Amino acid substitutions may substantially alter protein stability and function. However, the contribution of substitutions that arise from alternate translation (deviations from the genetic code) is unknown. Here to add...Amino acid substitutions may substantially alter protein stability and function. However, the contribution of substitutions that arise from alternate translation (deviations from the genetic code) is unknown. Here to address this issue, we analysed deep proteomic, transcriptomic and genomic data from more than 1,000 human samples, including 6 cancer types and 26 healthy human tissues. This global analysis identified 60,803 fragmentation spectra corresponding to 8,746 unique substitutions in proteins derived from 1,767 genes, including 1,955 confidently localized sites. Some substitutions were shared across samples, whereas others exhibited strong tissue-type and cancer specificity. Notably, products of alternate translation were more abundant than their canonical counterparts for hundreds of proteins, which suggests that there is sense-codon recoding. Recoded proteins included transcription factors, proteases, signalling proteins and proteins associated with neurodegeneration. Mechanisms that contribute to substitution abundance included protein stability, codon frequency, codon-anticodon mismatches and RNA modifications. We also characterized how alternatively translated proteoform ratios vary across protein domains, tissue types and cancers. These ratios were positively associated with intrinsically disordered regions and genetic polymorphisms in the gnomAD database, although the polymorphisms could not account for the substitutions. The sequence, relative abundance and the tissue specificity of alternatively translated proteins were conserved between humans and mice. These results demonstrate the contribution of alternate translation to the diversification of mammalian proteomes and its association with protein stability, tissue-specific proteomes and disease.
Medical artificial intelligence (AI) models hold the promise to improve global access to high-quality diagnostics. However, the training data underlying these models often contain sensitive patient information that may b...Medical artificial intelligence (AI) models hold the promise to improve global access to high-quality diagnostics. However, the training data underlying these models often contain sensitive patient information that may be exposed through privacy attacks. Previous research has primarily quantified the success of these attacks in aggregate, across all records in a dataset. Thus, the privacy risk faced by individual patients, who often contribute multiple similar records to a training dataset, is poorly understood. Here we present one of the first patient-level privacy audits of AI models for medical diagnostic applications. We focus on membership inference attacks (MIAs), which seek to determine whether the data of a given individual were used to train a model. Across a diverse range of medical datasets, we show that MIAs can achieve near-perfect success rates for individual patients, even when the aggregate performance does not substantially deviate from random guessing. We further find that the number of patients with high attack success increases substantially with model capacity, and that underrepresented groups-stratified by disease status, self-reported race, insurance, sex or imaging protocol-face disproportionately high attack success. Together, our findings show that aggregate privacy metrics can severely underestimate individual privacy risk. Whether the disparate risk profiles we observe extend to attacks beyond MIAs remains an open question, motivating the further development of risk assessment and mitigation techniques that cater to all data-contributing patients.
The horizon of a black hole, the 'surface of no return', is characterized by its rotation frequency Ω and surface gravity κ. A striking signature is that any infalling object appears to orbit at Ω owing to frame dragging...The horizon of a black hole, the 'surface of no return', is characterized by its rotation frequency Ω and surface gravity κ. A striking signature is that any infalling object appears to orbit at Ω owing to frame dragging, while its emitted signals decay exponentially at a rate set by κ as a consequence of gravitational redshift. Recent theoretical work predicts that gravitational waves from binary black-hole mergers carry direct imprints of the properties of the merger remnant in the form of a 'direct wave'. This gravitational-wave component oscillates near 2Ω, reflecting the horizon's frame dragging, and decays at an increasing rate characterized by κ, with additional screening from the black hole's spacetime. Here we report observational evidence of a direct wave in GW250114, with a 90% credible matched-filter signal-to-noise ratio of ( ) in the LIGO Hanford (Livingston) detector. The measured properties are in full agreement with theoretical predictions for a Kerr black hole. These findings establish an observational channel to directly measure frame-dragging effects in black-hole ergospheres and explore (near-)horizon physics in dynamical, strong-gravity regimes.
Seagrass ecosystems underpin coastal biodiversity and provide vital ecosystem services, including shoreline protection, food security and climate mitigation. Despite growing recognition as a nature-based climate solution...Seagrass ecosystems underpin coastal biodiversity and provide vital ecosystem services, including shoreline protection, food security and climate mitigation. Despite growing recognition as a nature-based climate solution, seagrasses are among the least mapped and most poorly understood vegetated coastal ecosystems. Here we present, to our knowledge, the first global 10-m spatial resolution maps and change analysis of seagrass extent in clear, shallow coastal waters, derived from 4.75 million Sentinel-2 MSI satellite images for two periods (2019-2020 and 2023-2024). Using a deep-learning classifier trained on curated reference data, we identified 148,506 km of seagrass globally, including 5,961 km of intertidal and 142,545 km of subtidal areas. Sixty-nine per cent of global seagrass extent is concentrated in The Bahamas, Cuba, the USA, Australia and Indonesia, yet only 21% of seagrass areas are located within marine-protected areas. Over the 4 years of the study, 5,969 km (4%) of seagrass was lost, and an additional 6,221 km (4.2%) was degraded from dense to sparse cover in tropical regions. Our findings identify seagrass meadow hotspots and vulnerable regions to inform conservation and climate policy.
