Around 40% of the US population and 1 in 6 individuals worldwide have obesity, with the incidence surging globally1,2. Various dietary interventions, including carbohydrate, fat and, more recently, amino acid restriction, have been explored to combat this epidemic3-6. Here we investigated the impact of removing individual amino acids on the weight profiles of mice. We show that conditional cysteine restriction resulted in the most substantial weight loss when compared to essential amino acid restriction, amounting to 30% within 1 week, which was readily reversed. We found that cysteine deficiency activated the integrated stress response and oxidative stress response, which amplify each other, leading to the induction of GDF15 and FGF21, partly explaining the phenotype7-9. Notably, we observed lower levels of tissue coenzyme A (CoA), which has been considered to be extremely stable10, resulting in reduced mitochondrial functionality and metabolic rewiring. This results in energetically inefficient anaerobic glycolysis and defective tricarboxylic acid cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen-rich compounds and amino acids. In summary, our investigation reveals that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism and stress signalling compared with other amino acid restrictions. These findings suggest strategies for addressing a range of metabolic diseases and the growing obesity crisis.

Skeletal editing comprises the structural reorganization of compounds. Such editing can be achieved through atom swapping, atom insertion, atom deletion or reorganization of the compound's backbone structure1,2. Conducted at a late stage in drug development campaigns, skeletal editing enables diversification of an existing pharmacophore, enhancing the efficiency of drug development. Instead of constructing a heteroarene classically from basic building blocks, structural variants are readily accessible directly starting from a lead compound or approved pharmacophore. Here we present C to N atom swapping in indoles at the C2 position to give indazoles through oxidative cleavage of the indole heteroarene core and subsequent ring closure. Reactions proceed through ring-opened oximes as intermediates. These ring deconstructed intermediates can also be diverted into benzimidazoles resulting in an overall C to N atom swapping with concomitant skeletal reorganization. The same structural diverting strategies are equally well applicable to benzofurans leading to either benzisoxazoles or benzoxazoles. The compound classes obtained through these methods-indazoles3,4, benzisoxazoles5, benzimidazoles6,7 and benzoxazoles8-are biologically relevant moieties found as substructures in natural products and pharmaceuticals. The procedures introduced substantially enlarge the methods portfolio in the emerging field of skeletal editing.

Quasars, powered by gas accretion onto supermassive black holes1,2, rank among the most energetic objects in the Universe3,4. Although they are thought to be ignited by galaxy mergers5-11 and affect the surrounding gas12-15, observational constraints on both processes remain scarce16-18. Here we describe a major merging system at redshift z ≈ 2.7 and demonstrate that radiation from the quasar in one galaxy directly alters the gas properties in the other galaxy. Our findings reveal that the galaxies, with centroids separated by only a few kiloparsecs and approaching each other at a speed of approximately 550 km s-1, are massive, are forming stars and contain a substantial molecular mass. Yet, dusty molecular gas seen in absorption against the quasar nucleus is highly excited and confined within cloudlets with densities of approximately 105 to 106 cm-3 and sizes of less than 0.02 pc, several orders of magnitude more compact than those observed in intervening (non-quasar) environments. This is also approximately 105 times smaller than currently resolvable through molecular-line emission at high redshifts. We infer that, wherever it is exposed to the quasar radiation, the molecular gas is disrupted, leaving behind surviving dense clouds too small to give birth to new stars. Our results not only underscore the role of major galaxy mergers in triggering quasar activity but also reveal localized negative feedback as a profound alteration of the internal gas structure, which probably hampers star formation.

