Acetohydroxyacid synthase (AHAS), also known as acetolactate synthase, is a FAD and ThDP-Mg2+-dependent enzyme that catalyses the first step in the biosynthesis of the branched chain amino acids (BCAAs)1. It is the target for over 50 commercial herbicides2. AHAS requires both catalytic and regulatory subunits for maximal activity and functionality. Herein, our structures of the hexadecameric Saccharomyces

COVID-19 has rapidly affected mortality worldwide1. There is unprecedented urgency to understand who is most at risk of severe outcomes, requiring new approaches for timely analysis of large datasets. Working on behalf of NHS England, here we created OpenSAFELY: a secure health analytics platform covering 40% of all patients in England, holding patient data within the existing data centre of a major

Species often include multiple ecotypes that are adapted to different environments1. However, it is unclear how ecotypes arise and how their distinctive combinations of adaptive alleles are maintained despite hybridization with non-adapted populations2,3,4. Here, by resequencing 1,506 wild sunflowers from 3 species (Helianthus annuus, Helianthus petiolaris and Helianthus argophyllus), we identify 37 large

In metazoans, the secreted proteome participates in intercellular signalling and innate immunity, and builds the extracellular matrix scaffold around cells. Compared with the relatively constant intracellular environment, conditions for proteins in the extracellular space are harsher, and low concentrations of ATP prevent the activity of intracellular components of the protein quality-control machinery

Reducing the energy bandwidth of electrons in a lattice below the long-range Coulomb interaction energy promotes correlation effects. Moiré superlattices—which are created by stacking van der Waals heterostructures with a controlled twist angle1,2,3—enable the engineering of electron band structure. Exotic quantum phases can emerge in an engineered moiré flat band. The recent discovery of correlated

Active optical control over matter is desirable in many scientific disciplines, with prominent examples in all-optical magnetic switching1,2, light-induced metastable or exotic phases of solids3,4,5,6,7,8 and the coherent control of chemical reactions9,10. Typically, these approaches dynamically steer a system towards states or reaction products far from equilibrium. In solids, metal-to-insulator transitions

Bacterial toxins represent a vast reservoir of biochemical diversity that can be repurposed for biomedical applications. Such proteins include a group of predicted interbacterial toxins of the deaminase superfamily, members of which have found application in gene-editing techniques1,2. Because previously described cytidine deaminases operate on single-stranded nucleic acids3, their use in base editing

The suprachiasmatic nucleus (SCN) serves as the body’s master circadian clock that adaptively coordinates changes in physiology and behaviour in anticipation of changing requirements throughout the 24-h day–night cycle1,2,3,4. For example, the SCN opposes overnight adipsia by driving water intake before sleep5,6, and by driving the secretion of anti-diuretic hormone7,8 and lowering body temperature9

The possibility of voyaging contact between prehistoric Polynesian and Native American populations has long intrigued researchers. Proponents have pointed to the existence of New World crops, such as the sweet potato and bottle gourd, in the Polynesian archaeological record, but nowhere else outside the pre-Columbian Americas1,2,3,4,5,6, while critics have argued that these botanical dispersals need

The mitochondrial electron transport chain (ETC) is necessary for tumour growth1,2,3,4,5,6 and its inhibition has demonstrated anti-tumour efficacy in combination with targeted therapies7,8,9. Furthermore, human brain and lung tumours display robust glucose oxidation by mitochondria10,11. However, it is unclear why a functional ETC is necessary for tumour growth in vivo. ETC function is coupled to

Sexual dimorphism arises from genetic differences between male and female cells, and from systemic hormonal differences1,2,3. How sex hormones affect non-reproductive organs is poorly understood, yet highly relevant to health given the sex-biased incidence of many diseases4. Here we report that steroid signalling in Drosophila from the ovaries to the gut promotes growth of the intestine specifically

The discovery of a radioactively powered kilonova associated with the binary neutron-star merger GW170817 remains the only confirmed electromagnetic counterpart to a gravitational-wave event1,2. Observations of the late-time electromagnetic emission, however, do not agree with the expectations from standard neutron-star merger models. Although the large measured ejecta mass3,4 could be explained by

