Browse Articles

Temperature and developmental stage govern intestinal susceptibility to human coronavirus 229E

Human coronaviruses have been primarily associated with upper respiratory tract infections, yet cases of gastrointestinal symptoms in COVID-19 patients have highlighted their potential to cause systemic disease. Here, we detail the infection of intestinal epithelia by an endemic, low-pathogenic human coronavirus, human alphacoronavirus 229E, using patient-derived human intestinal enteroids (HIEs) from donors of various ages. Using fetal, pediatric, and adult HIEs, we investigated how physiologically relevant temperatures: 37 °C and 32 °C, reflecting gastrointestinal and upper-airway conditions, respectively, modulate epithelial responses and viral infection dynamics. We show that there is temperature-dependent transcriptional reprogramming, indicating strong temperature-dependent regulation of virus replication and epithelial responses. Among the seasonal coronaviruses tested, only HCoV-229E productively infects HIEs. At 32 °C, HCoV-229E replicates efficiently in enteroids from all donor ages and releases high titers of infectious progeny. In contrast, at 37 °C, productive replication is largely confined to fetal and a subset of pediatric tissues, revealing a developmental and temperature-sensitive restriction on infection. Confocal and flow cytometry analyses identify enterocytes as the primary target cells for HCoV-229E. Furthermore, we show that camostat, a serine protease inhibitor, significantly reduces HCoV-229E replication in HIEs, confirming a critical role for host serine protease activity. Collectively, these findings establish HIEs as a relevant model for HCoV-229E–host interactions and reveal temperature- and age-dependent determinants governing intestinal permissiveness to this seasonal coronavirus.

Profile of John P. Smol

John P. Smol has spent more than four decades demonstrating how lake sediment cores can reveal environmental changes spanning decades to centuries. His pioneering work established paleolimnology as a credible scientific discipline, first, by documenting the impact of acid rain on North American lakes in the 1980s and, later, by tracking Arctic climate warming. Through continuous monitoring of High Arctic ponds and lakes, Smol has shown how ice cover duration influences aquatic ecosystems. His recent research reveals that even the deepest Arctic lakes are now crossing ecological thresholds due to accelerated warming, with implications for Indigenous fisheries and northern communities.

A potential overestimation of CO ₂ physiological effects on evapotranspiration

It is generally believed that CO 2 physiological forcing can partially mitigate land surface drying under global warming by reducing stomatal conductance and evapotranspiration. Most of this type of study focuses on the direct regulation by vegetation physiology, overlooking interactive feedback from the atmosphere. Using fully coupled earth system model simulations, we find that the physiological benefit may have been optimistically overestimated. Vegetation-induced energy change may in turn further affect atmospheric vapor pressure deficit (VPD), exerting extra evapotranspiration demand indirectly. Indirect VPD feedback over northern mid-high latitudes could offset 54% (±26%) of evapotranspiration reduction driven by stomatal closure under current CO 2 condition, and that proportion increases to 68% (±18%) at 4 × CO 2 . The enhanced VPD feedback is largely driven by vegetation-mediated albedo decline and temperature rise in northern mid-high latitudes, which intensifies evapotranspiration loss as stomatal constraints are minimal. These are important findings, substantially limiting the physiological benefits of CO 2 with extra pressure on surface aridification and water resources.

Adaptive mechanochemical mechanisms of the nucleus during confined cell migration

Cell migration through spatially confined microenvironments occurs in many biological processes such as embryonic development, immune surveillance, and cancer metastasis. A major bottleneck during such migration is the nucleus, which acts not only as a rigid mechanical obstacle but also as a crucial mechanosensor that modulates downstream signaling pathways. However, it remains poorly understood how nuclear deformation and mechanosensation together regulate cell migration through confined spaces. Here, we propose a three-dimensional (3D) mechanochemical model of confined nuclear translocation that integrates nuclear deformation with deformation-induced calcium signaling and subsequent regulation of cytoskeletal contractility. We show that cells undergo adaptive nuclear deformation, including nuclear envelope elongation and 3D buckling, to efficiently navigate confinements of varying sizes. There exists a biphasic relation between nuclear velocity and confinement size, arising from the interplay between nuclear deformability and mechanosensitive feedback. We demonstrate that local nuclear envelope rupture can occur under large deformation, enabling nuclear translocation through extreme confinements, as observed in prior experiments. Furthermore, we elucidate the critical roles of chromatin organization in nuclear translocation. This work reveals key mechanochemical mechanisms driving confined cell migration and provides a theoretical framework for studying nuclear dynamics across physiological and pathological contexts.

