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Tissue-selective chemoattractants direct lymphocytes to epithelial surfaces to establish local immune environments, regulate immune responses to food antigens and commensal organisms, and protect from pathogens. Homeostatic chemoattractants for small intestines, colon and skin are known1,2, but chemotropic mechanisms selective for respiratory tract and other non-intestinal mucosal tissues remain poorly understood. Here we leveraged diverse omics datasets to identify GPR25 as a lymphocyte receptor for CXCL17, a chemoattractant cytokine whose expression by epithelial cells of airways, upper gastrointestinal and squamous mucosae unifies the non-intestinal mucosal tissues and distinguishes them from intestinal mucosae. Single-cell transcriptomic analyses show that GPR25is induced on innate lymphocytes before emigration to the periphery, and is imprinted in secondary lymphoid tissues on activated B and T cells responding to immune challenge. GPR25characterizes B and T tissue resident memory cells and regulatory T lymphocytes in non-intestinal mucosal tissues and lungs in humans and mediates lymphocyte homing to barrier epithelia of the airways, oral cavity, stomach, and biliary and genitourinary tracts in mouse models. GPR25is also expressed by T cells in cerebrospinal fluid and CXCL17by neurons, suggesting a role in central nervous system (CNS) immune regulation. We reveal widespread imprinting of GPR25on regulatory T cells, suggesting a mechanistic link to population genetics evidence that GPR25is protective in autoimmunity3,4. Our results define a GPR25–CXCL17 chemoaffinity axis with the potential to integrate immunity and tolerance at non-intestinal mucosae and the CNS.

Advanced urothelial cancer is a frequently lethal disease characterized by marked genetic heterogeneity1. In this study, we investigated the evolution of genomic signatures caused by endogenous and external mutagenic processes and their interplay with complex structural variants (SVs). We superimposed mutational signatures and phylogenetic analyses of matched serial tumours from patients with urothelial cancer to define the evolutionary dynamics of these processes. We show that APOBEC3-induced mutations are clonal and early, whereas chemotherapy induces mutational bursts of hundreds of late subclonal mutations. Using a genome graph computational tool2, we observed frequent high copy-number circular amplicons characteristic of extrachromosomal DNA (ecDNA)-forming SVs. We characterized the distinct temporal patterns of APOBEC3-induced and chemotherapy-induced mutations within ecDNA-forming SVs, gaining new insights into the timing of these mutagenic processes relative to ecDNA biogenesis. We discovered that most CCND1amplifications in urothelial cancer arise within circular ecDNA-forming SVs. ecDNA-forming SVs persisted and increased in complexity, incorporating additional DNA segments and contributing to the evolution of treatment resistance. Oxford Nanopore Technologies long-read whole-genome sequencing followed by de novo assembly mapped out CCND1ecDNA structure. Experimental modelling of CCND1ecDNA confirmed its role as a driver of treatment resistance. Our findings define fundamental mechanisms that drive urothelial cancer evolution and have important therapeutic implications.

The mammalian brain consists of millions to billions of cells that are organized into many cell types with specific spatial distribution patterns and structural and functional properties1–3. Here we report a comprehensive and high-resolution transcriptomic and spatial cell-type atlas for the whole adult mouse brain. The cell-type atlas was created by combining a single-cell RNA-sequencing (scRNA-seq) dataset of around 7 million cells profiled (approximately 4.0 million cells passing quality control), and a spatial transcriptomic dataset of approximately 4.3 million cells using multiplexed error-robust fluorescence in situ hybridization (MERFISH). The atlas is hierarchically organized into 4 nested levels of classification: 34 classes, 338 subclasses, 1,201 supertypes and 5,322 clusters. We present an online platform, Allen Brain Cell Atlas, to visualize the mouse whole-brain cell-type atlas along with the single-cell RNA-sequencing and MERFISH datasets. We systematically analysed the neuronal and non-neuronal cell types across the brain and identified a high degree of correspondence between transcriptomic identity and spatial specificity for each cell type. The results reveal unique features of cell-type organization in different brain regions—in particular, a dichotomy between the dorsal and ventral parts of the brain. The dorsal part contains relatively fewer yet highly divergent neuronal types, whereas the ventral part contains more numerous neuronal types that are more closely related to each other. Our study also uncovered extraordinary diversity and heterogeneity in neurotransmitter and neuropeptide expression and co-expression patterns in different cell types. Finally, we found that transcription factors are major determinants of cell-type classification and identified a combinatorial transcription factor code that defines cell types across all parts of the brain. The whole mouse brain transcriptomic and spatial cell-type atlas establishes a benchmark reference atlas and a foundational resource for integrative investigations of cellular and circuit function, development and evolution of the mammalian brain.

Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development1–5. This also applies to the PI3K signalling pathway, which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation. Here we report the discovery of UCL-TRO-1938 (referred to as 1938 hereon), a small-molecule activator of the PI3Kα isoform, a crucial effector of growth factor signalling. 1938 allosterically activates PI3Kα through a distinct mechanism by enhancing multiple steps of the PI3Kα catalytic cycle and causes both local and global conformational changes in the PI3Kα structure. This compound is selective for PI3Kα over other PI3K isoforms and multiple protein and lipid kinases. It transiently activates PI3K signalling in all rodent and human cells tested, resulting in cellular responses such as proliferation and neurite outgrowth. In rodent models, acute treatment with 1938 provides cardioprotection from ischaemia–reperfusion injury and, after local administration, enhances nerve regeneration following nerve crush. This study identifies a chemical tool to directly probe the PI3Kα signalling pathway and a new approach to modulate PI3K activity, widening the therapeutic potential of targeting these enzymes through short-term activation for tissue protection and regeneration. Our findings illustrate the potential of activating kinases for therapeutic benefit, a currently largely untapped area of drug development.

Increased rates of deformation and seismicity are well-established precursors to volcanic eruptions, and their interpretation forms the basis for eruption warnings worldwide. Rates of ground displacement and the number of earthquakes escalate before many eruptions1–3, as magma forces its way towards the surface. However, the pre-eruptive patterns of deformation and seismicity vary widely. Here we show how an eruption beginning on 19 March 2021 at Fagradalsfjall, Iceland, was preceded by a period of tectonic stress release ending with a decline in deformation and seismicity over several days preceding the eruption onset. High rates of deformation and seismicity occurred from 24 February to mid-March in relation to gradual emplacement of an approximately 9-km-long magma-filled dyke, between the surface and 8 km depth (volume approximately 34 × 106m3), as well as the triggering of strike-slip earthquakes up to magnitude MW5.64. As stored tectonic stress was systematically released, there was less lateral migration of magma and a reduction in both the deformation rates and seismicity. Weaker crust near the surface may also have contributed to reduced seismicity, as the depth of active magma emplacement progressively shallowed. This demonstrates that the interaction between volcanoes and tectonic stress as well as crustal layering need to be fully considered when forecasting eruptions.

Studies of the self-assembly of pyruvate dehydrogenase of Escherichia coli show that the catalytic activity is proportional to the state of assembly and uncover a novel functional connection of active sites in this multienzyme complex.

Embryonal stem (ES) cell lines, established in culture from peri-implantation mouse blastocysts1–3, can colonize both the somatic and germ-cell lineages of chimaeric mice following injection into host blastocysts4,5. Recently, ES cells with multiple integrations of retro viral sequences have been used to introduce these sequences into the germ-line of chimaeric mice5, demonstrating an alternative to the microinjection of fertilized eggs6for the production of transgenic mice. However, the properties of ES cells raise a unique possibility: that of using the techniques of somatic cell genetics to select cells with genetic modifications such as recessive mutations, and of introducing these mutations into the mouse germ line. Here we report the realization of this possibility by the selection in vitro of variant ES cells deficient in hypoxanthine guanine phosphoribosyl transferase (HPRT; EC 2.4.2.8), their use to produce germline chimaeras resulting in female offspring heterozygous for HPRT-deficiency, and the generation of HPRT-deficient preimplantation embryos from these females. In human males, HPRT deficiency causes Lesch–Nyhan syndrome7, which is characterized by mental retardation and self-mutilation.

RECONSTRUCTION of the climatic and hydrologic history of ocean basins has been based on either oxygen isotope palaeothermometry or studies of foraminiferal assemblages preserved in deep sea sediments. We report here the application of both methods to deep sea sediments collected from the Arctic Ocean by the Lamont–Doherty Geological Observatory. Oxygen isotope determinations were made on two selected cores from the central Arctic basin to test the validity of the palaeoceanographic interpretations based on microfaunal analysis1–3. Details of the cores are given in Fig. 1 and Table 1. Analyses of the cores have already been published in detail: here we wish to summarize what we have discovered about the history of the Arctic Ocean1–4.

