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Lysosomes have crucial roles in regulating eukaryotic metabolism and cell growth by acting as signalling platforms to sense and respond to changes in nutrient and energy availability1. LYCHOS (GPR155) is a lysosomal transmembrane protein that functions as a cholesterol sensor, facilitating the cholesterol-dependent activation of the master protein kinase mechanistic target of rapamycin complex 1 (mTORC1)2. However, the structural basis of LYCHOS assembly and activity remains unclear. Here we determine several high-resolution cryo-electron microscopy structures of human LYCHOS, revealing a homodimeric transmembrane assembly of a transporter-like domain fused to a G-protein-coupled receptor (GPCR) domain. The class B2-like GPCR domain is captured in the apo state and packs against the surface of the transporter-like domain, providing an unusual example of a GPCR as a domain in a larger transmembrane assembly. Cholesterol sensing is mediated by a conserved cholesterol-binding motif, positioned between the GPCR and transporter domains. We reveal that the LYCHOS transporter-like domain is an orthologue of the plant PIN-FORMED (PIN) auxin transporter family, and has greater structural similarity to plant auxin transporters than to known human transporters. Activity assays support a model in which the LYCHOS transporter and GPCR domains coordinate to sense cholesterol and regulate mTORC1 activation.

Engineering the genetic code of an organism has been proposed to provide a firewall from natural ecosystems by preventing viral infections and gene transfer1–6. However, numerous viruses and mobile genetic elements encode parts of the translational apparatus7–9, potentially rendering a genetic-code-based firewall ineffective. Here we show that such mobile transfer RNAs (tRNAs) enable gene transfer and allow viral replication in Escherichia colidespite the genome-wide removal of 3 of the 64 codons and the previously essential cognate tRNA and release factor genes. We then establish a genetic firewall by discovering viral tRNAs that provide exceptionally efficient codon reassignment allowing us to develop cells bearing an amino acid-swapped genetic code that reassigns two of the six serine codons to leucine during translation. This amino acid-swapped genetic code renders cells resistant to viral infections by mistranslating viral proteomes and prevents the escape of synthetic genetic information by engineered reliance on serine codons to produce leucine-requiring proteins. As these cells may have a selective advantage over wild organisms due to virus resistance, we also repurpose a third codon to biocontain this virus-resistant host through dependence on an amino acid not found in nature10. Our results may provide the basis for a general strategy to make any organism safely resistant to all natural viruses and prevent genetic information flow into and out of genetically modified organisms.

Shear stress on arteries produced by blood flow is important for vascular development and homeostasis but can also initiate atherosclerosis1. Endothelial cells that line the vasculature use molecular mechanosensors to directly detect shear stress profiles that will ultimately lead to atheroprotective or atherogenic responses2. Plexins are key cell-surface receptors of the semaphorin family of cell-guidance signalling proteins and can regulate cellular patterning by modulating the cytoskeleton and focal adhesion structures3–5. However, a role for plexin proteins in mechanotransduction has not been examined. Here we show that plexin D1 (PLXND1) has a role in mechanosensation and mechanically induced disease pathogenesis. PLXND1 is required for the response of endothelial cells to shear stress in vitro and in vivo and regulates the site-specific distribution of atherosclerotic lesions. In endothelial cells, PLXND1 is a direct force sensor and forms a mechanocomplex with neuropilin-1 and VEGFR2 that is necessary and sufficient for conferring mechanosensitivity upstream of the junctional complex and integrins. PLXND1 achieves its binary functions as either a ligand or a force receptor by adopting two distinct molecular conformations. Our results establish a previously undescribed mechanosensor in endothelial cells that regulates cardiovascular pathophysiology, and provide a mechanism by which a single receptor can exhibit a binary biochemical nature.

