Nature 485, 7398 (2012). doi:10.1038/485279a

The US National Institutes of Health should rethink plans to limit a nationwide study of children. It must not miss a rare opportunity to probe the causes of childhood diseases.

Nature 485, 7398 (2012). doi:10.1038/485279b

Independent experts should be kept from undue suspicion as well as undue influence.

Nature 485, 7398 (2012). doi:10.1038/485280a

Proposals for a UK law on defamation highlight the power of scientific protest.

Nature 485, 7398 (2012). http://www.nature.com/doifinder/10.1038/485281a

Author: Russell Garwood

Creationists seize on any perceived gaps in our knowledge of evolutionary processes. But scientists can and should fight back, says Russell Garwood.

Nature 485, 7398 (2012). doi:10.1038/485282a

The giant asteroid Vesta resembles a planet more than it does other asteroids, according to Christopher Russell at the University of California, Los Angeles, and his colleagues. In six separate studies, the researchers report their analysis of data from NASA's Dawn spacecraft, which has been

Nature 485, 7398 (2012). doi:10.1038/485282b

A tumour's response to chemotherapy is shaped by interactions between the tumour and its microenvironment.Mikala Egeblad at Cold Spring Harbor Laboratory in New York and her colleagues used in vivo microscopy to monitor tumours' responses to the chemotherapy drug doxorubicin in mice. They

Nature 485, 7398 (2012). doi:10.1038/485282c

A decrease in the amount of time spent in contact with the natural environment and changes in the population of microbes resident on the skin could be contributing to the increase in inflammatory disorders such as allergies.To test these ideas, Ilkka Hanski at the

Nature 485, 7398 (2012). doi:10.1038/485282d

One way to improve memory in people with a disorder that can precede Alzheimer's disease is to dampen activity in a part of the brain known as the hippocampus, rather than to boost it as previously thought.Michela Gallagher at Johns Hopkins University in Baltimore,

Nature 485, 7398 (2012). doi:10.1038/485282e

Crystals of photosynthetic protein complexes extracted from plant cells can generate extraordinarily high voltages when placed on a conducting surface and stimulated by light.Each of the light-transducing complexes known as photosystem I can generate about 1 volt during photosynthesis in the plant. Nathan Nelson

Nature 485, 7398 (2012). doi:10.1038/485283a

Special glasses that fire near-infrared signals onto a device implanted into the retina could one day help to restore vision in blind people. This system would require fewer implanted components such as wires and coils to power the device than other proposed retinal prostheses.James

Nature 485, 7398 (2012). doi:10.1038/485283b

Most candidate multi-planet systems spotted by the Kepler space telescope probably contain true exoplanets, according to a statistical analysis.Kepler spots potential planets beyond our Solar System by looking for tiny dips in brightness as the planets pass in front of their host stars. The

Nature 485, 7398 (2012). doi:10.1038/485283c

In an underground chamber in Guatemala, archaeologists have discovered the earliest evidence so far of Mayan astronomical tables: dates, numbers and depictions of lunar deities painted or carved on the walls some 1,200 years ago.William Saturno at Boston University in Massachusetts and his colleagues

Nature 485, 7398 (2012). doi:10.1038/485283d

Highly read on www.jneurosci.org in April'Waking up' from an unconscious state requires the activation of only primitive areas deep in the brain — not the higher cortical areas indicated in previous studies on anaesthetized people.Harry Scheinin at the University of Turku in

Nature 485, 7398 (2012). http://www.nature.com/doifinder/10.1038/485284a

The week in science: Scientific journals to be protected in UK libel reform; Mars rover awakens; and the Global Fund emerges from a fund-raising crisis.

Nature 485, 7398 (2012). http://www.nature.com/doifinder/10.1038/485287a

Author: Meredith Wadman

Frustration mounts as ambitious US project is scaled back.

Nature 485, 7398 (2012). http://www.nature.com/doifinder/10.1038/485289a

Author: Alison Abbott

Scandal adds to fears that country’s research reform is in peril.

Nature 485, 7398 (2012). http://www.nature.com/doifinder/10.1038/485290a

Author: Eric Hand

Bright and brief, γ-ray bursts hold clues to cosmic history.

Nature 485, 7398 (2012). http://www.nature.com/doifinder/10.1038/485293a

Author: Amy Maxmen

The WHO releases action plan to tackle the spread of insecticide-resistant mosquitoes.

Nature 485, 7398 (2012). http://www.nature.com/doifinder/10.1038/485294a

Author: Declan Butler

European Parliament reprimands food advisory body for industry links.

Nature 485, 7398 (2012). http://www.nature.com/doifinder/10.1038/485295a

Author: Quirin Schiermeier

President Putin to back scheme for students to study abroad.

Nature 485, 7398 (2012). http://www.nature.com/doifinder/10.1038/485296a

Author: Sharon Levy

Shape-shifting coyotes have evolved to take advantage of a landscape transformed by people. Scientists are now discovering just how wily the creatures are.