Two recent developments suggest a route to predetermined alterations in mammalian germlines. These are, first, the characterization of mouse embryonic stem (ES) cells1that can still enter the germline after genetic manipulation in culture2,3and second, the demonstration that homologous recombination between a native target chromosomal gene and exogenous DNA can be used in culture to modify specifically the target locus4. We here use gene targetting functionally to correct the mutant hypoxanthine-guanine phosphoribosyl transferase (HPRT) gene in the ES cell line which has previously been isolated and used to produce an HPRT-deficient mouse5. This modification of a chosen gene in pluripotent ES cells demonstrates the feasibility of this route to manipulating mammalian genomes in predetermined ways.

Animal experiments have suggested that the pineal gland produces an anti-gonadotropic hormone. The hamster, for example, undergoes reproductive collapse when kept in short-day periods, an effect which is abolished by pinealectomy1. Although there is little direct evidence about the endocrine role of the pineal gland in man, it has been noted that tumours of the pineal gland in young boys are associated with precocious puberty and the human pineal gland has been suggested to produce a substance that holds sexual maturation in check2. This observation has been extended by Kitay3, who has shown that destructive tumours are associated with precocious puberty whereas hyperactive tumours are associated with delayed puberty. However, no studies have described any change of pineal function with normal puberty. Because two pineal indoles, melatonin4and methoxytryptophol5, have been shown to be antigonadotropic when administered to animals6–10, we have now measured them in schoolchildren. Our findings show that in young boys there is an abrupt fall in the concentration of melatonin with advancing development suggesting that it may play an important physiological role in the control of human puberty.

THE optical diffractometer1developed by Lipson and others is being used in this laboratory for work on the structure of deoxyribose nucleic acid. This instrument has already proved its value, in work on structures of smaller molecules, as a rapid means of obtaining diffraction patterns due to trial structures, and it should clearly lend itself to application in the field of macromolecular structure in cases where enough is already known of the chemistry to enable trial structures to be produced. In the usual form, a projection of the trial structure is represented by holes punched in an opaque mask, and the Fourier transform of this mask is obtained optically. A difficulty arises, however, in the application to large molecules, in that there is a minimum size of hole (about 0.5 mm. diameter) that can be punched in the mask. As a consequence, a large molecule can only be represented by covering a large area of the mask with holes. This gives a diffraction pattern on a very small scale, and it is found difficult to obtain the pattern without some distortion due to slight imperfections in the lens system.

The microorganisms that colonize pregnant mice have been shown to prime the innate immune system in newborn offspring, preparing them for life in association with microbes.

NUMBERED aluminium bands which are used to study the movements of bats are also of value in providing specific information concerning age1. In Britain, the first large scale bat-banding experiment was commenced in Devon in 1948 (ref. 2) and during recent years it has been gratifying to note the continued survival of a number of greater horseshoe bats (Rhinolophus ferrumequinum) banded during the early stages of that experiment. Of particular interest has been the finding, on October 28, 1967, of greater horseshoe No. 918 (male). This bat, found in a small mine adit near Holne, in south Devon, was originally banded in a cave at Buckfastleigh, about 3 miles away, on March 4, 1949. Its age, when first handled, was not known, but because for this species birth invariably occurs only in mid-summer, usually early in July, this bat could not have been born later than July 1948. At the time of its most recent finding it must therefore have been at least 19.25 yr old.

Bruce Ames and Kim Hooper reply to a recent criticism of their inquiry into the relation between mutagenic potency in the Ames test and carcinogenic potency.

THE action of silver difiuoride on tetrasulphur tetranitride has been shown to yield the thiazyl fluorides SNF and SNF31, but little is known about the action of other fiuorinating agents on sulphur nitride. We have examined the action of several liquid and gaseous fluorides on sulphur nitride, and also the reaction of sulphur tetrafluoride with ammonia.

THE contrasting magnetic behaviour (Table 1 and Fig. 1) of the α- and β-forms of RuCl3is of interest in relation to the different types of stereochemical arrangements1shown by the transition metal halides: it has also allowed the presence of α-RuCl3, produced in the usual method of preparation of β-RuCl3, to be detected. A material, hitherto considered2,3as yet another form of RuCl3, is now shown to be Ru2IVOCl6(Table 1), a member of a class of oxide chlorides of binuclear ruthenium in which the average oxidation state of ruthenium changes from +4 through +3.5 to +3.

