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Early spliceosome assembly can occur through an intron-defined pathway, whereby U1 and U2 small nuclear ribonucleoprotein particles (snRNPs) assemble across the intron1. Alternatively, it can occur through an exon-defined pathway2–5, whereby U2 binds the branch site located upstream of the defined exon and U1 snRNP interacts with the 5′ splice site located directly downstream of it. The U4/U6.U5 tri-snRNP subsequently binds to produce a cross-intron (CI) or cross-exon (CE) pre-B complex, which is then converted to the spliceosomal B complex6,7. Exon definition promotes the splicing of upstream introns2,8,9and plays a key part in alternative splicing regulation10–16. However, the three-dimensional structure of exon-defined spliceosomal complexes and the molecular mechanism of the conversion from a CE-organized to a CI-organized spliceosome, a pre-requisite for splicing catalysis, remain poorly understood. Here cryo-electron microscopy analyses of human CE pre-B complex and B-like complexes reveal extensive structural similarities with their CI counterparts. The results indicate that the CE and CI spliceosome assembly pathways converge already at the pre-B stage. Add-back experiments using purified CE pre-B complexes, coupled with cryo-electron microscopy, elucidate the order of the extensive remodelling events that accompany the formation of B complexes and B-like complexes. The molecular triggers and roles of B-specific proteins in these rearrangements are also identified. We show that CE pre-B complexes can productively bind in transto a U1 snRNP-bound 5′ splice site. Together, our studies provide new mechanistic insights into the CE to CI switch during spliceosome assembly and its effect on pre-mRNA splice site pairing at this stage.

Incoming policies will cause the European Union to harvest more wood, shift one-fifth of cropland to bioenergy and outsource deforestation, analysis shows.

Starting with the launch of the Human Genome Project three decades ago, and continuing after its completion in 2003, genomics has progressively come to have a central and catalytic role in basic and translational research. In addition, studies increasingly demonstrate how genomic information can be effectively used in clinical care. In the future, the anticipated advances in technology development, biological insights, and clinical applications (among others) will lead to more widespread integration of genomics into almost all areas of biomedical research, the adoption of genomics into mainstream medical and public-health practices, and an increasing relevance of genomics for everyday life. On behalf of the research community, the National Human Genome Research Institute recently completed a multi-year process of strategic engagement to identify future research priorities and opportunities in human genomics, with an emphasis on health applications. Here we describe the highest-priority elements envisioned for the cutting-edge of human genomics going forward—that is, at ‘The Forefront of Genomics’.

Scanning probe techniques can leverage atomically precise forces to sculpt matter at surfaces, atom by atom. These forces have been applied quasi-statically to create surface structures1–7and influence chemical processes8,9, but exploiting local dynamics10–14to realize coherent control on the atomic scale remains an intriguing prospect. Chemical reactions15–17, conformational changes18,19and desorption20have been followed on ultrafast timescales, but directly exerting femtosecond forces on individual atoms to selectively induce molecular motion has yet to be realized. Here we show that the near field of a terahertz wave confined to an atomically sharp tip provides femtosecond atomic-scale forces that selectively induce coherent hindered rotation in the molecular frame of a bistable magnesium phthalocyanine molecule. Combining lightwave-driven scanning tunnelling microscopy21–24with ultrafast action spectroscopy10,13, we find that the induced rotation modulates the probability of the molecule switching between its two stable adsorption geometries by up to 39 per cent. Mapping the response of the molecule in space and time confirms that the force acts on the atomic scale and within less than an optical cycle (that is, faster than an oscillation period of the carrier wave of light). We anticipate that our strategy might ultimately enable the coherent manipulation of individual atoms within single molecules or solids so that chemical reactions and ultrafast phase transitions can be manipulated on their intrinsic spatio-temporal scales.

The U2 small nuclear ribonucleoprotein (snRNP) has an essential role in the selection of the precursor mRNA branch-site adenosine, the nucleophile for the first step of splicing1. Stable addition of U2 during early spliceosome formation requires the DEAD-box ATPase PRP52–7. Yeast U2 small nuclear RNA (snRNA) nucleotides that form base pairs with the branch site are initially sequestered in a branchpoint-interacting stem–loop (BSL)8, but whether the human U2 snRNA folds in a similar manner is unknown. The U2 SF3B1 protein, a common mutational target in haematopoietic cancers9, contains a HEAT domain (SF3B1HEAT) with an open conformation in isolated SF3b10, but a closed conformation in spliceosomes11, which is required for stable interaction between U2 and the branch site. Here we report a 3D cryo-electron microscopy structure of the human 17S U2 snRNP at a core resolution of 4.1 Å and combine it with protein crosslinking data to determine the molecular architecture of this snRNP. Our structure reveals that SF3B1HEATinteracts with PRP5 and TAT-SF1, and maintains its open conformation in U2 snRNP, and that U2 snRNA forms a BSL that is sandwiched between PRP5, TAT-SF1 and SF3B1HEAT. Thus, substantial remodelling of the BSL and displacement of BSL-interacting proteins must occur to allow formation of the U2–branch-site helix. Our studies provide a structural explanation of why TAT-SF1 must be displaced before the stable addition of U2 to the spliceosome, and identify RNP rearrangements facilitated by PRP5 that are required for stable interaction between U2 and the branch site.