Nature 485, 7398 (2012). http://www.nature.com/doifinder/10.1038/485298a

Author: Ed Yong

In the wake of high-profile controversies, psychologists are facing up to problems with replication.

Nature 485, 7398 (2012). doi:10.1038/485301a

Authors: Robert Doubleday & James Wilsdon

Chief scientific advisers need better support and networks to ensure that science advice to governments is robust, say Robert Doubleday and James Wilsdon.

Nature 485, 7398 (2012). doi:10.1038/485303a

Author: Jay M. Pasachoff

The June 2012 transit of Venus across the Sun offers an opportunity to check our methods for spotting distant planets crossing far-away stars, says Jay M. Pasachoff.

Nature 485, 7398 (2012). doi:10.1038/485305a

Author: Owen Gingerich

Owen Gingerich enjoys two histories of the expeditions that aimed to measure the passage of Venus across the face of the Sun.

Nature 485, 7398 (2012). doi:10.1038/485306a

Author: Josie Glausiusz

Josie Glausiusz celebrates an environmental history of the human breast.

Nature 485, 7398 (2012). doi:10.1038/485307a

Whether sprinting, swimming, lifting or leaping, elite athletes in action are phenomenal — and, as biochemist and sports scientist Chris Cooper shows in this pacy account, some are also assisted by performance-enhancing drugs. To understand a problem that is unlikely to disappear from sport completely,

Nature 485, 7398 (2012). doi:10.1038/485308a

Author: Jascha Hoffman

Bioacoustician Bernie Krause has travelled the world for decades to gather animal sounds for his Wild Sanctuary archive (www.wildsanctuary.com). Following the release of his book about this work, The Great Animal Orchestra, he talks about the calls of the wild.

Nature 485, 7398 (2012). doi:10.1038/485309a

Author: Tommy Ohlsson

Neutrinos have been in the news again — and not just because of the debate over last year's OPERA experiment at the Gran Sasso National Laboratory in Italy, the results of which gave rise to the mistaken claim that the particles could travel faster than

Nature 485, 7398 (2012). doi:10.1038/485309b

Authors: Govindasamy Agoramoorthy & Chiranjib Chakraborty

Legislation that came into effect in India this month aims to deal with the environmental effects of electronic waste in the country. According to a government report, this waste stream has increased by a factor of more than five in seven years and is expected

Nature 485, 7398 (2012). doi:10.1038/485309c

Author: Jean R. S. Vitule

Brazil's aquatic biodiversity is under threat from a proposed law that aims to boost degraded fishery resources. If approved, the law — put forward by Nelson Meurer of the Brazilian National Congress — would allow the cultivation of non-native fish species in freshwater aquaculture cages,

Nature 485, 7398 (2012). doi:10.1038/485309d

Author: Richard M. Baldarelli

Jocelyn Rice points out perceived shortcomings of the experimental autoimmune encephalomyelitis mouse in modelling multiple sclerosis and in advancing effective human treatments for this disease (Nature484, S9; 2012; online only). However, her title ('Animal models: Not close enough') seems to

Nature 485, 7398 (2012). doi:10.1038/485309e

Author: Frank J. van Rijnsoever

Luk Van Langenhove argues that the social sciences should be made more relevant (Nature484, 442; 2012). But the problem is rather that society remains largely unaware of the thousands of social-science studies produced every year that are relevant to global

Nature 485, 7398 (2012). doi:10.1038/nj7398-405a

Author: Roberta Kwok

Creating electronic textbooks requires ingenuity, teamwork and multimedia savvy.

Nature 485, 7398 (2012). doi:10.1038/nj7398-407a

Author: Alexandra Bell

After launching a career in Germany, sustainability institute director aims to help society by reducing pollution.

Nature 485, 7398 (2012). doi:10.1038/485410a

Author: Alex Shvartsman

The generation gap.

Nature. doi:10.1038/485S2a

Author: Tony Scully

The number of people living with, and dying of, diabetes across the world is shocking: 90 million Chinese live with diabetes and 1.3 million died in 2011; 23% of Qatari adults have developed diabetes. Here we chart the extent of the global epidemic and present some of the implications for national governments by Tony Scully.

Nature. doi:10.1038/485S4a

Author: Sarah DeWeerdt

In type 1 diabetes, the immune system goes haywire and depletes insulin-producing cells. Drugs that interfere with this process could one day reverse the disease's course.

Nature. doi:10.1038/485S6a

Author: Elie Dolgin

Artificial pancreases promise to take the decision-making — and human mistakes — out of managing type 1 diabetes.

Nature. doi:10.1038/485S9a

Author: Carla Greenbaum

Recent research suggests that the fight against type 1 diabetes is focusing too narrowly on the adaptive immune system, says Carla Greenbaum.

