Browse Articles

Letter by Zhao Regarding Article, “Device-Related Complications in Transvenous Versus Subcutaneous Defibrillator Therapy During Long-Term Follow-Up: The PRAETORIAN-XL Trial”

Absolute hand determination of glycofibrils from natural sources in cryo-EM

Glycans are not only one of the four fundamental macromolecular classes that constitute life, but also the most abundant among these four across the Earth. However, compared with proteins and nucleic acids, our understanding of the structures and functional mechanisms of glycans remains limited. Moreover, it is generally challenging to obtain high-resolution three-dimensional structures of glycans. Recent studies have demonstrated the potential of the CryoSeek strategy in enabling high-throughput structural determination of glycans, thereby presenting novel avenues for their structural investigation. Meanwhile, unlike proteins, near atomic resolution density maps of glycofibrils do not inherently facilitate the determination of absolute hand, which is a prerequisite for building atomic models of glycofibrils. Existing absolute hand determination methods have severe limitations in the case of glycofibrils from natural sources. In this study, we introduce Ahaha, a straightforward and efficient method for determining such absolute hand in cryogenic electron microscopy. With their absolute hand measured by Ahaha, we built atomic models of four glycofibrils derived from a natural water sample, facilitating the study of glycans. The online service of Ahaha is available at https://cryoseek.org/ahaha .

Endothelial Transcription Factor EB Protects Against Doxorubicin-Induced Endothelial Toxicity and Cardiac Dysfunction

BACKGROUND: Doxorubicin (DOX), an effective chemotherapeutic drug for various cancers, has been demonstrated to induce cardiovascular toxicity in cancer survivors. Endothelial cell (EC) dysfunction is recognized to play a critical role in the onset and severity of cardiotoxicity associated with DOX. TFEB (transcription factor EB), a master regulator of autophagy and lysosome biogenesis, regulates cardiovascular homeostasis. In the present study, we aimed to test whether endothelial TFEB protects against EC damage and alleviates cardiac dysfunction induced by DOX treatment. METHODS: EC-specific TFEB transgenic mice, EC-specific TFEB knockout mice, and their corresponding littermate controls were administered DOX intravenously. Survival curves were generated, and cardiac functions were measured in mice. The effects of TFEB on mitochondrial reactive oxygen species production, autophagic flux, and apoptosis were evaluated in human and mouse cardiac microvascular ECs treated with DOX. RNA sequencing, single-cell RNA sequencing, and chromatin immunoprecipitation with quantitative polymerase chain reaction (ChIP-qPCR) was performed to dissect molecular mechanisms in DOX-treated ECs in vitro and in vivo. Mice with endothelium-specific deficiency of Dab2 gene (Disabled homolog 2) were subjected to measurement of cardiac function and fibrosarcoma growth under DOX treatment. RESULTS: EC-specific TFEB transgenic mice showed significantly reduced mortality and improved cardiac function, together with attenuation of perivascular fibrosis after DOX treatment. By contrast, EC-specific TFEB knockout exacerbated DOX-induced cardiac dysfunction in mice. Furthermore, we observed that TFEB enhanced autophagy and reduced oxidative stress in cardiac microvascular ECs treated with DOX. In addition, TFEB preserved EC barrier integrity, alleviated proinflammatory cytokine release from cardiac microvascular ECs, and maintained the EC–cardiomyocyte communication, contributing to the protective effects of EC TFEB on cardiomyocyte function. Mechanistically, DAB2, a clathrin- and cargo-binding endocytic adaptor protein, was identified as a TFEB target gene in ECs. Accordingly, DAB2 knockdown attenuated the inhibitory effects of TFEB on apoptosis and the secretion of proinflammatory cytokines from cardiac microvascular ECs. In vivo, EC-specific Dab2 deficiency abolished the protective effect of EC TFEB on DOX-induced cardiac dysfunction. CONCLUSIONS: Taken together, endothelial TFEB protects against EC damage and cardiac dysfunction, constituting a potential target for treating cardiotoxicity induced by DOX. Our study provides new mechanistic insights into cardiotoxicity associated with chemotherapy.

