Browse Articles

Restoring the interplay between the endoplasmic reticulum and mitochondria by gene therapy improves Charcot–Marie–Tooth type 2A disease

Charcot–Marie–Tooth disease type 2A (CMT2A) is the most common axonal CMT and is associated with an early onset and severe motor neuropathy. CMT2A is mainly caused by dominant mutations in the MFN2 gene, encoding mitofusin-2, a GTPase located in the outer membrane of the mitochondria and endoplasmic reticulum (ER). Mutations in MFN2 affect mitochondrial dynamics. We previously demonstrated that mutated MFN2 further disrupts contacts between the ER and the mitochondria, leading to axonal degeneration. There are no treatments for CMT2A, and those currently under development primarily focus on restoring mitochondrial function. Here, we provide proof of concept that neuronal overexpression of wild-type MFN2 (MFN2 WT ) provides therapeutic benefit in transgenic CMT2A mice as well as in CMT2A-motor neurons derived from induced pluripotent stem cells. Intrathecal delivery of an AAV9 vector expressing MFN2 WT effectively targets motor and sensory neurons, restoring ER–mitochondria contacts and mitochondrial morphology, thereby preserving both neuromuscular junction integrity and motor function. Strikingly, therapeutic efficacy is also achieved by administering the vector after the onset of symptoms. Importantly, AAV administration was well tolerated, with no evidence of hepatotoxicity or dorsal root ganglion inflammation. We further show that CMT2A pathology can be corrected in vitro and in vivo using an ER-targeting MFN1 isoform that selectively enhances ER–mitochondria contacts. These results establish that restoring contacts between the ER and mitochondria using gene therapy is a promising therapeutic avenue for CMT2A.

Electrical stimulation induces differentiation onset consistent with a therapeutic approach in neuroblastoma cells

Investigating the relationship between ATP synthase and the TCA cycle by crosslinking mass spectrometry

Abstract Mitochondrial oxidative phosphorylation (OXPHOS) comprises multi-subunit protein complexes that operate in coordination with the tricarboxylic acid (TCA) cycle to generate ATP. Although these systems are metabolically interconnected, complex II is generally regarded as the only direct structural link between OXPHOS and TCA cycle. Here, we combine in-solution crosslinking mass-spectrometry (XL-MS), quantitative proteomics, complexome profiling and blue native PAGE (BN-PAGE) to explore how ATP synthase (complex V) is positioned within the mitochondrial metabolic network under physiological and pathological conditions. We demonstrate that in murine wild-type hearts, the F₁ catalytic head of ATP synthase forms extensive contacts with TCA cycle enzymes, establishing a previously unanticipated spatial link between OXPHOS and central carbon metabolism. We further report that loss of the mitochondrial RNA-stabilizing protein LRPPRC, which disrupts mtDNA gene expression in the mouse heart, results in ATP synthase destabilization and enhanced F 1 -TCA cycle interactions. Moreover, ATP synthase dysfunction promotes binding of the ATPase inhibitory factor 1 (ATIF1) to the F₁ head via its N-terminal inhibitory region, shifting the ATP synthase toward an energy-preserving state. Together, our findings show that impaired mitochondrial gene expression leads to secondary ATP synthase remodeling and reshaping of its interaction landscape, revealing how mitochondria may adapt to bioenergetic stress.

Diminished transcriptional activity and splicing changes drive gene length–biased rewiring in the aging transcriptome

Transcription by RNA polymerase II (RNAPII), which is essential for protein-coding gene expression and cellular function, is increasingly understood to become dysregulated with aging. Here, we use a multimodal approach to comprehensively characterize age-dependent changes in RNAPII-mediated transcription in both mouse and human tissues. Short-read total RNA sequencing (RNA-seq) to profile nascent transcription reveals a global reduction in overall transcriptional activity/frequency in aged tissues, without apparent change in elongation rates. Transcriptomic analysis reveals a shift toward preferential expression of short genes in aged tissues, with notable upregulation of short stress-response genes and downregulation of long neurodevelopmental genes in the aged mouse brain. These results are recapitulated by analysis of total RNA-seq data from human tissues. Leveraging long-read RNA-seq, we determine that the representation of aberrant mono-exonic and intron-retention splice isoforms is increased in the aged mouse brain. Finally, we characterize the composition of RNAPII transcriptional machinery, finding that interactions between RNAPII and the Mediator complex are decreased in the chromatin of aged mouse liver and brain. Collectively, these analyses provide insight for future aging studies and reveal potential transcriptional control targets for anti-aging drug development.