Nature. doi:10.1038/485S10a

Author: Erika Jonietz

Decades of study into the causes of diabetes have produced no definitive answers.

Nature. doi:10.1038/485S12a

Author: Lauren Gravitz

Your gut microflora might be aiding and abetting diabetes.

Nature. doi:10.1038/485S14a

Author: Priya Shetty

Epigenetics and lifestyle are conspiring to inflict a massive epidemic of type 2 diabetes in the subcontinent.

Nature. doi:10.1038/485S17a

Author: Thomas Mandrup-Poulsen

Promising drugs to treat diabetes stumble in the latter stages of clinical testing. Thomas Mandrup-Poulsen explains why — and how to fix it.

Nature. doi:10.1038/485S18a

Author: Scott P. Edwards

While type 1 diabetes might be promising ground for a vaccine, the most effective way to avoid type 2 remains good old-fashioned diet and exercise.

Nature 485, 7398 (2012). http://www.nature.com/doifinder/10.1038/485283e

The story 'Graphene's silicon cousin' (Nature485, 9; 2012) should have said that silicon was deposited onto a silver surface heated to more than 200 °C. The silicon was heated to more than 1,000 °C.

Nature 485, 7398 (2012). http://www.nature.com/doifinder/10.1038/485295b

In the Editorial 'Price of freedom' (Nature485, 148; 2012), we stated that 'plenty of European scientists will be lost'. 'European scientists' should have been 'Europan science', as we meant to refer to science on the Jovian moon Europa.

Nature 485, 7398 (2012). doi:10.1038/nature11193

Authors: Jasper Kok

High-resolution spacecraft images show surprisingly large rates of sand transport on Mars. This finding suggests that the planet's surface is a more active environment than previously thought. See Letter p.339

Nature 485, 7398 (2012). doi:10.1038/485313a

Authors: Manfred Lein

Strong laser fields allow electrons to tunnel out of atoms. The response of such electrons to a second laser field supports the idea that they start tunnelling at a time defined by a complex number, but exit atoms at a 'real' time. See Letter p.343

Nature 485, 7398 (2012). doi:10.1038/485314a

Authors: Marta Filizola & Lakshmi A. Devi

The search for safe, non-addictive versions of morphine and other opioid drugs has just received a boost with the solving of the crystal structures of the receptors to which the drugs bind. See Articles p.321 & p.327, Letters p.395 & p.400

Nature 485, 7398 (2012). doi:10.1038/485317a

Authors: Andrew Jackson

Restoring voluntary actions to paralysed patients is an ambition of neural-interface research. A study shows that people with tetraplegia can use brain control of a robotic arm to reach and grasp objects. See Letter p.372

Nature 485, 7398 (2012). doi:10.1038/485318a

Authors: Dheeraj Malhotra & Jonathan Sebat

The expression level of a single gene can determine head size in zebrafish, mirroring a human anatomical feature associated with neurological disorders such as autism and schizophrenia. See Letter p.363

Nature 485, 7398 (2012). doi:10.1038/485319a

Authors: Bruce Buffett

New calculations show that the electrical resistance of Earth's liquid-iron core is lower than had been thought. The results prompt a reassessment of how the planet's magnetic field has been generated and maintained over time. See Letter p.355

Nature 485, 7398 (2012). http://www.nature.com/doifinder/10.1038/485320a

In the News & Views article 'Cancer biology: The director's cut' by Antonio Gentilella and George Thomas (Nature485, 50–51; 2012), the messenger RNA transcript encoding YB1 was incorrectly referred to as a 59 TOP mRNA. The transcript should

Nature 485, 7398 (2012). doi:10.1038/nature10954

Authors: Aashish Manglik, Andrew C. Kruse, Tong Sun Kobilka, Foon Sun Thian, Jesper M. Mathiesen, Roger K. Sunahara, Leonardo Pardo, William I. Weis, Brian K. Kobilka & Sébastien Granier

Opium is one of the world’s oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many undesirable side effects (sedation, apnoea and dependence) by binding to and

Nature 485, 7398 (2012). doi:10.1038/nature10939

Authors: Huixian Wu, Daniel Wacker, Mauro Mileni, Vsevolod Katritch, Gye Won Han, Eyal Vardy, Wei Liu, Aaron A. Thompson, Xi-Ping Huang, F. Ivy Carroll, S. Wayne Mascarella, Richard B. Westkaemper, Philip D. Mosier, Bryan L. Roth, Vadim Cherezov & Raymond C. Stevens

Opioid receptors mediate the actions of endogenous and exogenous opioids on many physiological processes, including the regulation of pain, respiratory drive, mood, and—in the case of κ-opioid receptor (κ-OR)—dysphoria and psychotomimesis. Here we report the crystal structure of the human κ-OR in complex with the

