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The most distant galaxies detected were seen when the Universe was a scant 5% of its current age. At these times, progenitors of galaxies such as the Milky Way were about 10,000 times less massive. Using the James Webb Space Telescope (JWST) combined with magnification from gravitational lensing, these low-mass galaxies can not only be detected but also be studied in detail. Here we present JWST observations of a strongly lensed galaxy at zspec= 8.296 ± 0.001, showing massive star clusters (the Firefly Sparkle) cocooned in a diffuse arc in the Canadian Unbiased Cluster Survey (CANUCS)1. The Firefly Sparkle exhibits traits of a young, gas-rich galaxy in its early formation stage. The mass of the galaxy is concentrated in 10 star clusters (49–57% of total mass), with individual masses ranging from 105M⊙to 106M⊙. These unresolved clusters have high surface densities (>103M⊙pc−2), exceeding those of Milky Way globular clusters and young star clusters in nearby galaxies. The central cluster shows a nebular-dominated spectrum, low metallicity, high gas density and high electron temperature, hinting at a top-heavy initial mass function. These observations provide our first spectrophotometric view of a typical galaxy in its early stages, in a 600-million-year-old Universe.

Cancer-specific TCF1+stem-like CD8+T cells can drive protective anticancer immunity through expansion and effector cell differentiation1–4; however, this response is dysfunctional in tumours. Current cancer immunotherapies2,5–9can promote anticancer responses through TCF1+stem-like CD8+T cells in some but not all patients. This variation points towards currently ill-defined mechanisms that limit TCF1+CD8+T cell-mediated anticancer immunity. Here we demonstrate that tumour-derived prostaglandin E2 (PGE2) restricts the proliferative expansion and effector differentiation of TCF1+CD8+T cells within tumours, which promotes cancer immune escape. PGE2does not affect the priming of TCF1+CD8+T cells in draining lymph nodes. PGE2acts through EP2and EP4(EP2/EP4) receptor signalling in CD8+T cells to limit the intratumoural generation of early and late effector T cell populations that originate from TCF1+tumour-infiltrating CD8+T lymphocytes (TILs). Ablation of EP2/EP4signalling in cancer-specific CD8+T cells rescues their expansion and effector differentiation within tumours and leads to tumour elimination in multiple mouse cancer models. Mechanistically, suppression of the interleukin-2 (IL-2) signalling pathway underlies the PGE2-mediated inhibition of TCF1+TIL responses. Altogether, we uncover a key mechanism that restricts the IL-2 responsiveness of TCF1+TILs and prevents anticancer T cell responses that originate from these cells. This study identifies the PGE2–EP2/EP4axis as a molecular target to restore IL-2 responsiveness in anticancer TILs to achieve cancer immune control.

High-intensity femtosecond pulses from an X-ray free-electron laser enable pump–probe experiments for the investigation of electronic and nuclear changes during light-induced reactions. On timescales ranging from femtoseconds to milliseconds and for a variety of biological systems, time-resolved serial femtosecond crystallography (TR-SFX) has provided detailed structural data for light-induced isomerization, breakage or formation of chemical bonds and electron transfer1,2. However, all ultrafast TR-SFX studies to date have employed such high pump laser energies that nominally several photons were absorbed per chromophore3–17. As multiphoton absorption may force the protein response into non-physiological pathways, it is of great concern18,19whether this experimental approach20allows valid conclusions to be drawn vis-à-vis biologically relevant single-photon-induced reactions18,19. Here we describe ultrafast pump–probe SFX experiments on the photodissociation of carboxymyoglobin, showing that different pump laser fluences yield markedly different results. In particular, the dynamics of structural changes and observed indicators of the mechanistically important coherent oscillations of the Fe–CO bond distance (predicted by recent quantum wavepacket dynamics21) are seen to depend strongly on pump laser energy, in line with quantum chemical analysis. Our results confirm both the feasibility and necessity of performing ultrafast TR-SFX pump–probe experiments in the linear photoexcitation regime. We consider this to be a starting point for reassessing both the design and the interpretation of ultrafast TR-SFX pump–probe experiments20such that mechanistically relevant insight emerges.