Carbon has a central role in biology and organic chemistry, and its solid allotropes provide the basis of much of our modern technology1. However, the liquid form of carbon remains nearly uncharted2, and the structure of liquid carbon and most of its physical properties are essentially unknown3. But liquid carbon is relevant for modelling planetary interiors4,5 and the atmospheres of white dwarfs6, as an intermediate state for the synthesis of advanced carbon materials7,8, inertial confinement fusion implosions9, hypervelocity impact events on carbon materials10 and our general understanding of structured fluids at extreme conditions11. Here we present a precise structure measurement of liquid carbon at pressures of around 1 million atmospheres obtained by in situ X-ray diffraction at an X-ray free-electron laser. Our results show a complex fluid with transient bonding and approximately four nearest neighbours on average, in agreement with quantum molecular dynamics simulations. The obtained data substantiate the understanding of the liquid state of one of the most abundant elements in the universe and can test models of the melting line. The demonstrated experimental abilities open the path to performing similar studies of the structure of liquids composed of light elements at extreme conditions.

The decline in malaria deaths has recently stalled owing to several factors, including the widespread resistance of Anopheles vectors to the insecticides used in long-lasting insecticide-treated nets (LLINs)1,2. One way to mitigate insecticide resistance is to directly kill parasites during their mosquito-stage of development by incorporating antiparasitic compounds into LLINs. This strategy can prevent onward parasite transmission even when insecticides lose efficacy3,4. Here, we performed an in vivo screen of compounds against the mosquito stages of Plasmodium falciparum development. Of the 81 compounds tested, which spanned 28 distinct modes of action, 22 were active against early parasite stages in the mosquito midgut lumen, which in turn prevented establishment of infection. Medicinal chemistry was then used to improve antiparasitic activity of the top hits from the screen. We generated several endochin-like quinolones (ELQs) that inhibited the P. falciparum cytochrome bc1 complex (CytB). Two lead compounds that targeted separate sites in CytB (Qo and Qi) showed potent, long-lasting and stable activity when incorporated and/or extruded into bed net-like polyethylene films. ELQ activity was fully preserved in insecticide-resistant mosquitoes, and parasites resistant to these compounds had impaired development at the mosquito stage. These data demonstrate the promise of incorporating ELQ compounds into LLINs to counteract insecticide resistance and to reduce malaria transmission.

Current approaches used to track stem cell clones through differentiation require genetic engineering1,2 or rely on sparse somatic DNA variants3,4, which limits their wide application. Here we discover that DNA methylation of a subset of CpG sites reflects cellular differentiation, whereas another subset undergoes stochastic epimutations and can serve as digital barcodes of clonal identity. We demonstrate that targeted single-cell profiling of DNA methylation5 at single-CpG resolution can accurately extract both layers of information. To that end, we develop EPI-Clone, a method for transgene-free lineage tracing at scale. Applied to mouse and human haematopoiesis, we capture hundreds of clonal differentiation trajectories across tens of individuals and 230,358 single cells. In mouse ageing, we demonstrate that myeloid bias and low output of old haematopoietic stem cells6 are restricted to a small number of expanded clones, whereas many functionally young-like clones persist in old age. In human ageing, clones with and without known driver mutations of clonal haematopoieis7 are part of a spectrum of age-related clonal expansions that display similar lineage biases. EPI-Clone enables accurate and transgene-free single-cell lineage tracing on hematopoietic cell state landscapes at scale.

Decades of research have demonstrated that recovery from serious neurological injury will require synergistic therapeutic approaches. Rewiring spared neural circuits after injury is a long-standing goal of neurorehabilitation1,2. We hypothesized that combining intensive, progressive, task-focused training with real-time closed-loop vagus nerve stimulation (CLV) to enhance synaptic plasticity3 could increase strength, expand range of motion and improve hand function in people with chronic, incomplete cervical spinal cord injury. Here we report the results from a prospective, double-blinded, sham-controlled, randomized study combining gamified physical therapy using force and motion sensors to deliver sham or active CLV (ClinicalTrials.gov identifier NCT04288245). After 12 weeks of therapy composed of a miniaturized implant selectively activating the vagus nerve on successful movements, 19 people exhibited a significant beneficial effect on arm and hand strength and the ability to perform activities of daily living. CLV represents a promising therapeutic avenue for people with chronic, incomplete cervical spinal cord injury.