A receptor-like mechanosensitive protein governs preprophase band positioning for asymmetric cell divisions and SC morphogenesis

Asymmetric cell division underpins cellular diversity in multicellular plants. These divisions are mechanosensitive, and preprophase band (PPB) formation hinges on cell-wall mechanical properties in plant cells. Yet, the spatial control mechanism governing this process in plants remains elusive. During grass stomatal development, mechanical cues originate from differential growth rates and cell wall modifications at the interface of guard mother cell/subsidiary mother cell (SMC). In this work, we have identified a maize receptor-like protein, KAI1, that functions as a master regulator of subsidiary cell formation within the stomatal complex. KAI1 governs division-plane orientation in SMCs through mechanochemical signaling: It perceives cell wall rigidity via pectin interaction, and subsequently recruits tubulin for PPB positioning, thereby directing division-plane specification. This work uncovers a plant-unique mechanosensitive protein that mediates extracellular matrix cues to cytoskeletal reorganization during asymmetric division for cell diversity. Our findings establish that KAI1 governs a cell wall mechanics-dependent PPB positioning to control the exact division plane alignment of the SMC. This mechanism subsequently mediates the regulation of SMC polarization and subsidiary cell morphogenesis during stomatal development.

GAS6 regulates mucosal langerhans cell homeostasis through cell-intrinsic and niche-dependent mechanisms

Barrier tissues with stratified epithelia rely on Langerhans cells (LCs) to maintain immune surveillance. While TAM signaling regulates skin LC homeostasis, its role in mucosal LC development remains unclear. Here, we identify the TAM ligand GAS6 as a central regulator of oral mucosal LC biology. GAS6 preserves epithelial integrity and restrains local inflammation, while fine-tuning LC abundance by controlling their retention within the tissue. At the precursor level, GAS6 facilitates the proliferation and differentiation of predendritic cells (pre-DCs), particularly pre-DC1. Moreover, GAS6 preferentially supports AXL + pre-DC-derived LCs, without affecting AXL + MERTK + monocyte-derived LCs, leading to a greater contribution of monocytes to the mucosal LC pool. Together, these findings identify GAS6 as a dual-level orchestrator of mucosal LC development and homeostasis.

Correction for McWilliams, There is no horizontal gravity force in geopotential coordinates

Resource declines shape phenological and morphological responses to climate change

Biodiversity is declining, with cascading effects of defaunation expected across trophic levels. Widespread population declines may drive general biotic responses to global change and determine their fitness effects. We find that a 62% decrease in insect biomass over a half-century altered the morphology, survival, and breeding phenology of an aerial insectivore, the tree swallow ( Tachycineta bicolor ). Low-insect years resulted in decreased tree swallow body mass, with the fitness landscape shifting to favor smaller individuals. Earlier, more temporally variable, and less-pronounced peaks in insect abundance eroded the benefits of phenological synchronization across trophic levels. This phenomenon—which we term trophic decay—led to advantageous phenological mismatch in low-insect years. Our results suggest classic responses to climate change must be evaluated within the context of widespread resource declines.

Identification of a master regulator Msd1 that governs meiotic entry in a global basidiomycete pathogen

Meiosis is a hallmark of sexual reproduction. Although the core meiotic machinery is evolutionarily conserved from unicellular yeasts to Metazoan, the key regulators responsible for initiating meiosis vary across species and remain largely unidentified in major eukaryotic lineages, including the major phylum Basidiomycota in the Kingdom Fungi. The basidiomycete fungus Cryptococcus neoformans is a critical pathogen listed by the World Health Organization that causes life-threatening meningoencephalitis worldwide. Meiosis not only indirectly facilitates cryptococcal pathogenicity through generating genetically diverse spores but also directly contributes to host adaptation and disease progression. Here, we identified a novel transcription factor Msd1 that is responsible for activating meiosis in C. neoformans . Deletion of MSD1 impaired multiple sexual development events and strikingly abolished meiosis and subsequent sporogenesis (gametogenesis). Conversely, overexpression of MSD1 alone is sufficient to drive meiosis and the formation of meiotic spores, even in the absence of the external mating-inducing cues or when the mating pathway is genetically inactivated. Mechanistically, we demonstrated that Msd1 initiates meiotic entry by targeting two interconnected pathways. First, Msd1 activates the transcription of multiple evolutionarily conserved core meiosis-specific genes such as meiotic recombinase Dmc1. Second, Msd1 activates two RNA-binding proteins, Csa1 and Csa2, which ensure spatiotemporal expression of the aforementioned meiosis-specific genes to drive meiosis and sporogenesis. Collectively, our findings demonstrate that meiosis and the sequential sexual development events are spatiotemporally orchestrated by the master regulator Msd1, and is the first reported regulator initiating meiotic entry in a basidiomycete fungus.