In the wake of USAID cuts, we can create a Demographic and Health Survey Program founded on more equitable data infrastructure and stronger research integrity

Letter by Shi and Zeng Regarding Article, “Partnership Model of Regionalized Care for Congenital Heart Disease in Resource-Limited Settings: Results From the ASSIST Project”

Terrestrial ecosystem nitrogen cycling in response to field warming: Global patterns and future trends

Nitrogen cycling regulates terrestrial ecosystem productivity and carbon sequestration, yet its response to climate warming remains uncertain. Here, we compiled the most comprehensive dataset to date, integrating 7,941 observations from 413 field warming experiments worldwide with random forest regression and Community Land Model (CLM) simulations. Field warming significantly accelerated nitrogen cycling, increasing N 2 O emissions (+24.7%), mineralization (+25.8%), nitrification (+51.7%), and denitrification (+41.1%). Soil inorganic nitrogen also increased, while plant nitrogen remained largely unchanged. Elevated natural abundance of 15 N indicated that warming alleviates nitrogen limitation and promotes more open nitrogen cycles. Soil moisture, ecosystem type, and warming magnitude were key drivers. N 2 O emission and nitrification further intensified with increased warming magnitude in random forest analyses. In contrast, CLM5-BGC simulated weak responses in N 2 O emissions and nitrification and negative changes in nitrogen mineralization, substantially diverging from field observations. These discrepancies highlight the omission of microbial processes and the oversimplification of large-scale ecosystem feedbacks, respectively. Uniquely, this study provides a direct comparison among empirical data, random forest regression, and CLM simulations, revealing discrepancies and their potential causes. Collectively, our findings demonstrate that terrestrial nitrogen cycling is more responsive to climate warming than previously recognized and underscore the importance of integrating multiple analytical approaches to synthesize cross-scale ecological data.

Letter by Yu and Li Regarding Article, “The Impact of Fontan Circulatory Failure on Heart Transplant Survival: A 20-Center Retrospective Cohort Study”

Efficient evaluation of optical quantum modules via two-photon high-dimensional interference

The rapid advancement of quantum information technology has increased the demand for precise testing and calibration of quantum modules, especially in optical quantum circuits where module reliability directly impacts system performance. To address this need, we propose a two-photon quantum module evaluation method based on high-dimensional Hong–Ou–Mandel interference. Our method uses multi-degree-of-freedom photon encoding to enable rapid and accurate evaluation of optical quantum modules. Compared to traditional methods such as quantum process tomography and direct fidelity estimation, our method not only simplifies implementation but also significantly minimizes the measurement resources required. Notably, the resource demands remain invariant as the system dimensionality scales, ensuring efficient evaluation even in high-dimensional quantum systems. We validated this method on a programmable silicon photonic chip, demonstrating its ability to accurately evaluate optical quantum module performance while significantly reducing resource consumption. This quantum module evaluation method holds promise for broader applications in the field of optical quantum information technologies.

Bradycardia in Athletes: New Insights

Phenotypic CRISPR screens identify NLRX1 as an essential activator of the human mitochondrial permeability transition

The mitochondrial permeability transition (mPT) is an evolutionarily conserved destructive process that permeabilizes the inner mitochondrial membrane in response to calcium overload. The molecular mechanism underlying the mPT is not established. To unambiguously identify essential proteins, we designed two phenotypic assays for mitochondrial calcium overload and applied them to FACS-based CRISPR screening in human cells, ultimately evaluating 19,113 genes. The first screen studied mitochondrial membrane potential (MMP) collapse in response to calcium overload. Top-ranked genes were the essential proteins of the mitochondrial calcium uniporter complex, MCU and EMRE, reflecting that the calcium-induced MMP collapse results from mitochondrial calcium entry and not the mPT. The second screen measured the permeability of the inner mitochondrial membrane. Here, the fluorescent interaction of a membrane impermeant ~600 Da dye and a mitochondrial-targeted HaloTag protein was studied under mPT activating conditions; calcium overload and the thiol-reactive molecule phenylarsine oxide. With secondary validation, we identified four protein-encoding genes that delayed or prevented the mPT under knockout: NF2, REST, BPTF, and NRLX1. Knockout of the nonmitochondrial proteins BPTF, NF2, or REST increased mitochondrial calcium retention capacity (CRC). However, calcium release or sensitivity to cyclosporin A (CsA) persisted, indicative of mPT sensitizers. Only knockout of the mitochondrial matrix protein, NLRX1, increased CRC, abolished calcium release, and was CsA-insensitive. This top-ranked hit of the mitochondrial permeability screen meets the definition of an essential mPT activator. Integral membrane proteins, including all previously proposed mPT candidates, were not essential activators.