The isotopic composition of lavas associated with mantle plumes has previously been interpreted in the light of core-mantle interaction, suggesting that mantle plumes may transport core material to Earth's surface1-5. However, a definitive fingerprint of Earth's core in the mantle remains unconfirmed. Precious metals, such as ruthenium (Ru), are highly concentrated in the metallic core but extremely depleted in the silicate mantle. Recently discovered mass-independent Ru isotope variations (ε100Ru) in ancient rocks show that the Ru isotope composition of accreted material changed during later stages of Earth's growth6, indicating that the core and mantle must have different Ru isotope compositions. This illustrates the potential of Ru isotopes as a new tracer for core-mantle interaction. Here we report Ru isotope anomalies for ocean island basalts. Basalts from Hawaii have higher ε100Ru than the ambient mantle. Combined with unradiogenic tungsten (W) isotope ratios, this is diagnostic of a core contribution to their mantle sources. The combined Ru and W isotope systematics of Hawaiian basalts are best explained by simple core entrainment but addition of core-derived oxide minerals at the core-mantle boundary is a possibility.

Close-in companion stars are expected to adversely influence the formation and orbital stability of circumstellar (S-type) planets by tidally truncating protoplanetary discs1-4, impeding mutual accretion of planetesimals5-8 and narrowing dynamically stable regions9. This explains the observed dearth of S-type planets in tight binary star systems10-13. ν Octantis, whose stellar components have a mean separation of 2.6 AU, has long been suspected of hosting a circum-primary planet in a retrograde and exceptionally wide orbit that resides midway between the stars14-20. Strong theoretical grounds against its formation and the absence of observational precedents, however, have challenged the reality of the planet. Here we present new radial velocity measurements that consolidate the planet hypothesis. Stable fits to all radial velocity data require the planetary orbit to be retrograde and practically coplanar. We also report the critical discovery from adaptive optics imaging that the companion star is a white dwarf. Our exploration of credible primordial binary orbital settings shows that the minimum separation between the stars was 1.3 AU initially, which overlaps the current planetary orbit and makes any scenarios in which the circum-primary planetary orbit formed coevally with the young stars hardly conceivable. The retrograde planet must have originated from a circumbinary orbit or a second-generation protoplanetary disc, showing the role of binary stellar evolution in the formation and evolution of planetary systems.

Bar structures are present in about half of local disk galaxies1 and play pivotal roles in secular galaxy evolution. Bars impose a non-axisymmetric perturbation on the rotating disk and transport gas inwards to feed the central starburst and, possibly, the activity of the nuclear supermassive black hole2. They are believed to be long-lived structures3,4 and are now identified at redshift z > 2 (refs. 5,6). However, little is known about the onset and effects of bars in the early cosmic epoch because the spectroscopy of distant bars at sufficient resolution is prohibitively expensive. Here we report on a kinematic study of a galactic bar at redshift 2.467, 2.6 billion years after the Big Bang. We observed the carbon monoxide and atomic carbon emission lines of the dusty star-forming galaxy J0107a and found the bar of J0107a has gas distribution and motion in a pattern identical to local bars7-9. At the same time, the bar drives large-scale non-circular motions that dominate over disk rotation, funnelling molecular gas into its centre at a rate of approximately 600 solar masses per year. Our results show that bar-driven dynamical processes and secular evolution were already at play 11.1 billion years ago, powering active star formation amid the gas-rich and far-infrared luminous growth phase in a massive disk galaxy.

One-carbon homologs are structurally-related and functionally-identical organic molecules, whose chain-lengths differ by a single methylene (-CH2-) unit1. Across many classes of molecule-including pharmaceutical agents, natural products, agrochemicals, fragrances and petroleum products-the physicochemical characteristics displayed by members of a homologous series subtly differ from one compound to another, which can impart remarkable differences to their function2. The efficient generation of homologs is, therefore, an important strategy in molecular discovery programs3,4. Despite the availability of homologation strategies for several functional groups5,6, direct and general methods for one-carbon chain extension in alkenes remain an unmet synthetic need7,8. We report a catalytic one-carbon homologation process that is effective for many classes of alkene in simple and complex molecules. By leveraging the intrinsic reactivity of a novel multifaceted allyl-sulfone reagent, a streamlined one-pot process, involving cross-metathesis and a fragmentation/retro-ene cascade, formally inserts a single methylene unit to the alkene chain. Amongst applications of this process to several structurally and functionally complex molecules, we demonstrate how this practical transformation generates previously unexplored homologs of Cyclosporine-A9. These homologs show modulated pharmacological and biological properties and could provide promising leads as cyclophilin inhibitors, a target that has great potential in many disease areas10.

