Germline mutation rates per generation are strikingly similar across animals, despite vast differences in life histories. Analogously, in at least one somatic cell type, mutation burdens at the end of lifespans are compa...Germline mutation rates per generation are strikingly similar across animals, despite vast differences in life histories. Analogously, in at least one somatic cell type, mutation burdens at the end of lifespans are comparable across mammals. These observations point to a key role for natural selection in shaping mutation rates. This Essay summarizes the patterns identified to date and outlines existing theories for how selection pressures might shape mutation rates in animal germline and soma. An understanding of what sets the mutation rate of a given cell type in a species requires better integration of genetics and development with population processes of selection and genetic drift.
Neural activity depends on energy metabolism, yet the extent to which regional variation in cortical metabolic architecture reflects the functional and perceptual demands of visual processing remains unclear. In the prim...Neural activity depends on energy metabolism, yet the extent to which regional variation in cortical metabolic architecture reflects the functional and perceptual demands of visual processing remains unclear. In the primate visual system, retinotopic eccentricity, the topographic mapping of visual space relative to gaze, provides a large-scale organizational axis along which spatial resolution and selectivity for behaviorally relevant visual categories vary systematically. Here, we tested whether cortical metabolic architecture reflects this axis by aligning in vivo fMRI maps of eccentricity and visual category selectivity with ex vivo cytochrome oxidase (CO) histology, a marker of oxidative metabolism, in macaque visual cortex. We found that the middle lateral (ML) face-selective region, which is biased toward central vision, exhibited higher CO intensity than the lateral place patch (LPP), a scene-selective region biased toward peripheral vision. More broadly, CO intensity covaried with eccentricity within both ML and LPP and across occipitotemporal visual cortex, though eccentricity only partially accounted for the elevated CO in ML. These findings reveal a close correspondence between cortical metabolic architecture and retinotopic organization, suggesting that the distribution of cortical metabolic resources is shaped by both visual field organization and the processing demands of perceptual specialization.
Tarafder AK, Graham M, Davis LK
… +11 more, Pratt S, Böhning J, Manivannan P, Wang Z, Clemente CM, Weimann A, Floto RA, Owens RJ, O'Toole GA, Pearce P, Bharat TAM
All bacterial biofilms contain an extracellular matrix rich in filamentous molecules that self-associate, conferring emergent properties to bacteria, including antibiotic tolerance. Pseudomonas aeruginosa is a human path...All bacterial biofilms contain an extracellular matrix rich in filamentous molecules that self-associate, conferring emergent properties to bacteria, including antibiotic tolerance. Pseudomonas aeruginosa is a human pathogen that forms biofilms in diverse infectious settings, where the upregulation of a filamentous bacteriophage Pf4, has been shown to be a key virulence factor that protects bacteria from antibiotics. Here, we modeled biophysical characteristics of biofilm-linked liquid crystalline droplets formed by Pf4, which predicted that sub-stoichiometric phage binders had the ability to disrupt liquid crystals by changing the surface properties of the phage. We tested this prediction by developing nanobodies targeting the outer surface of the Pf4 phage, which disrupted in vitro reconstituted droplets, promoted antibiotic diffusion into bacteria, disrupted P. aeruginosa biofilm formation under a variety of conditions, and abolished antibiotic tolerance of biofilms. The inhibition strategy illustrated in this study could be extended to biofilms of other pathogenic bacteria, where filamentous molecules are pervasive in the extracellular matrix. Furthermore, our findings exemplify how targeting a biophysical mechanism, rather than a defined biochemical target, is a promising avenue for intervention, with the potential of applying this concept to other disease-related contexts.
The type VI secretion system (T6SS) is a widespread nanoweapon deployed by bacteria to eliminate competitors in polymicrobial environments, allowing niche colonization or host invasion. Fluorescence microscopy recordings...The type VI secretion system (T6SS) is a widespread nanoweapon deployed by bacteria to eliminate competitors in polymicrobial environments, allowing niche colonization or host invasion. Fluorescence microscopy recordings have shown that T6SS expression and/or activation is heterogeneous in clonal populations of many bacterial species. However, it is still unknown whether T6SS heterogeneity is genetically controlled or arises from stochastic processes and what its physiological relevance is. Here, we report that enteroaggregative Escherichia coli (EAEC) exhibits stable phenotypic heterogeneity in T6SS expression. Under iron-limiting conditions, the Sci1 T6SS is expressed in only a subset of the population, creating distinct ON and OFF subpopulations in a reversible, heritable, and epigenetically controlled equilibrium. This heterogeneity is governed by the interplay between the iron-responsive regulator Fur- and Dam-dependent DNA methylation at the sci1 promoter. Mutations in Fur binding sites or GATC methylation motifs shift the population to homogeneous ON or OFF states, respectively. Functional analyses reveal that while ON cells mediate antibacterial activity, OFF cells buffer the population against lethal retaliatory responses from defensive T6SS⁺ competitors. Our results suggest that T6SS heterogeneity in EAEC represents a finely tuned attenuation strategy optimizing the trade-off between competitive killing and survival in hostile microbial communities. This work uncovers a novel layer of regulation in T6SS deployment and highlights phenotypic heterogeneity as an adaptive trait in interbacterial warfare.
