Browse Articles

Structural insights into the activation and inhibition of the ADAM17–iRhom2 complex

The endopeptidase activity of ADAM (a disintegrin and metalloproteinase)-17, the primary processor of several EGFR ligands and tumor necrosis factor-alpha (TNF-α), is essential for proper embryonic development and immune regulation. Dysregulated ADAM17 activity is prevalent in a wide array of human diseases, including cancer, chronic inflammation, and SARS-CoV-2 viral progression. Initially translated as an inactive zymogen, ADAM17 maturation and enzymatic function are tightly regulated by its obligate binding partners, the inactive rhomboid proteins (iRhom) -1 and -2. Here, we present the cryo-EM structure of the ADAM17 zymogen bound to iRhom2. Our findings elucidate the interactions within the ADAM17–iRhom2 complex, the inhibitory mechanisms of the therapeutic MEDI3622 antibody and ADAM17 prodomain, and the previously unknown role of a membrane-proximal cytoplasmic reentry loop of iRhom2 involved in the mechanism of activation. Importantly, we perform cellular assays to validate our structural findings and provide further insights into the functional implications of these interactions, paving the way for developing therapeutic strategies targeting this biomedically critical enzyme complex.

A synchrotron-like pumped ring resonator for water waves

The wave-like behavior of matter in quantum physics has spurred insightful analogies between the dynamics of particles and waves in classical systems. In this study, drawing inspiration from synchrotrons that resonate to accelerate ions along a closed path, we introduce a synchrowave: a waveguide designed to generate and sustain traveling water waves within an annular channel. In analogy to unavoidable energy losses in conventional particle accelerators due to electromagnetic radiation and inelastic collisions, the system displays undesired water-wave dampening, which we address through the synchronized action of underwater wavemakers. Our analogies extend the resonance mechanisms of synchrotrons to generate and sustain gravity waves in closed waveguides efficiently. A proof-of-concept experiment at a laboratory scale demonstrates the unique capability of this technique to build up anomalously large traveling waves displaying a flat response in the long-wave limit. Besides quantifying the performance of wave generation, our findings offer a framework for both industrial and computational applications, opening up unexplored possibilities in hydraulics, coastal science, and engineering. In a broader context, our experimental apparatus and methods highlight the versatility of a simple yet powerful concept: a closed-path continuous-energy-pumping scheme to effectively harvest prominent resonant responses within wave-supporting systems displaying weak dissipation.

Human–AI collectives most accurately diagnose clinical vignettes

AI systems, particularly large language models (LLMs), are increasingly being employed in high-stakes decisions that impact both individuals and society at large, often without adequate safeguards to ensure safety, quality, and equity. Yet LLMs hallucinate, lack common sense, and are biased—shortcomings that may reflect LLMs’ inherent limitations and thus may not be remedied by more sophisticated architectures, more data, or more human feedback. Relying solely on LLMs for complex, high-stakes decisions is therefore problematic. Here, we present a hybrid collective intelligence system that mitigates these risks by leveraging the complementary strengths of human experience and the vast information processed by LLMs. We apply our method to open-ended medical diagnostics, combining 40,762 differential diagnoses made by physicians with the diagnoses of five state-of-the art LLMs across 2,133 text-based medical case vignettes. We show that hybrid collectives of physicians and LLMs outperform both single physicians and physician collectives, as well as single LLMs and LLM ensembles. This result holds across a range of medical specialties and professional experience and can be attributed to humans’ and LLMs’ complementary contributions that lead to different kinds of errors. Our approach highlights the potential for collective human and machine intelligence to improve accuracy in complex, open-ended domains like medical diagnostics.