The development of the human brain involves unique processes (not observed in many other species) that can contribute to neurodevelopmental disorders1–4. Cerebral organoids enable the study of neurodevelopmental disorders in a human context. We have developed the CRISPR–human organoids–single-cell RNA sequencing (CHOOSE) system, which uses verified pairs of guide RNAs, inducible CRISPR–Cas9-based genetic disruption and single-cell transcriptomics for pooled loss-of-function screening in mosaic organoids. Here we show that perturbation of 36 high-risk autism spectrum disorder genes related to transcriptional regulation uncovers their effects on cell fate determination. We find that dorsal intermediate progenitors, ventral progenitors and upper-layer excitatory neurons are among the most vulnerable cell types. We construct a developmental gene regulatory network of cerebral organoids from single-cell transcriptomes and chromatin modalities and identify autism spectrum disorder-associated and perturbation-enriched regulatory modules. Perturbing members of the BRG1/BRM-associated factor (BAF) chromatin remodelling complex leads to enrichment of ventral telencephalon progenitors. Specifically, mutating the BAF subunit ARID1Baffects the fate transition of progenitors to oligodendrocyte and interneuron precursor cells, a phenotype that we confirmed in patient-specific induced pluripotent stem cell-derived organoids. Our study paves the way for high-throughput phenotypic characterization of disease susceptibility genes in organoid models with cell state, molecular pathway and gene regulatory network readouts.

Vision is initiated by the rhodopsin family of light-sensitive G protein-coupled receptors (GPCRs)1. A photon is absorbed by the 11-cisretinal chromophore of rhodopsin, which isomerizes within 200 femtoseconds to the all-transconformation2, thereby initiating the cellular signal transduction processes that ultimately lead to vision. However, the intramolecular mechanism by which the photoactivated retinal induces the activation events inside rhodopsin remains experimentally unclear. Here we use ultrafast time-resolved crystallography at room temperature3to determine how an isomerized twisted all-transretinal stores the photon energy that is required to initiate the protein conformational changes associated with the formation of the G protein-binding signalling state. The distorted retinal at a 1-ps time delay after photoactivation has pulled away from half of its numerous interactions with its binding pocket, and the excess of the photon energy is released through an anisotropic protein breathing motion in the direction of the extracellular space. Notably, the very early structural motions in the protein side chains of rhodopsin appear in regions that are involved in later stages of the conserved class A GPCR activation mechanism. Our study sheds light on the earliest stages of vision in vertebrates and points to fundamental aspects of the molecular mechanisms of agonist-mediated GPCR activation.

Thousands of genetic variants in protein-coding genes have been linked to disease. However, the functional impact of most variants is unknown as they occur within intrinsically disordered protein regions that have poorly defined functions1–3. Intrinsically disordered regions can mediate phase separation and the formation of biomolecular condensates, such as the nucleolus4,5. This suggests that mutations in disordered proteins may alter condensate properties and function6–8. Here we show that a subset of disease-associated variants in disordered regions alter phase separation, cause mispartitioning into the nucleolus and disrupt nucleolar function. We discover de novo frameshift variants in HMGB1that cause brachyphalangy, polydactyly and tibial aplasia syndrome, a rare complex malformation syndrome. The frameshifts replace the intrinsically disordered acidic tail of HMGB1 with an arginine-rich basic tail. The mutant tail alters HMGB1 phase separation, enhances its partitioning into the nucleolus and causes nucleolar dysfunction. We built a catalogue of more than 200,000 variants in disordered carboxy-terminal tails and identified more than 600 frameshifts that create arginine-rich basic tails in transcription factors and other proteins. For 12 out of the 13 disease-associated variants tested, the mutation enhanced partitioning into the nucleolus, and several variants altered rRNA biogenesis. These data identify the cause of a rare complex syndrome and suggest that a large number of genetic variants may dysregulate nucleoli and other biomolecular condensates in humans.

CRISPR defence systems such as the well-known DNA-targeting Cas9 and the RNA-targeting type III systems are widespread in prokaryotes1,2. The latter orchestrates a complex antiviral response that is initiated through the synthesis of cyclic oligoadenylates after recognition of foreign RNA3–5. Among the large set of proteins that are linked to type III systems and predicted to bind cyclic oligoadenylates6,7, a CRISPR-associated Lon protease (CalpL) stood out to us. CalpL contains a sensor domain of the SAVED family7fused to a Lon protease effector domain. However, the mode of action of this effector is unknown. Here we report the structure and function of CalpL and show that this soluble protein forms a stable tripartite complex with two other proteins, CalpT and CalpS, that are encoded on the same operon. After activation by cyclic tetra-adenylate (cA4), CalpL oligomerizes and specifically cleaves the MazF homologue CalpT, which releases the extracytoplasmic function σ factor CalpS from the complex. Our data provide a direct connection between CRISPR-based detection of foreign nucleic acids and transcriptional regulation. Furthermore, the presence of a SAVED domain that binds cyclic tetra-adenylate in a CRISPR effector reveals a link to the cyclic-oligonucleotide-based antiphage signalling system.

