Physics

Continuous glucose monitors (CGMs) provide detailed glucose profiles, but their relevance to health outcomes in individuals without diabetes remains unclear. Here we assess time in range (TIR3.9–5.6 and TITR3.9-7.8) and glycaemic variability in individuals (N = 3,634; age 46 ± 12 y; 83% female; BMI 27 ± 6 kg/m²) from PREDICT 1 (NCT03479866), PREDICT 2 (NCT03983733), and PREDICT 3 (NCT04735835) without diabetes or prediabetes, and explore associations with demographic, diet, lifestyle, cardiometabolic markers, and predicted cardiovascular risk. Outcomes are non-pre-defined exploratory analyses. Higher TIR3.9–5.6 is associated with lower HbA1c, OGTT glucose, carbohydrate intake, and higher protein intake. Sleep duration is inversely correlated with mean glucose. TIR3.9–5.6 provided moderate discrimination for predicted ASCVD 10-year risk (AUC = 0.75). While CGM metrics show potential to capture some components of glycaemic physiology, longer-term health outcomes are required to demonstrate whether CGM monitoring has utility for health management in euglycaemic individuals. Here, the authors show that continuous glucose metrics capture some components of glycaemic physiology in euglycaemic individuals. An evaluation of health outcomes longer-term would be required to assess whether continuous glucose monitoring has utility for health management in this population.

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neurodegenerative disorder caused by expansion of a polyglutamine tract in the androgen receptor (AR). Here, we show that polyglutamine-expanded AR accumulates in the nucleus of motor neurons and induces aberrant upregulation of glutamatergic synaptic genes through dysfunction of the master transcriptional repressor REST during early postnatal development in a mouse model of SBMA (AR-97Q mice). Reducing mutant AR or restoring REST function using antisense oligonucleotides during the neonatal period attenuated the upregulation of glutamatergic synaptic genes and ameliorated the disease phenotype and histopathology in AR-97Q mice. Furthermore, we observed increased calcium activity in induced pluripotent stem cell-derived motor neurons from SBMA patients compared to those from healthy controls, reflecting neuronal hyperexcitability. Late-onset neurodegeneration in SBMA is attributable to early synaptic defects and the resulting hyperexcitability of motor neurons, which may represent therapeutic targets. Early synaptic dysregulation underlies late-onset neurodegeneration in SBMA. Aberrant upregulation of REST target glutamatergic synaptic genes by polyglutamine-expanded AR induces motor neuron hyperexcitability, highlighting a therapeutic window.

Gamma-glutamyl carboxylase (GGCX) is the sole enzyme responsible for gamma carboxylation of glutamate in a vitamin K-dependent manner. This process is crucial for blood coagulation, bone metabolism, vascular calcification, and other biological processes because gamma carboxylation is essential for the maturation of clotting factors, anticoagulation factors, and some coagulation-unrelated factors. Despite these essential roles, the catalytic mechanism of GGCX remains incompletely understood. Here, we present the cryo-EM structures of human GGCX complexed with five typical substrates, including two clotting factors and three coagulation-unrelated factors. These structures not only elucidate the recognition mechanism for the propeptide but also reveal three distinct modes for substrate loading. Among them, the GGCX-MGP complex structure reveals a specific mode to load a substrate with an active glutamate residue at the N-terminus of the propeptide. Moreover, these structural observations are supported by our in vitro carboxylation and epoxidation assays.

Irrigated agriculture enhances crop yields and climate resilience but also contributes to CO₂ emissions through energy use. Here, we apply energy system modeling to evaluate cost-emission trade-offs in electrified irrigation across the United States, integrating hourly energy production and historical water demand. We find that current practices are highly inefficient, leading to 23% (0.89 billion US dollar) higher costs and 39% (3.8 million metric tons of CO2) more CO2 emissions compared to the cost-optimal scenario, primarily due to reliance on diesel water pumps and limited solar photovoltaic adoption. Under cost-optimal conditions, 6.6 gigawatt of solar photovoltaic is deployed, and electric water pump installation capacity increase by 14% (11.3 106 m3h-1) relative to current levels. Emission reductions of 85% are achievable at marginal additional cost (+0.7%), whereas reaching net-zero roughly doubles system costs relative to business-as-usual. Renewable-powered electrified irrigation can thus deliver substantial, low-cost emission reductions but requires operational adaptation to solar-based systems. Irrigated agriculture is vital for food security but relies on energy- and carbon-intensive pumping. This study shows that switching to renewable-powered irrigation is not only environmentally compelling but also an economic opportunity.