Galaxy redshift surveys map the cosmic web and provide a key observational test of whether the Universe becomes statistically homogeneous and isotropic on sufficiently large scales, as assumed by the cosmological princip...Galaxy redshift surveys map the cosmic web and provide a key observational test of whether the Universe becomes statistically homogeneous and isotropic on sufficiently large scales, as assumed by the cosmological principle underpinning the standard cosmological model. In this framework, beyond the nonlinear regime of structure formation, inhomogeneous and anisotropic features are expected to fade rapidly, reflecting the near-isotropic primordial density field and its subsequent gravitational evolution. Although supported by the small amplitude of cosmic microwave background anisotropies, this view is increasingly challenged by the complex network of large-scale structures and voids in the galaxy distribution, as well as by independent probes reporting possible large-scale deviations from statistical homogeneity and isotropy. Here we show that the galaxy distribution exhibits persistent anisotropic structures extending to scales on the order of one gigaparsec. Using the Angular Distribution of Pairwise Distances (ADPD), a parameter-free statistic that measures directional correlations, we detect anisotropy signals exceeding those in isotropic controls and geometry-matched ΛCDM mock catalogues with conservative significance greater than 3σ. These results provide direct evidence that directional coherence persists to larger scales than predicted in the standard framework, challenging the assumption of large-scale isotropy. They call for a reassessment of how homogeneity and isotropy are realized in the observed Universe and motivate new tests of cosmological models based on directional statistics.
Gordzevich R, Xu M, Wang W
… +12 more, Cook MA, Hackenberger D, Deisinger JP, Tu MM, Carfrae LA, George M, Rachwalski K, Koteva K, Sychantha D, Wei A, Wright GD, Brown ED
Natural products remain a major source of antibiotics, but discovery efforts have traditionally treated biosynthetic gene clusters as sources of individual bioactive molecules. Increasing evidence has suggested that micr...Natural products remain a major source of antibiotics, but discovery efforts have traditionally treated biosynthetic gene clusters as sources of individual bioactive molecules. Increasing evidence has suggested that microorganisms can instead encode coordinated multi-metabolite systems, yet the genetic architectures and biological logic of such systems remain poorly understood. Here we show that Streptomyces spp. encode a highly conserved biosynthetic megacluster that produces four structurally distinct natural product families-stravidins, acidomycin, dapamycins, and 2-methyl-7-keto-8-aminopelargonic acid (α-Me-KAPA)-alongside the biotin-binding protein streptavidin. These components converge on bacterial biotin metabolism through complementary mechanisms, including enzyme inhibition, prodrug activation, cofactor mimicry and biotin sequestration. The encoded metabolites are co-produced and act synergistically across Gram-negative and mycobacterial species, with stravidin S2 and α-Me-KAPA showing enhanced efficacy in combination in a mouse model of multidrug-resistant Escherichia coli infection. This megacluster reveals a genetically encoded chemical arsenal that functions as a naturally evolved combination therapy against a conserved metabolic pathway. More broadly, our findings suggest that higher-order biosynthetic architectures may represent an overlooked reservoir of antibiotic mechanisms and support a shift from discovering isolated natural products to reconstructing native synergistic systems.
Digital cameras and displays use picture elements (pixels) that perform a single function: detecting or emitting light intensity. To exploit the full information content of electromagnetic waves, more advanced elements a...Digital cameras and displays use picture elements (pixels) that perform a single function: detecting or emitting light intensity. To exploit the full information content of electromagnetic waves, more advanced elements are required. This has driven the development of multifunctional components that, for example, simultaneously detect and emit intensity or extract intensity and spectral information. However, no pixel exists that both senses and generates optical wavefronts with full control over amplitude, phase and polarization, limiting bidirectional control and feedback of sophisticated light fields. Here we present a route to such pixels by demonstrating a versatile platform of miniaturized diffractive elements based on Fourier optics. We use plasmonic surface waves, which propagate coherently and efficiently across metallic surfaces. When these plasmons are launched towards wavy microstructures designed with simple Fourier analysis, arbitrary and background-free optical wavefronts are generated. Conversely, incoming light can be sensed, and its amplitude, phase and polarization can be fully characterized. By combining or superposing several such components, we create multifunctional 'Fourier pixels' that provide compact and accurate control over the optical field. Our approach, which we extend to photonic waveguide modes, establishes a scalable, universal architecture for vectorially programmable pixels with applications in adaptive optics, holographic displays, optical communication and quantum information processing.