Nature 485, 7398 (2012). doi:10.1038/nature11040

Authors: Ian S. Patten, Sarosh Rana, Sajid Shahul, Glenn C. Rowe, Cholsoon Jang, Laura Liu, Michele R. Hacker, Julie S. Rhee, John Mitchell, Feroze Mahmood, Philip Hess, Caitlin Farrell, Nicole Koulisis, Eliyahu V. Khankin, Suzanne D. Burke, Igor Tudorache, Johann Bauersachs, Federica del Monte, Denise Hilfiker-Kleiner, S. Ananth Karumanchi & Zoltan Arany

Peripartum cardiomyopathy (PPCM) is an often fatal disease that affects pregnant women who are near delivery, and it occurs more frequently in women with pre-eclampsia and/or multiple gestation. The aetiology of PPCM, and why it is associated with pre-eclampsia, remain unknown. Here we show that

Nature 485, 7398 (2012). doi:10.1038/nature11022

Authors: N. T. Bridges, F. Ayoub, J-P. Avouac, S. Leprince, A. Lucas & S. Mattson

Strong and sustained winds on Mars have been considered rare, on the basis of surface meteorology measurements and global circulation models, raising the question of whether the abundant dunes and evidence for wind erosion seen on the planet are a current process. Recent studies showed sand activity, but could not determine whether entire dunes were moving—implying large sand fluxes—or whether more localized and surficial changes had occurred. Here we present measurements of the migration rate of sand ripples and dune lee fronts at the Nili Patera dune field. We show that the dunes are near steady state, with their entire volumes composed of mobile sand. The dunes have unexpectedly high sand fluxes, similar, for example, to those in Victoria Valley, Antarctica, implying that rates of landscape modification on Mars and Earth are similar.

Nature 485, 7398 (2012). doi:10.1038/nature11025

Authors: Dror Shafir, Hadas Soifer, Barry D. Bruner, Michal Dagan, Yann Mairesse, Serguei Patchkovskii, Misha Yu. Ivanov, Olga Smirnova & Nirit Dudovich

The tunnelling of a particle through a barrier is one of the most fundamental and ubiquitous quantum processes. When induced by an intense laser field, electron tunnelling from atoms and molecules initiates a broad range of phenomena such as the generation of attosecond pulses, laser-induced electron diffraction and holography. These processes evolve on the attosecond timescale (1 attosecond ≡ 1 as = 10−18 seconds) and are well suited to the investigation of a general issue much debated since the early days of quantum mechanics—the link between the tunnelling of an electron through a barrier and its dynamics outside the barrier. Previous experiments have measured tunnelling rates with attosecond time resolution and tunnelling delay times. Here we study laser-induced tunnelling by using a weak probe field to steer the tunnelled electron in the lateral direction and then monitor the effect on the attosecond light bursts emitted when the liberated electron re-encounters the parent ion. We show that this approach allows us to measure the time at which the electron exits from the tunnelling barrier. We demonstrate the high sensitivity of the measurement by detecting subtle delays in ionization times from two orbitals of a carbon dioxide molecule. Measurement of the tunnelling process is essential for all attosecond experiments where strong-field ionization initiates ultrafast dynamics. Our approach provides a general tool for time-resolving multi-electron rearrangements in atoms and molecules—one of the key challenges in ultrafast science.

Nature 485, 7398 (2012). doi:10.1038/nature11122

Authors: Tamas Kosa, Ludmila Sukhomlinova, Linli Su, Bahman Taheri, Timothy J. White & Timothy J. Bunning

Liquid crystals are traditionally classified as thermotropic, lyotropic or polymeric, based on the stimulus that governs the organization and order of the molecular system. The most widely known and applied class of liquid crystals are a subset of thermotropic liquid crystals known as calamitic, in which adding heat can result in phase transitions from or into the nematic, cholesteric and smectic mesophases. Photoresponsive liquid-crystal materials and mixtures can undergo isothermal phase transitions if light affects the order parameter of the system within a mesophase sufficiently. In nearly all previous examinations, light exposure of photoresponsive liquid-crystal materials and mixtures resulted in order-decreasing photo-induced isothermal phase transitions. Under specialized conditions, an increase in order with light exposure has been reported, despite the tendency of the photoresponsive liquid-crystal system to reduce order in the exposed state. A direct, photo-induced transition from the isotropic to the nematic phase has been observed in a mixture of spiropyran molecules and a nematic liquid crystal. Here we report a class of naphthopyran-based materials that exhibit photo-induced conformational changes in molecular structure capable of yielding order-increasing phase transitions. Appropriate functionalization of the naphthopyran molecules leads to an exceedingly large order parameter in the open form, which results in a clear to strongly absorbing dichroic state. The increase in order with light exposure has profound implications in optics, photonics, lasing and displays and will merit further consideration for applications in solar energy harvesting. The large, photo-induced dichroism exhibited by the material system has been long sought in ophthalmic applications such as photochromic and polarized variable transmission sunglasses.