The growing antibiotic resistance and high mortality rates associated with methicillin-resistant Staphylococcus aureus (MRSA) pose a global health threat, highlighting the urgent need for novel therapeutic strategies. Phenol-soluble modulin α3 (PSMα3) is a critical virulence factor in MRSA pathogenesis and immune evasion. However, its underlying mechanisms remain unclear. Here, we demonstrate that PSMα3 promotes both M1 macrophage polarization and necroptosis. These processes are mechanistically linked through an interaction between the interferon-stimulated gene factor 3 (ISGF3) and necrosome complexes, with formyl peptide receptor 2 (FPR2) serving as the key receptor. Based on this mechanism, we show that targeting signal transducer and activator of transcription 1 (STAT1), a key component of the ISGF3 complex, with the clinically approved drug fludarabine effectively mitigates MRSA infection in murine sepsis and pneumonia models. These findings reveal the mechanisms of MRSA pathogenesis and highlight the potential of anti-virulence strategies as innovative therapeutic approaches against MRSA infections. Methicillin-resistant Staphylococcus aureus (MRSA) is a key pathogenic bacterium and poses a significant therapeutic challenge due to its developing resistance to therapeutics. Here the authors establish a role for the MRSA virulence factor phenol-soluble modulin α3 in promoting macrophage M1 polarization and necroptosis via the host receptor FPR2 and the ISGF3 complex, and suggest the use of fludarabine to target the STAT1 component of this axis in models of MRSA infection.

Abstract Designing electrolyte materials for high-energy lithium metal batteries requires navigating vast, discrete chemical spaces, where intricate interphasial and electrolyte chemistries render component interactions largely unclear. Traditional trial-and-error methods struggle with discontinuous electrolyte-performance relationships and inefficient adaptation to new molecular candidates, hindering discovery. Here, we propose a two-stage deep active learning framework with knowledge transfer for rapid electrolyte design. In stage one, deep active learning with deep kernel learning selects informative experiments and models discontinuous relationships between formulation and performance, improving sample efficiency and reducing experimental cost. In stage two, target statistic coding quantifies what was learned and transfers it to new design settings, such as expanded formulation spaces and newly introduced components, using only a small number of additional measurements. Using this framework, we found electrolytes that increase the average lifetime of lithium metal symmetric cells by threefold after three learning iterations, and we rapidly identified improved formulations for Li 0 | |LiNi 0.8 Co 0.1 Mn 0.1 O 2 full cells in expanded chemical spaces. This work provides an experiment-driven, sample-efficient route to explore complex electrolyte formulation spaces and quantify inter-component correlations, as well as a realistic, high-cost, small-data benchmark for probabilistic surrogate modeling and sequential decision-making in discrete chemical spaces.

Abstract Peritoneal metastases (PM) occur in 10% of patients with colorectal cancer (CRC) and are linked to poor outcomes. Although dysregulated innate lymphoid cells (ILC) have been described in CRC, their function in CRC-PM remains unclear. Here, we analyze tumor samples from CRC and CRC-PM patients using single-cell RNA sequencing (11 patients), flow cytometry (8 patients) and differentiation assays (24 patients). Healthy colon, primary CRC and CRC-PM tumors are infiltrated by heterogeneous populations of ILC3, ILC2, ILC1, tissue resident (tr)NK cells and conventional (c)NK cells. Compared to healthy colons, primary CRC and CRC-PM tumors are depleted of ILC3 but enriched for ILC1, trNK cells and cNK cells. CRC and CRC-PM tumors harbor two immature ILC populations, early NK and naïve (n)ILC, with nILCs being transcriptionally skewed toward ILC1 and trNK cells. Indeed, co-culture of isolated nILCs with OP9-DL1 cells induces intratumoral nILC differentiation into ILC1/trNK-like cells. These findings help understand the immune pathogenesis of CRC and CRC-PM and provide insights for future ILC1 and NK cell-based therapies.

Abstract Photoinduced transition metal catalysis offers innovative strategies for fostering novel chemical reactions and improving established ones. In this work, we present a highly efficient, photoinduced Mn(II)-bipyridine catalyzed C–N, C-O and C-S coupling reaction between aryl halides—particularly less reactive aryl chlorides—and nucleophiles containing nitrogen, oxygen, and sulfur. This protocol does not need an external photocatalyst, as the single Mn(II)–bipyridine complex simultaneously serves as both the light-harvester and the metal catalyst. This method exhibits excellent substrate scope, covering eight different nitrogen sources for C-N coupling, as well as C-O coupling with alcohols, C-S coupling with thiophenols, encompassing more than 150 examples, with yields reaching up to 94%. Mechanistic studies suggest that this reaction may be initiated and sustained by the Mn(I) species through the photoinduced homolysis of the catalyst precursor bipyridine-Mn(II)(OAc) 2 , likely proceeding via a Mn(I)/Mn(III) catalytic cycle.