Extra gene coding capacity of SARS-CoV-2 provides a virus engineering platform for in vitro and in vivo applications

The genomic flexibility of orthocoronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is showcased by the presence of accessory genes, which vary in number among virus species and strains. Given this flexibility, the viral coding capacity can be artificially expanded to express a heterologous gene from the viral genome, thereby enabling the development of a viral vector platform. Here, we systematically explored the extra gene coding capacity of SARS-CoV-2 by inserting an extra reporter gene at every intergenic region in its genome. We revealed the entire scheme of its extra gene expression and identified a genomic location that stably expresses reporter genes while maintaining the wild-type viral phenotype. Using this construct, we developed a set of fluorescent and luminescent reporter SARS-CoV-2 viruses available for in vivo flow cytometry and in vitro antiviral screening. Flow cytometric analysis with these reporter viruses revealed cell type–specific dynamics of SARS-CoV-2 infection in the lung tissue of K18-hACE2 mice. Our findings offer a platform for SARS-CoV-2 genome engineering, providing a set of reporter viruses for research applications.

Sex differences in <i>Drosophila</i> intestinal metabolism contribute to sexually dimorphic infection outcome and alter gut pathogen virulence

Sexual dimorphism in infection outcomes is widespread, yet its underlying mechanisms remain incompletely understood. Utilizing Pseudomonas entomophila intestinal infection in Drosophila, we demonstrate that sex differences in intestinal redox processes contribute to female-biased susceptibility to infection. Female inability to overcome pathogen-induced oxidative stress results in defecation blockage, pathogen persistence, and host death. Male flies exhibit increased carbohydrate metabolism and pentose phosphate pathway activity—a key antioxidant defense system. This allows males to withstand oxidative stress-induced defecation blockage and clear the pathogen from the intestine, resulting in survival. Notably, we uncovered that Duox-dependent processes contribute to pathology independently of total ROS levels. In parallel, P. entomophila showed increased expression of several virulence factors, including RNA-binding protein Hfq, in the female gut, contributing to female-biased virulence of P. entomophila . Thus, the effect of the gut metabolic environment on host defenses and pathogen virulence determines the sex differences in intestinal infection outcomes.

Antonio García-Bellido: A brief history of flies, lineages, and a new developmental genetic logic

Antonio García-Bellido was a pioneer of developmental biology in Spain who had the rare ability to see beyond the trees and grasp not just the forest, but entire landscapes. Intellectually and personally, he was indefatigable, uncompromising, and wholly committed to science. He led his trainees by example in his unflagging demands on honoring the data above all else. Antonio discovered the existence of “developmental compartments” in the wing of Drosophila and proposed that these territories corresponded to the realm of action of homeotic genes. He was a fierce defender of hypotheses that he thought best explained available data but did not cling blindly to ideas when they no longer served to understand the phenomena at hand. With his distinctive style he founded a successful school of Drosophila developmental geneticists that will sorely miss his unparalleled passion for science.

p53 overrides <i>METTL5</i> loss–induced tumor suppression via mitochondrial respiration