Understanding how a subset of expressed genes dictates cellular phenotype is a considerable challenge owing to the large numbers of molecules involved, their combinatorics and the plethora of cellular behaviours that they determine1,2. Here we reduced this complexity by focusing on cellular organization—a key readout and driver of cell behaviour3,4—at the level of major cellular structures that represent distinct organelles and functional machines, and generated the WTC-11 hiPSC Single-Cell Image Dataset v1, which contains more than 200,000 live cells in 3D, spanning 25 key cellular structures. The scale and quality of this dataset permitted the creation of a generalizable analysis framework to convert raw image data of cells and their structures into dimensionally reduced, quantitative measurements that can be interpreted by humans, and to facilitate data exploration. This framework embraces the vast cell-to-cell variability that is observed within a normal population, facilitates the integration of cell-by-cell structural data and allows quantitative analyses of distinct, separable aspects of organization within and across different cell populations. We found that the integrated intracellular organization of interphase cells was robust to the wide range of variation in cell shape in the population; that the average locations of some structures became polarized in cells at the edges of colonies while maintaining the ‘wiring’ of their interactions with other structures; and that, by contrast, changes in the location of structures during early mitotic reorganization were accompanied by changes in their wiring.

The prevailing view of metazoan gene regulation is that individual genes are independently regulated by their own dedicated sets of transcriptional enhancers. Past studies have reported long-range gene–gene associations1–3, but their functional importance in regulating transcription remains unclear. Here we used quantitative single-cell live imaging methods to provide a demonstration of co-dependent transcriptional dynamics of genes separated by large genomic distances in living Drosophilaembryos. We find extensive physical and functional associations of distant paralogous genes, including co-regulation by shared enhancers and co-transcriptional initiation over distances of nearly 250 kilobases. Regulatory interconnectivity depends on promoter-proximal tethering elements, and perturbations in these elements uncouple transcription and alter the bursting dynamics of distant genes, suggesting a role of genome topology in the formation and stability of co-transcriptional hubs. Transcriptional coupling is detected throughout the fly genome and encompasses a broad spectrum of conserved developmental processes, suggesting a general strategy for long-range integration of gene activity.

NLRP3 is an intracellular sensor protein that when activated by a broad spectrum of exogenous and endogenous stimuli leads to inflammasome formation and pyroptosis1,2. The conformational states of NLRP3 and the way antagonistic small molecules act at the molecular level remain poorly understood2,3. Here we report the cryo-electron microscopy structures of full-length human NLRP3 in its native form and complexed with the inhibitor CRID3 (also named MCC950)4. Inactive, ADP-bound NLRP3 is a decamer composed of homodimers of intertwined leucine-rich repeat (LRR) domains that assemble back-to-back as pentamers. The NACHT domain is located at the apical axis of this spherical structure. One pyrin domain dimer is in addition formed inside the LRR cage. Molecular contacts between the concave sites of two opposing LRR domains are mediated by an acidic loop that extends from an LRR transition segment. Binding of CRID3 considerably stabilizes the NACHT and LRR domains relative to each other. CRID3 binds into a cleft, connecting four subdomains of the NACHT with the transition LRR. Its central sulfonylurea group interacts with the Walker A motif of the NLRP3 nucleotide-binding domain and is sandwiched between two arginine residues, which explains the specificity of NLRP3 for this chemical entity. With the determination of the binding site of this key therapeutic agent, specific targeting of NLRP3 for the treatment of autoinflammatory and autoimmune diseases and rational drug optimization is within reach.

