a low-heterozygosity Fraxinus excelsior tree from Gloucestershire, UK, annotating 38,852 protein-coding genes of which 25% appear ash specific when compared with the genomes of ten other plant species. Analyses of paralogous genes suggest a whole-genome duplication shared with olive (Olea europaea, Oleaceae). We also re-sequence 37 F. excelsior trees from Europe, finding evidence for apparent long-term decline in effective population size. Using our reference sequence, we re-analyse association transcriptomic data, yielding improved markers for reduced susceptibility to ash dieback. Surveys of these markers in British populations suggest that reduced susceptibility to ash dieback may be more widespread in Great Britain than in Denmark. We also present evidence that susceptibility of trees to H. fraxineus is associated with their iridoid glycoside levels. This rapid, integrated, multidisciplinary research response to an emerging health threat in a non-model organism opens the way for mitigation of the epidemic.



Structural variation in amyloid-β fibrils from Alzheimer's disease clinical subtypes

2017-01-04

Aggregation of amyloid-β peptides into fibrils or other self-assembled states is central to the pathogenesis of Alzheimer’s disease. Fibrils formed in vitro by 40- and 42-residue amyloid-β peptides (Aβ40 and Aβ42) are polymorphic, with variations in molecular structure that depend on fibril growth conditions. Recent experiments suggest that variations in amyloid-β fibril structure in vivo may correlate with variations in Alzheimer’s disease phenotype, in analogy to distinct prion strains that are associated with different clinical and pathological phenotypes. Here we investigate correlations between structural variation and Alzheimer’s disease phenotype using solid-state nuclear magnetic resonance (ssNMR) measurements on Aβ40 and Aβ42 fibrils prepared by seeded growth from extracts of Alzheimer’s disease brain cortex. We compared two atypical Alzheimer’s disease clinical subtypes—the rapidly progressive form (r-AD) and the posterior cortical atrophy variant (PCA-AD)—with a typical prolonged-duration form (t-AD). On the basis of ssNMR data from 37 cortical tissue samples from 18 individuals, we find that a single Aβ40 fibril structure is most abundant in samples from patients with t-AD and PCA-AD, whereas Aβ40 fibrils from r-AD samples exhibit a significantly greater proportion of additional structures. Data for Aβ42 fibrils indicate structural heterogeneity in most samples from all patient categories, with at least two prevalent structures. These results demonstrate the existence of a specific predominant Aβ40 fibril structure in t-AD and PCA-AD, suggest that r-AD may relate to additional fibril structures and indicate that there is a qualitative difference between Aβ40 and Aβ42 aggregates in the brain tissue of patients with Alzheimer’s disease.



Hypoxia induces heart regeneration in adult mice

2016-10-31

The adult mammalian heart is incapable of regeneration following cardiomyocyte loss, which underpins the lasting and severe effects of cardiomyopathy. Recently, it has become clear that the mammalian heart is not a post-mitotic organ. For example, the neonatal heart is capable of regenerating lost myocardium, and the adult heart is capable of modest self-renewal. In both of these scenarios, cardiomyocyte renewal occurs via the proliferation of pre-existing cardiomyocytes, and is regulated by aerobic-respiration-mediated oxidative DNA damage. Therefore, we reasoned that inhibiting aerobic respiration by inducing systemic hypoxaemia would alleviate oxidative DNA damage, thereby inducing cardiomyocyte proliferation in adult mammals. Here we report that, in mice, gradual exposure to severe systemic hypoxaemia, in which inspired oxygen is gradually decreased by 1% and maintained at 7% for 2 weeks, results in inhibition of oxidative metabolism, decreased reactive oxygen species production and oxidative DNA damage, and reactivation of cardiomyocyte mitosis. Notably, we find that exposure to hypoxaemia 1 week after induction of myocardial infarction induces a robust regenerative response with decreased myocardial fibrosis and improvement of left ventricular systolic function. Genetic fate-mapping analysis confirms that the newly formed myocardium is derived from pre-existing cardiomyocytes. These results demonstrate that the endogenous regenerative properties of the adult mammalian heart can be reactivated by exposure to gradual systemic hypoxaemia, and highlight the potential therapeutic role of hypoxia in regenerative medicine.



mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide

2016-12-26

Although long non-coding RNAs (lncRNAs) are non-protein-coding transcripts by definition, recent studies have shown that a fraction of putative small open reading frames within lncRNAs are translated. However, the biological significance of these hidden polypeptides is still unclear. Here we identify and functionally characterize a novel polypeptide encoded by the lncRNA LINC00961. This polypeptide is conserved between human and mouse, is localized to the late endosome/lysosome and interacts with the lysosomal v-ATPase to negatively regulate mTORC1 activation. This regulation of mTORC1 is specific to activation of mTORC1 by amino acid stimulation, rather than by growth factors. Hence, we termed this polypeptide ‘small regulatory polypeptide of amino acid response’ (SPAR). We show that the SPAR-encoding lncRNA is highly expressed in a subset of tissues and use CRISPR/Cas9 engineering to develop a SPAR-polypeptide-specific knockout mouse while maintaining expression of the host lncRNA. We find that the SPAR-encoding lncRNA is downregulated in skeletal muscle upon acute injury, and using this in vivo model we establish that SPAR downregulation enables efficient activation of mTORC1 and promotes muscle regeneration. Our data provide a mechanism by which mTORC1 activation may be finely regulated in a tissue-specific manner in response to injury, and a paradigm by which lncRNAs encoding small polypeptides can modulate general biological pathways and processes to facilitate tissue-specific requirements, consistent with their restricted and highly regulated expression profile.