A central challenge in developing quantum computers and long-range quantum networks is the distribution of entanglement across many individually controllable qubits1. Colour centres in diamond have emerged as leading solid-state ‘artificial atom’ qubits2,3 because they enable on-demand remote entanglement4, coherent control of over ten ancillae qubits with minute-long coherence times5 and memory-enhanced

The transient receptor potential ion channel TRPA1 is expressed by primary afferent nerve fibres, in which it functions as a low-threshold sensor for structurally diverse electrophilic irritants, including small volatile environmental toxicants and endogenous algogenic lipids1. TRPA1 is also a ‘receptor-operated’ channel whose activation downstream of metabotropic receptors elicits inflammatory pain

Zika virus (ZIKV) belongs to the family Flaviviridae, and is related to other viruses that cause human diseases. Unlike other flaviviruses, ZIKV infection can cause congenital neurological disorders and replicates efficiently in reproductive tissues1,2,3. Here we show that the envelope protein (E) of ZIKV is polyubiquitinated by the E3 ubiquitin ligase TRIM7 through Lys63 (K63)-linked polyubiquitination

Technologies such as batteries, biomaterials and heterogeneous catalysts have functions that are defined by mixtures of molecular and mesoscale components. As yet, this multi-length-scale complexity cannot be fully captured by atomistic simulations, and the design of such materials from first principles is still rare1,2,3,4,5. Likewise, experimental complexity scales exponentially with the number of

Astrocytes take up glucose from the bloodstream to provide energy to the brain, thereby allowing neuronal activity and behavioural responses1,2,3,4,5. By contrast, astrocytes are under neuronal control through specific neurotransmitter receptors5,6,7. However, whether the activation of astroglial receptors can directly regulate cellular glucose metabolism to eventually modulate behavioural responses

Enhanced silicate rock weathering (ERW), deployable with croplands, has potential use for atmospheric carbon dioxide (CO2) removal (CDR), which is now necessary to mitigate anthropogenic climate change1. ERW also has possible co-benefits for improved food and soil security, and reduced ocean acidification2,3,4. Here we use an integrated performance modelling approach to make an initial techno-economic

Connections between the gut and brain monitor the intestinal tissue and its microbial and dietary content1, regulating both physiological intestinal functions such as nutrient absorption and motility2,3, and brain-wired feeding behaviour2. It is therefore plausible that circuits exist to detect gut microorganisms and relay this information to areas of the central nervous system that, in turn, regulate

The coexistence of superconducting and correlated insulating states in magic-angle twisted bilayer graphene1,2,3,4,5,6,7,8,9,10,11 prompts fascinating questions about their relationship. Independent control of the microscopic mechanisms that govern these phases could help uncover their individual roles and shed light on their intricate interplay. Here we report on direct tuning of electronic interactions

Chemokines and their receptors mediate cell migration, which influences multiple fundamental biological processes and disease conditions, such as inflammation and cancer1. Although ample efforts have been invested into the structural investigation of the chemokine receptors and receptor–chemokine recognition2–4, less is known about endogenous chemokine-induced receptor activation and G protein coupling

When waves propagate through a weak disordered potential with correlation length larger than the wavelength, they form channels (branches) of enhanced intensity that keep dividing as the waves propagate1. This fundamental wave phenomenon is known as branched flow. It was first observed for electrons1,2,3,4,5,6 and for microwave cavities7,8, and it is generally expected for waves with vastly different

Mutations in proteolipid protein 1 (PLP1) result in failure of myelination and neurological dysfunction in the X-linked leukodystrophy Pelizaeus-Merzbacher disease (PMD)1,2. Most PLP1 mutations, including point mutations and supernumerary copy variants, lead to severe and fatal disease. PLP1-null patients and mice, however, can display comparatively mild phenotypes, suggesting that PLP1-suppression