The dominant feature of large-scale mass transfer in the modern ocean is the Atlantic meridional overturning circulation (AMOC). The geometry and vigour of this circulation influences global climate on various timescales. Palaeoceanographic evidence suggests that during glacial periods of the past 1.5 million years the AMOC had markedly different features from today1; in the Atlantic basin, deep waters of Southern Ocean origin increased in volume while above them the core of the North Atlantic Deep Water (NADW) shoaled2. An absence of evidence on the origin of this phenomenon means that the sequence of events leading to global glacial conditions remains unclear. Here we present multi-proxy evidence showing that northward shifts in Antarctic iceberg melt in the Indian–Atlantic Southern Ocean (0–50° E) systematically preceded deep-water mass reorganizations by one to two thousand years during Pleistocene-era glaciations. With the aid of iceberg-trajectory model experiments, we demonstrate that such a shift in iceberg trajectories during glacial periods can result in a considerable redistribution of freshwater in the Southern Ocean. We suggest that this, in concert with increased sea-ice cover, enabled positive buoyancy anomalies to ‘escape’ into the upper limb of the AMOC, providing a teleconnection between surface Southern Ocean conditions and the formation of NADW. The magnitude and pacing of this mechanism evolved substantially across the mid-Pleistocene transition, and the coeval increase in magnitude of the ‘southern escape’ and deep circulation perturbations implicate this mechanism as a key feedback in the transition to the ‘100-kyr world’, in which glacial–interglacial cycles occur at roughly 100,000-year periods.

In 1986, electron microscopy was used to reconstruct by hand the entire nervous system of a roundworm, the nematode Caenorhabditis elegans1. Since this landmark study, high-throughput electron-microscopic techniques have enabled reconstructions of much larger mammalian brain circuits at synaptic resolution2,3. Nevertheless, it remains unknown how the structure of a synapse relates to its physiological transmission strength—a key limitation for inferring brain function from neuronal wiring diagrams. Here we combine slice electrophysiology of synaptically connected pyramidal neurons in the mouse somatosensory cortex with correlated light microscopy and high-resolution electron microscopy of all putative synaptic contacts between the recorded neurons. We find a linear relationship between synapse size and strength, providing the missing link in assigning physiological weights to synapses reconstructed from electron microscopy. Quantal analysis also reveals that synapses contain at least 2.7 neurotransmitter-release sites on average. This challenges existing release models and provides further evidence that neocortical synapses operate with multivesicular release4–6, suggesting that they are more complex computational devices than thought, and therefore expanding the computational power of the canonical cortical microcircuitry.

Cyclic GMP–AMP synthase (cGAS) is an innate immune sensor for cytosolic microbial DNA1. After binding DNA, cGAS synthesizes the messenger 2'3'-cyclic GMP–AMP (cGAMP)2–4, which triggers cell-autonomous defence and the production of type I interferons and pro-inflammatory cytokines via the activation of STING5. In addition to responding to cytosolic microbial DNA, cGAS also recognizes mislocalized cytosolic self-DNA and has been implicated in autoimmunity and sterile inflammation6,7. Specificity towards pathogen- or damage-associated DNA was thought to be caused by cytosolic confinement. However, recent findings place cGAS robustly in the nucleus8–10, where tight tethering of chromatin is important to prevent autoreactivity to self-DNA8. Here we show how cGAS is sequestered and inhibited by chromatin. We provide a cryo-electron microscopy structure of the cGAS catalytic domain bound to a nucleosome, which shows that cGAS does not interact with the nucleosomal DNA, but instead interacts with histone 2A–histone 2B, and is tightly anchored to the ‘acidic patch’. The interaction buries the cGAS DNA-binding site B, and blocks the formation of active cGAS dimers. The acidic patch robustly outcompetes agonistic DNA for binding to cGAS, which suggests that nucleosome sequestration can efficiently inhibit cGAS, even when accessible DNA is nearby, such as in actively transcribed genomic regions. Our results show how nuclear cGAS is sequestered by chromatin and provides a mechanism for preventing autoreactivity to nuclear self-DNA.

The three-dimensional organization of the genome supports regulated gene expression, recombination, DNA repair, and chromosome segregation during mitosis. Chromosome conformation capture (Hi-C)1,2analysis has revealed a complex genomic landscape of internal chromosomal structures in vertebrate cells3–7, but the identical sequence of sister chromatids has made it difficult to determine how they topologically interact in replicated chromosomes. Here we describe sister-chromatid-sensitive Hi-C (scsHi-C), which is based on labelling of nascent DNA with 4-thio-thymidine and nucleoside conversion chemistry. Genome-wide conformation maps of human chromosomes reveal that sister-chromatid pairs interact most frequently at the boundaries of topologically associating domains (TADs). Continuous loading of a dynamic cohesin pool separates sister-chromatid pairs inside TADs and is required to focus sister-chromatid contacts at TAD boundaries. We identified a subset of TADs that are overall highly paired and are characterized by facultative heterochromatin and insulated topological domains that form separately within individual sister chromatids. The rich pattern of sister-chromatid topologies and our scsHi-C technology will make it possible to investigate how physical interactions between identical DNA molecules contribute to DNA repair, gene expression, chromosome segregation, and potentially other biological processes.