Chronic myeloid leukaemia (CML) is driven by the activity of the BCR–ABL1 fusion oncoprotein. ABL1 kinase inhibitors have improved the clinical outcomes for patients with CML, with over 80% of patients treated with imatinib surviving for more than 10 years. Second-generation ABL1 kinase inhibitors induce more potent molecular responses in both previously untreated and imatinib-resistant patients with CML. Studies in patients with chronic-phase CML have shown that around 50% of patients who achieve and maintain undetectable BCR–ABL1 transcript levels for at least 2 years remain disease-free after the withdrawal of treatment. Here we characterize ABL001 (asciminib), a potent and selective allosteric ABL1 inhibitor that is undergoing clinical development testing in patients with CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia. In contrast to catalytic-site ABL1 kinase inhibitors, ABL001 binds to the myristoyl pocket of ABL1 and induces the formation of an inactive kinase conformation. ABL001 and second-generation catalytic inhibitors have similar cellular potencies but distinct patterns of resistance mutations, with genetic barcoding studies revealing pre-existing clonal populations with no shared resistance between ABL001 and the catalytic inhibitor nilotinib. Consistent with this profile, acquired resistance was observed with single-agent therapy in mice; however, the combination of ABL001 and nilotinib led to complete disease control and eradicated CML xenograft tumours without recurrence after the cessation of treatment.

SHP099, a selective inhibitor of signalling meditator SHP2 with drug-like properties, has an allosteric mechanism of action whereby it stabilizes SHP2 in an auto-inhibited conformation, and suppresses RAS–ERK signalling and proliferation in receptor-tyrosine-kinase-driven cancer cell lines and mouse tumour xenograft models.

TRAVEL-TIME residuals of teleseismic PP waves, reflected approximately halfway between the source and receiver, may give information on seismic velocity near the reflection point. Effects due to structure near the source and receiver are minimised by subtracting the residual of the direct P-wave from that of the PP arrival1. If these differential PP–P residuals are available for closely spaced reflection points, a contour map of compressional wave delays for the reflecting region can be obtained, which may then be related to crustal and upper mantle structure. The contours of two-way delay times for P-waves reflected beneath Atlantic Canada have been presented1, and show an area of late reflections south of the Grand Banks, centred at about 42° N, 52 °W. This area coincides with the Fogo seamounts (Fig. 1) and the relationship between these near-surface features and the P delays is examined here in more detail.

In the British Quaternary, two post-Cromerian interglacials, the Hoxnian and the Ipswichian, are recognized1. Evidence of additional interglacials in this interval is widely accepted in the oceanic record of Quaternary events2, and the possibility that at least one additional interglacial of this age is represented in Britain has been discussed3–5. However, in the absence of datable interglacial deposits which are seen to overlie one another, the issue has remained controversial. We describe here deposits at Marsworth, UK (Fig. 1) where there is evidence of two temperate episodes, and of intervening periglacial conditions. Stratigraphical superposition is established beyond any reasonable doubt. The later deposit relates to the temperate woodland stage of the Ipswichian Interglacial. Dating of the earlier temperate material by the 230Th/234U disequilibrium method indicates an interglacial episode not previously established in the British Quaternary.

Strains of yeast carrying mutations in many of the steps in pathways repairing radiation-induced damage to DNA have enhanced spontaneous mutation rates. Most strains isolated because they have enhanced spontaneous mutation carry mutations in DNA repair systems. This suggests that much spontaneous mutation arises by mutagenic repair of spontaneous lesions.

A MAGNETIC and seismic reflection survey in the Magnetic Quiet Zone shows that basement topography and magnetic anomalies are lineated parallel to the boundary of the quiet zone. Two narrow zones of reversed polarity are identified. The results imply that the zone boundary is an isochron separating a period of seafloor spreading in which rapid geomagnetic reversals occurred from a period in which few reversals occurred.

