Browse Articles

Tubulin flux at spastin-induced nanodamage sites regulates microtubule rescue frequency and EB1 lifetimes

Severing enzymes nanodamage microtubules by extracting tubulin subunits. This extraction is accompanied by spontaneous repair with soluble tubulin. Here, we show that GTP-, and not GDP–tubulin, incorporates preferentially at nanodamage sites where it recruits end binding protein-1 (EB1). Using GTP hydrolysis-defective recombinant tubulin mutants we show that the tubulin GTPase is a timer for EB1 association at repair sites. Tubulin on-rate controls both the size and lifetime of the spastin-catalyzed GTP-islands which promote rescues. Consistent with this, first, rescue rates in the presence of repair vary steeply with tubulin concentration, unlike in the absence of repair, and second, spastin-catalyzed lattice remodeling, and not passive binding of the enzyme alone, increases rescue rates. Furthermore, we show that, when overexpressed at low levels in cells, spastin catalyzes microtubule repair and affects microtubule growth. Thus, microtubule severing proceeds through GTP–tubulin repair intermediates both in vitro and in cells. Our work demonstrates that severing enzymes exert their effects on microtubule function through tubulin extraction and repair and strongly supports microtubule dynamics regulation through tubulin dimer exchange along the lattice.

Reply to Ritson-Williams et al. and Loya and van Woesik: Coral replacement research is vital due to uncertainty and unprecedented stress

Oxidative stress and serum deprivation influence the evolution of newly formed tetraploid cells during tumorigenesis

We recently found that newly formed tetraploid (4N) cells in culture quickly lose extra centrosomes after whole genome doubling (WGD). This is inconsistent with the high incidence of centrosome number abnormalities in human cancers and with the observation that 4N cells from mouse tumors carry extra centrosomes, suggesting that centrosome numbers could be affected by certain conditions in the tumor microenvironment (TME). To determine the effect of the TME on the evolution of newly formed 4N cells, we induced WGD in DLD1 colorectal cancer cells and analyzed centrosome and chromosome numbers in mouse tumor samples. We found that the 4N cells displayed a proliferation defect in vivo, that they could enhance the recruitment of stromal cells to the tumor site, and that they were more likely to harbor extra centrosomes compared to 4N cell populations evolved in vitro. Combining a mathematical model that tracks the coevolution of ploidy and centrosome numbers in different cell populations with Bayesian inference, we identified centrosome overduplication as the mechanism underlying the supernumerary centrosome phenotype. Finally, through in vitro evolution experiments, we found that deprivation of growth factors and oxidative stress could explain, respectively, the proliferation defect and the supernumerary centrosomes identified in our in vivo experiments. Overall, our work shows that oxidative stress plays a major role in centrosome overduplication, particularly in 4N cells, suggesting that supernumerary centrosomes and WGD may coexist in certain tumors. Moreover, our findings suggest that the oncogenic effects of WGD could be due, in part, to stromal cell recruitment.

Growth under pressure: The pros and cons of polyploidy induced by stress

In native environments, organisms are faced with an array of acute or chronic stresses. These stresses include toxins, pathogens, and physical injury. An increasingly recognized response to diverse stresses is whole genome doubling or polyploidy. This transformative cellular property alters genome integrity, cellular structure, and tissue architecture. Whether polyploidy is a positive, negative, or neutral outcome of a stress is a current topic of investigation in numerous contexts including during fungal infection of plants and animals, during regeneration of wounded tissues, and in human diseases such as cancer. In this review, we highlight the wide range of stresses that promote polyploidy in fungal, plant, and animal contexts. Specifically, we highlight major mechanisms that lead to stress-induced polyploidy within somatic or germline tissues through alteration of the cell cycle. We discuss the impact of such stress-induced polyploidy on genomes, cells, and tissues and emphasize commonalities across organisms and biological scales. A common theme that has emerged is that polyploidy facilitates numerous subsequent genomic and cellular changes following abrupt stresses, and these changes can impact tissue architecture and function.