Light-driven sodium pumps actively transport small cations across cellular membranes1. These pumps are used by microorganisms to convert light into membrane potential and have become useful optogenetic tools with applications in neuroscience. Although the resting state structures of the prototypical sodium pump Krokinobacter eikastusrhodopsin 2 (KR2) have been solved2,3, it is unclear how structural alterations over time allow sodium to be translocated against a concentration gradient. Here, using the Swiss X-ray Free Electron Laser4, we have collected serial crystallographic data at ten pump–probe delays from femtoseconds to milliseconds. High-resolution structural snapshots throughout the KR2 photocycle show how retinal isomerization is completed on the femtosecond timescale and changes the local structure of the binding pocket in the early nanoseconds. Subsequent rearrangements and deprotonation of the retinal Schiff base open an electrostatic gate in microseconds. Structural and spectroscopic data, in combination with quantum chemical calculations, indicate that a sodium ion binds transiently close to the retinal within one millisecond. In the last structural intermediate, at 20 milliseconds after activation, we identified a potential second sodium-binding site close to the extracellular exit. These results provide direct molecular insight into the dynamics of active cation transport across biological membranes.

Predator–prey cycles rank among the most fundamental concepts in ecology, are predicted by the simplest ecological models and enable, theoretically, the indefinite persistence of predator and prey1–4. However, it remains an open question for how long cyclic dynamics can be self-sustained in real communities. Field observations have been restricted to a few cycle periods5–8and experimental studies indicate that oscillations may be short-lived without external stabilizing factors9–19. Here we performed microcosm experiments with a planktonic predator–prey system and repeatedly observed oscillatory time series of unprecedented length that persisted for up to around 50 cycles or approximately 300 predator generations. The dominant type of dynamics was characterized by regular, coherent oscillations with a nearly constant predator–prey phase difference. Despite constant experimental conditions, we also observed shorter episodes of irregular, non-coherent oscillations without any significant phase relationship. However, the predator–prey system showed a strong tendency to return to the dominant dynamical regime with a defined phase relationship. A mathematical model suggests that stochasticity is probably responsible for the reversible shift from coherent to non-coherent oscillations, a notion that was supported by experiments with external forcing by pulsed nutrient supply. Our findings empirically demonstrate the potential for infinite persistence of predator and prey populations in a cyclic dynamic regime that shows resilience in the presence of stochastic events.

Size control is fundamental in tissue development and homeostasis1,2. Although the role of cell proliferation in these processes has been widely studied, the mechanisms that control embryo size—and how these mechanisms affect cell fate—remain unknown. Here we use the mouse blastocyst as a model to unravel a key role of fluid-filled lumen in the control of embryo size and specification of cell fate. We find that there is a twofold increase in lumenal pressure during blastocyst development, which translates into a concomitant increase in cell cortical tension and tissue stiffness of the trophectoderm that lines the lumen. Increased cortical tension leads to vinculin mechanosensing and maturation of functional tight junctions, which establishes a positive feedback loop to accommodate lumen growth. When the cortical tension reaches a critical threshold, cell–cell adhesion cannot be sustained during mitotic entry, which leads to trophectoderm rupture and blastocyst collapse. A simple theory of hydraulically gated oscillations recapitulates the observed dynamics of size oscillations, and predicts the scaling of embryo size with tissue volume. This theory further predicts that disrupted tight junctions or increased tissue stiffness lead to a smaller embryo size, which we verified by biophysical, embryological, pharmacological and genetic perturbations. Changes in lumenal pressure and size can influence the cell division pattern of the trophectoderm, and thereby affect cell allocation and fate. Our study reveals how lumenal pressure and tissue mechanics control embryo size at the tissue scale, which is coupled to cell position and fate at the cellular scale. A mouse blastocyst model reveals how lumenal pressure, cell cortical tension and tissue stiffness act at the tissue scale to regulate embryo size, which in turn influences the division pattern of trophectoderm cells and their fate specification.