Five years before the 2022 multi-country mpox outbreak, Nigeria and Cameroon reported their first cases in over three decades.1,2 While Nigeria's outbreak is recognized as an ongoing human epidemic, the drivers of Cameroon's resurgence remain unclear.3,4 The rate of zoonoses remains uncertain in both countries, and gaps in genomic data obscure the timing, zoonotic and geographic origin of mpox virus (MPXV) emergence in humans. To address these uncertainties, we generated 118 MPXV genomes from Nigeria and Cameroon from 2018-2023. Our findings show that, in contrast to Nigeria, cases in Cameroon are the result of repeated zoonoses, with two distinct zoonotic lineages circulating across the Nigeria-Cameroon border. Our findings suggest that shared animal populations in the cross-border forest ecosystems drive virus emergence and spread. Accordingly, we identify the closest zoonotic outgroup to the Nigerian human epidemic lineage (hMPXV-1) in a southern Nigerian border state. We estimate that the shared ancestor of the zoonotic outgroup and hMPXV-1 circulated in animals in southern Nigeria in late 2013. We estimate that hMPXV-1 emerged in humans in August 2014 in the southern Rivers State and circulated undetected for three years. Rivers State acted as the main source of viral spread across the human epidemic. Our study sheds light on MPXV's recent establishment in the human population and highlights the risk of persistent zoonotic emergence of MPXV in the complex border regions of Cameroon and Nigeria.

Aside from movement initiation and control, the primary motor cortex (M1) has been implicated in pain modulation mechanisms. A large body of clinical data has demonstrated that stimulation and behavioral activation of M1 result in clinically important pain relief in patients with specific chronic pain syndromes. However, despite its clinical importance, the full range of circuits for motor cortex-related analgesia (MCRA) remains an enigma. This review draws on insights from experimental and clinical data and provides an overview of the neurobiological mechanisms of MCRA, with particular emphasis on its neurocircuitry basis. Based on structural and functional connections of the M1 within the pain connectome, neural circuits for MCRA are discussed at different levels of the neuroaxis, specifically, the endogenous pain modulation system, the thalamus, the extrapyramidal system, non-noxious somatosensory systems, and cortico-limbic pain signatures. We believe that novel insights from this review will expedite our understanding of M1-induced pain modulation and offer hope for successful mechanism-based refinements of this interventional approach in chronic pain management.

Ku70 and Ku80 form Ku, a ring-shaped complex that initiates the non-homologous end-joining (NHEJ) DNA repair pathway.1 Ku binds to double-stranded DNA (dsDNA) ends and recruits other NHEJ factors (e.g., LIG4, DNA-PKcs). While Ku can bind to double-stranded RNA (dsRNA)2 and trap mutated-DNA-PKcs on ribosomal RNA (rRNA),3,4 the physiological role on Ku-RNA interaction in otherwise wildtype cells remains unclear. Intriguingly, Ku is dispensable for murine development5,6 but essential in human cells.7 Despite similar genome sizes, human cells express ~100-fold more Ku than mouse cells, implying functions beyond NHEJ - possibly through a dose-sensitive interaction with dsRNA, which binds Ku 10~100 times weaker than dsDNA.2,8 Investigating Ku's essentiality in human cells, we found that Ku-depletion - unlike LIG4 - induces profound interferon (IFN) and NF-kB signaling via dsRNA-sensor MDA5/RIG-I and MAVS. Prolonged Ku-degradation further activates other dsRNA sensors, especially PKR (suppressing translation) and OAS/RNaseL (cleaving rRNA), leading to growth arrest and cell death. MAVS, RIG-I, or MDA5 knockouts suppressed IFN signaling and, like PKR knockouts, all partially rescued Ku-depleted human cells. Ku-irCLIP analyses revealed Ku binding to diverse dsRNA, predominantly stem-loops in primate-specific antisense Alu elements9 in introns and 3'-UTRs. Ku expression rose sharply in higher primates, correlating tightly with Alu-expansion (r = 0.94/0.95). Thus, Ku plays a vital role in accommodating Alu-expansion in primates by limiting dsRNA-induced innate immunity, explaining both Ku's elevated expression and its essentiality in human cells.