Genome evolution through polyploidy: Enhancing plant stress resilience in agriculture

Polyploidy, also known as whole genome duplication, is a major evolutionary force in plants, driving diversification and the generation of novel phenotypic variation, including superior abiotic and biotic stress tolerance. The enhanced stress resilience observed in certain polyploids is hypothesized to arise from dynamic epigenetic and genetic changes, including variations in gene content and cis-regulatory elements (CREs), that emerge following polyploidization. These changes directly impact various regulatory, signaling, and metabolic pathways associated with stress response and adaptation. Within polyploid populations, processes like gene duplications, fractionation, and homoeologous exchanges actively shape novel gene content variation, while, simultaneously, alterations in CREs (DNA sequences controlling gene expression) lead to diverse regulatory patterns. This dynamic interplay between changes in gene content and regulation further contributes to expanded phenotypic variation, including enhanced stress resilience. We discuss how advanced genomic and epigenomic techniques, such as pangenomics and single-cell assay for transposase-accessible chromatin with sequencing, are used to uncover these variations and outline new bioinformatic approaches to reveal the underlying genetics of stress resilience and adaptation. Finally, we summarize what remains poorly understood to guide future research, with the goal of unlocking the full potential for enhancing resilience in polyploid crops.

Atomic layer-deposited nucleation layers to control zinc morphology and suppress hydrogen evolution

Aqueous zinc (Zn) batteries are among the most promising candidates for safe, low-cost, and sustainable grid-scale energy storage. However, their practical application is significantly constrained by inhomogeneous Zn electrodeposition and the competitive hydrogen evolution reaction (HER). Here, we introduce an electrodeposition architecture to mitigate these challenges. Using atomic layer deposition, we coat the copper current collector with ZnO and Al 2 O 3 nanofilms—positioned below the plated Zn. Our strategy marks a significant departure from previous works in which thin films are situated above Zn foil to function as artificial solid electrolyte interphases. Notably, we achieve substantial performance improvements with our 2-nm-thick ZnO coatings, including long cycle life (>1,400 cycles) and high Coulombic efficiencies (>99.8%). Our mechanistic investigation suggests that these improvements arise from HER suppression and controlled Zn morphology. This work offers an interface engineering approach to fundamentally understand Zn nucleation and growth processes. We anticipate that our electrodeposition architecture could be applied to enhance the cyclability of other aqueous battery systems.

Electrical stimulation promotes longevity and regeneration in a colonial chordate

Endogenous bioelectric currents regulate development and regeneration, but their influence on organismal longevity and stem cell–mediated repair is not well understood. We demonstrate that a brief, clinically safe pulse of electrical current (PEC) produces lasting rejuvenation in the colonial chordate Botryllus schlosseri . In this species where all differentiated tissues are replaced weekly and progenitor populations mediate the weekly de novo generation of new organs, organismal aging is directly driven by alterations of the precursor pool. Electrically stimulated colonies exhibited increased growth, enhanced reproductive activity, and significantly improved survival, along with improved stem cell associated function. Whole-transcriptome analysis revealed a biphasic “reboot and rebound” program across all functional paths. An acute 2-h “reboot” was defined by the synchronized downregulation of the genomic engine, mitochondrial respiratory chain, contractile apparatus, and extracellular matrix (ECM) integrity. This systemic pause transitioned into a massive 24-h “rebound”, characterized by the global reactivation of these paths, including a metabolic surge, cytoskeletal rebuilding, and ECM scaffold synthesis. Notably, PEC induced a conserved immunometabolic shift from a proinflammatory to a reparative signature, mimicking exercise-induced shifts observed in mammals. Our findings identify that PEC acts directly on progenitor-cell-driven pathways to restore homeostatic vitality, offering insights into the reversal of age-related decline.

HHIP’s dynamic role in epithelial wound healing reveals a potential mechanism of COPD susceptibility

Genetic variants near Hedgehog interacting protein ( HHIP ) have been consistently associated with increased risk for chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide. However, HHIP ’s role in COPD pathogenesis remains elusive. Canonically, HHIP is a negative regulator of the Hedgehog pathway and downstream GLI1 and GLI2 activation. The Hedgehog pathway plays an important role in wound healing, specifically in activating transcription factors that drive the epithelial–mesenchymal transition (EMT), which in its intermediate state (partial EMT) is necessary for the collective movement of cells closing a wound. Herein, we use a systems biology approach to propose a mechanism to explain HHIP’s role in faulty epithelial wound healing, which could contribute to the development of emphysema, a key feature of COPD. Using two different Boolean models, we show dysfunctional HHIP results in a lack of negative feedback on GLI, triggering a full EMT, where cells become mesenchymal and do not properly close the wound. We validate these Boolean models with experimental evidence gathered from published scientific literature. Finally, we show evidence supporting our hypothesis in single-cell and single-nucleus RNA-Seq data from different COPD cohorts and Hhip heterozygous knockout mice. Overall, our analyses suggest that aberrant wound healing due to dysfunctional HHIP, combined with chronic epithelial damage through cigarette smoke exposure, may be a primary cause of COPD-associated emphysema.