Nature 485, 7398 (2012). doi:10.1038/nature11097

Authors: Robert J. Allen, Steven C. Sherwood, Joel R. Norris & Charles S. Zender

Observational analyses have shown the width of the tropical belt increasing in recent decades as the world has warmed. This expansion is important because it is associated with shifts in large-scale atmospheric circulation and major climate zones. Although recent studies have attributed tropical expansion in the Southern Hemisphere to ozone depletion, the drivers of Northern Hemisphere expansion are not well known and the expansion has not so far been reproduced by climate models. Here we use a climate model with detailed aerosol physics to show that increases in heterogeneous warming agents—including black carbon aerosols and tropospheric ozone—are noticeably better than greenhouse gases at driving expansion, and can account for the observed summertime maximum in tropical expansion. Mechanistically, atmospheric heating from black carbon and tropospheric ozone has occurred at the mid-latitudes, generating a poleward shift of the tropospheric jet, thereby relocating the main division between tropical and temperate air masses. Although we still underestimate tropical expansion, the true aerosol forcing is poorly known and could also be underestimated. Thus, although the insensitivity of models needs further investigation, black carbon and tropospheric ozone, both of which are strongly influenced by human activities, are the most likely causes of observed Northern Hemisphere tropical expansion.

Nature 485, 7398 (2012). doi:10.1038/nature11031

Authors: Monica Pozzo, Chris Davies, David Gubbins & Dario Alfè

The Earth acts as a gigantic heat engine driven by the decay of radiogenic isotopes and slow cooling, which gives rise to plate tectonics, volcanoes and mountain building. Another key product is the geomagnetic field, generated in the liquid iron core by a dynamo running on heat released by cooling and freezing (as the solid inner core grows), and on chemical convection (due to light elements expelled from the liquid on freezing). The power supplied to the geodynamo, measured by the heat flux across the core–mantle boundary (CMB), places constraints on Earth’s evolution. Estimates of CMB heat flux depend on properties of iron mixtures under the extreme pressure and temperature conditions in the core, most critically on the thermal and electrical conductivities. These quantities remain poorly known because of inherent experimental and theoretical difficulties. Here we use density functional theory to compute these conductivities in liquid iron mixtures at core conditions from first principles—unlike previous estimates, which relied on extrapolations. The mixtures of iron, oxygen, sulphur and silicon are taken from earlier work and fit the seismologically determined core density and inner-core boundary density jump. We find both conductivities to be two to three times higher than estimates in current use. The changes are so large that core thermal histories and power requirements need to be reassessed. New estimates indicate that the adiabatic heat flux is 15 to 16 terawatts at the CMB, higher than present estimates of CMB heat flux based on mantle convection; the top of the core must be thermally stratified and any convection in the upper core must be driven by chemical convection against the adverse thermal buoyancy or lateral variations in CMB heat flow. Power for the geodynamo is greatly restricted, and future models of mantle evolution will need to incorporate a high CMB heat flux and explain the recent formation of the inner core.

Nature 485, 7398 (2012). doi:10.1038/nature11056

Authors: Jason D. Fridley

The phenology of growth in temperate deciduous forests, including the timing of leaf emergence and senescence, has strong control over ecosystem properties such as productivity and nutrient cycling, and has an important role in the carbon economy of understory plants. Extended leaf phenology, whereby understory species assimilate carbon in early spring before canopy closure or in late autumn after canopy fall, has been identified as a key feature of many forest species invasions, but it remains unclear whether there are systematic differences in the growth phenology of native and invasive forest species or whether invaders are more responsive to warming trends that have lengthened the duration of spring or autumn growth. Here, in a 3-year monitoring study of 43 native and 30 non-native shrub and liana species common to deciduous forests in the eastern United States, I show that extended autumn leaf phenology is a common attribute of eastern US forest invasions, where non-native species are extending the autumn growing season by an average of 4 weeks compared with natives. In contrast, there was no consistent evidence that non-natives as a group show earlier spring growth phenology, and non-natives were not better able to track interannual variation in spring temperatures. Seasonal leaf production and photosynthetic data suggest that most non-native species capture a significant proportion of their annual carbon assimilate after canopy leaf fall, a behaviour that was virtually absent in natives and consistent across five phylogenetic groups. Pronounced differences in how native and non-native understory species use pre- and post-canopy environments suggest eastern US invaders are driving a seasonal redistribution of forest productivity that may rival climate change in its impact on forest processes.

