Physics

Gastrointestinal dysfunction often precedes motor symptoms in Parkinson's disease (PD), suggesting the enteric nervous system (ENS) is central to early pathogenesis. How α-synuclein contributes to ENS dysfunction, and how inflammation modulates this, remains unclear. Here we show that Tumor Necrosis Factor alpha enhances α-synuclein accumulation in induced pluripotent stem cell-derived enteric neurons and glia, and impairs the malate-aspartate shuttle, a key pathway for mitochondrial energy production. This drives a metabolic shift toward glutamine oxidation in patient cells. This metabolic impairment reduces overall mitochondrial function, which is partially rescued by the neuroprotective compound Chicago-Sky-Blue 6B. Furthermore, transcriptomic and histological analyses of human gut tissue from inflammatory bowel disease patients reveal that inflammation-associated metabolic suppression and α-synuclein upregulation occur beyond PD, representing general hallmarks of intestinal inflammation. These findings highlight a conserved metabolic vulnerability in the ENS and establish patient-derived enteric lineages as a robust platform to model inflammatory ENS pathology.

Nitrogen (N) availability regulates primary productivity and hence directly affects global oceanic carbon sequestration. Global fjords account for up to 11% of marine carbon burial. However, N loss via sediment burial remains largely unquantified. Here, we show that global fjords are hotspots of N burial, accounting for up to 18% of oceanic N burial despite only covering 0.1% of the ocean area. Burial is the dominant N loss mechanism, exceeding microbial N loss via denitrification and anammox, which are generally considered the major N loss mechanisms. Microbial N loss dominates in anoxic fjords and appears to be a function of temperature and nutrient availability. Overall, fjords efficiently sequester excess N in sediments over long time scales. Accelerated warming will promote both N burial from increased primary production and microbial N loss from warmer temperatures, affecting N budgets in fjords and in the ocean in general.

T helper 17 cells play essential roles in mucosal immunity and autoimmunity, yet the mechanisms that protect these cells from oxidative DNA damage remain poorly defined. Here we show, in a murine model, that the nucleotide excision repair sensor Xeroderma Pigmentosum Complementation Group C preserves genomic stability and metabolic fitness during T helper 17 cell differentiation. Loss of this factor reduces interleukin 17 production and increases mitochondrial reactive oxygen species and oxidative DNA damage, resulting in altered metabolic programs. Mechanistically, Xeroderma Pigmentosum Complementation Group C interacts with the base excision repair enzyme 8-oxoguanine DNA glycosylase, and its absence enhances oxidative lesion incision activity, indicating defective coordination between DNA repair pathways. Restoring antioxidant capacity rescues cytokine production and limits DNA damage in deficient cells. Together, these findings identify Xeroderma Pigmentosum Complementation Group C as a key coordinator of DNA repair and redox control required for T helper 17 cell function in inflammatory settings.

The mechanics of fracture healing in calcite remain poorly constrained yet are fundamental to managing fluid transport in geothermal reservoirs and hydrocarbon systems. Here, we apply microfocused synchrotron Laue X-ray diffraction and infrared spectroscopy to investigate subcritical crack healing in a 1 mm-thick calcite crystal subjected to controlled loading in a double-torsion device. Over a 44-hour period following load removal, we map the evolution of residual strain fields surrounding the crack tip and observe a progressive increase in compressive strain perpendicular to the crack plane accompanied by infrared spectroscopic signatures that reveal enhanced accumulation of water at the healed interface. The correlation between strain evolution and surface chemistry suggests that spontaneous crack healing in calcite is driven by dynamic anelastic relaxation coupled with irreversible fluid-mineral interactions. These findings offer insight into time-dependent crack closure processes in carbonates and highlight the role of chemically-mediated plasticity in subsurface fracture evolution.

Thiol functionalities are indispensable in both biological and synthetic chemistry. However, unlike the powerful silylation strategies for hydroxyl groups, widespread applications in sulfur chemistry are severely hampered by the weak and hydrolytically labile nature of the Si-S bond. Here, we report that tris(trimethylsilyl)silane (TTMSS), a unique trisilyl-substituted reagent, efficiently enables the rapid hydrosilylation of disulfides under exceptionally mild conditions. This reaction affords robust silyl sulfides that show significantly enhanced hydrolytic stability compared to conventional analogues. The robust platform enables a practical, readily available strategy for orthogonal thiol protection and late-stage disulfide modification in complex molecules. Crucially, this finding reveals that the kinetic and thermodynamic properties of the Si-S bond can be finely tuned by strategic silyl substitution, establishing a general principle that reinvigorates silyl-protective methods for challenging sulfur chemistry.