Revealing unseen dynamical regimes of ecosystems from population time-series data

Many dynamical systems can exist in alternative regimes for which small changes in an environmental driver can cause sudden jumps between regimes. In ecology, predicting the regime of population fluctuations under unobserved levels of an environmental driver has remained an unsolved challenge with important implications for conservation and management. Here, we show that integrating time-series data and information on a putative driver into a Gaussian Process regression model for the system’s dynamics allows us to predict dynamical regimes without the need to specify the equations of motion of the system. As a proof of concept, we demonstrate that we can accurately predict fixed-point, cyclic, or chaotic dynamics under unseen levels of a control parameter for a range of simulated population dynamics models. For a model with an abrupt population collapse, we show that our approach goes beyond an early warning signal by characterizing the regime that follows the tipping point. We then apply our approach to data from an experimental microbial food web and from a lake planktonic food web. We find that we can reconstruct transitions away from chaos in the microbial food web and anticipate the dynamics of the oligotrophic regime in the planktonic food web. These results lay the groundwork for making rational decisions about preventing, or preparing for, regime shifts in natural ecosystems and other dynamical systems.

Reflection and refraction of directrons at the interface

Reflection and refraction are ubiquitous phenomena with extensive applications, yet minimizing energy loss and information distortion during these processes remains a significant challenge. This study examines the behavior of structurally stable solitons, known as directrons, in nematic liquid crystals interacting with an interface where the director field orientation changes, despite identical physical properties, external potentials, and boundary anchoring in the two regions. During reflection and refraction, the directrons maintain nearly constant structure and velocity, ensuring energy conservation and information integrity. Microscopic analyses of the director field and macroscopic evaluations of effective potential are employed to elucidate the dependence of reflection and refraction probabilities on the directron’s incident angle and the orientation difference across the interface. The findings provide valuable insights into the dynamics of solitary waves in structured liquid crystal systems, offering significant implications for the development of tunable photonic devices, reconfigurable optical systems, and nanoscale material engineering.

The bunkbed conjecture is false

We give an explicit counterexample to the bunkbed conjecture introduced by Kasteleyn in 1985. The counterexample is given by a planar graph on 7,222 vertices and is built on the recent work of Hollom (2024).

Targeting ryanodine receptors with allopurinol and xanthine derivatives for the treatment of cardiac and musculoskeletal weakness disorders

Ryanodine receptors (RyRs) are intracellular Ca 2+ channels essential for muscle contraction. Caffeine, a xanthine derivative, has been known for decades to increase muscle contraction and enhance activation of RyRs by increasing the sensitivity to Ca 2+ . We previously showed that xanthine, the only physiologically relevant xanthine derivative, also binds to and activates RyR2. Most xanthine derivatives and analogs are safe and widely prescribed, with the most popular being the xanthine oxidoreductase inhibitor allopurinol (~15M yearly prescriptions in USA). We propose that xanthine derivatives and analogs that enhance RyRs activity could be used for lead optimization and eventually for the treatment of the diseases that exhibit decreased muscle contraction and reduced RyRs activity, such as RyR1-related diseases, sarcopenia, and heart failure. Here, we show by cryo-EM that xanthine derivatives, analogs, and other related compounds bind to the xanthine/caffeine binding site and activate RyR1, and identify 4-oxopyrimidine as the minimal motif necessary for such interaction.

Transgenerational epigenetic effect of kings’ aging on offspring’s caste fate mediated by sperm DNA methylation in termites

The discovery of transgenerational epigenetic inheritance and the unraveling of its molecular mechanisms are currently solving previously puzzling challenges that Mendelian genetics based solely on DNA could not explain, leading to significant paradigm shifts across various fields of biology. There has been a long-standing controversy over the factors determining the caste fate of individuals in social insects. Increasing evidence supports heritable influences on division of labor. Here, we provide evidence that transgenerational epigenetic inheritance influences caste determination in a termite. We demonstrate that the age of the king influences the caste fate of offspring, with young kings’ progeny showing a higher tendency for reproductive differentiation compared to offspring from older kings (under controlled conditions). Then, we conducted a high-quality chromosome-level genome assembly for the Japanese subterranean termite Reticulitermes speratus . Genome-wide methylome analysis of kings’ sperm reveals a drastic change in DNA methylation patterns with aging. Among 39,399,411 CpG sites, 21,611 sites showed significant age differences in methylation levels. We identified 13 genes whose methylation levels are significantly different between young and old kings and suggestively correlated with the offspring’s differentiation into the reproductive pathway. Our results suggest that sperm DNA methylation, which changes with the age of kings, is a potential transgenerational epigenetic factor involved in offspring caste differentiation in a termite. These findings may have broad applicability to caste differentiation in social insects and to phenotypic plasticity more generally.