Unified strain taxonomies are needed for the epidemiological surveillance of bacterial pathogens and international communication in microbiological research. Core genome multilocus sequence typing (cgMLST) holds great pr...Unified strain taxonomies are needed for the epidemiological surveillance of bacterial pathogens and international communication in microbiological research. Core genome multilocus sequence typing (cgMLST) holds great promise for standardized high-resolution strain genotyping. However, this approach faces challenges including classification instability and disconnection of new nomenclature from widely adopted classical MLST identifiers. This Essay discusses the cgMLST-based Life Identification Number (LIN) method, recently proposed as a stable multilevel strain taxonomy system applicable to most bacterial pathogens, covering how LIN codes are implemented and used in practice for precise strain definitions and epidemiological tracking.
Artificial intelligence (AI) is rapidly transforming scientific writing by expanding access and efficiency, yet it risks decoupling writing from thinking. Scientific writing is a core cognitive and epistemic practice tha...Artificial intelligence (AI) is rapidly transforming scientific writing by expanding access and efficiency, yet it risks decoupling writing from thinking. Scientific writing is a core cognitive and epistemic practice that must be cultivated and preserved alongside AI use.
In plants, a subset of miRNA precursors can yield multiple mature miRNAs; however, how they simultaneously regulate a single biological process remains poorly understood. Cadmium (Cd) is a non-essential heavy metal toxic...In plants, a subset of miRNA precursors can yield multiple mature miRNAs; however, how they simultaneously regulate a single biological process remains poorly understood. Cadmium (Cd) is a non-essential heavy metal toxic to plants, posing serious risks to human health via the food chain. As rice is a major dietary source of Cd, elucidating the molecular mechanisms underlying Cd accumulation is crucial for ensuring food safety. Here, we show that a pair of miRNAs derived from the MIR408 precursor cooperatively represses Cd uptake in roots by targeting distinct genes, consequently reducing Cd accumulation in rice grains. miR408-5p inhibits translation of Heavy metal-associated Isoprenylated Plant Protein 9 (HIPP19), which is specifically expressed in exodermis and endodermis cells and facilitates Cd binding. Meanwhile, miR408-3p cleaves Uclacyanin 7 (UCL7) mRNA, leading to enhance the activity of superoxide dismutases (SODs), and increase production of reactive oxygen species (ROS), particularly hydrogen peroxide (H2O2), which in turn suppresses Cd absorption and accumulation. Furthermore, knockout mutants of HIPP19 and UCL7, as well as MIR408 overexpressing lines, exhibit significantly decreased Cd content in grains, while the accumulation of other essential metals remains comparable to that of wild-type plants. These findings establish a promising strategy for producing "low-Cd rice" without compromising agronomic traits for food safety.
Schlafens proteins (SLFNs) are interferon-inducible regulators of RNA metabolism that influence antiviral defense and cell fate. Human SLFN14 is a ribosome-associated endoribonuclease whose pathogenic variants cause auto...Schlafens proteins (SLFNs) are interferon-inducible regulators of RNA metabolism that influence antiviral defense and cell fate. Human SLFN14 is a ribosome-associated endoribonuclease whose pathogenic variants cause autosomal dominant inherited thrombocytopenia (IT), but the molecular basis of this disorder remains unclear. Here, using HEK293T cells expressing human SLFN14 variants, we show that SLFN14 represses global protein synthesis through selective cleavage of type II tRNAs. IT-linked mutations alter SLFN14 RNA substrate specificity, enhancing depletion of type II tRNAs while reducing rRNA cleavage. This shift promotes ribosome stalling at codons decoded by type II tRNAs, triggering global translational arrest, stress signaling, and cell death. These findings reveal how altered RNA targeting by SLFN14 can drive disease and highlight selective tRNA targeting as a mechanism than regulates translation and cell fate.