The transient receptor potential melastatin 3 (TRPM3) channel is a key mediator of peripheral pain signaling, and pathogenic mutations in TRPM3 are linked to neurodevelopmental delay and epilepsy. Despite the therapeutic promise of TRPM3 modulators, the molecular mechanisms by which ligands modulate channel gating remain poorly understood. Here, we combine cryo-electron microscopy (cryo-EM) with functional analyses to characterize a promiscuous ligand-binding pocket formed by transmembrane helices S1-S4. This pocket accommodates several chemically diverse plant-derived and synthetic agonists and antagonists. We show stereoselectivity of TRPM3 for the (R)-enantiomer of the flavonoid antagonist isosakuranetin and the (R)-enantiomer of the synthetic agonist CIM0216. Mutations within this pocket-including variants identified in patients -alter ligand affinity and, in some cases, invert the functional outcome of ligand binding. These findings reveal the stereoselectivity and functional plasticity of the TRPM3 ligand-binding pocket, highlighting how subtle changes in the molecular interactions can produce divergent effects on channel gating, with important ramifications for TRPM3-targeted drug development and therapy.

Pooled perturbation screens can reveal cellular regulatory networks, yet scaling these techniques for large-scale screens in animals remains challenging. Here we present MIC-Drop-seq, a technique that addresses these challenges by combining high-throughput CRISPR gene disruption in zebrafish embryos with phenotyping by multiplexed single-cell RNAseq. In one MIC-Drop-seq experiment, we simultaneously identified changes in gene expression and cell abundance across 74 cell types resulting from loss of function of 50 transcription factors. These observations recapitulate many known phenotypes, while also uncovering previously uncharacterized roles for transcription factors in brain and mesoderm development. A key advantage of whole-animal screens is that they reveal how changes in one cell type affect the development of other cell types. Surprisingly, such cell-extrinsic phenotypes are abundant, indicating that transcription factors frequently exert effects beyond the cells where they are expressed to adjacent cells. We propose that MIC-Drop-seq will facilitate efforts to dissect the complete gene regulatory networks that guide animal development.

Antibiotic resistance is a growing public health threat, with over 2.8 million antibiotic-resistant infections and 35,000 attributable deaths annually in the U.S. Here, we sought to use wastewater monitoring to assess community-level burden of antibiotic resistance. This study quantifies concentrations of antibiotic resistance genes (ARGs) by digital droplet PCR in wastewater solids obtained from 163 wastewater treatment plants in 40 states in the United States. We measure 11 ARGs that confer resistance to beta-lactams (bla_CMY, bla_CTX-M, bla_KPC, bla_NDM, bla_OXA-48, bla_TEM, bla_VIM), colistin (mcr-1), methicillin (mecA), tetracycline (tetW), and vancomycin (vanA). The South has higher overall ARG concentrations compared to the Midwest. We pair these data with national data sets including antibiotic use, social vulnerability, size of animal agriculture operations, location of healthcare facilities, and presence of airports to investigate potential drivers of resistance. We also generate predictive maps of ARG concentrations for counties with data within the range of our training set in the United States. We show social vulnerability indicators (housing burden and access to health insurance) and indicators of international travel are associated with increased ARG concentrations in wastewater, while antibiotic usage is only weakly positively associated. Our results provide a national baseline of ARG concentrations and highlight the complexity of factors driving spread of antibiotic resistance.

Advances in drug discovery and clinical research have shifted the bottleneck in medicines development to chemistry, manufacturing, and controls activities, a critically step for regulatory approval. This includes formulation and process development of a new drug product, which traditionally requires extensive resources, often leading to suboptimal outcomes. These development processes must adapt to follow the advances in drug discovery and clinical research and ultimately shorten timelines while ensuring product quality and safety. In this work, we present an integrated platform for tablet formulation and process development that couples a digital formulator, an in-silico optimisation tool using a predictive material-to-tablet model, with a self-driving tableting data factory, which applies Bayesian optimisation within an automated, fully integrated per-tablet manufacturing to testing workflow. The results demonstrate a reduction in the time from material characterisation to in-specification tablets to 6 h and a reduction in API material use by 65% compared to current state-of-the-art methods.