Nature 485, 7398 (2012). doi:10.1038/nature11091

Authors: Christelle Golzio, Jason Willer, Michael E. Talkowski, Edwin C. Oh, Yu Taniguchi, Sébastien Jacquemont, Alexandre Reymond, Mei Sun, Akira Sawa, James F. Gusella, Atsushi Kamiya, Jacques S. Beckmann & Nicholas Katsanis

Copy number variants (CNVs) are major contributors to genetic disorders. We have dissected a region of the 16p11.2 chromosome—which encompasses 29 genes—that confers susceptibility to neurocognitive defects when deleted or duplicated. Overexpression of each human transcript in zebrafish embryos identified KCTD13 as the sole message capable of inducing the microcephaly phenotype associated with the 16p11.2 duplication, whereas suppression of the same locus yielded the macrocephalic phenotype associated with the 16p11.2 deletion, capturing the mirror phenotypes of humans. Analyses of zebrafish and mouse embryos suggest that microcephaly is caused by decreased proliferation of neuronal progenitors with concomitant increase in apoptosis in the developing brain, whereas macrocephaly arises by increased proliferation and no changes in apoptosis. A role for KCTD13 dosage changes is consistent with autism in both a recently reported family with a reduced 16p11.2 deletion and a subject reported here with a complex 16p11.2 rearrangement involving de novo structural alteration of KCTD13. Our data suggest that KCTD13 is a major driver for the neurodevelopmental phenotypes associated with the 16p11.2 CNV, reinforce the idea that one or a small number of transcripts within a CNV can underpin clinical phenotypes, and offer an efficient route to identifying dosage-sensitive loci.

Nature 485, 7398 (2012). doi:10.1038/nature10987

Authors: C. Ethier, E. R. Oby, M. J. Bauman & L. E. Miller

Patients with spinal cord injury lack the connections between brain and spinal cord circuits that are essential for voluntary movement. Clinical systems that achieve muscle contraction through functional electrical stimulation (FES) have proven to be effective in allowing patients with tetraplegia to regain control of hand movements and to achieve a greater measure of independence in daily activities. In existing clinical systems, the patient uses residual proximal limb movements to trigger pre-programmed stimulation that causes the paralysed muscles to contract, allowing use of one or two basic grasps. Instead, we have developed an FES system in primates that is controlled by recordings made from microelectrodes permanently implanted in the brain. We simulated some of the effects of the paralysis caused by C5 or C6 spinal cord injury by injecting rhesus monkeys with a local anaesthetic to block the median and ulnar nerves at the elbow. Then, using recordings from approximately 100 neurons in the motor cortex, we predicted the intended activity of several of the paralysed muscles, and used these predictions to control the intensity of stimulation of the same muscles. This process essentially bypassed the spinal cord, restoring to the monkeys voluntary control of their paralysed muscles. This achievement is a major advance towards similar restoration of hand function in human patients through brain-controlled FES. We anticipate that in human patients, this neuroprosthesis would allow much more flexible and dexterous use of the hand than is possible with existing FES systems.

Nature 485, 7398 (2012). doi:10.1038/nature11076

Authors: Leigh R. Hochberg, Daniel Bacher, Beata Jarosiewicz, Nicolas Y. Masse, John D. Simeral, Joern Vogel, Sami Haddadin, Jie Liu, Sydney S. Cash, Patrick van der Smagt & John P. Donoghue

Paralysis following spinal cord injury, brainstem stroke, amyotrophic lateral sclerosis and other disorders can disconnect the brain from the body, eliminating the ability to perform volitional movements. A neural interface system could restore mobility and independence for people with paralysis by translating neuronal activity directly into control signals for assistive devices. We have previously shown that people with long-standing tetraplegia can use a neural interface system to move and click a computer cursor and to control physical devices. Able-bodied monkeys have used a neural interface system to control a robotic arm, but it is unknown whether people with profound upper extremity paralysis or limb loss could use cortical neuronal ensemble signals to direct useful arm actions. Here we demonstrate the ability of two people with long-standing tetraplegia to use neural interface system-based control of a robotic arm to perform three-dimensional reach and grasp movements. Participants controlled the arm and hand over a broad space without explicit training, using signals decoded from a small, local population of motor cortex (MI) neurons recorded from a 96-channel microelectrode array. One of the study participants, implanted with the sensor 5 years earlier, also used a robotic arm to drink coffee from a bottle. Although robotic reach and grasp actions were not as fast or accurate as those of an able-bodied person, our results demonstrate the feasibility for people with tetraplegia, years after injury to the central nervous system, to recreate useful multidimensional control of complex devices directly from a small sample of neural signals.