Aging affects us all, but we still do not know how the process evolves or if we can modulate its pace. This issue of PLOS Biology presents a Collection of articles that explores different aspects of aging, discussing wha...Aging affects us all, but we still do not know how the process evolves or if we can modulate its pace. This issue of PLOS Biology presents a Collection of articles that explores different aspects of aging, discussing what challenges still need to be overcome.
Perceived stimulus intensity is a core feature of sensory experience, yet how it emerges in the human olfactory system remains unknown. Here, we demonstrate that oscillatory dynamics in the human olfactory bulb (OB) and...Perceived stimulus intensity is a core feature of sensory experience, yet how it emerges in the human olfactory system remains unknown. Here, we demonstrate that oscillatory dynamics in the human olfactory bulb (OB) and piriform cortex (PC) primarily encode subjective perceived intensity rather than physical concentration. Using noninvasive electrobulbogram recordings, we show that early gamma-band activity in the OB reflects bottom-up transmission of perceived intensity to the PC, which in turn sends top-down beta-band feedback that modulates OB activity via phase-amplitude coupling and transient beta bursts. This bidirectional communication supports a dynamic updating mechanism that maintains perceptual constancy across varying environmental odor concentrations. Our findings reveal a previously uncharacterized oscillatory framework for intensity coding in the human olfactory system, highlighting the primacy of perception over stimulus properties and offering a mechanistic basis for predictive processing in early sensory circuits.
Flexible goal‑directed navigation requires integrating changing goal information with a stable spatial map, yet how cortico-hippocampal circuits accomplish this remains unclear. We simultaneously recorded medial orbitofr...Flexible goal‑directed navigation requires integrating changing goal information with a stable spatial map, yet how cortico-hippocampal circuits accomplish this remains unclear. We simultaneously recorded medial orbitofrontal cortex (mOFC) and dorsal CA1 (dCA1) while rats learned daily changing goal locations on a cheeseboard maze. Rats rapidly learned new goal locations and retained memory for them in the post‑probe session. Both regions contained goal‑related neuronal representations, but their profiles differed: dCA1 showed stronger spatial specificity, whereas mOFC showed more prominent learning‑related updating of goal‑related activity. Combining dCA1 and mOFC activity improved decoding of behavioral stage and learning block relative to either region alone, consistent with complementary contributions to ongoing behavior and learning state. Across learning, these population‑level differences were accompanied by stronger theta‑range synchronization and theta-gamma coupling during navigation than during goal periods. A recurrent network model with dynamic synaptic efficacy captured qualitative features of efficient acquisition and flexible goal updating, providing a candidate computational framework for how learning‑related temporal coordination could contribute to adaptive navigation.
Classifying ovaries solely as reproductive organs has obscured their role as systemic regulators of female physiology. This Perspective makes the case that ovarian aging is a primary determinant of healthspan and belongs...Classifying ovaries solely as reproductive organs has obscured their role as systemic regulators of female physiology. This Perspective makes the case that ovarian aging is a primary determinant of healthspan and belongs at the center of geroscience.
Aging is typically framed as a one-way, irreversible accumulation of molecular damage in cells and tissues, leading to progressive functional decline. Yet mammalian reproduction, and particularly female reproduction, rev...Aging is typically framed as a one-way, irreversible accumulation of molecular damage in cells and tissues, leading to progressive functional decline. Yet mammalian reproduction, and particularly female reproduction, reveals a striking exception to this rule. Despite residing within an aging organism and within a fast-aging ovarian tissue environment, oocytes give rise to embryos that begin life with restored developmental potential and youthful molecular organization. By reframing ovarian biology as a model for rejuvenation rather than solely as a site of reproductive decline, this Essay proposes that the ovary offers a powerful blueprint for advancing the biology of aging and longevity.
Globally, the growing proportion of older individuals is imposing personal and societal costs. However, interventions that slow aging are possible; for example, dampened nutrient signaling pathway activity in animal mode...Globally, the growing proportion of older individuals is imposing personal and societal costs. However, interventions that slow aging are possible; for example, dampened nutrient signaling pathway activity in animal models promotes better health later in life. Recent findings indicate that such interventions have long-term effects even when applied transiently in early adulthood, forming a "physiological memory." Similar memory has been extensively documented in human epidemiology, where the health of older people is shaped by their earlier environmental exposures, such as diet composition. This Essay argues that the study of the biology of aging should encompass determinants of healthspan across the entire life course.
The field of human adult neurogenesis has been controversial despite mounting evidence. The authors propose moving beyond debating the existence of adult neurogenesis and towards discovering strategies to harness endogen...The field of human adult neurogenesis has been controversial despite mounting evidence. The authors propose moving beyond debating the existence of adult neurogenesis and towards discovering strategies to harness endogenous stem cell potential for resilience against cognitive aging.