Harvesting low-grade heat is a sustainable way to power wearable electronics, and quasi-solid-state ionic thermoelectric cells offer a flexible, low-cost option. Their use, however, has been limited by a key trade-off: miniaturization reduces the internal thermal gradient and compromises performance. Here, we address this challenge with an ultrathin asymmetric architecture that separates thermal energy harvesting from the conventional reliance on a sustained through-plane temperature gradient. The design couples thermally driven ionic modulation at one interface with engineered pseudocapacitive charge storage at the other. Our 1-mm-thick device delivers an open-circuit voltage of 0.1 V, a power density of 1.6 W m^-2, and an energy density of 1500 J m^-2 using near-body heat. An array of 20 cells generates 1.9 V and a peak power of 23 W m^-2, enabling continuous smartwatch operation. This strategy provides a practical route to ultrathin ionic thermoelectric cells for self-powered wearable systems.

mRNA vaccines against SARS-CoV-2 have been widely adopted to combat the COVID-19 pandemic. However, myocarditis has emerged as a rare but severe adverse effect, predominantly affecting young males. Here, we show that mitochondrial vulnerability is associated with mRNA vaccine-associated myocarditis. In our case-control study, patients with postvaccination myocarditis exhibited mitochondrial abnormalities. To examine the impact of mitochondrial damage, mRNA vaccines were administered to Polg^+/D257A mice, which heterozygously express a proofreading-deficient mitochondrial DNA polymerase that sensitizes mitochondria to stress. mRNA vaccination in Polg^+/D257A mice reduced left ventricular ejection fraction and induced cardiac immune cell infiltration. Bazedoxifene, a selective estrogen receptor modulator, prevented the reduction of cardiac function in Polg^+/D257A mice, suggesting a protective role for estrogen signaling. Notably, mRNA vaccination induced mitochondrial reactive oxygen species, resulting in RIPK3 activation, a necroptosis-related kinase, in cardiomyocytes. Collectively, we propose that mitochondrial vulnerability is a potential risk factor for myocarditis following mRNA vaccination, possibly through reactive oxygen species-mediated necroptosis signaling.

Sialic acid O-acetylation is implicated in the modulation of sialoglycan recognition and ganglioside biology. The sugar modification is catalyzed by CASD1, a Golgi membrane protein that encompasses a luminal catalytic domain and a multipass transmembrane domain. The mechanism of how acetyl-CoA is provided to the Golgi remains poorly understood. Here, we show that the acetyl-CoA transporter SLC33A1 provides acetyl-CoA to the luminal domain of CASD1 and that patient-derived SLC33A1 variants linked to inherited neurodevelopmental and neurodegenerative disorders impair ganglioside 9-O-acetylation. Under conditions that enable the formation of 7,9-di-O-acetylated sialoglycans, genetic inactivation of SLC33A1 impaired di-O-acetylation, but unexpectedly, still enabled mono-O-acetylation. Structure prediction and site-directed mutagenesis revealed a second active site in CASD1 that shares striking similarities with the catalytic acetyl-CoA binding transmembrane tunnel of the lysosomal acetyltransferase HGSNAT. Together, our data provide strong evidence that CASD1 has dual functionalities and catalyzes 7,9-di-O-acetylation through SLC33A1-dependent luminal acetylation and SLC33A1-independent transmembrane acetylation.

CRISPR‒Cas systems represent powerful tools for genome regulation. However, the large size of Cas proteins limits their efficient delivery via an adeno-associated virus (AAV), thereby restricting their clinical translation. Here, we engineer the IS200/IS605 transposon-encoded nuclease TnpB, along with its ωRNA scaffold, to create an enhanced TnpB system, which serves as a compact toolkit for gene activation, genome editing, and base editing. The gene activator enTnpBa increases expression by 2889-fold with a minimized 93 nt ωRNA and robustly activates endogenous genes in mammalian cells. We develop a single-AAV-based regimen for immune activation (AAV-ImmunAct) that delivers enTnpBa to activate CXCL9, IL-15, and IFN-γ. AAV-ImmunAct effectively enhances T cell migration and activation, increases killing of cancer cell lines and patient-derived organoids, and synergizes with anti-PD-1 therapy in humanized mice. Here, we establish enTnpB as a compact and versatile platform for genome regulation and a promising tool for cancer immunotherapy.