Carbon stocks in vegetation have a key role in the climate system. However, the magnitude, patterns and uncertainties of carbon stocks and the effect of land use on the stocks remain poorly quantified. Here we show, using state-of-the-art datasets, that vegetation currently stores around 450 petagrams of carbon. In the hypothetical absence of land use, potential vegetation would store around 916 petagrams of carbon, under current climate conditions. This difference highlights the massive effect of land use on biomass stocks. Deforestation and other land-cover changes are responsible for 53–58% of the difference between current and potential biomass stocks. Land management effects (the biomass stock changes induced by land use within the same land cover) contribute 42–47%, but have been underestimated in the literature. Therefore, avoiding deforestation is necessary but not sufficient for mitigation of climate change. Our results imply that trade-offs exist between conserving carbon stocks on managed land and raising the contribution of biomass to raw material and energy supply for the mitigation of climate change. Efforts to raise biomass stocks are currently verifiable only in temperate forests, where their potential is limited. By contrast, large uncertainties hinder verification in the tropical forest, where the largest potential is located, pointing to challenges for the upcoming stocktaking exercises under the Paris agreement.

Recent hydrological modelling and Earth observations have located and quantified alarming rates of groundwater depletion worldwide. This depletion is primarily due to water withdrawals for irrigation, but its connection with the main driver of irrigation, global food consumption, has not yet been explored. Here we show that approximately eleven per cent of non-renewable groundwater use for irrigation is embedded in international food trade, of which two-thirds are exported by Pakistan, the USA and India alone. Our quantification of groundwater depletion embedded in the world’s food trade is based on a combination of global, crop-specific estimates of non-renewable groundwater abstraction and international food trade data. A vast majority of the world’s population lives in countries sourcing nearly all their staple crop imports from partners who deplete groundwater to produce these crops, highlighting risks for global food and water security. Some countries, such as the USA, Mexico, Iran and China, are particularly exposed to these risks because they both produce and import food irrigated from rapidly depleting aquifers. Our results could help to improve the sustainability of global food production and groundwater resource management by identifying priority regions and agricultural products at risk as well as the end consumers of these products.

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 of the human C* spliceosome is very similar to that of the yeast pre-Prp16 C complex. However, in C* the branched intron region is separated from the catalytic centre by approximately 20 Å, and its position close to the U6 small nuclear RNA ACAGA box is stabilized by interactions with the PRP8 RNase H-like and PRP17 WD40 domains. RNA helicase PRP22 is located about 100 Å from the catalytic centre, suggesting that it destabilizes the spliced mRNA after step two from a distance. Comparison of the structure of the yeast C and human C* complexes reveals numerous RNP rearrangements that are likely to be facilitated by PRP16, including a large-scale movement of the U2 small nuclear RNP.

In many Deep Sea Drilling Project (DSDP) drill holes, chalks and/or limestones and even dolomites overlie oceanic basement rocks. These occurrences have often been interpreted as the result of increased calcium carbonate dissolution and reprecipitation as cement and overgrowths (recrystallization) at higher prevailing temperatures, either near an oceanic ridge system or at greater burial depths (burial diagnesis). We report here detailed chemical and isotopic analyses of carbonate sediments recovered from a drill hole on the western flank of the East Pacific Rise during Leg 92 of DSDP. This hole was drilled on 4.6-Myr old oceanic crust and recovered chalks directly overlying oceanic basement at a depth as shallow as 8 m below the sediment/water interface. Oceanic basement was not reached in this hole because of the hardness of deeper chalks, or, more likely, limestones. The chemical and isotopical evidence, detailed below, shows that considerable calcite recrystallization did occur in an aqueous medium similar to normal seawater and at relatively low temperature. This suggests that the observed recrystallization of calcareous ooze to chalk and limestone took place not as a result of burial diagenesis at higher temperatures, but as a result of extensive advective pore water flow through the sediments, which would allow recrystallization of calcium carbonate to take place. This process was, and apparently still is, widespread in the south-east Pacific Ocean.

Sill intrusions into highly porous sediments in the Guaymas Basin, Gulf of California, lead to low-grade metamorphism, thermal alteration and migration of organic compounds, marked changes in interstitial water chemistry, and large-scale expulsion of heated pore fluids. The latter process creates space for the intruding magma and initiates a hydrothermal system, which can explain the observed hydrothermal deposits around fault scarps on the basin floor.

The principal cause of 18O depletion, Ca2+increases, and Mg2+decreases in the pore fluids of cores from leg 35 of the Deep Sea Drilling Project (DSDP) is the alteration of basalt, volcanic ash, and igneous components of terrigenous material. Post-depositional diagenetic reactions have produced smectites, zeolites, K-feldspar, and celadonite as the main authigenic products. 18O/16O data from calcite and clay minerals suggest that these reactions took place over a range of times, temperatures (10–60 °C), and pore fluid 18O/16O compositions. At site 323, the sediments 30–74 m above basement are enriched in Mn, Fe, Cu, Ni, Co, Mo and Sr. Below these horizons, Ba shows a sharp increase towards basement. The 13C/12C values (δ = −18.4 to −21.2‰ PDB) of authigenic calcites in the sediments reflect an organic matter source for the carbon.

This corrects the article DOI: 10.1038/nature21403

CHERT in the Pacific, Atlantic, Indian and Southern Oceans occurs both as nodules and as layers or lenses1. Associated sediments include carbonate, biogenous silica, brown clay and volcanic ash. Chert is usually found in Middle Eocene or older sediments; the actual time of chert formation is, however, not known.