The tumor suppressor p53 is pivotal in repressing tumorigenesis under physiological conditions. Paradoxically, we find that wild-type (WT) p53 plays an oncogenic role in relieving METTL5 depletion–caused cancer regression by sustaining mitochondrial respiration. The methyltransferase METTL5 is upregulated in non–small cell lung cancer (NSCLC) and associated with advanced tumor grade and poor prognosis. Depletion of METTL5 impairs NSCLC cell proliferation and migration in vitro and in vivo, with p53-null cells displaying enhanced sensitivity. While METTL5 -depletion inhibits cytoplasmic translation in both p53-WT and p53-null cells, only cells lacking p53 exhibit severe tumor regression due to defective mitochondrial protein synthesis and consequent respiratory dysfunction. Mechanistically, p53 binds 5’UTR of TOMM40 , the crucial gatekeeper of mitochondrial protein import, to enforce its exclusion from translation. METTL5 loss promotes p53 nuclear retention via inhibiting MDM2-mediated p53 ubiquitination, alleviating its translational suppression of TOMM40 , and supporting oxidative phosphorylation. Remarkably, the combination targeting of p53 and METTL5 synergistically attenuates the proliferation and migration in p53-WT cancer cells. Our study elucidates the essential role of p53 in supporting tumor viability upon METTL5 deficiency by maintaining mitochondrial respiration. Meanwhile, it provides a molecular foundation for developing therapeutic strategies regarding cancers with WT p53.

Enhanced rock weathering has greater promise as a sustainable farming practice than a CO ₂ removal technology

Creating common virtual ground: Protocols to democratize open VR research

By immersing participants in consistent virtual environments, VR enhances study realism, reduces confounding variables, and improves procedural control, offering a promising solution for scientists interested in studying behavior “in the wild.” The availability and documentation of data enabled by VR also help address replicability challenges. Despite vast potential, VR research is hindered by fragmentation, proprietary tools, and a lack of standardized practices, which limit its overall impact. This collaborative study presents an interactive checklist to support VR research from across disciplines to meet three essential protocols—interoperability, procedural standardization, and data sharing—that address these challenges by promoting open science and providing a common, easy-to-evaluate format for researchers to present projects to ethics boards, reviewers, and beyond. Together, these protocols can help VR research overcome replication barriers, democratize access to advanced tools, and establish VR as a robust method for rigorous, replicable scientific inquiry.

IRE1 regulates the proteostasis of TDP-43/TARDBP in ALS/FTD through ribosome-associated quality control

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders characterized by motor neuron degeneration, leading to muscle weakness, atrophy, and cognitive impairments. A defining pathological hallmark of ALS/FTD is the cytosolic mislocalization and accumulation of TAR DNA-binding protein 43 (TDP-43), highlighting its critical role in ALS pathogenesis. However, the molecular mechanisms underlying TDP-43 proteostasis remain poorly understood. Through a genetic screening approach, we identify inositol-requiring enzyme 1 (IRE1), an endoplasmic reticulum-resident transmembrane protein, as a potent suppressor of TDP-43 protein levels. Furthermore, we show that ribosome-associated quality control (RQC) factors play a crucial role in regulating TDP-43 proteostasis and cellular toxicity. Activation of the RQC pathway prevents excessive accumulation of TDP-43 and associated toxicity. Mechanistically, our findings suggest that IRE1 regulates TDP-43 protein level by promoting the degradation of aberrant TDP-43 translation product through the RQC pathway. IRE1 acts canonically to enhance the transcription of the RQC core component Clbn/NEMF and noncanonically to physically interact with Clbn/NEMF, thereby ameliorating TDP-43-induced proteotoxicity. Moreover, ectopic expression or pharmacological activation of IRE1 alleviates TDP-43 pathology and restores cognitive function in the TDP-43 A315T ALS mouse models. Collectively, our study identifies a role for IRE1 in the translational quality control of TDP-43 and establishes its potential as a therapeutic target for ALS/FTD.

Deviance detection via competitive inhibition between local neocortical ensembles

The process by which neocortical neurons and circuits amplify their response to an unexpected change in stimulus, typically referred to as deviance detection (DD), has traditionally been thought to be the product of specialized cell types and/or routing from distinct brain areas. Here, we explore a different theory, whereby DD emerges intrinsically from local network-level interactions driven by a deviant increase or decrease in exogenous input to a neocortical column. We propose that deviance-driven neural dynamics are generated by ensembles of excitatory and inhibitory neurons that have a fundamental inhibitory connectivity motif: competitive inhibition between reciprocally connected neural representations under modulation from feed-forward selective (dis)inhibition. Implementing this motif in two computational models with different levels of biophysical abstraction, we were able to simulate a variety of phenomena pertaining to the experimentally observed shifts in neural tuning during DD across neurons, time, and stimulus history. We further tested hypotheses related to our theory and examined the robustness of emergent phenomena consistent with prior experimental observations. Our results show that ensemble priming via competitive inhibition under modulation from selective (dis)inhibition can serve as a local mechanism for encoding short-term stimulus memory, enabling deviance-driven shifts in stimulus representation. This work establishes a theoretical paradigm that resolves previously confounding aspects of predictive sensory processing in Neocortex, and we provide a number of corollary predictions that can be tested in future in vivo studies.