Nature 485, 7398 (2012). doi:10.1038/nature11082

Authors: Jesse R. Dixon, Siddarth Selvaraj, Feng Yue, Audrey Kim, Yan Li, Yin Shen, Ming Hu, Jun S. Liu & Bing Ren

The spatial organization of the genome is intimately linked to its biological function, yet our understanding of higher order genomic structure is coarse, fragmented and incomplete. In the nucleus of eukaryotic cells, interphase chromosomes occupy distinct chromosome territories, and numerous models have been proposed for how chromosomes fold within chromosome territories. These models, however, provide only few mechanistic details about the relationship between higher order chromatin structure and genome function. Recent advances in genomic technologies have led to rapid advances in the study of three-dimensional genome organization. In particular, Hi-C has been introduced as a method for identifying higher order chromatin interactions genome wide. Here we investigate the three-dimensional organization of the human and mouse genomes in embryonic stem cells and terminally differentiated cell types at unprecedented resolution. We identify large, megabase-sized local chromatin interaction domains, which we term ‘topological domains’, as a pervasive structural feature of the genome organization. These domains correlate with regions of the genome that constrain the spread of heterochromatin. The domains are stable across different cell types and highly conserved across species, indicating that topological domains are an inherent property of mammalian genomes. Finally, we find that the boundaries of topological domains are enriched for the insulator binding protein CTCF, housekeeping genes, transfer RNAs and short interspersed element (SINE) retrotransposons, indicating that these factors may have a role in establishing the topological domain structure of the genome.

Nature 485, 7398 (2012). doi:10.1038/nature11049

Authors: Elphège P. Nora, Bryan R. Lajoie, Edda G. Schulz, Luca Giorgetti, Ikuhiro Okamoto, Nicolas Servant, Tristan Piolot, Nynke L. van Berkum, Johannes Meisig, John Sedat, Joost Gribnau, Emmanuel Barillot, Nils Blüthgen, Job Dekker & Edith Heard

In eukaryotes transcriptional regulation often involves multiple long-range elements and is influenced by the genomic environment. A prime example of this concerns the mouse X-inactivation centre (Xic), which orchestrates the initiation of X-chromosome inactivation (XCI) by controlling the expression of the non-protein-coding Xist transcript. The extent of Xic sequences required for the proper regulation of Xist remains unknown. Here we use chromosome conformation capture carbon-copy (5C) and super-resolution microscopy to analyse the spatial organization of a 4.5-megabases (Mb) region including Xist. We discover a series of discrete 200-kilobase to 1 Mb topologically associating domains (TADs), present both before and after cell differentiation and on the active and inactive X. TADs align with, but do not rely on, several domain-wide features of the epigenome, such as H3K27me3 or H3K9me2 blocks and lamina-associated domains. TADs also align with coordinately regulated gene clusters. Disruption of a TAD boundary causes ectopic chromosomal contacts and long-range transcriptional misregulation. The Xist/Tsix sense/antisense unit illustrates how TADs enable the spatial segregation of oppositely regulated chromosomal neighbourhoods, with the respective promoters of Xist and Tsix lying in adjacent TADs, each containing their known positive regulators. We identify a novel distal regulatory region of Tsix within its TAD, which produces a long intervening RNA, Linx. In addition to uncovering a new principle of cis-regulatory architecture of mammalian chromosomes, our study sets the stage for the full genetic dissection of the X-inactivation centre.

Nature 485, 7398 (2012). doi:10.1038/nature11070

Authors: Cristina Gontan, Eskeatnaf Mulugeta Achame, Jeroen Demmers, Tahsin Stefan Barakat, Eveline Rentmeester, Wilfred van IJcken, J. Anton Grootegoed & Joost Gribnau

Evolution of the mammalian sex chromosomes has resulted in a heterologous X and Y pair, where the Y chromosome has lost most of its genes. Hence, there is a need for X-linked gene dosage compensation between XY males and XX females. In placental mammals, this is achieved by random inactivation of one X chromosome in all female somatic cells. Upregulation of Xist transcription on the future inactive X chromosome acts against Tsix antisense transcription, and spreading of Xist RNA in cis triggers epigenetic changes leading to X-chromosome inactivation. Previously, we have shown that the X-encoded E3 ubiquitin ligase RNF12 is upregulated in differentiating mouse embryonic stem cells and activates Xist transcription and X-chromosome inactivation. Here we identify the pluripotency factor REX1 as a key target of RNF12 in the mechanism of X-chromosome inactivation. RNF12 causes ubiquitination and proteasomal degradation of REX1, and Rnf12 knockout embryonic stem cells show an increased level of REX1. Using chromatin immunoprecipitation sequencing, REX1 binding sites were detected in Xist and Tsix regulatory regions. Overexpression of REX1 in female embryonic stem cells was found to inhibit Xist transcription and X-chromosome inactivation, whereas male Rex1+/− embryonic stem cells showed ectopic X-chromosome inactivation. From this, we propose that RNF12 causes REX1 breakdown through dose-dependent catalysis, thereby representing an important pathway to initiate X-chromosome inactivation. Rex1 and Xist are present only in placental mammals, which points to co-evolution of these two genes and X-chromosome inactivation.