Bruch’s membrane heparan sulfate retains lipoproteins in the early stages of age-related macular degeneration

Lipoprotein retention in Bruch’s membrane is a key event in the pathobiology of early and intermediate age-related macular degeneration (AMD). However, the mechanism of lipoprotein retention in BrM is unknown. Given the established role of glycosaminoglycans (GAG) in binding lipoproteins, our laboratory sought to determine the role of GAGs in AMD BrM. In this study, BrM GAG content in AMD pathobiology was analyzed in human postmortem tissue. Strikingly, increased levels of highly sulfated heparan sulfate were present in AMD Bruch’s membrane as compared to non-AMD samples. In addition, using scanning electron microscopy of postmortem AMD tissue, we show aggregates of lipoprotein-like particles on the retinal pigmented epithelium side of Bruch’s membrane adjacent to heparan sulfate. We also show that heparin displaces lipoproteins rich in apolipoprotein A1 from human BrM, suggesting their identity as high-density lipoproteins. Using human BrM immobilized to quartz crystal microbalance biosensor (QCM) chips, we show that heparan sulfate is required for lipoprotein binding to BrM and soluble heparan sulfate can remove lipoproteins bound to BrM. Thus, our data establish that heparan sulfate regulates lipoprotein deposition in AMD BrM. These findings provide a foundation for targeted therapies capable of either preventing lipoprotein accumulation or removing drusen in the early and intermediate stages of AMD prior to vision loss.

A unifying principle for multispecies coexistence under resource fluctuations

Resource fluctuations are ubiquitous in nature and yet are generally assumed to play a limited role in the maintenance of biodiversity. We challenge this assumption by analyzing resource competition dynamics under conditions where prevailing theory does not hold. We show that multispecies coexistence can be sustained when species are able to specialize on different temporal patterns of resource variability, including the asymmetries and periodic extremes commonly observed in natural systems. We further show how this partitioning of the statistical moments of the resource distribution provides a unified framework for explaining coexistence in variable resource environments. The multiplicity of niches we find in a single fluctuating resource highlights the potential for anthropogenic changes in resource regimes to drive cascading biodiversity losses.

The green algae CO2 concentrating mechanism and photorespiration jointly operate during acclimation to low CO2

Abstract Due to low availability of CO2 in aquatic environment, microalgae have evolved a CO2 concentrating mechanism (CCM). It has long been thought that operation of CCM would suppress photorespiration by increasing the CO2 concentration at the Rubisco active site, but experimental evidence is scarce. To better explore the function of photorespiration in algae, we first characterized a Chlamydomonas reinhardtii mutant defected in low-CO2 inducible 20 (LCI20) and show that LCI20 is a chloroplast-envelope glutamate/malate transporter playing a role in photorespiration. By monitoring growth and glycolate excretion in mutants deficient in either CCM or photorespiration, we conclude that: (i.) CCM induction does not depend on photorespiration, (ii.) glycolate excretion together with glycolate dehydrogenase down-regulation prevents the toxic accumulation of non-metabolized photorespiratory metabolites, and (iii.) photorespiration is active at low CO2 when the CCM is operational. This work provides a foundation for a better understanding of the carbon cycle in the ocean where significant glycolate concentrations have been found.

RACK1 promotes the development and function of alveolar macrophages through directly binding to and stabilizing PPARγ