In the future, monsoon rainfall over densely populated South Asia is expected to increase, even as monsoon circulation weakens1-3. By contrast, past warm intervals were marked by both increased rainfall and a strengthening of monsoon circulation4-6, posing a challenge to understanding the response of the South Asian summer monsoon to warming. Here we show consistent South Asian summer monsoon changes in the mid-Pliocene, Last Interglacial, mid-Holocene and future scenarios, characterized by an overall increase in monsoon rainfall, a weakening of the monsoon trough-like circulation over the Bay of Bengal and a strengthening of the monsoon circulation over the northern Arabian Sea, as revealed by a compilation of proxy records and climate simulations. Increased monsoon rainfall is thermodynamically dominated by atmospheric moisture following the rich-get-richer paradigm, and dynamically dominated by the monsoon circulation driven by the enhanced land warming in subtropical western Eurasia and northern Africa. The coherent response of monsoon dynamics across warm climates reconciles past strengthening with future weakening, reinforcing confidence in future projections. Further prediction of South Asian summer monsoon circulation and rainfall by physics-based regression models using past information agrees well with climate model projections, with spatial correlation coefficients of approximately 0.8 and 0.7 under the high-emissions scenario. These findings underscore the promising potential of past analogues, bolstered by palaeoclimate reconstruction, in improving future South Asian summer monsoon projections.

Hilbert space dimension is a key resource for quantum information processing1,2. Not only is a large overall Hilbert space an essential requirement for quantum error correction, but a large local Hilbert space can also be advantageous for realizing gates and algorithms more efficiently3-7. As a result, there has been considerable experimental effort in recent years to develop quantum computing platforms using qudits (d-dimensional quantum systems with d > 2) as the fundamental unit of quantum information8-19. Just as with qubits, quantum error correction of these qudits will be necessary in the long run, but so far, error correction of logical qudits has not been demonstrated experimentally. Here we report the experimental realization of an error-corrected logical qutrit (d = 3) and ququart (d = 4), which was achieved with the Gottesman-Kitaev-Preskill bosonic code20. Using a reinforcement learning agent21,22, we optimized the Gottesman-Kitaev-Preskill qutrit (ququart) as a ternary (quaternary) quantum memory and achieved beyond break-even error correction with a gain of 1.82 ± 0.03 (1.87 ± 0.03). This work represents a novel way of leveraging the large Hilbert space of a harmonic oscillator to realize hardware-efficient quantum error correction.

When two massive objects (black holes, neutron stars or stars) in our universe fly past each other, their gravitational interactions deflect their trajectories1,2. The gravitational waves emitted in the related bound-orbit system-the binary inspiral-are now routinely detected by gravitational-wave observatories3. Theoretical physics needs to provide high-precision templates to make use of unprecedented sensitivity and precision of the data from upcoming gravitational-wave observatories4. Motivated by this challenge, several analytical and numerical techniques have been developed to approximately solve this gravitational two-body problem. Although numerical relativity is accurate5-7, it is too time-consuming to rapidly produce large numbers of gravitational-wave templates. For this, approximate analytical results are also required8-15. Here we report on a new, highest-precision analytical result for the scattering angle, radiated energy and recoil of a black hole or neutron star scattering encounter at the fifth order in Newton's gravitational coupling G, assuming a hierarchy in the two masses. This is achieved by modifying state-of-the-art techniques for the scattering of elementary particles in colliders to this classical physics problem in our universe. Our results show that mathematical functions related to Calabi-Yau (CY) manifolds, 2n-dimensional generalizations of tori, appear in the solution to the radiated energy in these scatterings. We anticipate that our analytical results will allow the development of a new generation of gravitational-wave models, for which the transition to the bound-state problem through analytic continuation and strong-field resummation will need to be performed.