Germ cell tumors (GCTs) pose significant diagnostic challenges because of the limited performance of existing tumor markers. Here, we used phage immunoprecipitation sequencing (PhIP-Seq) to develop a unique immunosignature panel to improve diagnosing and differentiating GCT. Using 427 serum samples (150 GCT, 277 controls), we developed and validated an immunosignature panel (GCT-iSIGN) comprising 24 peptides from 16 unique proteins. This panel achieved 93% sensitivity, 99% specificity, and an area under the curve (AUC) of 0.98, identifying 23/24 biomarker-negative GCT cases. A secondary model (Sem-iSIGN), consisting of 17 peptides from five proteins, differentiated seminoma from nonseminoma with 96% specificity, 65% sensitivity, and AUC of 0.77. RNA sequencing data from The Cancer Genome Atlas confirmed differential overexpression of target antigens in testicular cancer. ELISA validation of ERVK7 and LUZP4 and immunohistochemical detection of ERVK7, MUC4, ZNF91, and LUZP4 in tumor tissues supported target expression. This study highlights PhIP-Seq immunoprofiling to identify serum-based immunosignature panels that can serve as biomarkers for GCTs. This approach addresses the shortcomings of conventional markers and offers a scalable, cost-effective tool for improving cancer diagnosis and management.

Genetically modified crops have provided economic and social benefits since becoming commercially available. One of the most successful and widely used applications is the integration of genes from the soil bacterium Bacillus thuringiensis for protection against damaging pests. Here, we leverage a robust dataset of 85,133 field-trial maize observations spanning all major production regions in South Africa from 1980-2018 to estimate yield gains associated with the first wave of genetically modified cultivars and explore the potential dynamic erosion of these gains since resistance was reported among first wave of single gene Bacillus thuringiensis cultivars. Leveraging the cultivars commercial release year, we find that genetically modified yield gains increased dynamically from their initial introduction in 2000, peaking at approximately 0.55 MT/ha around 2006, after which they significantly eroded to near-zero by 2014. Interestingly, this erosion was followed by a dramatic rebound in gains, reaching an in-sample high of approximately 0.75 MT/ha.

Horizontal gene transfer plays a key role in bacterial evolution, yet its efficiency under natural conditions, especially between genetically distinct strains, remains unclear. Using Staphylococcus aureus as a model, we found that gene transfer via various mechanisms is significantly restricted between strains from different clonal complexes (CCs), with the notable exception of lateral transduction, which occurs at high frequency. Interestingly, some strains exhibited a promiscuous ability to accept diverse mobile genetic elements. These strains were defective in key immune defences, specifically the Type I restriction-modification systems that normally protect against foreign DNA. A broader analysis revealed that such immune-deficient mutants are widespread within S. aureus populations. Our study uncovered a trade-off that may account for their persistence in nature: although these mutants are more susceptible to phage attack, they gain an evolutionary advantage by acquiring new genes - such as those conferring antibiotic resistance - which would enhance survival under selective pressure. These immune-deficient cells act as gateways for foreign DNA, which, once integrated and advantageous, can spread within the same CC. Our findings highlight the role of immune-deficient bacteria in facilitating the emergence of novel virulence factors and antibiotic resistance, emphasising their importance in shaping bacterial evolution.

Many proteins function as switches, transducing the concentrations of environmental chemicals into cellular responses. It is not well understood how signal processing by switches is genetically encoded. Here, using a massively parallel approach, GluePCA, we present >40,000 measurements and a complete map of how mutations alter the quantitative activation function of a receptor switch, the plant hormone sensor PYL1. Close to 90% of missense variants tune the dose-response of the receptor, often causing correlated changes in sensitivity, basal activity, maximum response and induction steepness. Based on theory we predict and then validate the underlying latent mechanism as a change in protein stability. Beyond this, signalling parameters can be independently tuned, with large effects in interface-distal positions and a modular genetic architecture across the receptor's structure. Rare single amino acid substitutions confer phenotypic innovation, including inverted and band-stop activation functions. Our data demonstrate the feasibility of dose-response profile quantification at massive scale and reveal the remarkable evolutionary malleability of a protein switch.