Periodic driving can be used to control the properties of a many-body state coherently and to realize phases that are not accessible in static systems. For example, exposing materials to intense laser pulses makes it possible to induce metal–insulator transitions, to control magnetic order and to generate transient superconducting behaviour well above the static transition temperature. However, pinning down the mechanisms underlying these phenomena is often difficult because the response of a material to irradiation is governed by complex, many-body dynamics. For static systems, extensive calculations have been performed to explain phenomena such as high-temperature superconductivity. Theoretical analyses of driven many-body Hamiltonians are more challenging, but approaches have now been developed, motivated by recent observations. Here we report an experimental quantum simulation in a periodically modulated hexagonal lattice and show that antiferromagnetic correlations in a fermionic many-body system can be reduced, enhanced or even switched to ferromagnetic correlations (sign reversal). We demonstrate that the description of the many-body system using an effective Floquet–Hamiltonian with a renormalized tunnelling energy remains valid in the high-frequency regime by comparing the results to measurements in an equivalent static lattice. For near-resonant driving, the enhancement and sign reversal of correlations is explained by a microscopic model of the system in which the particle tunnelling and magnetic exchange energies can be controlled independently. In combination with the observed sufficiently long lifetimes of the correlations in this system, periodic driving thus provides an alternative way of investigating unconventional pairing in strongly correlated systems experimentally.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease that is characterized by motor neuron loss and that leads to paralysis and death 2–5 years after disease onset. Nearly all patients with ALS have aggregates of the RNA-binding protein TDP-43 in their brains and spinal cords, and rare mutations in the gene encoding TDP-43 can cause ALS. There are no effective TDP-43-directed therapies for ALS or related TDP-43 proteinopathies, such as frontotemporal dementia. Antisense oligonucleotides (ASOs) and RNA-interference approaches are emerging as attractive therapeutic strategies in neurological diseases. Indeed, treatment of a rat model of inherited ALS (caused by a mutation in Sod1) with ASOs against Sod1 has been shown to substantially slow disease progression. However, as SOD1 mutations account for only around 2–5% of ALS cases, additional therapeutic strategies are needed. Silencing TDP-43 itself is probably not appropriate, given its critical cellular functions. Here we present a promising alternative therapeutic strategy for ALS that involves targeting ataxin-2. A decrease in ataxin-2 suppresses TDP-43 toxicity in yeast and flies, and intermediate-length polyglutamine expansions in the ataxin-2 gene increase risk of ALS. We used two independent approaches to test whether decreasing ataxin-2 levels could mitigate disease in a mouse model of TDP-43 proteinopathy. First, we crossed ataxin-2 knockout mice with TDP-43 (also known as TARDBP) transgenic mice. The decrease in ataxin-2 reduced aggregation of TDP-43, markedly increased survival and improved motor function. Second, in a more therapeutically applicable approach, we administered ASOs targeting ataxin-2 to the central nervous system of TDP-43 transgenic mice. This single treatment markedly extended survival. Because TDP-43 aggregation is a component of nearly all cases of ALS, targeting ataxin-2 could represent a broadly effective therapeutic strategy.

Letter to the Editor

A study of pancreatic ductal adenocarcinoma shows that cancer cell proliferation is associated with increased expression of proteins that control programmed necrotic cell death and suppress the adaptive immune system.

We have determined the 8,332-nucleotide structure of the genome of Moloney murine leukaemia virus. The coding frame for the gag gene is the same as that for pol, separated only by a single amber triplet. The pol gene encodes 132,000 daltons of protein, larger than the 70,000 daltons required for the reverse transcriptase. The env gene overlaps the pol gene.

All-trans-retinoic acid (RA) induces striking digit pattern duplications when locally applied to the developing chick limb bud1–4. Instead of the normal digit pattern (234) a mirror-symmetrical 432234 pattern can be specified. Hence, RA closely mimics posterior limb bud tissue (the zone of polarizing activity, ZPA) that causes very similar duplications when grafted to an anterior site of a host limb bud5. This resemblance raises an intriguing possibility: that RA is related to the as yet unidentified inducer substance thought to be released by the ZPA1,6. Here we report that chick limb buds contain endogenous RA and we show that RA, but not its biosynthetic precursor retinol, forms a concentration gradient across the limb anlage with a high-point in the posterior domain of the limb bud, the part that also contains the ZPA.