Navigating high-order protein fitness landscapes via deep learning on directed evolution trajectories

Accurately predicting the fitness effects of high-order mutations is a grand challenge in understanding and engineering proteins. Existing models, including pretrained protein language models, struggle to capture the multiresidue interactions that govern these effects. Here, we introduce DENet, a deep learning framework that harnesses the rich comutation information within directed evolution (DE) trajectories to reconstruct high-resolution fitness landscapes for deciphering and engineering of complex protein variants. Applied to the cancer target KRAS, DENet-guided screening systematically identified high-order mutants with potent activities and uncovered hidden allosteric mechanisms. For MEK1, DENet nominated complex variants with >1,000-fold increased drug resistance, revealed synergistic tail mutations, and retrospectively identified over 75% of known clinical mutations, largely outperforming existing models. To broaden the framework’s applicability, we developed an in silico strategy that simulates directed evolution to infer comutation information from widely available single-mutant datasets. DENet provides a quantitative framework for navigating complex fitness landscapes, uniting the rational engineering of multimutation proteins with the elucidation of their mechanisms and clinical implications.

A loaf of bread and a jug of wine: The origins of the ultimate culinary pairing

Ecological replacement versus process-based recovery of Caribbean reefs

Uncovering ParB-dependent and -independent subclasses of T-dioxygenases from bacteriophage

5-Methylpyrimidine dioxygenases (5mYOXs) are iron (II)/2-oxoglutarate-dependent enzymes that catalyze the postreplicative oxidation of DNA 5-methylpyrimidines. Here, we define two subclasses of phage thymine (T) 5mYOXs: a stand-alone enzyme and a second requiring an activator. Using bioinformatic tools, we show that the activator is homologous to the bacterial chromosomal segregation (CS) protein ParB, retaining the N - terminal nucleotide-binding domain (NBD), responsible for CTP binding and hydrolysis in CS, and the C-terminal dimerization domain (CTD), but lacking an obvious DNA-binding domain. In vivo, we demonstrate that ParB activates its cognate 5mYOX with relative specificity and that both NBD and CTD are required for function. Unlike CS-ParBs, mutation of conserved NTP-binding/hydrolysis residues does not affect the role of 5mYOX-associated ParB, suggesting a lack of CTP requirement or a regulatory mechanism not captured under our conditions. For 5mYOXs, we define subclass-specific domains essential for T oxidation and provide evidence for abolishing ParB dependency upon swapping a variable insert from a ParB-independent 5mYOX into a dependent one. In vitro, reconstitution of subclass representatives, 5mYOX97 and 176, confirms their activity as postreplicative T-dioxygenases. Both enzymes function on a wide range of DNA substrates [single and double-stranded (ds), linear, and circular]. The enzymes differ in their sequence preference and support iterative oxidation of T and 5-methylcytosine. Notably, 5mYOX176 requires activation by ParB176 only when acting on dsDNA. These findings establish an activator-dependent subclass within the iron (II)/2-oxoglutarate-dependent dioxygenase superfamily and expand the functional landscape of both 5mYOX and ParBs, suggesting regulatory mechanisms for T oxidation in bacteriophage.

Harnessing polyploidy for climate-resilient crops: Lessons from the evolutionary model, allotetraploid cotton

Escalating pressures of global climate change necessitate developing agricultural systems and crop varieties with enhanced resilience. Polyploidy, the state of possessing multiple complete sets of chromosomes arising from whole genome duplication (WGD), is a major evolutionary force in plants, often conferring novel genetic and regulatory capacities that facilitate adaptation. Allotetraploid cotton ( Gossypium spp.), which formed through the merger of distinct A and D subgenomes approximately 1 to 1.6 Mya, is an exemplary model for elucidating polyploid genome evolution and molecular mechanisms underlying stress adaptation. Whereas combining divergent genomes introduces genetic novelty and hybrid vigor, long-term adaptive success and enhanced resilience rely on complex regulatory reprogramming subsequent to the merger event. In cotton, and by extension other polyploids, this reprogramming involves dynamic structural genomic rearrangements, functional diversification of duplicated genes, and pervasive alterations in epigenetic landscapes. These processes reshape transcriptional networks, leading to homoeologous expression bias and novel regulatory interactions. These polyploidy-specific phenomena underpin differential subgenome contributions to key developmental processes and adaptive responses to major abiotic stresses including drought, salinity, and extreme temperature. A comprehensive understanding of these interconnected genetic and epigenetic control mechanisms, the resulting landscape of subgenome coordination or independence, and associated physiological consequences, are essential for designing effective strategies to breed climate-resilient crops. Here, we synthesize current insights from cotton, emphasizing their broader significance for harnessing polyploidy as a tool for future crop improvement amid global environmental change.