Purely organic phosphors have emerged as promising materials for various optical applications. Herein, we report a single-component organic phosphorescent crystal, 1,1'-(2,5-dibromoterephthaloyl)bis(glutarimide) (BrGlu), which exhibits fully reversible, pseudopolymorph-dependent phosphorescence color switching. Under standard crystallization conditions, BrGlu forms green-emitting crystal (G-crystal), while crystallization in the presence of CHCl₃ yields blue-emitting solvent-inclusion crystal (B-crystal). Notably, G-crystal converts into B-crystal upon exposure to CHCl_3, whereas the blue crystals revert to green upon heating, demonstrating a reversible phosphorescence-to-phosphorescence switching mechanism. Through a combination of experimental analyses and quantum chemical calculations, we elucidate the underlying mechanism governing this triplet emission color transformation: syn-anti conformational reorientation of bromine-carbonyl substituents: upon solvent inclusion, hydrogen bonding stabilizes the syn-rotamer to yield bright-blue phosphorescence, whereas gentle heating reverts the system to the anti-rotamer for green emission. Exploiting this property, we develop an advanced data encryption platform featuring a dual-layer security system-phosphorescence emission combined with thermal- or solvent-induced stimuli-response-significantly enhancing security in secure data encryption and anti-counterfeiting.

Auroral emissions play a critical role in coupling the magnetosphere and atmosphere at magnetized planets. At Jupiter, isolated auroral patches equatorward of the main auroral oval have been associated with magnetospheric injections, yet the key conditions driving these emissions remain unclear. Here we combine in situ particle and wave measurements and remote-sensing auroral observations from Juno to uncover the origins of Jupiter's patchy aurora. By examining both low-altitude and equatorial crossings, our results reveal that not all injections lead to auroral enhancements. Instead, auroral patches arise directly from electron precipitation driven by wave-particle interactions, while injections play a supportive role in facilitating wave growth and electron precipitation. These findings highlight the central role of plasma waves in auroral generation and in coupling Jupiter's magnetosphere and ionosphere, providing broader implications for wave-driven auroral processes across planetary magnetospheres.

The confinement of reactants within catalytic cavities is important for achieving efficient and selective chemical transformations. Macrocyclic organic covalent hosts, which mimic enzymatic environments, offer well-defined, tunable cavities capable of substrate accommodation. These robust and synthetically accessible hosts can be engineered into catalysts by functionalizing their rims, where substrate selectivity emerges from size- or shape-complementary binding. This positioning brings reactive sites into proximity with catalytic functional groups at the rims of covalent hosts, accelerating reactions. Cationic intermediates are pivotal in many chemical transformations, and stabilizing these reactive species within confined microenvironments could unlock unconventional selectivity for synthesizing high-value compounds. Despite this potential, leveraging the cavities of covalent hosts to stabilize and confine cationic intermediates for regioselective reactions remains underexplored. Here we report that the π-basic cavity of pillar[n]arenes can effectively stabilize bromiranium intermediates generated during olefin halogenation, confining them in a controlled microenvironment. This strategy overrides the intrinsic Markovnikov preference, enabling highly selective anti-Markovnikov halogenation. Furthermore, we extend this catalytic system to achieve size-selective anti-Markovnikov halogenation of olefins. This approach opens new pathways for selective transformations through the confinement of a cationic intermediate.