Alveolar macrophages (AMs) are indispensable to prevent pulmonary alveolar proteinosis and clear inhaled pathogens. Receptor for activated C kinase 1 (RACK1) is a versatile adaptor protein that regulates multiple signaling pathways. Whether RACK1 is implicated in AM alterations remains elusive. Alveolar type 2 cells-derived granulocyte-macrophage colony-stimulating factor and autocrine transforming growth factor-β1 drive the transcription of Pparg , the gene encoding AM signature transcription factor peroxisome proliferator-activated receptor-γ (PPARγ). The regulation of PPARγ stability during AM development and maintenance remains unexplored. Here, we report that myeloid RACK1 deficiency results in the scarcity of mature AMs and pulmonary alveolar proteinosis. A mixed bone marrow chimera approach reveals a cell-intrinsic role of RACK1 in AM differentiation. Bulk RNA-sequencing indicates a considerable loss of AM identity, impaired PPAR signaling, but a largely unchanged Pparg messenger RNA (mRNA) level in the absence of RACK1. Indeed, myeloid deletion of Rack1 halts AM differentiation in vivo and blocks the ability of PPARγ agonist to induce AM-like cells in vitro. Mechanistically, RACK1 directly binds to and stabilizes PPARγ by preventing its ubiquitination and degradation. Moreover, myeloid RACK1 deficiency renders mice susceptible to Streptococcus pneumoniae infection.

Unveiling hidden particle-level defects in glasses

The dependence of the amino acid backbone conformation on the translated synonymous codon is not statistically significant

The correlation between synonymous codon usage and secondary structure in translated proteins has been widely demonstrated. This usage plays a capital role in tuning translational rates and protein folding kinetics, indirectly influencing multiple biological processes. A recent report [A. A. Rosenberg, A. Marx, A. M. Bronstein, Nat. Commun. 13 , 2815 (2022).] suggests that the translated synonymous codon influences the ( ϕ , ψ ) dihedral angles within secondary structure elements. If true, this conclusion would have strong consequences in several scientific fields, including structural biology and protein design, where results would depend on DNA sequence rather than protein sequence. Here, we show that the original statistical methodology used in the referred study was formally incorrect. Furthermore, when using a correct approach, we demonstrate that the influence of the codon on the distribution of the dihedral angles is not statistically significant for any type of secondary structure.

Single-cell analysis reveals immune cell abnormalities underlying the clinical heterogeneity of patients with systemic sclerosis

Monoclonal humanized monovalent antibody blocking therapy for anti-NMDA receptor encephalitis

Abstract Anti-NMDA receptor (NMDAR) encephalitis is a devastating disease with severe psychiatric and neurological symptoms believed to be caused by pathogenic autoantibodies that bind to the N-terminal domain (NTD) of the NMDAR GluN1 subunit (GluN1-NTD) crosslinking adjacent NMDARs and driving their internalization. Here we describe ART5803, a humanized monovalent antibody, as a potential therapy for anti-NMDAR encephalitis. ART5803 binds with a high affinity (KD = 0.69 nM) to GluN1-NTD without affecting NMDAR activity or inducing internalization. ART5803 blocks NMDAR internalization induced by patients’ pathogenic autoantibodies, and restores NMDAR function. A marmoset animal model was developed using sustained intracerebroventricular (ICV) administration of a human pathogenic autoantibody to evoke behavioral and motor abnormalities. ART5803 ICV infusion or peripheral injections rapidly reversed these abnormalities. These data, together with the pharmacokinetic profile in cynomolgus monkeys, indicate a therapeutic potential for intravenous (IV)-administered ART5803 as a fast-acting and efficacious option for anti-NMDAR encephalitis.

Enzymatic carbon–fluorine bond cleavage by human gut microbes

Fluorinated compounds are used for agrochemical, pharmaceutical, and numerous industrial applications, resulting in global contamination. In many molecules, fluorine is incorporated to enhance the half-life and improve bioavailability. Fluorinated compounds enter the human body through food, water, and xenobiotics including pharmaceuticals, exposing gut microbes to these substances. The human gut microbiota is known for its xenobiotic biotransformation capabilities, but it was not previously known whether gut microbial enzymes could break carbon–fluorine bonds, potentially altering the toxicity of these compounds. Here, through the development of a rapid, miniaturized fluoride detection assay for whole-cell screening, we identified active gut microbial defluorinases. We biochemically characterized enzymes from diverse human gut microbial classes including Clostridia, Bacilli, and Coriobacteriia, with the capacity to hydrolyze (di)fluorinated organic acids and a fluorinated amino acid. Whole-protein alanine scanning, molecular dynamics simulations, and chimeric protein design enabled the identification of a disordered C-terminal protein segment involved in defluorination activity. Domain swapping exclusively of the C-terminus conferred defluorination activity to a nondefluorinating dehalogenase. To advance our understanding of the structural and sequence differences between defluorinating and nondefluorinating dehalogenases, we trained machine learning models which identified protein termini as important features. Models trained on 41-amino acid segments from protein C termini alone predicted defluorination activity with 83% accuracy (compared to 95% accuracy based on full-length protein features). This work is relevant for therapeutic interventions and environmental and human health by uncovering specificity-determining signatures of fluorine biochemistry from the gut microbiome.