Dental enamel is a principal component of teeth1, and has evolved to bear large chewing forces, resist mechanical fatigue and withstand wear over decades2. Functional impairment and loss of dental enamel, caused by developmental defects or tooth decay (caries), affect health and quality of life, with associated costs to society3. Although the past decade has seen progress in our understanding of enamel

Forests provide a series of ecosystem services that are crucial to our society. In the European Union (EU), forests account for approximately 38% of the total land surface1. These forests are important carbon sinks, and their conservation efforts are vital for the EU’s vision of achieving climate neutrality by 20502. However, the increasing demand for forest services and products, driven by the bioeconomy

The interiors of giant planets remain poorly understood. Even for the planets in the Solar System, difficulties in observation lead to large uncertainties in the properties of planetary cores. Exoplanets that have undergone rare evolutionary processes provide a route to understanding planetary interiors. Planets found in and near the typically barren hot-Neptune ‘desert’1,2 (a region in mass–radius

The mammalian immune system implements a remarkably effective set of mechanisms for fighting pathogens1. Its main components are haematopoietic immune cells, including myeloid cells that control innate immunity, and lymphoid cells that constitute adaptive immunity2. However, immune functions are not unique to haematopoietic cells, and many other cell types display basic mechanisms of pathogen defence3

Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis1,2,3,4,5. However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance6. In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome

Valence electrons contribute a small fraction of the total electron density of materials, but they determine their essential chemical, electronic and optical properties. Strong laser fields can probe electrons in valence orbitals1,2,3 and their dynamics4,5,6 in the gas phase. Previous laser studies of solids have associated high-harmonic emission7,8,9,10,11,12 with the spatial arrangement of atoms

Plant hormones coordinate responses to environmental cues with developmental programs1, and are fundamental for stress resilience and agronomic yield2. The core signalling pathways underlying the effects of phytohormones have been elucidated by genetic screens and hypothesis-driven approaches, and extended by interactome studies of select pathways3. However, fundamental questions remain about how information

Mammalian cells reorganize their proteomes in response to nutrient stress through translational suppression and degradative mechanisms using the proteasome and autophagy systems1,2. Ribosomes are central targets of this response, as they are responsible for translation and subject to lysosomal turnover during nutrient stress3,4,5. The abundance of ribosomal (r)-proteins (around 6% of the proteome;

The vascular interface of the brain, known as the blood–brain barrier (BBB), is understood to maintain brain function in part via its low transcellular permeability1,2,3. Yet, recent studies have demonstrated that brain ageing is sensitive to circulatory proteins4,5. Thus, it is unclear whether permeability to individually injected exogenous tracers—as is standard in BBB studies—fully represents blood-to-brain

The mechanistic target of rapamycin complex 1 (mTORC1) is a key metabolic hub that controls the cellular response to environmental cues by exerting its kinase activity on multiple substrates1,2,3. However, whether mTORC1 responds to diverse stimuli by differentially phosphorylating specific substrates is poorly understood. Here we show that transcription factor EB (TFEB), a master regulator of lysosomal

The cortex organizes sensory information to enable discrimination and generalization1,2,3,4. As systematic representations of chemical odour space have not yet been described in the olfactory cortex, it remains unclear how odour relationships are encoded to place chemically distinct but similar odours, such as lemon and orange, into perceptual categories, such as citrus5,6,7. Here, by combining chemoinformatics

The measurement of minuscule forces and displacements with ever greater precision is inhibited by the Heisenberg uncertainty principle, which imposes a limit to the precision with which the position of an object can be measured continuously, known as the standard quantum limit1,2,3,4. When light is used as the probe, the standard quantum limit arises from the balance between the uncertainties of the

Ribosomes accurately decode mRNA by proofreading each aminoacyl-tRNA that is delivered by the elongation factor EF-Tu1. To understand the molecular mechanism of this proofreading step it is necessary to visualize GTP-catalysed elongation, which has remained a challenge2,3,4. Here we use time-resolved cryogenic electron microscopy to reveal 33 ribosomal states after the delivery of aminoacyl-tRNA by