In Bilateria with centralized nervous systems (e.g., in vertebrates or arthropods), the minimum of the BMP signaling activity gradient defines the position of the central nervous system. BMP-dependent patterning of the s...In Bilateria with centralized nervous systems (e.g., in vertebrates or arthropods), the minimum of the BMP signaling activity gradient defines the position of the central nervous system. BMP-dependent patterning of the secondary body axis is ancestral for Bilateria and possibly also for the bilaterian sister clade Cnidaria. However, the variety of levels of centralization of the nervous systems in Bilateria-from diffuse to fully centralized-as well as the lack of centralization of the nervous system in Cnidaria, suggest that BMP signaling cannot be perceived as a universally "anti-neural" signal. Here we use transgenic reporter lines in the anthozoan cnidarian Nematostella to show that BMP signaling is active in distinct neuronal populations. Moreover, attenuation of BMP signaling followed by RNA-Seq shows that BMP signaling is a positive regulator of many neuronal genes, including the top-tier neural progenitor marker soxB(2). Furthermore, we analyze BMP signaling activity in the cubozoan jellyfish Tripedalia and the scyphozoan jellyfish Stomolophus and prove that BMP signaling in parts of the diffuse nervous system is not an anthozoan but an ancestral cnidarian feature, shared by anthozoans and medusozoans. Finally, we show that the highly centralized ventral nervous system of the nonmodel spiralian, the chaetognath Spadella, forms out of paired BMP signaling-positive domains on the lateral sides of the embryo. Together, our data suggest that one of the ancestral roles of BMP signaling may have been in promoting neurogenesis. We propose that the "anti-neural" function of BMP signaling in vertebrates and arthropods is a consequence of its global role in the dorsoventral patterning of the ectoderm.
Predicting survival of ectotherms in stressful and variable thermal environments is an essential challenge in this era of heat waves and climate change. Recent thermal death time (TDT) models, based on an exponential rel...Predicting survival of ectotherms in stressful and variable thermal environments is an essential challenge in this era of heat waves and climate change. Recent thermal death time (TDT) models, based on an exponential relationship between average time to death (or failure) tf and temperature, enable accounting for average survival responses to both the magnitude and duration of stressful temperatures. However, extending these deterministic and probabilistic models to predict patterns of survival in fluctuating temperatures currently requires additional assumptions: e.g., that injury accumulation due to heat stress is additive across temperatures, and that the shape of the cumulative survival curve does not change with temperature. We evaluate these assumptions and their consequences by using a parametric survival model and available data on failure (knockdown) times of adult Drosophila. We find that the variance in log(tf) increases with increasing constant temperatures in most Drosophila species, resulting in changes in the shape of the failure density and survival curves across temperatures. We compare predictions of three deterministic and probabilistic models that differ in their TDT assumptions using D. melanogaster data in fluctuating (but stressful) temperatures. All three models consistently underestimate observed median failure times except at extremely high temperatures, suggesting non-additivity of heat injury accumulation. Our parametric model, incorporating temperature-dependent variance, provides more accurate predictions of cumulative survival curves in fluctuating temperatures. Our findings highlight the importance of understanding both mean and variation in failure times, and how these change across temperatures, for modeling survival in fluctuating thermal environments.
Ticks transmit numerous viruses that pose significant threats to human and animal health, however, the molecular interactions between ticks and viruses remain poorly understood. Using Langat virus (LGTV)-a surrogate for...Ticks transmit numerous viruses that pose significant threats to human and animal health, however, the molecular interactions between ticks and viruses remain poorly understood. Using Langat virus (LGTV)-a surrogate for tick-borne encephalitis virus (TBEV), we show that the JAK/STAT pathway promotes viral infection in Haemaphysalis longicornis. Rather than directly interacting with viral proteins, this proviral effect is mediated by a low-density lipoprotein receptor-related protein (LRP), whose expression is regulated by STAT. Silencing LRP in H. longicornis reduced LGTV infection, while ectopic expression of LRP enhanced it. Unlike its mammalian counterparts, H. longicornis LRP lacks a transmembrane domain and localizes intracellularly. Functionally, LRP promotes lipophagy, leading to lipid droplets breakdown and providing energy to support viral replication. Together, these findings reveal a non-canonical mechanism by which the JAK/STAT pathway facilitates LGTV replication through STAT-dependent regulation of an atypical, intracellular LRP that drives lipophagy.