Aneuploidy-induced proteostasis disruption impairs mitochondrial functions and mediates aggregation of mitochondrial precursor proteins through SQSTM1/p62

Abstract Aneuploidy, or aberrant chromosomal content, disrupts cellular proteostasis through altered expression of numerous proteins. Aneuploid cells accumulate SQSTM1/p62-positive cytosolic bodies, exhibit impaired protein folding, and show altered proteasomal and lysosomal activity. Here, we employ p62 proximity- and affinity-based proteomics to elucidate p62 interactors in aneuploid cells and observe an enrichment of mitochondrial proteins. Increased protein aggregation and colocalization of p62 with both novel interactors and mitochondrial proteins is further confirmed by microscopy. Compared to parental diploids, aneuploid cells suffer from mitochondrial defects, including perinuclearly-clustered mitochondrial networks, elevated reactive oxygen species levels, reduced mitochondrial DNA abundance, and impaired protein import, leading to cytosolic accumulation of mitochondrial precursor proteins. Overexpression of heat shock proteins in aneuploid cells mitigates protein aggregation and decreases the colocalization of p62 with the mitochondrial protein TOMM20. Thus, proteotoxic stress caused by chromosome gains results in the sequestration of mitochondrial precursor proteins into cytosolic p62-bodies, thereby compromising mitochondrial function.

Stable heritability of type 1 diabetes in a Swedish Nationwide Cohort Study

Abstract Incidence of type 1 diabetes is increasing globally, which is hypothesized to be due to environmental influences. We leverage Swedish nationwide registers linked to all children (n = 2,928,704) born in 1982–2010 to investigate if the heritability of childhood-onset type 1 diabetes has changed over time and how alterations in environmental factors have contributed to the rising type 1 diabetes incidence. The heritability is estimated at 0.83 (95% confidence interval: 0.79, 0.86) and stable over the observation period (0.80 [0.71, 0.86] in 1982, 0.83 [0.79, 0.86] in 2000, and 0·83 [0.79, 0.86] in 2010, respectively). Environmental factors including maternal smoking during pregnancy and childhood adiposity explain <10% of the increasing type 1 diabetes incidence. In this work, the heritability of childhood-onset type 1 diabetes has remained high and stable over the last 30 years. Our findings indicate that the available environmental factors are not the major contributors to the rise in type 1 diabetes in Sweden.

Nutrient storage links past thermal exposure to current performance in phytoplankton

The growth of populations and organisms often depends on their previous history of environmental exposure: a phenomenon referred to as “phenotypic memory.” The field of ecology presently lacks a mechanistic theory describing phenotypic memory and, as such, evaluating the ecological consequences of this phenomenon is a major challenge. Here, we show that internal nutrient storage connects past thermal experience to current growth in phytoplankton. We develop a mechanistic model showing that delays in the response of nutrient stores to changing temperatures produces phenotypic memory. By testing this model against experimental data of phytoplankton growth rates following temperature perturbations, we find general patterns in the population consequences of phenotypic memory: Prior exposure to warm temperatures depletes nutrient stores, and, in doing so, slows growth during subsequent temperature exposure and restricts the breadth of the thermal niche (i.e., the range of acute temperature exposures yielding a positive growth rate). Our model reveals how phenotypic memory produces temporal variation in critical thermal minima and maxima and predicts that the thermal niche is constricted by long-term exposure to warm temperatures (e.g., during summer months), but that high frequency temperature fluctuations can expand a population’s thermal niche. This work provides a mechanistic framework for considering the ecological implications of phenotypic memory.