DURING the preparation for the press, in 1895, of the “Diary and Consultation Book of the Agent, Governor and Council of Fort St. George”, for 1682—5, Mr. A. T. Pringle, the editor, inquired if I could throw any light on the origin of caliature, a name for redwood (Pterocarpus santalinus), frequently referred to as an article of trade in Madras. Presuming the name to be that of a port on the east coast, it has evidently disappeared from nearly all the available gazetteers and modern atlases. Inquiries were made in London, Holland, and Java with no results; but recent researches in the libraries of Calcutta have been more successful, and the following notes on the early trade of the country form an interesting chapter on the history of red-sanders wood.

CAIRNS1observed in the United States that a species of Aphelenchus fed on and destroyed mushroom mycelium. During the past eight years, nearly 300 samples of mushroom compost have been examined at Rothamsted. Harmful nematodes usually present were Aphelenchoides composticola2, Ditylenchus myceliophagus3, and occasionally Paraphelenchus myceliophthorus4. The effect of these three species on the growth of mycelium and the yield of mushrooms has been described by Goodey5. Of the 300 samples examined, four contained Aphelenchus avenae6; two of these contained a few A. avenae together with many Diplogaster sp. and Panagrolaimus sp. The other two samples came from different houses on the same mushroom farm and had 6,000 and 18,000 A. avenae/100 gm. compost respectively; Rhabditis sp. and Panagrolaimus sp. were even more numerous.

ELECTRON probe X-ray microanalysis permits the determination on a micro-scale of local distribution and concentration of elements in a sample. In a preliminary enquiry, the tests of calcareous Foraminifera have been investigated.

THE valuable work of I. M. Tonkin and T. S. Work on two new anti-malarial drugs1has brought to light the action of a well-known Eastern remedy. Dichroa febrifuga, of the family Saxifragacese, is a shrub found from China and north-eastern India to Java and the Philippine Islands. In the form of a decoction, the leaves and stems have been used in Indo-China for quotidian, tertian and quartan ague. When in India more than fifty years ago, a native physician sent to me some stems of the plant as a fever remedy and suggested that it might contain an alkaloid similar to quinine. The drug yielded no alkaloid but a glucoside, and differing from other astringent plants of this family it afforded no tannin. Later, a sample of the same drug was sent as a fever medicine used by the Chinese in Malaya. It is satisfactory to note that recent pharmacological research confirms the suitability of the specific name—febrifuga—given to the plant by Loureiro (Fl. Cochinale) so long ago as 1790.

I have read with much interest the communication by W. A. King-Webster and J. S. Kenny1in which it is suggested that roosting bats can play a considerable part in cave excavation where the rock is soft. In particular, reference is made to the existence, in the roof of a limestone cave in Mt. Tamana (Trinidad), of bell-shaped cavities ranging in depth from 3 ft. to 6 ft., and in diameter at the mouth from 1½ ft. to 2½ ft., and which are used by sleeping bats. The suggestion is made that the habit of the bats of alighting at the lower edge of the bell and then jostling upwards into a central position, by continuation over innumerable years, has led to the excavation of these cavities, with maximum removal of rock at the mouth of the bell.

ON p. 348 Dr. Kidd asks if it is known to be a common thing for dogs to carry hedgehogs in their mouths. I can only answer for my own dog, a fox-terrier. Last season a hedgehog strayed into our garden, and appeared anxious to stay; but the dog carried it in his mouth repeatedly, and so teased it in various ways, that we were not surprised when the hedgehog beat a permanent retreat by absconding. The curious circumstance in the affair was that the dog appeared to carry the hedgehog, rolled in a ball, without causing his lips to bleed; in this particular, Carlo seems to be cleverer than Dr. Kidd's dog!

IN the Travancore Court of the British Empire Exhibition at Wembley several interesting products of this enterprising State were displayed. Among the medicinal products there were two substances named “Kalpal” and “Kalmadom.” From a description drawn up by Dr. Kunjan Pillai, these are said to be deposits found in the clefts and hollows of high rocks “in the form of a brownish - white foam which on exposure becomes harder with time and has the consistence of lime-plaster.” The decomposed rock is washed with water to remove foreign matter, as lichens, leaves, etc., and the sediment is made up into balls and dried in the sun. The lumps reduced to powder are said to be a valuable medicine for kidney complaints.