Targeted spreader identification via lexicographic core decomposition

Impact of early career medical research funding on subsequent publication outcomes and research income for female and male applicants in the United Kingdom

Abstract The current debate in science funding of early-career researchers is shifting from exploring its effects on future outcomes to understanding who is more likely to benefit from it. In this paper, we explore the effect of research funding among male and female applicants. Using propensity score weighting on data from the Medical Research Council in the United Kingdom, we examine the effect on research income, scientific productivity (publications), as well as scientific influence (citations, relative citation ratio, field citation ratio and Altmetrics score). Successful applicants in both groups secure more future research funding than unsuccessful ones. In addition, successful female applicants receive more citations and are better cited in their field than female applicants who did not receive funding. There is no statistically significant difference in scientific productivity or influence between successful and unsuccessful male applicants.

Correction for Lollar and Warr, Decadal record of continental H ₂ reservoirs reveals potential for subsurface microbial life and natural H ₂ exploration

A unified constitutive model for yielding single-lining tunnel supports with resistance limiters under large deformation

Optimal dismantling of directed networks

The global diversity and decline of glacier animals

Glacier environments host an unrecognized number of animals that are at high risk of extinction due to global warming. Yet, the absence of comprehensive analyses has hampered the development of a coordinated agenda for research and conservation. By assembling a global dataset of terrestrial and freshwater animals in glacial habitats, we show that glacier environments host at least 152 animal species from 14 classes and 7 phyla. This diversity is underestimated for nearly all the groups and we detected widespread taxonomical, ecological, and geographical biases. Glacier animals exhibited diverse ecological patterns, with 73 species reported exclusively from glacial habitats (glacier specialists). Biogeographical patterns showed clear differences between groups, with some taxa (tardigrades, rotifers) found mostly in polar areas and others (insects, springtails) associated with tropical and temperate mountains. Glacier regions with a lower temperature showed a higher richness of glacier specialists. Glacier animals were widespread across the metazoan tree of life; the ability to disperse passively by wind emerged as the strongest driver of the occurrence of glacier animals. By linking the distribution of glacier specialists to scenarios of glacier retreat, we identified areas and species that are likely to experience abrupt declines in the next few decades, as well as species that could face complete habitat loss. Our results call for urgent actions to secure the future of glacier environments and their singular, understudied fauna.

Comparative assessment of behavioural alterations induced by common laboratory solvents in zebrafish (Danio rerio) larvae

A cannabidiol-sensitive region involved in the allosteric modulation of the α7 nicotinic receptor

Cannabidiol (CBD), a nonpsychoactive phytocannabinoid from Cannabis sativa , modulates the α7 nicotinic acetylcholine receptor (α7 nAChR), a key target in neurological, neurodegenerative, and inflammatory disorders. However, the molecular basis of this modulation remains unresolved. By combining single-channel recordings, molecular dynamics (MD) simulations, and targeted mutagenesis, we identify an allosteric region governing CBD action. CBD produces a marked inhibition of α7 channel activity, followed by a recovery phase characterized by infrequent prolonged openings. MD simulations in closed and desensitized conformations reveal partially overlapping putative CBD-binding sites at the extracellular end of the transmembrane domain. Mutations in M1 and M4 residues within these sites differentially reshape CBD modulation: Some attenuate its inhibitory action, whereas others potentiate the increase in open-channel duration. Strikingly, the M4-L487A mutation converts CBD into a strong positive allosteric modulator, demonstrating that subtle perturbations of this region can invert the direction of modulation. Functional outcomes do not map to discrete sites, indicating that CBD engages an extended allosteric network involved in CBD dual modulation. These findings identify a CBD-sensitive regulatory region, define molecular basis of α7 modulation by CBD, and provide a framework for designing next-generation modulators of pentameric ligand-gated ion channels.

Characterization of tryptolinophyllins from the treefrog Boana boans expands the structural and functional diversity of the trypytophyllin family of peptides

Polycatechol-based iron predators disrupt fungal iron homeostasis to drive selective antifungal action

Fungal infections pose a growing global health challenge, exacerbated by a scarcity of effective treatments and rising drug resistance. Although cationic polymers emerge as promising antifungal candidates owing to structural tunability, design flexibility, and resistance to proteolytic degradation, their clinical utility has been hampered by nonselective membrane-disruption mechanisms. Herein, we develop a class of polycatechols- termed fungal iron predators (FIPs), exhibit exceptional fungicidal activity and markedly low cytotoxicity. These FIPs can efficiently infiltrate fungal cells, selectively sequester labile iron, and disrupt iron homeostasis and metabolism. The ensuing iron starvation provokes severe mitochondrial dysfunction and energy collapse, culminating in fungal cell death. Through systemic optimization of cationic density and catechol stoichiometry, we obtained an FIP variant demonstrating potent antifungal activity with high selectivity toward fungi over mammalian cells, minimal propensity to induce resistance, and supplementary antioxidant properties. Remarkably, this FIP candidate shows robust therapeutic performance across multiple in vivo models of fungal infection. Critically, this work established a groundbreaking paradigm in polymer design: shifting the antifungal mechanism from traditional nonspecific membrane disruption to targeted intracellular metabolic interference. The general applicability of this strategy across diverse cationic polymer backbones opens avenues for developing next generation of precision antifungal agents.