Skin capillary endothelial cells form a network of spatiotemporally conserved Ca ²⁺ activity

Ca 2+ signaling and its regulation are important for endothelial cell (EC) function and signaling. Yet, the spatiotemporal organization of Ca 2+ activity and its regulation across a vascular plexus is poorly understood in an in vivo mammalian context. To overcome this gap in knowledge, we developed an intravital imaging approach to resolve Ca 2+ activity with single-cell resolution in skin vasculature of adult mice via multiphoton microscopy. Here, we tracked thousands of Ca 2+ events in the skin capillary plexus during homeostasis and observed signaling heterogeneity between ECs, with just over half displaying Ca 2+ activity at any given time. Longitudinal tracking of the same mice revealed that the same capillary ECs maintain Ca 2+ activity over days to weeks. Interestingly, activity dynamics, such as frequency and event duration, are not conserved at a single-cell level but are maintained at an EC population level. Molecularly, conditional deletion of the gap junction protein Connexin 43 (Cx43cKO) in ECs leads to a subset of ECs displaying sustained Ca 2+ activity, biasing signaling dynamics of the whole network toward chronically persistent activity over time. Sustained capillary Ca 2+ activity results in vascular permeability and flow dysregulation. Last, through pharmacological targeting of known agonists/antagonists, we showed that inhibition of L-type Voltage Gated Ca 2+ channels non-cell-autonomously restores Ca 2+ activity, blood flow, and barrier function in Cx43cKO mice. Collectively, our work provides insight into the spatial and temporal characteristics, extent, and regulation of Ca 2+ activity in skin capillaries of live mice.

Unique fingerprint of marine ectotherm body size change during hyperthermal crises

The term “Lilliput Effect” describes a substantial decrease in the average body size of fossil assemblages during major environmental perturbations in Earth’s history, which is reported in many paleontological studies. The limited regional, temporal and taxonomic focus of most studies, however, has sparked discussions concerning its generality. Additionally, even though a negative relationship between warming and body size has been established in recent marine ectotherms, the environmental and mechanistic drivers of the Lilliput effect are still debated. We compiled close to 9,000 body size changes from fossil, historical, and modern body size studies, to show that a decrease in body size is indeed a general response of marine ectotherms to environmental crises. The magnitude and temporal variability of size changes at the species-level are significantly higher during hyperthermal than nonhyperthermal events, suggesting differing mechanisms of body size decrease depending on the environmental stressor. Our results further show that ancient environmental perturbations with a higher magnitude of warming were associated with a greater dwarfing. This implies that warming was a major driver of body size decreases during hyperthermal events throughout the Phanerozoic, and future warming will impact current trajectories of body size reduction in modern marine ectotherms.

MDM2 suppresses c-Myc synthesis by binding to the 5’ mRNA translation regulatory sequence

The p53 tumor suppressor and the c-Myc oncogene are among the most frequently deregulated genes in human cancers, yet the molecular cross talk between these pathways remains poorly understood. MDM2 is a key negative regulator of p53 and a target for emerging cancer therapies designed to activate p53. Likewise, targeting c-Myc is a long-standing but challenging goal in cancer therapy. Here, we report that the small MDM2-binding drug Milademetan promotes an interaction between MDM2 and the 5’ untranslated region of the c-Myc mRNA, causing a suppression of c-Myc mRNA translation without affecting c-Myc RNA levels. The interaction also occurs under nonproliferative conditions in the absence of drug. Milademetan-mediated c-Myc depletion is accompanied by the induction of apoptosis and suppression of cell proliferation and prevents tumor growth, independently of p53 status. These findings reveal an unexpected mechanism by which MDM2 coordinates two of the most frequently altered pathways in cancer and provide a rationale for targeting c-Myc-driven tumors, including those lacking functional p53, through MDM2 modulators.