Abundance of Naturally Occurring Mononuclear Diploid Cardiomyocytes Is Associated With Cardiac Regeneration

Differential disease tolerance mediates sex-biased illness severity in sepsis

Sepsis in humans, as well as mouse models of infection, demonstrates sex-biased outcomes in which males tend to have a higher incidence, higher severity, and higher mortality compared to females. Despite this important sex-bias in sepsis outcomes, little is known about its mechanistic drivers nor therapeutic implications. Much of the foundational data on sepsis pathogenesis is derived from animal studies that included only male subjects, potentially contributing to the notable paucity of successful mouse-to-human translation of sepsis therapeutics. In this study, we demonstrate that male-biased illness severity and organ dysfunction in mouse models of bacterial sepsis are mediated by impaired disease tolerance in males, involving impaired tolerogenic shifts in mitochondrial oxidative metabolism compared to females. Microbiological and immunological analyses of sepsis between males and females revealed that sex-biased disease tolerance was independent of infection resistance mechanisms, as well as canonical immune/inflammatory dysregulation. Therapeutic potentiation of mitochondrial tolerance with doxycycline neutralized sexual dimorphism of illness severity and organ dysfunction through a male-predominant treatment effect. These data reveal that biological sex is a fundamental determinant of illness severity and treatment responsiveness in sepsis through modulation of disease tolerance, which may be harnessed therapeutically to address sex-biased outcomes in sepsis.

Correction to: Histone Lactylation–Mediated Metabolic Remodeling in Vascular Smooth Muscle Cells Aggravates Aortic Aneurysm and Dissection by Promoting Lactate Accumulation

Class-I myosin responds to changes in membrane tension during clathrin-mediated endocytosis in human induced pluripotent stem cells

Clathrin-mediated endocytosis (CME) is an essential cellular process that needs to operate efficiently across a wide range of conditions. Internalization of the endocytic site involves forces generated by membrane-bound proteins and Arp2/3-mediated branched actin filament assembly to bend the plasma membrane from flat to omega-shaped. In mammalian CME, the requirement for a branched actin filament network varies depending on cell type and differences in membrane tension. However, how the actin network adapts to changes in load in order to ensure robustness of this process over a range of membrane tensions is not understood. Here, we combine live-cell imaging and superresolution microscopy of genome-edited human induced pluripotent stem cells to investigate the role of the mammalian class-I myosin, Myosin1E (Myo1E), in load adaptation. Under normal conditions, sites that recruit Myo1E are rare and exhibit slow CME dynamics. However, as membrane tension increases and CME dynamics are slowed globally, Myo1E is recruited to more sites, likely to increase actin assembly and motor activity, resulting in increased force generation to rescue stalled sites and promote internalization. Loss of Myo1E results in increased Arp2/3 complex lifetime at CME sites under normal conditions, and at high membrane tension, these sites fail to recruit as many Arp2/3 molecules. We propose that Myo1E is recruited to CME sites that have stalled due to increased membrane tension, where it helps build a more effective branched actin network by generating force through motor activity and recruiting additional Arp2/3 complexes to rescue stalled sites.