Nuclear processes, such as V(D)J recombination, are orchestrated by the three-dimensional organization of chromosomes at multiple levels, including compartments1 and topologically associated domains (TADs)2,3 consisting of chromatin loops4. TADs are formed by chromatin-loop extrusion5,6,7, which depends on the loop-extrusion function of the ring-shaped cohesin complex8,9,10,11,12. Conversely, the cohesin-release

On the 21st of February 2020 a resident of the municipality of Vo’, a small town near Padua, died of pneumonia due to SARS-CoV-2 infection1. This was the first COVID-19 death detected in Italy since the emergence of SARS-CoV-2 in the Chinese city of Wuhan, Hubei province2. In response, the regional authorities imposed the lockdown of the whole municipality for 14 days3. We collected information on

GABA (γ-aminobutyric acid) stimulation of the metabotropic GABAB receptor results in prolonged inhibition of neurotransmission that is central to brain physiology1. GABAB belongs to the Family C of G protein-coupled receptors (GPCRs), which operate as dimers to relay synaptic neurotransmitter signals into a cellular response through the binding and activation of heterotrimeric G proteins2,3. GABAB

The human GABAB receptor—a member of the class C family of G-protein-coupled receptors (GPCRs)—mediates inhibitory neurotransmission and has been implicated in epilepsy, pain and addiction1. A unique GPCR that is known to require heterodimerization for function2,3,4,5,6, the GABAB receptor has two subunits, GABAB1 and GABAB2, that are structurally homologous but perform distinct and complementary functions

Fundamental studies of chemical reactions often consider the molecular dynamics along a reaction coordinate using a calculated or suggested potential energy surface1,2,3,4,5. But fully mapping such dynamics experimentally, by following all nuclear motions in a time-resolved manner—that is, the motions of wavepackets—is challenging and has not yet been realized even for the simple stereotypical bimolecular

Autoimmune thyroid disease is the most common autoimmune disease and is highly heritable1. Here, by using a genome-wide association study of 30,234 cases and 725,172 controls from Iceland and the UK Biobank, we find 99 sequence variants at 93 loci, of which 84 variants are previously unreported2,3,4,5,6,7. A low-frequency (1.36%) intronic variant in FLT3 (rs76428106-C) has the largest effect on risk

Parkinson’s disease is characterized by loss of dopamine neurons in the substantia nigra1. Similar to other major neurodegenerative disorders, there are no disease-modifying treatments for Parkinson’s disease. While most treatment strategies aim to prevent neuronal loss or protect vulnerable neuronal circuits, a potential alternative is to replace lost neurons to reconstruct disrupted circuits2. Here

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13

Cytokines were the first modern immunotherapies to produce durable responses in patients with advanced cancer, but they have only modest efficacy and limited tolerability1,2. In an effort to identify alternative cytokine pathways for immunotherapy, we found that components of the interleukin-18 (IL-18) pathway are upregulated on tumour-infiltrating lymphocytes, suggesting that IL-18 therapy could enhance

Many proteins that bind specific DNA sequences search the genome by combining three-dimensional diffusion with one-dimensional sliding on nonspecific DNA1,2,3,4,5. Here we combine resonance energy transfer and fluorescence correlation measurements to characterize how individual lac repressor (LacI) molecules explore the DNA surface during the one-dimensional phase of target search. To track the rotation

Molecular noise is a natural phenomenon that is inherent to all biological systems1,2. How stochastic processes give rise to the robust outcomes that support tissue homeostasis remains unclear. Here we use single-molecule RNA fluorescent in situ hybridization (smFISH) on mouse stem cells derived from haematopoietic tissue to measure the transcription dynamics of three key genes that encode transcription

Laser additive manufacturing is attractive for the production of complex, three-dimensional parts from metallic powder using a computer-aided design model1,2,3. The approach enables the digital control of the processing parameters and thus the resulting alloy’s microstructure, for example, by using high cooling rates and cyclic re-heating4,5,6,7,8,9,10. We recently showed that this cyclic re-heating