Nature 485, 7398 (2012). doi:10.1038/nature10998

Authors: Johan W. Jonker, Jae Myoung Suh, Annette R. Atkins, Maryam Ahmadian, Pingping Li, Jamie Whyte, Mingxiao He, Henry Juguilon, Yun-Qiang Yin, Colin T. Phillips, Ruth T. Yu, Jerrold M. Olefsky, Robert R. Henry, Michael Downes & Ronald M. Evans

Although feast and famine cycles illustrate that remodelling of adipose tissue in response to fluctuations in nutrient availability is essential for maintaining metabolic homeostasis, the underlying mechanisms remain poorly understood. Here we identify fibroblast growth factor 1 (FGF1) as a critical transducer in this process in mice, and link its regulation to the nuclear receptor PPARγ (peroxisome proliferator activated receptor γ), which is the adipocyte master regulator and the target of the thiazolidinedione class of insulin sensitizing drugs. FGF1 is the prototype of the 22-member FGF family of proteins and has been implicated in a range of physiological processes, including development, wound healing and cardiovascular changes. Surprisingly, FGF1 knockout mice display no significant phenotype under standard laboratory conditions. We show that FGF1 is highly induced in adipose tissue in response to a high-fat diet and that mice lacking FGF1 develop an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with a high-fat diet. Further analysis of adipose depots in FGF1-deficient mice revealed multiple histopathologies in the vasculature network, an accentuated inflammatory response, aberrant adipocyte size distribution and ectopic expression of pancreatic lipases. On withdrawal of the high-fat diet, this inflamed adipose tissue fails to properly resolve, resulting in extensive fat necrosis. In terms of mechanisms, we show that adipose induction of FGF1 in the fed state is regulated by PPARγ acting through an evolutionarily conserved promoter proximal PPAR response element within the FGF1 gene. The discovery of a phenotype for the FGF1 knockout mouse establishes the PPARγ–FGF1 axis as critical for maintaining metabolic homeostasis and insulin sensitization.

Nature 485, 7398 (2012). doi:10.1038/nature11085

Authors: Aaron A. Thompson, Wei Liu, Eugene Chun, Vsevolod Katritch, Huixian Wu, Eyal Vardy, Xi-Ping Huang, Claudio Trapella, Remo Guerrini, Girolamo Calo, Bryan L. Roth, Vadim Cherezov & Raymond C. Stevens

Members of the opioid receptor family of G-protein-coupled receptors (GPCRs) are found throughout the peripheral and central nervous system, where they have key roles in nociception and analgesia. Unlike the ‘classical’ opioid receptors, δ, κ and μ (δ-OR, κ-OR and μ-OR), which were delineated by pharmacological criteria in the 1970s and 1980s, the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP, also known as ORL-1) was discovered relatively recently by molecular cloning and characterization of an orphan GPCR. Although it shares high sequence similarity with classical opioid GPCR subtypes (∼60%), NOP has a markedly distinct pharmacology, featuring activation by the endogenous peptide N/OFQ, and unique selectivity for exogenous ligands. Here we report the crystal structure of human NOP, solved in complex with the peptide mimetic antagonist compound-24 (C-24) (ref. 4), revealing atomic details of ligand–receptor recognition and selectivity. Compound-24 mimics the first four amino-terminal residues of the NOP-selective peptide antagonist UFP-101, a close derivative of N/OFQ, and provides important clues to the binding of these peptides. The X-ray structure also shows substantial conformational differences in the pocket regions between NOP and the classical opioid receptors κ (ref. 5) and μ (ref. 6), and these are probably due to a small number of residues that vary between these receptors. The NOP–compound-24 structure explains the divergent selectivity profile of NOP and provides a new structural template for the design of NOP ligands.

Nature 485, 7398 (2012). doi:10.1038/nature11111

Authors: Sébastien Granier, Aashish Manglik, Andrew C. Kruse, Tong Sun Kobilka, Foon Sun Thian, William I. Weis & Brian K. Kobilka

The opioid receptor family comprises three members, the µ-, δ- and κ-opioid receptors, which respond to classical opioid alkaloids such as morphine and heroin as well as to endogenous peptide ligands like endorphins. They belong to the G-protein-coupled receptor (GPCR) superfamily, and are excellent therapeutic targets for pain control. The δ-opioid receptor (δ-OR) has a role in analgesia, as well as in other neurological functions that remain poorly understood. The structures of the µ-OR and κ-OR have recently been solved. Here we report the crystal structure of the mouse δ-OR, bound to the subtype-selective antagonist naltrindole. Together with the structures of the µ-OR and κ-OR, the δ-OR structure provides insights into conserved elements of opioid ligand recognition while also revealing structural features associated with ligand-subtype selectivity. The binding pocket of opioid receptors can be divided into two distinct regions. Whereas the lower part of this pocket is highly conserved among opioid receptors, the upper part contains divergent residues that confer subtype selectivity. This provides a structural explanation and validation for the ‘message–address’ model of opioid receptor pharmacology, in which distinct ‘message’ (efficacy) and ‘address’ (selectivity) determinants are contained within a single ligand. Comparison of the address region of the δ-OR with other GPCRs reveals that this structural organization may be a more general phenomenon, extending to other GPCR families as well.