Plug-and-play assembly of biodegradable ionizable lipids for potent mRNA delivery and gene editing in vivo

mRNA-based gene editing therapeutics offer the potential to permanently cure diseases but are hindered by suboptimal delivery platforms. Here, we devise a robust combinatorial chemistry for the plug-and-play assembly of structurally diverse biodegradable ionizable lipids from amines/thiols and dialkyl maleates. After screening 500 ionizable lipids, we obtained structure−activity relationships essential for effective in vitro mRNA delivery with the help of machine learning. Furthermore, we identified a lead ionizable lipid candidate that produced potent lipid nanoparticles for the delivery of various gene editing tools in wild-type and genetically modified mice compared to literature and industry benchmark lipid nanoparticles. Mechanistically, our lipid nanoparticles show favorable physicochemical properties, which could synergistically contribute to the superior delivery performance. This study highlights the utility of this synthetic method as well as the generality of this platform for potent in vivo gene editing.

AI assists adversarial collaboration in debate on minority salience

The advancement of science depends on rigorous tests of competing hypotheses, yet many disputes are left unresolved. Adversarial collaboration—where opposing scientists jointly design decisive tests—is one proposed solution. We examine whether large language models (LLMs) can play a role by organizing information, structuring the debate and generating candidate experimental designs. This article reports an AI-assisted adversarial collaboration designed to resolve a debate in PNAS on minority salience—an overestimation of the percentage of minority faces in a visual display. The debate focused on whether there would be further overestimation when minorities in the displays were the same minorities in participants’ communities (or social environments). Using LLMs to extract and organize competing propositions, we identified central disagreements and generated initial experimental designs to test claims. Human collaborators refined the designs and created two preregistered experiments that factorially manipulated the ethnicity of minority faces and the ethnicity of participants’ communities. Data showed that people exaggerated the percentage of minorities in facial displays. Furthermore, overestimation was even greater when minorities in facial displays were also minorities in participants’ communities. When the two camps of researchers saw the results, their confidence in key hypotheses converged. We do not experimentally test AI-assisted adversarial collaboration relative to traditional adversarial collaboration or other forms of dispute resolution. Rather, our study illustrates how an AI tool can be used with adversarial collaboration to formalize claims, structure disagreements, lower barriers to collaboration, and serve as an impartial observer to strengthen perceptions of fairness.

Synaptic and neural pathway redundancy enables the robustness of a sensory-motor reflex and promotes predation escape in <i>Caenorhabditis elegans</i>

As a basic unit of the nervous system, the sensory-motor reflex circuit is fast and robust. However, it is not entirely clear how this robustness is achieved, given that various genetic perturbations can alter the function of the sensory neurons. By mapping the molecular basis of neuronal connections in the touch response circuit of Caenorhabditis elegans , we found prevalent genetic redundancy at neural pathway, synaptic, and molecular levels, which ensures that sensory signals can be relayed to command interneurons that control motor output. We also found developmental remodeling of the anterior circuit, which leads to the pruning of larval synapses, establishment of a second pathway that activates additional interneurons, and lateralization of the circuit. Finally, we found that the synapses that appeared to be functionally redundant in a simple touch assay contribute to the extent of reversal response in an additive manner, which may help the organism escape from predators.

In situ evidence of self-accelerating turbidity currents

Self-accelerating turbidity currents (SATCs) are hypothesized to be the primary mechanism for transporting vast amounts of sediment to the deep ocean. However, theoretical predictions of SATCs have preceded field observations by decades, leaving a critical gap in our understanding of this long-distance delivery process. Here, we present results from a four-year field survey of turbidity currents and bathymetric evolution in the Xiaolangdi Reservoir on the Yellow River (China), the world’s most sediment-laden river. We provide definitive in situ evidence of SATCs, characterized by synchronous down-channel increases in sediment mass and current momentum, alongside massive channel incision at the event scale. Notably, these SATCs occur in a low-gradient lacustrine setting, challenging the prevailing hypothesis that such phenomena are restricted to steep submarine channels or high velocity conditions. We identify a dimensionless threshold, incorporating current velocity, channel slope, and sediment settling velocity, that governs SATC formation across sublacustrine and marine environments. This threshold provides a robust framework for predicting SATC occurrence and informs engineering strategies to sustain reservoir capacity and restore sediment connectivity in dammed river systems.