PINN for stiff moving-boundary PDE to predict the locking point in superheated steam drying

Abstract Physics-informed neural networks (PINNs) often struggle to solve stiff partial differential equations (PDEs) with moving boundaries, such as convection-dominated droplet drying with shrinking domains and related Stefan-type phase-change problems. This study investigates a physics-guided PINN formulation for nanosuspension droplet drying in superheated steam, where an accurate prediction of the locking point is important, as it marks the onset of structure formation and significantly influences particle morphology and final powder characteristics. The formulation retains the standard PINN backbone and combines two problem-specific modifications: a logarithmic state-variable transformation to compress the solution dynamic range and improve the representation of steep near-surface gradients, and a Péclet number-based scaling of the surface residual to better balance the boundary and PDE training signals across the stiffness regimes. Compared with a numerically verified Crank–Nicolson (CN) reference solution, the proposed formulation showed the greatest advantage in the high-Péclet regime, where the boundary layer steepening and training difficulty were most pronounced. In the stiffest case considered, it substantially reduced the discrepancy from the numerically verified CN reference solution compared with both the baseline PINN and the unscaled log-transformed formulation, while also improving the locking-time prediction. These results show that a physics-guided state transformation, combined with residual scaling, can improve the robustness of PINNs for this class of stiff, moving-boundary drying problems.

Regulatory logic underlying neural crest contributions to the head versus the heart

Neural crest cells exhibit axial-level-specific transcriptional programs, yet the regulatory mechanisms underlying their fate decisions remain unclear. Here, we investigate whether differential transcription factor usage governs cardiac neural crest cell identity. Comparing ATAC-seq profiles of cardiac and cranial neural crest revealed open chromatin regions that were both shared and region-specific. Single-cell RNA sequencing further identified putative target genes, including signaling molecules and receptors. We uncovered two adjacent Cxcr4 enhancers: one specific to the cardiac crest containing a TGIF binding site, and another active in both cranial and cardiac crest containing a TFAP2B binding site. Mutating the TFAP2B site abolished cranial, but not cardiac, crest expression. Finally, we show that the cardiac crest-specific Cxcr4 enhancer also drives expression in zebrafish cardiac crest cells, suggesting evolutionary conservation across vertebrates. These findings suggest that transcription factors enriched in distinct neural crest subpopulations may bias cell fate by modulating enhancer activity, shedding light on the regulatory landscape governing neural crest diversity.

Early prediction and risk assessment of adverse drug combinations using ensemble learning

Accounting for uncertainty and bias in archaeological and historical evidence on wealth inequality

The archaeological and historical record allows us to study the patterns of economic inequalities associated with sharply contrasting institutions such as communal property in societies without states, private property among small holders, and slavery, in economies relying on radically different technologies, based for example on human energy alone, other animal power, and carbon-based power. But the price of using prehistoric and historical data to expand the range of institutions and technologies under study is a substantial and typically unknown level of uncertainty and unrepresentativeness in the resulting estimates. We provide methods and code that quantify the degree of uncertainty, an approach that we term BRIDGE (Bayesian-Resampling and Informed Priors with Data-driven Gini Estimation). We transform raw wealth data from 431 sites and dates into probability distributions representing likely levels of inequality that (insofar as possible) are representative of the underlying population (e.g., rectifying biases arising from small or nonrandom samples and the frequent absence of data on those entirely without wealth) and are comparable across differing asset types (e.g., burial goods, dwelling area, storage area, land cultivated), ownership units (individual or household), and scale (from villages to nations). These distributions are based on the raw data along with independent information that allows us to infer biases and levels of uncertainty. We also account for the propagation of uncertainty through every stage of the data generation and estimation process. We find that widely used methods (e.g., relying solely on conventional bootstrapping) provide misleading and for the most part substantially underestimated measures of uncertainty.

Rapid construction and analysis of cascading events for disaster investigation and assessment

Actuation driven pseudocrease mechanics in multistable curved-crease origami shells

Shells are lightweight load-bearing structures found ubiquitously throughout nature and engineering. Reconfigurable structures can change form and function, while multistable ones enable fast, large shape changes and the ability to maintain a deformed shape without the continuous input of work. Here we present a general design method for multistable shells inspired by curved-crease origami and the differential geometry of developable surfaces. Through detailed analysis of a reference multistable shell, we show that the shell naturally concentrates deformation along a band which we term a “pseudocrease.” We analyze the effect geometric parameters have on the mechanical behavior to provide an intuitive understanding of the mechanics underlying the multistability, in which bending and stretching energies within the shell compete. We validate the numerical models and trends through experiments using samples of varying geometries. The validation addresses applications across a variety of length scales and forms, including a magnetically controlled curved-crease robot capable of morphing, rolling, steering, and crawling. Our approach holds potential for designing reconfigurable shells with tailored stiffness, energy barrier, and shape across multiple application areas.