Kahsai AW, Pakharukova N, Kwon HY
… +32 more, Shah KS, Del Real CT, Shreiber BN, Liang-Lin JG, Shim PJ, Lee MA, Ngo VA, Schwalb AM, Pham U, Chundi A, Jiang H, Flores-Espinoza E, Liu S, Nibley PC, Bassford DK, Hahn H, Kunzle CA, Thomas BN, Kim J, Zhou Y, Wang J, Zhang X, Smith JS, Rein LAM, Thomsen ARB, Shenoy SK, Rajagopal S, Shi L, Ahn S, Rockman HA, Masoudi A, Lefkowitz RJ
β-Arrestins are multifunctional regulators of G-protein-coupled receptor (GPCR) signalling and orchestrate diverse downstream signalling events and physiological responses across the GPCR superfamily. Although GPCR pharm...β-Arrestins are multifunctional regulators of G-protein-coupled receptor (GPCR) signalling and orchestrate diverse downstream signalling events and physiological responses across the GPCR superfamily. Although GPCR pharmacology has advanced to target orthosteric and allosteric sites, as well as G proteins and GPCR kinases, direct chemical tools to modulate β-arrestin activities have remained conspicuously absent. Here we report the identification of small-molecule inhibitors that selectively target β-arrestins and delineate their mechanism of action through integrated pharmacological, biochemical, biophysical and structural analyses. These inhibitors disrupt β-arrestin engagement with agonist-activated GPCRs, impairing desensitization, internalization and β-arrestin-dependent physiological functions while sparing G protein-receptor coupling. Cryo-electron microscopy, molecular dynamics simulations and structure-guided mutagenesis reveal that one modulator, Cmpd-5, engages a pocket within the central crest of β-arrestin1 formed by the middle, C and lariat loops, a critical receptor-binding interface, stabilizing a distinct conformation that is incompatible with full β-arrestin-receptor engagement. Together, these findings establish a mechanistic framework for β-arrestin modulation, reveal a novel allosteric site for structure-based drug design, and open new avenues for transducer-targeted, pathway-specific GPCR therapeutic agents.
Archaeological, osteological and genetic evidence suggests that Neanderthals lived in small groups; however, less is known about whether these groups were part of isolated communities or belonged to larger, well-connecte...Archaeological, osteological and genetic evidence suggests that Neanderthals lived in small groups; however, less is known about whether these groups were part of isolated communities or belonged to larger, well-connected populations. The dense concentration of broadly contemporaneous Neanderthal sites in the Meuse Basin, Belgium, provides a rare opportunity to study regional populations at high resolution. Here we generated genetic data from 27 Neanderthals who lived less than approximately 52,500 years ago from ten archaeological sites in Belgium and France, including a high-coverage genome from a 45,000-year-old individual from Goyet, Belgium. We show that most of these individuals are more closely related to one another than to other contemporaneous late Neanderthals in Europe. Further, some of these individuals carry DNA from a Neanderthal lineage predating the split of late Neanderthals. Although these Neanderthals overlapped temporally with early modern humans in northwestern Europe from around 47,000 years ago, we find no evidence of recent gene flow from modern humans. They also do not show the genetic signatures of mating among close relatives found in Altai Neanderthals, suggesting that they lived in larger or better-connected groups. Moreover, genetic load did not accumulate over time, arguing against progressive genetic deterioration as a driver of Neanderthal extinction.
Optical refrigeration, or laser cooling of solids, offers a cryogen-free route to temperature control for quantum and electronic systems. Existing progress relies on a phonon-assisted up-conversion photoluminescence appr...Optical refrigeration, or laser cooling of solids, offers a cryogen-free route to temperature control for quantum and electronic systems. Existing progress relies on a phonon-assisted up-conversion photoluminescence approach, which remains constrained by stringent material and excitation requirements. Here we demonstrate a distinct route, interfacial-charge-transfer-driven optical cooling, in two-dimensional semiconductor heterostructures. Photo-excited carriers in WSe cross a type-II junction into MoSe or WS, extracting lattice energy nonradiatively-through a phonon-assisted interfacial charge transfer process. Raman and photoluminescence measurements show prominent low-temperature signatures in the WSe layer, with transient absorption spectroscopy identifying a phonon-assisted, barrier-activated interlayer charge transfer. Molecular dynamics simulations show a prominent interfacial thermal resistance sustaining the temperature gradient. This barrier-mediated phonon extraction bypasses the need for near-unity quantum efficiency or resonant excitation, offering a promising strategy for cryogen-free refrigeration and thermal management in quantum, optoelectronic and nanoscale systems.