AU Microscopii (AU Mic) is the second closest pre-main-sequence star, at a distance of 9.79 parsecs and with an age of 22 million years1. AU Mic possesses a relatively rare2 and spatially resolved3 edge-on debris disk extending from about 35 to 210 astronomical units from the star4, and with clumps exhibiting non-Keplerian motion5,6,7. Detection of newly formed planets around such a star is challenged

Formation of the body of vertebrate embryos proceeds sequentially by posterior addition of tissues from the tail bud. Cells of the tail bud and the posterior presomitic mesoderm, which control posterior elongation1, exhibit a high level of aerobic glycolysis that is reminiscent of the metabolic status of cancer cells experiencing the Warburg effect2,3. Glycolytic activity downstream of fibroblast growth

Cancers arise through the acquisition of oncogenic mutations and grow by clonal expansion1,2. Here we reveal that most mutagenic DNA lesions are not resolved into a mutated DNA base pair within a single cell cycle. Instead, DNA lesions segregate, unrepaired, into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. We characterize this process

Gratings1 and holograms2 use patterned surfaces to tailor optical signals by diffraction. Despite their long history, variants with remarkable functionalities continue to be developed3,4. Further advances could exploit Fourier optics5, which specifies the surface pattern that generates a desired diffracted output through its Fourier transform. To shape the optical wavefront, the ideal surface profile

Clonally expanded blood cells that contain somatic mutations (clonal haematopoiesis) are commonly acquired with age and increase the risk of blood cancer1,2,3,4,5,6,7,8,9. The blood clones identified so far contain diverse large-scale mosaic chromosomal alterations (deletions, duplications and copy-neutral loss of heterozygosity (CN-LOH)) on all chromosomes1,2,5,6,9, but the sources of selective advantage

Oceanic lithosphere carries volatiles, notably water, into the mantle through subduction at convergent plate boundaries. This subducted water exercises control on the production of magma, earthquakes, formation of continental crust and mineral resources. Identifying different potential fluid sources (sediments, crust and mantle lithosphere) and tracing fluids from their release to the surface has proved

The extent to which the biology of oncogenesis and ageing are shaped by factors that distinguish human populations is unknown. Haematopoietic clones with acquired mutations become common with advancing age and can lead to blood cancers1,2,3,4,5,6,7,8,9,10. Here we describe shared and population-specific patterns of genomic mutations and clonal selection in haematopoietic cells on the basis of 33,250 autosomal

Decrease in processing speed due to increased resistance and capacitance delay is a major obstacle for the down-scaling of electronics1,2,3. Minimizing the dimensions of interconnects (metal wires that connect different electronic components on a chip) is crucial for the miniaturization of devices. Interconnects are isolated from each other by non-conducting (dielectric) layers. So far, research has

Observation of the neutrinoless double β decay is the only practical way to establish that neutrinos are their own antiparticles1. Because of the small masses of neutrinos, the lifetime of neutrinoless double β decay is expected to be at least ten orders of magnitude greater than the typical lifetimes of natural radioactive chains, which can mimic the experimental signature of neutrinoless double β

During the COVID-19 pandemic, SARS-CoV-2 infected millions of people and claimed hundreds of thousands of lives. Virus entry into cells depends on the receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S). Although there is no vaccine, it is likely that antibodies will be essential for protection. However, little is known about the human antibody response to SARS-CoV-21–5. Here we report

Optical frequency combs have a wide range of applications in science and technology1. An important development for miniature and integrated comb systems is the formation of dissipative Kerr solitons in coherently pumped high-quality-factor optical microresonators2,3,4,5,6,7,8,9. Such soliton microcombs10 have been applied to spectroscopy11,12,13, the search for exoplanets14,15, optical frequency synthesis16

Calcified eggshells protect developing embryos against environmental stress and contribute to reproductive success1. As modern crocodilians and birds lay hard-shelled eggs, this eggshell type has been inferred for non-avian dinosaurs. Known dinosaur eggshells are characterized by an innermost membrane, an overlying protein matrix containing calcite, and an outermost waxy cuticle2,3,4,5,6,7. The calcitic