Understanding of the raised beach and other interglacial sequences in the southern part of the British Isles has been improved through use of the amino acid racemization technique. This method has permitted correlation of these isolated and fragmentary marine deposits1,2which, except for the Portland site, are located around the shores of the Bristol Channel1. By applying this technique with the U-series method, we have obtained a geochronometric date from the ‘8-m’ raised beach of the Belle Hougue Cave, Jersey, Channel Islands. Our results suggest that the 8-m raised beach of the Channel should be correlated with isotope stage 5, and that raised beaches above this altitude in the area may pre-date this stage, and thus also the Ipswichian interglacial which forms part of it.

RECENT theories of the opening of the Atlantic Ocean and the Labrador Sea and of the relationship of the assumed motions to the history of Baffin Bay lead to contradictory opinions about the nature of the crust beneath the bay. The fit of the continents1and the similarities of the rock types and their ages along the opposing coastlines of Greenland and Northern Canada2,3suggest that the two have separated by continental drift. Geophysical studies in the Labrador Sea (unpublished work of X. Le Pichon, R. D. Hyndman and G. Pautot) imply that Baffin Bay was formed by seafloor spreading and therefore that oceanic crust should lie beneath it. Conversely, from an interpretation of the geology along the coastlines, the present configuration of the bay has been attributed to the extension of continental material and subsequent faulting among its margins4. The latter hypothesis is supported by a study of surface waves5which showed that the Lg phase is transmitted across the area. This surface wave is generally associated only with continental crustal structure. The lack of any positive evidence which could be used to resolve this controversy prompted us to conduct the experiment described here.

MAGNETIC anomalies occur at several continental margins; for example, north-east of Newfoundland1, off the eastern seaboard of the US2and off south-western Africa3. Such anomalies are found over the outer parts of the continental shelves and over the continental slopes. They can be traced for many hundreds of kilometres, and have amplitudes of several hundreds of gamma. Studies from this laboratory showed that the anomalies north-east of Newfoundland could be caused by an edge-effect1. A magnetic continental crust has a common boundary with a magnetic oceanic crust and non-magnetic oceanic mantle. A pilot study suggests that such an edge-effect could also account for a substantial part of the magnetic anomalies at the continental margin off the eastern United States.

THE intensity of the Earth's magnetic field over the Atlantic Ocean has been measured on a number of flights organized by the Department of Mines and Technical Surveys of Canada and also under Project Magnet (U.S. Hydrographic Office). Some of these flights passed over the Mid-Atlantic Ridge and the magnetic observations show that there are large anomalies associated with the crest of the Ridge in some crossings, but not in all.

THE great diversity of African agricultural problems is well illustrated by these two volumes. In South Africa moisture dominates the situation, and, on the west coast, anthropology.

DR. C. E. MARSHALL has recently described a method (Proc. Roy. Soc. A, 126, pp. 427–439; 1930) by which he claims that the size distribution of particles in a weak suspension of clay or similar material with particles of 2μ–20μμ, diameter can be accurately determined. A high-speed laboratory centrifuge is used, each tube being nearly filled with a solution of cane-sugar or urea and a small quantity of the aqueous suspension (which has a lower density) is carefully poured on the top. A determination of the weight of sediment collected on the bottom of the tube in a measured time is used by Marshall to determine the weight of the particles which exceed a certain size, it being assumed that all the particles start from the top of the column at approximately the same time and settle through the solution in accordance with Stokes's Law. In discussing the method the author remarks: “It has not been found possible, so far, to apply these principles with any accuracy to the case of sedimentation under gravity. … Owing to slight variations in temperature or concentration the upper liquid sends down ‘streamers’ of suspension into the heavier liquid below.” In advocating the use of the high-speed centrifuge he says: “The boundary between the two liquids actually becomes more sharply denned as centrifuging proceeds, and even if ‘streamer’ formation has begun, the liquid of low density moves rapidly back into place under its action.”