Genome-wide in vivo screen identifies novel host regulators of metastatic colonization

2017-01-04

Metastasis is the leading cause of death for cancer patients. This multi-stage process requires tumour cells to survive in the circulation, extravasate at distant sites, then proliferate; it involves contributions from both the tumour cell and tumour microenvironment (‘host’, which includes stromal cells and the immune system). Studies suggest the early steps of the metastatic process are relatively efficient, with the post-extravasation regulation of tumour growth (‘colonization’) being critical in determining metastatic outcome. Here we show the results of screening 810 mutant mouse lines using an in vivo assay to identify microenvironmental regulators of metastatic colonization. We identify 23 genes that, when disrupted in mouse, modify the ability of tumour cells to establish metastatic foci, with 19 of these genes not previously demonstrated to play a role in host control of metastasis. The largest reduction in pulmonary metastasis was observed in sphingosine-1-phosphate (S1P) transporter spinster homologue 2 (Spns2)-deficient mice. We demonstrate a novel outcome of S1P-mediated regulation of lymphocyte trafficking, whereby deletion of Spns2, either globally or in a lymphatic endothelial-specific manner, creates a circulating lymphopenia and a higher percentage of effector T cells and natural killer (NK) cells present in the lung. This allows for potent tumour cell killing, and an overall decreased metastatic burden.



Variable chromatin structure revealed by in situ spatially correlated DNA cleavage mapping

2016-12-26

Chromatin structure at the length scale encompassing local nucleosome–nucleosome interactions is thought to play a crucial role in regulating transcription and access to DNA. However, this secondary structure of chromatin remains poorly understood compared with the primary structure of single nucleosomes or the tertiary structure of long-range looping interactions. Here we report the first genome-wide map of chromatin conformation in human cells at the 1–3 nucleosome (50–500 bp) scale, obtained using ionizing radiation-induced spatially correlated cleavage of DNA with sequencing (RICC-seq) to identify DNA–DNA contacts that are spatially proximal. Unbiased analysis of RICC-seq signal reveals regional enrichment of DNA fragments characteristic of alternating rather than adjacent nucleosome interactions in tri-nucleosome units, particularly in H3K9me3-marked heterochromatin. We infer differences in the likelihood of nucleosome–nucleosome contacts among open chromatin, H3K27me3-marked, and H3K9me3-marked repressed chromatin regions. After calibrating RICC-seq signal to three-dimensional distances, we show that compact two-start helical fibre structures with stacked alternating nucleosomes are consistent with RICC-seq fragmentation patterns from H3K9me3-marked chromatin, while non-compact structures and solenoid structures are consistent with open chromatin. Our data support a model of chromatin architecture in intact interphase nuclei consistent with variable longitudinal compaction of two-start helical fibres.



Structures of riboswitch RNA reaction states by mix-and-inject XFEL serial crystallography

2016-11-14

Riboswitches are structural RNA elements that are generally located in the 5′ untranslated region of messenger RNA. During regulation of gene expression, ligand binding to the aptamer domain of a riboswitch triggers a signal to the downstream expression platform. A complete understanding of the structural basis of this mechanism requires the ability to study structural changes over time. Here we use femtosecond X-ray free electron laser (XFEL) pulses to obtain structural measurements from crystals so small that diffusion of a ligand can be timed to initiate a reaction before diffraction. We demonstrate this approach by determining four structures of the adenine riboswitch aptamer domain during the course of a reaction, involving two unbound apo structures, one ligand-bound intermediate, and the final ligand-bound conformation. These structures support a reaction mechanism model with at least four states and illustrate the structural basis of signal transmission. The three-way junction and the P1 switch helix of the two apo conformers are notably different from those in the ligand-bound conformation. Our time-resolved crystallographic measurements with a 10-second delay captured the structure of an intermediate with changes in the binding pocket that accommodate the ligand. With at least a 10-minute delay, the RNA molecules were fully converted to the ligand-bound state, in which the substantial conformational changes resulted in conversion of the space group. Such notable changes in crystallo highlight the important opportunities that micro- and nanocrystals may offer in these and similar time-resolved diffraction studies. Together, these results demonstrate the potential of ‘mix-and-inject’ time-resolved serial crystallography to study biochemically important interactions between biomacromolecules and ligands, including those that involve large conformational changes.