Conscious and nonconscious thought: Insights from the neuroscience of decision-making

Conscious thought is often treated as a special class of neural processing, distinct from the nonconscious computations that guide most behavior. Here I offer a different perspective, grounded in the neuroscience of decision-making. I argue that conscious thought arises not from a unique mechanism but from a distinctive use of neural representations already engaged in nonconscious thought. Nonconscious thoughts are structured as interrogations that yield provisional intentions—decision-like commitments that guide action or inquiry without entering awareness. Using examples from perceptual decision-making and neurophysiology, I suggest that such thoughts depend on persistent neural representations that encode not only potential actions but the questions that give them meaning. These knowledge states may also preserve source-sensitive structure that supports a minimal experiential organization even when they remain nonconscious. Conscious thought, on this account, emerges when such a state is reformatted for potential report to another mind, or to oneself, recruiting theory of mind and narrative structure and placing its content in a space presumed to be shared. This proposal identifies a tractable bridge from nonconscious decision mechanisms to phenomenal consciousness, thereby placing part of the hard problem within empirical reach.

Genome-wide association mapping and targeted loss of function studies identify <i>Shroom3</i> as a driver of hyperpolyploidy and ventricular dilation

Various states of cardiomyocyte (CM) polyploidy have been associated with cardiac injury responses, including regeneration and heart failure. However, our understanding of the comprehensive mechanisms governing CM ploidy and its relationship with heart physiology is limited. To address this issue and uncover genetic regulators, we surveyed CM ploidy across a new genetic resource known as the Hybrid Rat Diversity Panel (HRDP) and found significant variation in ploidy phenotypes across the panel. Using select rat strains with divergent displays of CM ploidy, we found that CM hyperpolyploidization (≥8 N) positively correlates with various physiological parameters, namely left ventricular dilation and reduced ejection fraction. Genome-wide association mapping identified several loci significantly associated with frequency of hyperpolyploid CMs. Investigation of genes harboring damaging protein coding variants within these loci identified enrichment of cytoarchitectural genes, of which the ACTIN-binding protein, Shroom3 , was found to be strongly and specifically expressed in CMs and harbors 7 damaging protein coding variants. CM-specific deletion of Shroom3 resulted in increased hyperpolyploidization and left ventricular dilation with reduced ejection fraction. Furthermore, functional characterization of single-nucleotide variants resulting in amino acid changes within SHROOM3 confirmed two protein coding variants that disrupted SHROOM3–ACTIN interaction and led to altered expression of genes involved in DNA replication. This study elucidates the genetic determinants of CM ploidy phenotypes and solidifies a correlative relationship between CM ploidy and left ventricular function. Importantly, CM intrinsic expression of at least one gene mapped in this study, Shroom3 , is confirmed to regulate CM hyperpolyploidization and cardiac function.

Aging increases the cortical resources allocated to static balance maintenance

Maintaining balance requires a complex interplay between sensory and motor processes, and this ability deteriorates with age, impairing daily life activities and contributes to increased fall risks. Importantly, while cognitive-motor interference paradigms suggest an aging-related increase in the cortical involvement in balance regulation, direct evidence remains lacking. To clarify this issue, we assessed the effect of aging on sway-based corticokinematic coherence (CKC), which is a measure of the coupling between cortical electrophysiological signals and postural sway. To that end, we recorded the center-of-pressure fluctuations and electroencephalographic cortical activity of 64 young and 67 older healthy participants performing balance tasks during which sensory information was either removed or altered. We found that older adults showed increased cortical activity that appears to relate to different aspects of closed loop postural control during challenging balance conditions, and correlates with upright stance stability. They also showed increased delays between cortical activity and postural sway, indicative of slower central processing speed. Finally, despite the older cohort displaying significantly altered vestibulo-ocular reflexes, no relationship was found with CKC strength. Overall, our results provide direct evidence that cortical involvement in balance regulation increases with aging. They suggest the feasibility of assessing afferent and efferent processing during balance maintenance, paving the way for studies identifying neurophysiological determinants of fall risks.