Correction to: Selective mRNA Translation: A New Player in Ferroptosis After Myocardial Infarction

An accurate and efficient framework for modeling multimetal competitive adsorption on clay minerals

Multiple toxic metal elements usually coexist and thus their competitive adsorption always occurs in natural and engineered clay-rich systems. Currently, however, the competitive adsorption mechanisms of multicomponent metal systems on clay mineral surfaces are still unclear, hindering the accurate prediction of toxic metal distribution in soil-water environments. In this study, we uncovered the microscopic mechanism of competitive adsorption of multimetals on heterogeneous clay mineral surfaces using first principles calculation, which indicates that metal ion size largely dominates their complexation on clay mineral surfaces, and competitive adsorption of metals plays a key modulatory role in the adsorption process on clay minerals. By integrating theoretically and experimentally derived multiscale information, a state-of-the-art surface complexation model (SCM) framework has been developed for modeling competitive adsorption. Extensive tests showed that the SCM framework accurately and efficiently reproduces the toxic metal distribution, which enables the quantitative prediction and understanding in realistic environmental conditions. Our results have wide applications in future fundamental studies and the design of environmental materials for toxic metal removal from aquatic systems.

Microplastics and Nanoplastics: A New Perspective in Cardiovascular Prevention

Academic journals’ AI policies fail to curb the surge in AI-assisted academic writing

The rapid integration of generative AI into academic writing has prompted widespread policy responses from journals and publishers. However, the effectiveness of these policies remains unclear. Here, we analyze 5,114 journals and over 5.2 million papers to evaluate the real-world impact of AI usage guidelines. We show that despite 70% of journals adopting AI policies (primarily requiring disclosure), researchers’ use of AI writing tools has increased dramatically across disciplines, with no significant difference between journals with or without policies. Non-English-speaking countries, physical sciences, and high-OA journals exhibit the highest growth rates. Crucially, full-text analysis on 164 k scientific publications reveals a striking transparency gap: Of the 75 k papers published since 2023, only 76 (~0.1%) explicitly disclosed AI use. Our findings suggest that current policies have largely failed to promote transparency or restrain AI adoption. We urge a reevaluation of ethical frameworks to foster responsible AI integration in science.

Response by Schumacher and Cousino to Letter Regarding Article, “The Impact of Fontan Circulatory Failure on Heart Transplant Survival: A 20-Center Retrospective Cohort Study”

mtDNA leakage promotes neuron–glia crosstalk to induce epilepsy by cGAS–STING-driven neuroinflammation and serine metabolic reprogramming

Epilepsy is increasingly recognized as a disorder involving metabolic dysregulation beyond neural hyperexcitability, yet the underlying metabolic mechanisms remain poorly defined. Here, we identify a mitochondrion–immunity–metabolism axis that drives spontaneous chronic epilepsy. Brain-specific deletion of Mic19 impairs mitochondrial cristae structure and mitochondrial integrity in neurons, leading to activation of the Z-mitochondrial DNA (mtDNA)–ZBP1–RIPK3–mixed lineage kinase domain-like protein (MLKL) axis and p-MLKL-mediated pore formation on the mitochondrial membrane. This process results in cytosolic and extracellular leakage of mtDNA, which is subsequently taken up by microglia and triggers cyclic GMP-AMP synthase (cGAS)–STING-dependent inflammatory signaling. The resulting neuroinflammation promotes sustained activation of astrocytes. Critically, reactive astrocytes undergo profound metabolic reprogramming, marked by upregulated glycolysis and enhanced L-serine biosynthesis. Astrocyte-derived L-serine is subsequently transferred to neurons and converted into D-serine, a key NMDA receptor coagonist that enhances neuronal excitability. This metabolic shift in astrocytes exacerbates excitotoxicity and sustains epileptic activity. Importantly, pharmacologic inhibition of STING with H-151 treatment markedly suppresses seizures, reinforcing the therapeutic potential of targeting immunometabolic crosstalk in epilepsy. Our findings reveal that mtDNA-mediated cGAS–STING activation and D-serine act as important drivers of epilepsy initiation, offering mechanistic insights into neuron–microglia–astrocyte crosstalk and highlighting immunometabolic modulation as a promising therapeutic strategy for epilepsy.