New antimalarial drugs are needed to combat the current emergence and spread of Plasmodium falciparum parasite resistance to artemisinin-based combination therapies. Here, we characterize ZY19489, a triaminopyrimidine presently in a Phase Ib clinical trial. Asexual blood-stage parasites pressured with ZY19489 acquire low-grade resistance, mediated by a novel mutation in the P. falciparum chloroquine resistance transporter (PfCRT) that causes slow growth rates and a substantial fitness cost. ZY19489-resistant parasites lose their chloroquine resistance status and become hypersusceptible to piperaquine (PPQ), an artemisinin-based combination partner drug. Uptake studies in proteoliposomes loaded with drug-resistant PfCRT isoforms demonstrate that ZY19489 can block mutant PfCRT-mediated PPQ and chloroquine transport. In parasites, PfCRT mutant variants can mediate PPQ and chloroquine resistance via their efflux out of the digestive vacuole. Our findings evoke a scenario of an evolutionary trap whereby resistance to ZY19489 can block PPQ and chloroquine efflux and thereby restore their activity. Metabolomic studies show that ZY19489 leads to significantly reduced intracellular levels of short hemoglobin-derived peptides (a natural substrate of PfCRT) and accumulation of pyrimidine deoxynucleotides. Our results present a possible marker for tracking the evolution of clinical resistance to ZY19489 and a rationale for pairing this molecule with PPQ to generate a resistance-refractory combination.

Laser-driven neutron sources (LDNSs) offer unique advantages for fundamental physics and applications: ultrashort pulses providing superior energy resolution, high instantaneous flux, and a reduced footprint. While single-event neutron spectroscopy has been demonstrated with epithermal neutrons, its application for fast neutrons is more challenging and remains unproven. This demands stable multi-shot operation and detectors resilient to this particularly extreme environment. Here, a proof-of-concept experiment at the DRACO PW laser is presented. This setup stably produced ~ 10⁸ fast neutrons per shot sustained over more than 200 shots at a shot-per-minute rate. Neutron time-of-flight measurements with a diamond detector at only 150 cm from the source resolved individual neutron-induced reactions at a rate consistent with simulations informed by real-time diagnostics of accompanying gammas, ions, and electrons. Combined with the recent advances in the field, this work establishes LDNSs as a promising, scalable platform for future fast neutron-induced reaction studies, particularly those involving short-lived isotopes.

Crystalline constructions known as Cayley-Schreier lattices have been suggested as a platform for realizing arbitrary gauge fields in synthetic crystals with real hopping amplitudes. Here, we reveal that Cayley-Schreier lattices can naturally give rise to implementable lattice systems that incorporate non-Abelian gauge structures transforming into a space-group symmetry. We show that their symmetry sectors can be interpreted as blocks of pseudospin models-some of which correspond to true spinors-that can realize a wealth of different topological invariants in a single setup. We underpin these general results with concrete models and illustrate how they can be implemented in technologically available experimental platforms. Our work sets the stage for a systematic investigation of topological insulators and metals with non-Abelian gauge structures.

Recent advancements in deep neural networks (DNNs), particularly large-scale language models, have demonstrated remarkable capabilities in image and natural language understanding. Although scaling up model parameters with increasing volume of training data has progressively improved DNN capabilities, achieving complex cognitive abilities-such as understanding abstract concepts, reasoning, and adapting to novel scenarios, which are intrinsic to human cognition-remains a major challenge. In this study, we show that mental representation-guided supervised learning, utilizing a small set of brain signals, can effectively transfer human conceptual structures to DNNs, significantly enhancing their comprehension of abstract and even unseen concepts. Experimental results further indicate that the enhanced cognitive capabilities lead to substantial performance gains in challenging tasks, including few-shot/zero-shot learning and out-of-distribution recognition, while also yielding highly interpretable concept representations. These findings highlight that mental representation-guided supervision can effectively augment the complex cognitive abilities of large models, offering a promising pathway toward developing more human-like cognitive abilities in artificial systems.

Autoinflammation of unknown origin remains amongst the most enigmatic of systemic autoinflammatory disorders (SAID), with systemic autoinflammatory symptoms in the absence of a molecular or clinical diagnosis with a recognized SAID. Here, we aim to understand the immunological process behind patients with autoinflammation of unknown origin. We collect samples from 36 patients manifesting recent disease activity across 30 European medical centers, and employ deep immunophenotyping and plasma proteomics to compare to 58 healthy controls and an additional demographically similar cohort comprising 92 SAID patients. Machine-learning approaches identify key immunological changes, including the upregulation of CD38 and HLA across T cell subsets and the upregulation of acute-phase plasma proteins in autoinflammation of unknown origin patients. The immunological traits of these previously poorly characterised patients partially phenocopy Still's disease presentation. Thus, this study identifies potential biomarkers and disease mediators in autoinflammation of unknown origin.