MORDENITE is one of the more common low-temperature sedimentary zeolites1. It can be regarded as a hydration product of volcanic glasses and lavas and is, for example, formed by the crystallization of obsidian glass on exposure to a natural, acid hydrothermal solution at 230° C in a New Zealand borehole2. Such observations have led to the industrial development of sodium–mordenite syntheses from naturally occurring materials, particularly volcanic glasses and pumice, in well denned experimental coiiditions3. Thus synthetic mordenites are usually formed as hard or semi-hard aggregates of extremely small crystals (≤20µ diameter) after hydrothermal preparation at high pH (c. 11.5) and temperatures ranging from 100° to 260° C.

THE interesting letters in NATURE on the cellular structure of emulsions induced me to test the behaviour of clay which I have been accumulating for some time for evaporation experiments. The clay is obtained by the usual sedimentation method, and is that fraction of the soil which does not settle in twenty-four hours in a beaker containing dilute ammonia to a depth of 8.5 cm. The suspension is then evaporated to dryness in vacuo.

IT is surprising that the resonance theory of hearing continues to be revived in one form or another. As soon as the ear is considered in relation to the other sense organs, it becomes apparent that all forms of resonance theory are profoundly unsatisfactory and unphysiological.

IT is well known that glucose stimulates the release of insulin from the mammalian pancreas. It has recently been shown, in vitro, that glucose and mannose, but not a non-metabolized sugar such as galactose, will also stimulate insulin synthesis1. We have investigated the effects of glucose on the putative preceding stage, namely, the formation of new messenger RNA, using isolated islets of Langerhans from the duct-tied pancreas of the rat2,3. As the amount of tissue available for a given experiment is small (approximately 100 µg dry weight), we have investigated the incorporation of 6-14C-orotic acid into total nucleic acids of the islets.

SEDIMENT cores were obtained from the Iberia Abyssal Plain and the Biscay Abyssal Plain1on a cruise of R.R.S. Discovery II in 1958 organized by the Department of Geodesy and Geophysics of the University of Cambridge. These cores consist of beds of sediment deposited by turbidity currents, which are sometimes only a few cm thick but are more often 50–100 cm thick, and alternating with these beds is normal pelagic sediment, not thicker than about 40 cm. These cores have characteristics similar to those of abyssal plain sediments elsewhere described by Ericson and others2.

IN a comprehensive study of the fœtal circulation in the lamb, G. S. Dawes, Joan C. Mott and J. G. Widdicombe1showed that in the fœtus the left ventricular output exceeded that of the right ventricle. In a study of the ventricles of the post-natal human heart2, I showed, by observations of the weight of the ventricular mass and of its parts, that right ventricular atrophy is the normal event in the period immediately following birth, and that the weight ratio between right and left ventricles which is characteristic of adult hearts is normally found from the age of six months onwards. Additional unpublished observations on the thickness of the ventricular walls during the period of right ventricular atrophy suggest that in the human fœtus, as in the lamb, the output of the left ventricle exceeds that of the right. As experimental observations of the type performed on the fœtal lamb are unlikely to be made on a human fœtus, these observations may be of some interest.

IN Nature of March 12, p. 749, Drs. L. R. Cox and W. J. Rees reviewed a paper by the Japanese authors Kawaguti and Baba on a bivalved gastropod they had described under the generic name Tamanovalva. I should like to put on record a further occurrence of this remarkable group of molluscs. A single left valve (now in the Stanford University Collection, California) of what is probably a new species, with the characteristic spiral nucleus and central adductor muscle scar, was collected on Espritu Santo Island, near La Paz, Gulf of California, in beach drift, on November 1, 1959.

THE fourth International Conference on Soil Science was held in the building of the International Institute of Agriculture at Rome on May 12-19, when between 120 and 150 delegates from various countries were present. The Ministry of Agriculture appointed the following delegates from Great Britain: Dr.?.?. Comber, Dr. B. A. Keen, Mr. H. J. Page, and Mr. G. W. Robinson.

THE following remarks by Joule in his paper on the changes in temperature produced by the rarefaction and condensation of air (Phil. Mag., May, 1845) are worthy of notice:—