Debris disks are exoplanetary systems that contain planets, minor bodies (asteroids, Kuiper belt objects, comets and so on) and micrometre-sized debris dust1. Because water ice is the most common frozen volatile, it plays an essential role in the formation of planets2,3 and minor bodies. Although water ice has been commonly found in Kuiper belt objects and comets in the Solar System4, no definitive evidence for water ice in debris disks has been obtained to date1. Here we report the discovery of water ice in the HD 181327 debris disk using the near-infrared spectrograph onboard the James Webb Space Telescope. We detected the solid-state broad absorption feature of water ice at 3 µm including a distinct Fresnel peak at 3.1 µm, which is indicative of large, crystalline water-ice particles. Gradients in the water-ice feature as a function of stellocentric distance reveal a dynamic environment in which water ice is destroyed and replenished. We estimated the water-ice mass fractions as ranging from 0.1% at approximately 85 au to 21% at approximately 113 au, indicating the presence of a water-ice reservoir in the HD 181327 disk beyond the snow line. The icy bodies that release water ice in HD 181327 are probably the extra-solar counterparts of water-ice-rich Kuiper belt objects in our Solar System.

High-capacity lithium-ion batteries (LIBs) play a critical role as power sources across diverse applications, including portable electronics, electric vehicles (EVs) and renewable-energy-storage systems1. However, there is growing concern about the safety of integrated LIB systems, with reports of up to 9,486 incidents between 2020 and 2024 (ref. 2). To ensure the safe application of commercial LIBs, it is essential to capture internal signals that enable early failure diagnosis and warning. Monitoring non-uniform temperature and strain distributions within the jelly-roll structures of the battery provides a promising approach to achieving this goal3,4. Here we propose a miniaturized and low-power-consumption system capable of accurate sensing and wireless transmission of internal temperature and strain signals inside LIBs, with negligible influence on its performance. The acquisition of internal temperature signals and the area ratio between initial internal-short-circuited regions and battery electrodes enables quantitative analysis of thermal fusing and thermal runaway phenomena, leading to the evaluation of the intensity of battery thermal runaway and recognition of thermal abuse behaviours. This work provides a foundation for designing next-generation smart LIBs with safety warning and failure positioning capabilities.

Photonic double-zero-index media, distinguished by concurrently zero-valued permittivity and permeability, exhibit extraordinary properties not found in nature1-8. Notably, the notion of zero index can be substantially expanded by generalizing the constitutive parameters from null scalars to non-reciprocal tensors with non-zero matrix elements but zero determinants9,10. Here we experimentally realize this class of gyromagnetic double-zero-index metamaterials possessing both double-zero-index features and non-reciprocal hallmarks. As an intrinsic property, this metamaterial always emerges at a spin-1/2 Dirac point of a topological phase transition. We discover and demonstrate that a spatiotemporal reflection vortex singularity is always anchored to the Dirac point of the metamaterial, with the vortex charge being determined by the topological invariant leap across the phase transition. This establishes a unique bulk-spatiotemporal vortex correspondence that extends the protected boundary effects into the time domain and characterizes topological phase-transition points, setting it apart from any pre-existing bulk-boundary correspondence. Based on this correspondence, we propose and experimentally demonstrate a mechanism to deterministically generate optical spatiotemporal vortex pulses11,12 with firmly fixed central frequency and momentum, hence showing ultrarobustness. Our findings uncover connections between zero-refractive-index photonics, topological photonics and singular optics, which might enable the manipulation of space-time topological light fields using the inherent topology of extreme-parameter metamaterials.