Chemically synthesized peptides corresponding to two different regions of the VP1 polypeptide of foot-and-mouth disease virus (FMDV) produced high levels of serotype-specific virus neutralizing antibody in cattle, guinea pigs and rabbits. A single inoculation of one of these peptides protected guinea pigs against subsequent challenge with the virulent virus.

‘Identifier’ or ID sequences are present in 62% of the RNA polymerase II and III transcripts made in vitro from brain nuclei but in fewer than 4% of the transcripts made from the nuclei of other tissues. An homologous 160-nucleotide cytoplasmic poly(A)+RNA species, BC1, and a smaller species, BC2, are located in vivo exclusively in neural tissues. Cloned ID sequences are polymerase III templates in vitro. Our data suggest a model in which brain-specific polymerase III transcription of ID sequences located in introns of brain genes activates those genes in a primary manner for polymerase II transcription.

A Correction to this paper has been published: https://doi.org/10.1038/s41586-021-03322-8.

ESTIMATES of denudation often enter into geologic argument and have to be extrapolated backwards over geological intervals of time. The importance of human activity in the present-day erosional cycle has been pointed out by Douglas1and has been carefully evaluated by Judson2in a comparison of world-wide river load estimates with data from the nearly undisturbed Congo and Amazon basins. Judson concludes that man's intervention has increased the overall denudation rate from 9 to 24 billion tons a year: far more than enough to discredit the present rate as a geologic parameter. In this communication I attempt to verify Judson's pre-human estimate and to defend its general applicability to the past 300 million years.

Teeth from different people differ in their susceptibility to caries. The beginning and the development of tooth decay depend on the presence of bacterial plaque1and on the structure of the tooth enamel2. But it has not been established whether the organic or the inorganic component of the enamel (which is comprised principally of hydroxyapatite microcrystals organized in a firm matrix), is responsible for most of the resistance of teeth to caries. We report here that the electron spin resonance (ESR) lines of the CO33−defect of samples of enamel prepared from caries-resistant teeth differ significantly from the corresponding spectra of the caries-sensitive samples. We have traced these differences to the hydroxyapatite micro-crystalline alignment in the tooth enamel, and found that this alignment is specific to indivduals and is therefore probably nutritionally or genetically determine.

HARRISS1recently published a silica budget for the ocean from which he concludes that the losses outweigh the gains by something like 8 × 1015g yr−1(Table 1). At this rate only about three centuries would be required to reduce the average silica content of seawater to 0.2 p.p.m., the minimum concentration supposed adequate to support diatoms.

DR. HUXLEY and his co-authors have succeeded in producing a book which makes most stimulating reading. In all, twenty-two authors have contributed a chapter each and, as mentioned in the foreword, British authors predominate, since it was felt that this would facilitate the co-ordination of the articles. Where Great Britain could not supply a suitable authority on some subject, authors of other nationalities were invited to write a chapter. Some idea of the ground covered may be obtained from a few of the chapter headings taken at random: A museum zoologist's view of taxonomy; Mutations and geographical variation; Ecological aspects of plant taxonomy; Problems of the origin of species; Polymorphism and taxonomy; The statistical consequences of Mendelian heredity in relation to speciation; Taxonomic species and genetic systems; The new systematics of cultivated plants; and so forth. Minor systematics have naturally received the greatest share of attention for the very good reason that it is the minor units which most urgently require attention, and also, as it happens, they are the most amenable to experimental analysis.

THE heat capacity of anhydrous sodium sulphate has been measured recently in a water calorimeter by Kreidl and Simon1, who observed only one high-temperature transition, at about 238° C. However, there are two known polymorphic transitions between room temperature and 300° C.: (1) the transformation of the stable low-temperature form V to the intermediate form III and (2) transformation of III to the stable high-temperature form I. The heat of transition observed by Kreidl and Simon was nearly equal to the sum of the heats of the two known transitions. They concluded that in the presence of water, the transition V→ I occurs directly and reversibly, and supported this conclusion with X-ray diffraction data. More recently, Bird2has reported an irreversible transformation, V→ I, upon heating sodium sulphate in the absence of water. This occurred at a considerably lower temperature of about 176° C., and is based on comparison of high-temperature X-ray diffraction patterns.