Chlorine atoms (·Cl) exhibit high reactivity and exert a substantial influence on the atmospheric oxidation capacity and chlorine cycle in the troposphere. The photolysis of molecular chlorine (Cl2) is a crucial source of ·Cl. However, the daytime peaks of Cl2 concentration cannot be entirely accounted for by the currently known pathways. Here we show that the photolytic oxidation of ammonium chloride (NH4Cl), a ubiquitous component of atmospheric aerosol, serves as an important daytime source of Cl2. Laboratory experiments demonstrate that oxygen, water vapour, and acidity are indispensable for Cl2 generation and release, and that Cl2 production is enhanced in the presence of black carbon aerosol. Field observation combined with model simulation demonstrates that the mechanism explains 12-55% of daytime Cl2 concentration. These results reveal a photoactivation pathway for chlorine production that depends only on chlorine salts and solar radiation, with significant implications in regions with abundant chloride salts. Sunlight triggers ammonium chloride in aerosols to produce Cl2 gas, explaining 12-55% of daytime levels. This chlorine source, boosted by black carbon, impacts atmospheric oxidation.

Effective host defense against pathogens requires coordinated behavioral and immune responses, yet the mechanisms that couple epithelial sensing to these systemic defenses remain poorly understood. Here, we identify a proton-mediated gut-to-neuron signaling pathway that orchestrates host defense in C. elegans. Intestinal pathogens stimulate mechanosensitive Ca²⁺ influx into intestinal epithelial cells (IECs) through the TRP channel GON-2, activating the Na⁺/H⁺ exchanger NHX-6 via the calmodulin CMD-1 to drive basolateral proton release. These protons activate cholinergic motor neurons through the acid-sensing ion channel ASIC-1, enhancing cholinergic transmission to promote both pathogen avoidance and intestinal innate immunity. Notably, mouse NHE1 and ASIC1a can functionally substitute for their nematode counterparts. Together, these findings demonstrate a role for proton signaling in gut-to-neuron communication, revealing a potentially conserved mechanism that links epithelial sensing to neuroimmune defense.

Energetic materials are central to propulsion and detonation technologies, yet their performance is often limited by poor control over energy release across multiple length and time scales. Integrating highly reactive composites with molecular explosives while maintaining structural precision remains challenging. Here we show a three dimensional printing strategy that enables programmable energetic composites by combining highly reactive metastable composite systems with a crystalline high explosive through acoustic-assisted assembly. Uniform coating and intimate interfacial contact produce dense architectures with enhanced thermal reactivity, accelerated pressurisation and increased energy output under confined conditions. Printed filamentary and core-shell structures further enable multistage and geometry-dependent energy release, including sustained combustion, secondary pressurisation and intense fireball formation. Laser-driven and combustion experiments reveal that the energy release characteristics can be systematically tuned by composition and architecture. This work establishes a general route to structure-performance control in energetic materials and highlights additive manufacturing as a powerful platform for designing next-generation reactive and explosive systems.

Accurate histopathological diagnosis typically relies on multiple chemical stains, a process that is labor-intensive, tissue-consuming, and environmentally taxing. While virtual staining offers a faster, tissue-conserving alternative, its clinical adoption is hindered by the requirement for perfectly aligned paired data, which is difficult to obtain due to tissue distortion during chemical processing. We present a robust virtual staining framework that mitigates spatial mismatches through a cascaded registration mechanism. By decoupling image generation from spatial alignment, our method enables high-fidelity staining even from imperfectly paired or misaligned datasets without altering existing model architectures. Our approach significantly outperforms state-of-the-art models across five datasets, showing a remarkable 23.8% improvement in image quality for highly misaligned samples. In blinded evaluations, experienced pathologists achieved 52% accuracy in distinguishing virtual from chemical stains, indicating that the two were indistinguishable. This framework simplifies data acquisition and provides a scalable pathway for integrating virtual staining into routine clinical workflows.

Lunar mare basalts are often rich in titanium, hosted predominantly within the mineral ilmenite (Fe2+Ti4+O3). Here, we examine ilmenite in a ~ 3.8 billion-year-old mare basalt (Apollo rock 75035) using high-resolution electron microscopy and electron energy loss spectroscopy. A key finding is that 75035 ilmenite is itself enriched in Ti, beyond the end member of the conventional solid solution series. Using energy loss near-edge spectroscopy, we determine that the excess Ti is trivalent, with Ti3+ accounting for 13% of the total Ti content. This discovery confirms the presence of trivalent Ti in lunar ilmenite, long hypothesized based on the Moon’s reducing environment. Accounting for the change in implied stoichiometry, a review of literature data suggests that Ti3+ may be present in ilmenite across a wide range of lunar samples. We extrapolate known relationships from the literature to connect Ti3+ to redox conditions, estimating the oxygen fugacity during crystallization of 75035 to be below the iron-wüstite buffer, ΔIW≤ − 1.6. Further quantifying the relationship between Ti valence state and oxygen fugacity would allow Ti3+-bearing ilmenite to serve as an oxybarometer able to access the reducing conditions found on many planetary bodies. Lunar rocks, not subject to complex crustal dynamics, reveal evolutionary aspects of the Earth-Moon system. The authors find that lunar ilmenite (age: 3.78 Ga) can host excess titanium in a trivalent state due to redox conditions not found on Earth.